Immunosenescence and cancer: molecular hallmarks, tumor microenvironment remodeling, and age-specific immunotherapy challenges

Qianwen Liu; Jingfeng Li; Xiuqiao Sun; Jiayu Lin; Zhengwei Yu; Yue Xiao; Dan Li; Baofa Sun; Haili Bao; Yihao Liu

doi:10.1186/s13045-025-01735-w

. 2025 Aug 22;18:81. doi: 10.1186/s13045-025-01735-w

Immunosenescence and cancer: molecular hallmarks, tumor microenvironment remodeling, and age-specific immunotherapy challenges

Qianwen Liu ^1,^3,^#, Jingfeng Li ^1,^3,^#, Xiuqiao Sun ^1,^#, Jiayu Lin ^1,³, Zhengwei Yu ¹, Yue Xiao ^1,³, Dan Li ^1,³, Baofa Sun ^2,^✉, Haili Bao ^1,^✉, Yihao Liu ^1,^3,^✉

PMCID: PMC12374445 PMID: 40846970

Abstract

Immunosenescence, the age-related decline in immune function, profoundly impacts cancer progression and therapeutic outcomes by fostering a tumor-promoting microenvironment and impairing immune surveillance. This review delineates eleven molecular hallmarks of immunosenescence, including genomic instability, telomere attrition, epigenetic dysregulation, mitochondrial dysfunction, and chronic inflammation, which collectively drive immune cell dysfunction and systemic immunosuppression. Aging reshapes the tumor microenvironment (TME) through recruitment of immunosuppressive cells, senescence-associated secretory phenotypes (SASP), and metabolic reprogramming, contributing to therapy resistance and poor prognosis in elderly patients. While immunotherapies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell immunotherapy (CAR-T) cells show promise, their efficacy in aging populations is limited by T cell exhaustion, myeloid bias, and altered intercellular communication. Emerging strategies—including senolytics, epigenetic modulators (e.g., histone deacetylase (HDAC) inhibitor), and metabolic interventions (e.g., spermidine, nicotinamide mononucleotide (NMN))—highlight potential avenues to rejuvenate aged immunity. Single-cell multi-omics (single cell RNA-seq, single cell ATAC-seq) further unravel immune cell heterogeneity, revealing tissue-specific chromatin accessibility dynamics and novel targets like interleukin-34 (IL-34) for microglia-mediated neuroinflammation. However, challenges persist in translating preclinical findings to clinical practice, necessitating age-tailored trials and biomarker-driven approaches. By integrating mechanistic insights with translational innovations, this review underscores the urgency of addressing immunosenescence to optimize cancer immunotherapy for aging populations, ultimately bridging the gap between aging biology and precision oncology.

Introduction

Aging is an inevitable biological process causing profound physiological alterations, particularly in the immune system [1, 2]. Immunosenescence, defined as the progressive decline in immune function with age, increases susceptibility to infections, chronic inflammation, and cancer development in older adults [3, 4]. Changes in bone marrow hematopoietic function, together with thymic atrophy, cause an imbalance in the distribution of immune cell subpopulations [5]. In addition, immune cells themselves undergo various metabolic disorders, including mitochondrial dysfunction and disruption of energy metabolism pathways [6, 7]. These factors together lead to the secretion of pro-inflammatory factors by immune cells, causing chronic low-grade inflammation and inflammaging, which is a characteristic of immune aging [8]. Here, to better study and observe the phenomenon of immunosenescence, we propose three criteria for a marker that can be used to determine immunosenescence: (1) manifestation during aging; (2) causal acceleration of immune dysfunction when exacerbated; (3) potential for reversal through targeted interventions (essential for “core drivers”). Some correlates are integral to the process but classified as “contributing factors” due to insufficient direct intervention evidence. Based on these criteria, we identified 11 phenomena that mark immunosenescence: telomere attrition, epigenetic alterations, disabled autophagy, mitochondrial dysfunction, cellular senescence, hematopoietic stem cells (HSCs) myeloid bias, altered intercellular communication, chronic inflammation as “core drivers”, and genomic instability, loss of proteostasis, gut dysbiosis as ‘contributing factors’. When identifying these hallmarks, we also take the character of immunosenescence into consideration. Take an instance, though people are likely to regard stem cell exhaustion as one of the aging hallmarks, we think that in immunosenescence, HSC myeloid bias could describe aging driven by stem cell abnormalities better. However, it is important to note that these markers aren’t completely independent, but are interconnected. Collectively, these markers synergize to drive a systemic state of immunosenescence, characterized by impaired immune surveillance, reduced cytotoxic responses, and increased chronic inflammation which profoundly influences cancer occurrence, progression, and resistance to therapies [9].

As data shows, cancer incidence markedly increases with age, making it a prominent health issue in elderly populations, creating urgent needs to understand aging-cancer interactions in aging global population [10, 11]. Emerging evidence indicates that immunosenescence critically influences cancer progression and treatment response by shaping tumor-promoting microenvironments [12]. The tumor microenvironment (TME) is a dynamic environment comprising fibroblasts, vascular endothelial cells, immune cells, and non-cellular factors, including cytokines and the extracellular matrix (ECM) [13]. The aging TME can both promote and inhibit immune responses, depending on the regulatory networks and cellular interactions [14]. Most of the time, aging-induced changes within the TME, including elevated pro-inflammatory cytokines and the recruitment of immunosuppressive cells, are shown to accelerate immunosenescence and promote tumor growth [15]. However, situations may be different in various types of tumors [16].

Besides, aging-associated alterations in systemic immunity impair tumor recognition and clearance, influencing tumor development and metastasis, finally resulting in poorer prognosis and increased treatment resistance in elderly patients [17].

Tumor immunotherapy is a therapeutic method that enables the body to generate tumor-specific immune responses through active or passive means, and exerts its function of suppressing and killing tumor cells, which mainly includes molecular targeted therapy, immune checkpoint inhibitors [18], adoptive cell transfer (ACT) (such as dendritic cell (DC) vaccine, CAR-T cell therapy, CAR-natural killer (NK) cell therapy, tumor infiltrating lymphocytes (TILs) cell therapy and cytokine-induced killer (CIK) cell therapy) [19], cytokine therapy and tumor vaccines [20]. Nevertheless, with the alterations both in systemic immunity and TME as aging among tumor patients, the immunotherapy efficacies differ between young and aging populations with cancer [21]. Understanding these mechanisms is crucial as most cancer patients requiring treatment are elderly.

In short, this review aims to define key molecular and cellular features of immunosenescence based on a proposed framework and highlight the mechanistic role of immunosenescence in modulating cancer development, progression, and treatment response both systematically and locally. It further explores age-specific immune remodeling in the TME and discusses emerging strategies to overcome immunosenescence in cancer patients.

Hallmarks of Immunosenescence

Genomic instability

Many studies have shown the relationship between aging and genomic instability, and the same applies to immunosenescence. Genomic instability biomarkers, such as micronucleus (MNs) and centromere positive micronuclei (MNC+), have been reported in leukocytes [22]. The accumulation of DNA damage with aging, which is frequently caused by deficiencies in the DNA repair mechanism, such as the double-strand break (DSB) repair and mismatch repair results in the genomic instability in aging immune cells [23, 24]. In vitro experiments have demonstrated that the dysregulation of mismatch repair system genes, especially the reduction of MutL heterodimers in elderly cloned T cells, results in microsatellite instability (MSI) [24, 25]. For example, T cells, under age-related oxidative stress, experience mitochondrial DNA (mtDNA) translocation into the nucleus and integration near the telomeres, generating genetic alterations and elevated MNs with diminished proliferation [26]. Notably, macrophage-specific aging marker CD63 is upregulated in the absence of LaminA/C, leading to nucleotide excision repair (NER) and DNA damage, although mechanistic details remain elusive [27].

Transposons, as elements that affect gene expression and function, also mediate genomic instability in the leucocytes of aging organisms. Long interspersed elements-1 (LINE1) hypomethylation and ALU-J/sx destabilization are both involved in this process [22, 28]. Interestingly, LINE1 hypomethylation exhibits no significant correlation with MNC + levels, which potentially attributes to the small sample size; and regional differences are exhibited in LINE1 hypomethylation as aging [22, 29].

Telomere attrition

Telomere attrition, characterized by progressive shortening and reduced telomerase activity, exists in immunosenescence [30, 31]. Currently, leukocyte telomere length (LTL), measured via quantitative polymerase chain reaction (qPCR), flow-fluorescence in situ hybridization (flow-FISH) and terminal restriction fragment (TRF), is one of the key biological markers investigated in the field of aging research as a potential indicator of cellular senescence and overall biological age [32–34]. It should be noted that chronological aging does not always parallel biological aging, for example, more rapid LTL attrition may predict cognitive aging in healthy young adults. However, telomere attrition in the elderly is often faster than in younger individuals [35–37]. Currently, some biomarkers such as FetuinA [38] and certain metabolites [39] have been found to indirectly predict LTL. Through diverse detection techniques, an increasing number of factors have been shown to accelerate LTL shortening. Infectious pathogens (human immunodeficiency virus (HIV) [40], cytomegalovirus (CMV) [41], herpes simplex virus type 1 and human herpesvirus 6 [41]) are all independently associated with LTL attrition. HIV induces telomere attrition through inhibition of telomeric repeat binding factor 2 (TRF2), telomerase, topoisomerase I and II alpha (Top1/2a), and ataxia telangiectasia mutated (ATM) kinase activities, resulting in the accumulation of dysfunctional telomere-induced foci (TIF), the DNA damage marker γ H2A family member X (γH2AX), and topoisomerase cleavage complex (TOPcc), ultimately leading to telomere attrition and T cell senescence. However, since this experiment was conducted using an arsenic compound KML001 to artificially reproduce a process similar to HIV-induced CD4 + T cell senescence, the result requires in vivo validation [42]. Besides, While combination antiretroviral therapy (cART) has the potential to ameliorate the condition of HIV-infected patients, it concomitantly accelerates microglial aging by inhibiting telomerase activity and upregulating TRF-1, thereby increasing IL-1β expression and promoting neuroinflammation and HIV-associated neurocognitive disorders (HAND) [43].

Lifestyle [44–47], and other pathophysiological factors [48–57] can also lead to LTL shortening. Notably, the impact of specific factors exhibits gender disparities: high-intensity physical activity predominantly shortens telomeres in elderly women [53], while hostility primarily affects elderly men [55]. Paradoxically, cross-sectional data indicate that physical activity (PA) and physical fitness (PF) mitigate age-related telomere attrition regardless of gender [58], suggesting intensity-dependent effects. Although dialysis also accelerates telomere attrition, it also leads to compensatory increases in leucocyte telomere length, which may be related to the increase in peripheral immature leucocytes to replenish depleted ones [54].

Contradictory findings exist for other factors. Most studies believe that obesity accelerates telomere attrition [47, 59], and TRF1 upregulation mediates this process [60], but a longitudinal analyse shows no consistent association in the British Birth cohort [61], indicating that obesity may be a factor with regional differences. The impact of chronic psychosocial stress on telomere attrition has also shown contradictory results in different studies, possibly due to the heterogeneous study designs and the complex nature of chronic psychosocial stress from individual and environmental composition, including social connections, health-maintaining behaviors, and psychological resources [62, 63]. Besides, cortisol may be involved in the accelerating telomere attrition through neuroendocrine mechanisms [54].

In addition, LTL shortening is also associated with many age-related diseases [64–68]. Interestingly, a meta-analysis indicated that short LTL associated with biological aging rather than chronological age can serve as a predictor for myocardial infarction, but another study showed that this correlation only appeared in men [64, 69]. Fortunately, TA-65, a type of telomerase activator, could reverse immunosenescence in acute coronary syndrome (TACTIC) [70], indicating a possibility in the treatment of myocardial infarction. This suggests that attention should be paid to biological aging and potential risks of age-related diseases even in young people. Although LTL shortening is associated with atherosclerosis, one study showed that this association diminishes after adjustment for age [71]. When further exploring the molecular mechanisms of telomere attrition, in addition to leucocytes, it has been found that hematopoietic stem cells (HSC) in the elderly also have defects in telomerase and telomere length attrition, which may be inherited by descendant cells, leading to poorer hematopoietic potential and lower immune capacity in the elderly [72].

Epigenetic alterations

Epigenetic alterations often vary with biological aging. Epigenetic clock initially predicted biological age by analyzing methylation patterns at 353 CpG sites [73]. It utilizes not only cells in heterogeneous tissues, but also individual cell types, including neutrophils, monocytes, CD4 T cells and immortalized B cells as the marker to predict biological aging [73–76]. However, previous versions (Hannum clock [77], Horvath clock [73], Horvath Skin and Blood clock [78], and PhenoAge [79]) are often confounded by age-related shifts in immune cell composition, especially CD8 + T cell differentiation states within PBMCs. The novel IntrinClock overcomes this limitation by using CpG sites stable during CD8 + T cell differentiation, enabling consistent and more accurate biological age prediction across immune subsets [75, 80]. Changes in chronic inflammation are also linked to these epigenetic shifts. Below, we will provide an overview of these studies. However, limitations persist in linking global epigenetic alterations to immune cell phenotypic changes and functional decline.

Individuals in old age often experience a chronic, low-grade inflammatory state, which is also a characteristic of immunosenescence. Epigenetic abnormalities can cause and accelerate immunosenescence through both systemic and tissue-specific mechanisms. Systemically, ATAC-seq showed transition of CD8 + T cells to age-associated granzyme K (GZMK)-expressing CD8 + T (Taa) cells is regulated by the T-box family transcription factor eomesodermin (EOMES). Taa cells expand in both aged humans and mice, upregulating CD49d and acquiring efficient tissue homing capacity, which, together with their secretion of GZMK, may contribute to systemic inflammation [81]. Furthermore, age-related decrease of microRNA (miR)-17-92a in naïve-CD8 + T cells contributes to their reduction of quantity [82]. Additionally, a deficiency in miR-181a, whose target is SIRT1, has been shown to impact T cell function, leading to excessive replication stress and inflammatory cytokines in naive T cells from older individuals and miR-181ab1-deficient murine T cells. This replication stress is linked to reduced histone expression and delayed cell cycle progression, primarily due to the repression of histone gene transcription by SIRT1 by binding to the promoters and reducing histone acetylation. Furthermore, treatment with SIRT1 inhibitors decreases the secretion of inflammatory cytokines in mice with miR-181a-deficient T cells [83]. Besides, decreased expression of H2AX in CD8 + CD28-T cells, which are a subset related to aging, leads to less targets for miR-24, resulting in a decreased potential to activate the DDR response [84]. This, as we mentioned above, increases genome instability and causes immunosenescence. Finally, the contribution of chromatin remodeling to immunosenescence can’t be ignored. The large-scale chromatin reorganization distinguishes young and old bone marrow progenitor (pro-) B cells, which causes reduced interactions within topologically associated domains (TADs) with aging. Reduced TADs, containing genes important for B cell development, impair B lymphopoiesis [85].

Concurrently, tissue-localized epigenetic dysregulation fuels immunosenescence by inflammation. The downregulation of SET domain-bifurcated histone lysine methyltransferase 1 (SETDB1) induced by hyperglycemia activates the LINE-1 promoter, triggering the aging phenotype of macrophages and driving periodontal immunosenescence. This process can be reversed by metformin in preclinical models [72]. Aging intestinal stem cells in mice exhibit increased accessibility of inflammation-related loci on chromosomes due to chromatin remodeling, thus exacerbating gut inflammation, although the specific molecular mechanisms require further study [86]. Furthermore, interferons and their related signaling pathways play crucial roles in the inflammatory network, with abnormally high expression of transcription factors signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factors (IRFs) found in elderly individuals [87]. Subsequent research suggests that the abnormal expression of these transcription factors in the liver and kidneys of aged mice may be associated with a general open chromatin rearrangement related to aging, and dietary restriction (DR) can partially rescue the inflammatory environment by decreasing the chromatin accessibility of STAT1 and IRF regions [88]. This discovery provides a non-invasive and relatively harmless therapeutic approach to alleviate chronic inflammation in aging individuals.

Besides, inflammation reciprocally accelerates epigenetic aging, establishing a vicious cycle. Studies on human skin have shown that exposure to light can induce epidermal inflammation, thus promoting epigenetic aging characterized by methylation changes, which can persist for decades. However, it seems that not all photoexposed skin areas exhibit this phenomenon, and the reason for this variability remain unclear [89]. Infection can also accelerate epigenetic aging, although whether this effect is related to inflammation is yet to be determined. Hepatitis C virus (HCV) infection was found to correlate with epigenetic age acceleration (EAA), with the most pronounced in patients who developed hepatocellular carcinoma (HCC) after sustained virologic response (SVR), and this acceleration can be reversed by direct-acting antivirals (DAAs). Nevertheless, since this result was derived from the Horvath clock detecting DNA methylation in peripheral blood mononuclear cells (PBMCs) rather than liver cells, it cannot be determined whether the accelerated epigenetic aging in patients is directly caused by HCV or indirectly triggered by chronic inflammation [90]. One study suggested that infections leading to EAA are associated with exposure to susceptible environments and past infections rather than recent infections. A study comparing epigenetic aging in individuals from leprosy-endemic and non-endemic areas in Brazil found no difference in aging speed between infected and uninfected subjects within endemic areas, but significant EAA was observed in individuals from endemic areas compared to those from non-endemic areas [91]. These results all imply chronic inflammation’s enduring impact on epigenetic aging. Moreover, epigenetic age acceleration caused by both HCV and leprosy infection exists regional differences [90–92].

Epigenetic biomarkers show promise for clinical assessment of inflammation status and immunosenescence in elderly individuals. Notably, the epigenetic inflammation score (EIS) based on CpGs outperform conventional C-reactive protein (CRP) in assessing low-grade inflammation in elderly individuals [93]. Besides, the measurement of DNA methylation (DNAm) in peripheral blood cells has been used to predict immune cell infiltration in Alzheimer’s disease and atherosclerosis [94]. These studies reveal the potential of epigenetic changes in clinical applications.

Although in most cases, epigenetic changes related to aging and inflammation follow predicted patterns, such as methylation of promoter regions leading to gene downregulation and acetylation leading to gene upregulation, recent research has identified some exceptions [95, 96]. In the elderly, hypomethylation of the inflammation-related gene C-X-C Motif Chemokine Ligand 10 (CXCL10) increases its expression but paradoxically correlates with enhanced spatial memory in carriers of the single nucleotide polymorphism (SNP) rs56061981 in CXCL10, which eliminates the CpG-136 site and increases the gene activity [97]. This seemingly contradictory result requires further validation with larger sample size. Similarly, inflammatory-related genes which upregulate in the brain with aging (Age-up genes) show reduced histone H3 acetylated lysine 27 (H3K27ac), a histone mark typically associated with activation, and HDAC inhibitors (HDACi) suppress the expression of Age-up genes [98]. These results, combined with previous findings, indicate that the regulatory role of H3K27ac in the inflammatory environment of aging individuals is tissue-specific [96, 98]. Besides, HDACi also show therapeutic potential in prevention of CAR-T cells exhaustion by enhanced expression of transcription factors TCF4 and LEF1, thereby activating the Wnt/β-catenin signaling [99]. Figure 1a shows the molecule mechanism of how genomic instability, telomere attrition and epigenetic alterations lead to immunosnescence. Collectively, epigenetic alterations represent a fundamental mechanism driving chronic inflammation in immunosenescence. Furthermore, these anomalies underscore persistent challenges: immune cell heterogeneity confounding epigenetic assays, the unclear causal mechanism between specific epigenetic modifications and immune decline, and the contradictory tissue specificity of inflammation-driven epigenetic aging. In the future, it will be necessary to combine single-cell epigenomics to resolve immune cell subpopulation dynamics, target reversal of epigenetic-immune imbalances through interventional experiments, and explore the long-term effects of episodic memory on immunosenescence in the context of infections/environmental exposures. Beyond epigenetic changes, loss of protein homeostasis also emerges as a critical hallmark of immunosenescence, for impaired proteostasis contributes significantly to functional decline in the antigen presentation.

Fig. 1 — A focus on the core molecular mechanisms of immune senescence and chronic inflammatory networks. (a) Some factors (virus, unhealthy lifestyle) will lead to LTL attrition, which will cause some age-related diseases. SETDB1 downregulation caused by elevated glucose levels activates the LINE-1 promoter in macrophages, triggering an aging phenotype in immune cells. Furthermore, a general open chromatin rearrangement related to aging results in abnormally high expression of STAT1 and IRFs, finally leading to the activation of IFNs and their related signaling pathways. Genomic instability derived from many factors; MNs are one of them. The production of them is due to the mitochondrial DNA (mtDNA) translocation into the nucleus and integration near the telomeres. Besides, the reduced MutL heterodimers can lead to decreased efficiency of mismatch repair, resulting in MSI, and as well as the efficiency of double-strand break (DSB) repair. (b) Mitochondrial dysfunction primarily interferes with cellular homeostasis through various pathways, including abnormalities in mitochondrial membrane potential, increased ROS production, and mtDNA leakage. The proinflammatory signal is presented in red, while anti-inflammatory is in blue in the figure. These factors contribute to inflammation through the activation of the cGAS/STING pathway, activating the downstream molecules such as NF-κB and IRF-3. Suppressing mitochondrial autophagy and accumulating mtDNA damage are regulated by reducing the mTOR/TFEB signaling pathway, the mtOGG1 expression, and the PINK1/Parkin-mediated polyubiquitination of mitochondria. Moreover, ROS can promote inflammation by activating downstream signaling pathways, such as JNK kinase, through mitochondria-to-nucleus retrograde signaling. This process will then inhibit the negative regulation of 53BP1 on DSB end resection, leading to the release of CCFs and the activation of the downstream pathway. Furthermore, Guanylate binding protein 1 (Gbp1), under normal conditions, eliminates inflammation-induced dysfunctional mitochondria via the mitochondrial autophagy pathway (black line). In aging macrophages, Gbp1 expression is downregulated, leading to mitochondrial dysfunction (red line). This dysfunction activates the AMPK-p53 pathway, inducing cellular senescence and promoting an inflammatory response through the secretion of SASP (senescence-associated secretory phenotype) factors. Besides, APN deficiency leads to a significant increase in HDAC1, exacerbating mitochondrial damage. Several pathological factors can also exacerbate mitochondrial dysfunction in aging immune cells, such as Aβ, HIV TAT and QA. They can inhibit the SIRT1/NRF2 and SIRT3 pathway. (c) Mild chronic inflammation is considered a hallmark of aging and a core driving factor for age-related damage and diseases. In aging brains, the activation of the cGAS-STING signaling pathway leads to increased expression of type I IFN-related genes in many types of cells, finally increasing the inflammatory cytokines. Additionally, TNF-α, also induced by the activation of the microglial cGAS-STING pathway, drives neurodegeneration and activates the expression of adhesion molecules Vcam1 and Icam1 in brain venous endothelial cells in the aged subventricular zone (SVZ), finally promoting T cell infiltration. Furthermore, aged microglia secrets CCL3 to recruit peripheral CD8 memory T cells infiltrating the brain microenvironment. CD8 memory T cells then release SASP. However, how these molecule changes are associated with functional alteration in aging brain remain unclear. Chronic inflammation in the cochlea and cochlear nucleus (CN) is caused by macrophages, microglia and C1q deposition, ultimately in coordination to the development of age-related hearing loss (ARHL). Furthermore, the quantity of tissue-resident memory γδ T cells (CD44hi62LlowCD69+) increase in the visceral adipose tissue (VAT) of aging individuals. These γδ T cells promote low-grade chronic inflammation in adipose tissue by upregulating IL-17 A, which mediates the production of IL-6 produced by preadipocytes/adipose-derived stem cells(ADSCs). Finally, animal studies have found that dietary strategies are a feasible approach to improve age-related chronic inflammation, but the safety and effectiveness in human need further research

Loss of proteostasis

Proteostasis usually means the balanced state of processes such as protein synthesis, folding, repair, degradation, and renewal within cells [100]. Upon aging, proteostasis can be disrupted by many factors. Currently, discussions of impaired proteostasis in immunosenescence mainly revolve around the disabled autophagy and the dysregulated unfolded protein response (UPR) in macrophages and microglia. In macrophages, age-related autophagy reduction promotes pro-inflammatory M1 polarization [101]. Resveratrol stimulation significantly restores autophagic flux by increasing the number of autophagosomes in senescent macrophages (S-MΦs), reducing reactive oxygen species (ROS), thus promoting the M1-to-M2 transition [102]. Similarly, improvement in autophagy leading to the anti-inflammatory polarization of S-MΦs has also been observed with rapamycin treatment, which has been found to promote the degradation and myogenesis of vascular graft poly glycerol sebacate-polycaprolactone (PGS-PCL), a synthetic vascular graft material that can utilize the host’s regenerative capacity to transform in situ into a blood vessel-like structure, thereby improving vascular remodeling in aged rats [103]. Despite the macrophages in the peripheral environment in the aged, treatment targeting the autophagic defect in S-MΦs of the hematopoietic microenvironment is also under development. Icariin restores osteogenesis of senescent bone marrow mesenchymal stem cells (S-BMSCs) by activating autophagy in S-MΦs, suppressing SASP-mediated inflammation [104].

Microglia, a type of resident mononuclear macrophages in the central nervous system [105], also exhibit age-dependent autophagy impairment, which exacerbates neuroinflammation and cognitive decline. Perioperative neurocognitive disorders (PND), associated with neuroinflammation mediated by microglia with decreased autophagy, are cognitive impairments caused by surgery and anesthesia, with a higher incidence in elderly patients [106]. β-caryophyllene (BCP), a natural terpene that specifically activates CB2 receptors (CB2R), can inhibit the release of IL-1 (interleukin-1) and IL-6 inflammatory cytokines from microglia in the hippocampus and restore their autophagic capacity in aging mice [107]. Similarly, older patients with traumatic brain injury (TBI) have a higher mortality rate and worse prognosis than younger patients. This can be attributed to the decline in autophagy, the elevation of phagocytosis, the inflammatory phenotype and oxidative stress that occurs in microglia under the influence of ageing, which are further exacerbated by TBI, potentially aggravating neurodegeneration and a more serious neuroinflammation. Surprisingly, an enhancer of autophagy, trehalose, may inhibit microglia phagocytosis by acting upstream of the autophagy pathway, finally restoring motor and cognitive functions in aged TBI mice [108]. Notably, a microglial subset, autophagy-dependent age-acquired microglia (ADAM), emerges via IL-34- colony stimulating factor 1 receptor (CSF1R) - extracellular regulated protein kinases (ERK)/ (adenosine 5‘-monophosphate-activated protein kinase) AMPK signaling, limiting neuroinflammation. Nevertheless, this subset decreases when aging. Fortunately, IL-34 supplementation expands this, suggesting therapeutic potential for neurodegenerative diseases [109]. In the future, it will be essential to ascertain the potential reduction of the ADAM subset in age-related neurodegenerative diseases.

While much attention has been focused on autophagy, loss of proteostasis in aging also involves complex alterations in UPR signaling within those myeloid cells. In aging individuals, UPR displays varying expression changes in immune cells across different tissues, ultimately leading to the loss of protein homeostasis. Microglia cells in aging rats exhibit abnormal or overactive UPR, which impairs protein homeostasis. NT-020, a blend of polyphenols, has been shown to inhibit UPR signaling [110]. However, its causal role in microglial aging remains unclear. Conversely, tissue-resident macrophages in aged mice recovering from influenza A virus-induced pneumonia show upregulated proteostatic stress genes but downregulated UPR components [111]. These contradictory UPR expressions may stem from species-specific differences, tissue variability, or latent viral effects, necessitating further mechanistic studies across standardized models. Additionally, investigation into the immune functional alterations caused by protein homeostasis loss in aging individuals necessitates further exploration.

Age-related proteostatic failure directly impairs immune function by interfering with antigen presentation processes. In dendritic cells, oxidative stress induces protein damage (carbonylation, glycation, lipoxidation), forming insoluble aggregates in late endosomes that disrupt major histocompatibility complex (MHC) class II antigen presentation and endosomal proteostasis [112]. Proteasomes consist of immuno-proteasomes and standard proteasomes, each composed of different subunits. Aged mouse hepatocytes exhibit altered proteasome composition, with incomplete replacement of standard subunits by immuno-subunits, forming intermediate-type proteasomes. This shift correlates with reduced hydrolytic activity and may compromise MHC I antigen peptide generation, linking proteostatic decline to adaptive immune dysfunction [113, 114].

Disabled autophagy

Autophagy plays a crucial role in modulating the function of immune cells, influencing their inflammatory phenotype and immune responses. In addition to myeloid cells mentioned above, aging also impairs autophagy in lymphocytes, notably in T cells, compromising their maintenance, functionality, and immunotherapeutic responsiveness. A prominent feature of aged CD8⁺ T cells is the decline in autophagic activity, which undermines the maintenance of memory T cells and diminishes vaccine efficacy. This deterioration is mechanistically linked to spermidine biosynthesis decline, for the spermidine maintains T cell autophagy through the translation factor eukaryotic translation initiation factor 5 A (eIF5A) and the transcription factor EB (TFEB) usually [115–117]. Spermidine supplementation also rescues the antitumor activity of T-cell receptor-engineered T cells (TCR-Ts) by enhancing the proliferation and effector function and reducing inhibitory immunoreceptors expression (programmed death-1 (PD-1), T cell immunoglobulin domain and mucin domain-3 (TIM-3) or lymphocyte activation gene-3 (LAG-3)) caused by impaired autophagy [118].

Beyond CD8⁺ T cells, autophagy impairment in aging CD4⁺ T cells contributes to immune dysfunction by promoting a pro-inflammatory phenotype. Autophagy deficiency drives Th17 polarization via signal transducer and activator of transcription 3 (STAT3) activation, fueling chronic inflammation, and this process is reversible by metformin [119].

Surprisingly, declined autophagy in the aging process can also impact the immune response via non-immune tissue cells. Autophagy deficiency in liver cells triggers the cellular senescence and a SASP primarily consisting of C C motif ligand 2 (CCL2), which is regulated by nuclear respiratory factor 2 (NRF2)-dependent activation of forkhead box K1 (Foxk1), finally recruiting F4/80 + or CD11b + macrophages to indirectly produce inflammation. Deletion of C C motif receptor (Ccr2) significantly inhibits the accumulation of inflammatory cells in liver tissue [120].

In short, how loss of proteostasis and disabled autophagy relate to immunosenescence is described in Fig. 2a and b.

Mitochondrial defects

Mitochondria are crucial “energy factories”, determining the energy metabolism and physiological status of immune cells. For instance, mitochondrial metabolic reprogramming in CD4 + T cells is essential for their subsequent differentiation into specific subsets [121]. Overall, aging leads to impairments in both mitochondrial quality and function in immune cells, which promotes an inflammatory phenotype in these cells and further accelerates the immunosenescence, and some details are presented in Fig. 1b.

The decreased mitochondrial mass plays a central role in driving immunosenescence through mitochondria’s progressive dysfunction. The senescent T cell population (EMRA; effector memory CD45RA re-expressing T cells), which accumulates with aging, exhibits reduced mitochondrial mass [122, 123]. Interestingly, CD8 + EMRA cells show accelerated aging compared to CD4 + EMRA cells, also likely due to their lower mitochondrial mass, which leads to metabolic dysfunction [124]. Despite these changes, the transfer of functional mitochondria into CD4 + EMRA T cells restores mitochondrial function and aerobic metabolism, reducing ROS and enhancing infection control in vitro [125]. In contrast, aging memory CD4⁺ T cells exhibit a paradoxical increase in mitochondrial mass. This elevation enhances maximal oxygen consumption and spare respiratory capacity but triggers excessive ROS production. This ROS generation fuels SASP-mediated inflammation (IL-4, IL-6, IL-8, IL-9, interferon-γ(IFN-γ)), accelerating immunosenescence and leading to a Th17 profile [119, 126]. Furthermore, in aging CD8 + T cells, ROS-induced mtDNA leakage similarly activates cGAS/STING/IRF3, exacerbating inflammation and immune decline. The effects are mitigated by NMN supplementation [127]. These studies show an interesting result that aging may act differently on various stages of T cells, though all of them lead to immunosenescence.

Normally, age-related failures in mitochondrial quality control worsen the mitochondrial quality. In aged CD4 + T cells, autophagic deficits permit the accumulation of damaged mitochondria, declining mitochondrial function accompanied by reduced mitochondrial protein expression [128]. A similar phenomenon is observed in macrophages. Guanylate binding protein 1 (Gbp1), under normal conditions, eliminates inflammation-induced dysfunctional mitochondria via autophagy. However, downregulated GBP1 in macrophages from aged, high-fat diet-fed mice disrupts mitophagy, induces cellular senescence and promotes the secretion of SASP factors through AMPK-p53 pathway [129].

Pathological factors synergistically amplify mitochondrial damage and then promote aging in immune cells. For example, amyloid beta (Aβ) exacerbates ROS production and loss of mitochondrial membrane potential in microglia through the inhibition of the sirtuin 1 (SIRT1)/NRF2 pathway, a key regulator of mitochondrial health. This leads to a reduced phagocytic function. Promisingly, aspirin can alleviate this [130]. Furthermore, quinolinic acid (QA), a neurotoxic metabolite produced during the aberrant activation of microglia, inhibits mitolysosome formation, impairing the clearance of damaged mitochondria. Mitophagy inducers have been shown to inhibit this process [131]. Finally, human immunodeficiency virus-1 transcription activator (HIV TAT) elevates miR505 to inhibit the deacetylase SIRT3, exacerbating antioxidant deficiencies [132].

As mentioned above, excessive ROS production in aging immune cells is caused by dysfunctional mitochondria. In senescent immune cells, a decline in the mitochondrial membrane potential, the ATP synthesis, the autophagy and the accumulation of leakage mtDNA (induced by reducing the mammalian target of rapamycin (mTOR)/TFEB signaling pathway, the mitochondrial 8-oxoguanine DNA glycosylase (mtOGG1) expression and the PTEN-induced kinase 1(PINK1)/Parkin-mediated polyubiquitination of mitochondria) results in the dysfunctional mitochondria accumulation, amplifying ROS generation. Notably, while mtOGG1 declines similarly in aged male and female mice, only males respond to mtOGG1 overexpression therapies, highlighting unresolved sex-specific regulatory mechanisms [127, 133, 134]. ROS can promote inflammation by activating c-Jun N-terminal kinase (JNK) kinase through mitochondria-to-nucleus retrograde signaling, inhibiting the suppression of 53BP1 on double-strand break (DSB) end resection. This triggers cytoplasmic chromatin fragments (CCFs) release, activating the cyclic GMP-AMP synthase (cGAS)/ stimulator of interferon genes (STING)/ nuclear factor kappa-B (NF-κB) pathway to drive SASP [135].

Mitochondria-derived inflammation is also prominent in the central nervous system (CNS). The mtDNA-triggered cGAS/STING signaling upregulates type I interferons in microglia, oligodendrocytes, and astrocytes and promotes chronic inflammation in the brain, while microglial tumor necrosis factor-α (TNF-α) induces adhesion molecules vascular cell adhesion molecule-1 (VCAM1)/intercellular Cell Adhesion Molecule-1 (ICAM1) expression in brain venous endothelial cells in the aged subventricular zone (SVZ), finally promoting T cell infiltration [136, 137]. Furthermore, aged microglia secret CCL3 to recruit peripheral CD8 memory T cells. These infiltrating T cells then release Ccl4, Ccl5, IFN-γ, X-C motif chemokine ligand 1 (Xcl1), Factor-related apoptosis ligand (Fasl) in the aged SVZ, contributing to the formation of chronic inflammation [136]. Unfortunately, although studies have found that chronic inflammation in the elderly leads to psychomotor slowing [138], the relationship between the functional changes and the molecular mechanisms described above, or the impact of these on the physiological function of the elderly, is not yet fully understood. Furthermore, ROS overproduction impairs antigen processing in aging dendritic cells, where non-functional mitochondria, rather than mitochondrial mass contribute to reducing cross-presentation efficiency of cell-associated antigens and CD8 + T cell priming, exacerbating the immune dysfunction observed in aging [128, 139]. Mitochondrial permeability transition (PT) is another key feature of aging immune cells. It can lead to the mitochondrial dysfunction. In aging lymphocytes, mitochondrial PT is more easily activated, collapsing mitochondrial membrane potential, depleting ATP synthesis, and disrupting calcium homeostasis. These changes weaken lymphocyte signaling, contributing to immune dysfunction in aging [140, 141].

Mitochondrial metabolic reprogramming also plays a key role in immunosenescence. In aging T cells, SIRT1, a negative regulator of T cell activation, suppresses glycolysis via deacetylation of phosphoglycerate mutase-1 (PGAM-1), influencing immune function [142]. In addition, senescent macrophages shift toward pro-inflammatory M1 phenotypes with elevated glycolysis and inhibited mitochondrial respiration, mediated by mTOR- hypoxia inducible factor-1α (HIF1α)-glycolysis [143], mitogen-activated protein kinase (MAPK)-NFκB [144], and Toll-like receptor 4 (TLR4)-STAT1 [145] pathways. Notably, ROS- ataxia telangiectasia mutated (ATM)- checkpoint kinase2 (Chk2) activation enhances glycolysis through pyruvate kinase M2 (PKM2) phosphorylation, facilitating M1 polarization [146]. Interventions like citrulline supplementation show promise by inhibiting mTOR-HIF1α-glycolysis to delay immunosenescence [143].

In short, mitochondrial dysfunction is a central driver of immunosenescence, contributing to the decline in immune function that accompanies aging. The interplay between defective mitochondrial quality control, decreased mitochondrial mass, and excessive ROS production leads to inflammatory processes that further exacerbate the aging of immune cells. Although more research is needed to fully understand the precise mechanisms behind these processes, targeting mitochondrial dysfunction offers promising therapeutic avenues to alleviate the effects of aging on the immune system and improve immune responses in older individuals.

Cellular senescence

Cellular senescence, which has already been illustrated in other parts, exhibits its biomarkers, such as senescence-associated β-galactosidase (SA-β-Gal), cyclin-dependent kinase inhibitor 1 A (CDKN1A), p16INK4a (inhibitor of CDK4), whose elevation can be observed in nearly all cell senescence instances [147]. While these cellular aging markers are considered universal, it is important to note that the same type of immune cells upon aging can show different aging phenotype in different physiological and pathological conditions. The unique aging phenotype of these aging immune cells in different conditions is shown in Table 1. In Table 1, the column headers denote distinct immune-cell lineages that are known to undergo senescence, while each row lists functional or phenotypic descriptors (e.g., SASP cytokines, cytotoxicity loss, metabolic shift) that have been reported for the corresponding senescent subset.

Table 1.

The summarization of the functional changes of senescent immune cells under different conditions

	Neutrophils	Macrophages	T cells	B cells	NK cells
Inhibiting apoptosis	Sepsis [393]
Dysregulation of phagosomal function	Cystic fibrosis (CF) [394]
Secretion of exosome (piR-17560)	Breast cancer [395]
Impairing phagocytic activity	Atopy [396]
Higher phagocytic activity	Endotoxemia [397, 398]
NETs formation	Endotoxemia [397, 398]
Inflammation	Psoriasis [399]	Neuroinflammatory phenotype [400], Alzheimer’s disease (AD) [401], atherosclerosis [402], osteoporosis (SOP) [403, 404], obesity [405]	Rheumatoid arthritis (RA) [406], Severe infection [407], Brown adipose tissue [408], Elderly hypertension [409], Inflammatory bowel disease [410]
Secretion of grancalcin		Fracture [411]
Expression of fibrosis-associated factors		Pulmonary fibrosis (IPF) [412–414]
Production of Arginase-1		Glioblastoma [415]
Anti-tumor immunity			Melanoma [251, 416, 417]
TCR signaling			Lupus [418, 419]
Secretion of granzyme B (GZMB) and perforin-1 (PRF1)			Bacterial infection [420] (Increased)		Depression [421] (Decreased)
Delayed anti-virus ability			Systemic viral infection [83, 422]
Reduced IL-7R expression			Primary Sjögren’s syndrome (pSS) [423]
Decreased vaccine response				Obesity [424], HIV [425]
Decreased IgA production				Ileum infection [426]
Cytolytic activity					Chronic circadian disruption [427]

Open in a new tab

Besides, it is necessary to indicate that the aging of these immune cells, which lead to immunosenescence, is promoted by the “niche” comprised by stromal cells. For example, in liver cancer, laminin subunit alpha 4 (LAMA4) expressed by CD90 + eCAFs binds to integrin subunit alpha 6 (ITGA6) on the surface of T cells, activating downstream RAS signaling pathways and DNA damage responses, leading to CD8 + T cell senescence [148]. Apart from contacting directly, CAFs also secrete TGF-β to transform neutrophils into a tumor-promoting phenotype, accelerating the exhaustion of CD8 + T cells and forming an immunosuppressive microenvironment [149].

Fortunately, there exists agent which could reduce cellular senescence. Senolytic agent, plus STING inhibitor, could reduce the burden of stressed aging macrophages, improve mitochondrial integrity, and suppress STING, which will lead to overactivated inflammation after virus infection in aging mice and result in poor result. Finally, aging mice will be protected from respiratory infection after senolytic agent plus STING inhibitor treatment [150].

Hematopoietic stem cells (HSCs) myeloid bias

Aging reshapes hematopoietic stem cell (HSC) differentiation, favoring myeloid over lymphoid lineages (Fig. 2c). This phenomenon is independent of the proliferative and self-renewal abilities of HSCs but is mediated by changes in the clonal composition of the HSC compartment, ultimately leading to immunosenescence [151, 152]. Single-cell RNA-seq in aged mice shows preserved HSC proliferation; however, HSCs in aged mice exhibit delayed differentiation which occurs before the point that splits lymphoid fate from myeloid fate due to reduced Wnt signaling, probably linked to myeloid bias [153, 154]. Interestingly, when further searching the mechanism of myeloid bias, it has been observed that the impact of aging on HSCs varies among different subpopulations: the proportion of aged cells is significantly lower in myeloid-biased subsets compared to those lymphoid-biased [153]. Despite regarding the aging HSCs as a whole, this underscores the necessity of utilizing single cell sequencing techniques to subgroup aged individual’s HSCs based on their distinct functions and characteristics for further investigation. Biological noise, an indicator of variability in gene expression, is considered a potential driving force behind cellular differentiation. Notably, elevated biological noise in delta-like 1 homologue (Dlk1) expression (quantified by VarID2, a model based on single cell RNA-seq) correlates with myeloid bias. Dlk1 + LT-HSCs demonstrate enhanced in vivo and vitro self-renewal, contradicting previous views of age-independent whole HSC self-renewal [151, 152, 155]. This enhanced self-renewal and expansion capacity of myeloid-biased subsets have also been corroborated by another study with single-cell sequencing, driving clonal dominance in aged HSCs [156]. These findings highlight that bulk HSC analyses mask critical subset-specific functional differences underlying myeloid bias, necessitating single-cell approaches to dissect subset-driven mechanisms.

Many studies explored the mechanisms behind myeloid bias. The decreased CUL4-ROC1 E3 ubiquitin ligase (CRL4)/ DDB1 And CUL4 Associated Factor 1 (DCAF1)-mediated ubiquitination degradation signaling in aged HSCs leads to reduced ubiquitination of pseudouridine synthase 10 (PUS10), resulting in increased PUS10 level and myeloid differentiation [157]. Elevated period circadian clock 2 (Per2) in lymphoid-biased HSCs triggers p53 phosphorylation, selectively inducing apoptosis and depleting lymphoid subsets [158]. Aging increases platelet-biased HSCs, which enhance myeloid output while suppressing lymphoid-biased HSCs through competitive clonal dominance [159].

The occurrence of myeloid bias may be related to changes in the aging bone marrow niche. Elevated IL-1β and TNF-α levels, produced by dysfunctional stromal cells, promote myeloid differentiation and inhibit B-cell generation via chronic, low-grade inflammation [160–162]. Importantly, transplantation studies demonstrate that aged lymphoid-biased HSCs regain normal differentiation in young microenvironments, indicating the microenvironment-dependent reversibility of myeloid bias [162]. Some studies have found that this reversible bias is associated with epigenetic modifications [163]. Polycomb-group proteins promote and maintain cellular differentiation by suppressing gene expression, and genes associated with myeloid differentiation, which are non-Polycomb targets, show hypomethylation as well as high expression with increasing age, contributing to increased myeloid differentiation [164]. The downregulation of histone acetyltransferase Kat6b impairs multilineage differentiation in aging long-term (LT)-HSCs, leading to myeloid bias [165]. Notably, non-HSC sources compensate for most lineages except lymphocytes (particularly T cells), ultimately driving myeloid bias characterized by lymphoid reduction [166].

Multiple strategies aim to reverse this bias. Glycyrrhizic acid (GA) enhances lymphoid (especially CD8 + T cell) differentiation in Lin-CD117 + HSCs of aged mice by binding S100 calcium-binding 8 (S100A) protein, reshaping immunity [167]. Similarly, fecal microbiota transplantation (FMT) promotes HSC lymphoid differentiation via inflammation reduction and forkhead box protein O1 (FOXO1) upregulation, while reshaping gut microbiota metabolism to restore hematopoiesis through Lachnospiraceae expansion and tryptophan-associated metabolites [168]. Clinical efficacy remains unconfirmed.

Altered intercellular communication

Intercellular communication within the immune system primarily involves neuro-humoral regulation and intercellular signaling molecule exchange, with the latter predominantly manifesting as SASP, elucidated extensively elsewhere in the article. Here, the focus lies on the impact of neuro-humoral regulation on immune system aging (Fig. 3). Thymic involution, a key aging hallmark, is linked to age-related anterior hypothalamic changes, though its regulatory role remains debated. Intriguingly, anterior hypothalamic lesions suppress splenic and peripheral blood lymphocytes, reversible via thyrotropin-releasing hormone (TRH) acting directly on lymphocytes rather than the thyroid [169–171]. Apart from lymphocytes, corticotropin-releasing hormone (CRH) reduces splenic NK cell activity and cytotoxicity in aged rats, which reduces the immune function [172]. Additionally, declined pineal melatonin exacerbates thymic involution and reduces lymphocytes in peripheral blood and spleen. Melatonin treatment or pineal grafts restore immune function in aged mice [173].

Fig. 3 — Neuroendocrine regulation in immunosenescence. Involution of thymus is found to be associated with age-related changes in the regulation of the anterior hypothalamic area, although the role of the hypothalamus in either positive or negative regulation of the thymus remains contentious. Lesion of anterior hypothalamic area exerts inhibitory effects on lymphocytes in the spleen and peripheral blood. This aberration can be ameliorated by administering thyrotropin-releasing hormone (TRH), which acts directly on the lymphocytes. Moreover, CRH leads to decreased splenic NK activity and cytotoxicity. Additionally, decreased melatonin with aging also leads to the involution of thymus, decreased numbers of lymphocytes in peripheral blood and spleen, and M2 polarization of aging macrophages/microglia, which causes CNV. Besides, hormones are involved in regulating the aging individual’s circadian rhythm. For example, total B cells correlate negatively with cortisol during the day, while helper/inducer T cells correlate positively with cortisol; in the early morning, total T lymphocytes correlate negatively with cortisol, while suppressor/cytotoxic T cells correlate positively with cortisol

Hormonal dysregulation also impacts aging immune cells in age-related diseases. For instance, melatonin can inhibit choroidal neovascularization (CNV) by suppressing M2 polarization of aging macrophages/microglia through the IL-10/STAT3 pathway, offering potential targets for treating CNV and other age-related eye diseases [174].

Finally, hormones are involved in regulating the individual’s circadian rhythm, which is no exception for the aging immune system. In elderly subjects, total B cells inversely correlate with daytime cortisol, whereas helper/inducer T cells show positive correlations. Conversely, morning cortisol negatively associates with total T lymphocytes but positively links to suppressor/cytotoxic T cells [175]. These circadian-linked immune-cortisol relationships differ from younger individuals, though their functional relevance requires further study.

Chronic inflammation

Mild chronic inflammation, a hallmark of aging, drives age-related damage and diseases (Fig. 1c). Aging elevates inflammatory biomarkers (IL-6, IL-8, IL-2, IFN-γ, TNF-α) [176–178], reflecting heightened inflammation. Among these biomarkers, while IL-6 was traditionally viewed as a key marker, recent evidence suggests TNF-α better indicates chronic inflammation—though this is confined to community-dwelling elders with mild inflammation and requires broader validation [179].

There has been some research which found that central immune system exists chronic inflammation when aging. And the details have been mentioned above. Besides, a study suggests that elevated blood mtDNA correlates with elevated inflammatory biomarkers (TNF-α, IL-6, regulated upon activation normal T cell expressed and secreted (RANTES), and IL-1ra), implying that the inflammatory mechanisms present centrally may also exist peripherally [180]. Consistent with this study, in age-related hearing loss (ARHL), cochlear and cochlear nucleus (CN) inflammation driven by macrophages, microglia and complement component 1q (C1q deposition) involves NF-κB pathway and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome rather than cGAS-STING [181]. In addition to the nervous system, aging visceral adipose tissue (VAT) also exhibits increased tissue-resident memory γδ T cells (CD44hi62LlowCD69+) with a significant increase in the percentage and total quantity of pro-inflammatory IL-17 A + γδ T cells, which upregulates IL-17 A to promote chronic inflammation by inducing IL-6 production in preadipocytes/adipose-derived stem cells(ADSCs) [182].

Surprisingly, there have been clinical researches indicating that anti-inflammation is a prospective direction in reversing immunosenescence. Coffee consumption decreases the frequency of senescent T cells and the levels of the SASP by downregulation of the Janus kinase (JAK)/STAT and MAPK signaling, suggesting that coffee has anti-immunosenescence effects [183]. Besides, treating diabetic subjects with senolytic drug dasatinib plus quercetin (D + Q) shows reduced blood SASP factors after 11 days, though the mechanism remains unclear [184]. Dietary interventions in aging animals mitigate chronic inflammation: zinc supplementation lowers IL-6, monocyte chemotactic protein 1 (MCP1), and inflammatory cytokines of Th1/Th17 while boosting naïve CD4 + T cells [185]. Furthermore, L. paracasei KW3110 alters gut bacterial composition, reduces CD4 + T cells, which produce IFN-γ in the lamina propria of the small intestine (SI-LP), and the serum proinflammatory cytokines, to alleviate intestinal and retinal inflammation [186]. High-fiber diets elevate the butyrate-producing bacteria in the gut, dampening microglial proinflammatory signals to reduce central chronic inflammation [187]. Ingestion of silk peptide in aging mice reduces splenic mass and M1 macrophages in the gastrocnemius muscle, thereby ameliorating low-grade chronic inflammation in skeletal muscle [188]. However, human applicability remains uncertain. Adherence to EAT-Lancet or Mediterranean diets shows only minor, non-significant reductions in inflammatory biomarkers, potentially due to balanced nutrient profiles lacking targeted components [189]. Further research is needed to validate dietary strategies in humans.

Gut dysbiosis

Aging-associated gut dysbiosis, marked by increased harmful bacterial genera of the Clostridiaceae family and decreased beneficial genera like Lactobacillus within the Firmicutes phylum (Fig. 4), functions as a potent microenvironmental regulator. This dysbiosis creates conditions that indirectly trigger DCs' NF-κB activation via microbial factors, impairing tolerance and migration of DCs. Ultimately, this promotes pro-inflammatory CD4 + T cells while suppressing regulatory T cells (Tregs) induction. Specific dysbiosis-derived factors and functional consequences require further study [190]. Moreover, age-related dysbiosis elevates gut permeability and circulating microbial products, worsening systemic inflammation and compromising macrophages’ antibacterial function. Such inflammation impacts the central nervous system: in aging mice, dysbiosis disrupts brain and gut innate lymphoid cell plasticity, linking gut changes to age-related brain alterations [191].

Fig. 4 — Gut dysbiosis with aging induces immunosenescence and influences brain-gut axis. Aging individuals often experience gut dysbiosis, characterized by an increase in harmful bacterial genera a decrease in beneficial genera. This dysbiosis can lead to the activation of NF-κB signaling pathway of dendritic cells (DCs). Ultimately, this activates pro-inflammatory CD4 T cells while inhibiting Tregs induction. Additionally, the germinal center (GC) reactions in the gut decrease, manifested by a reduction in the frequency and quantity of B cells in the GC. Moreover, age-related gut dysbiosis triggers increased intestinal epithelial permeability and circulating bacterial products levels, exacerbating systemic inflammation and impairing macrophages’ antibacterial function. These systemic inflammatory changes can also affect the central nervous system, including altering the plasticity of innate lymphoid cells in the brain and the increased hippocampal TLR4/NF-κB inflammatory signaling pathway

Targeting gut dysbiosis alleviates immunosenescence in animal models. Fecal microbiota transplantation (FMT) between young and aged mice in the same strain restores the frequency and quantity of B cells in germinal center (GC) via adjuvant-like manner, highlighting strain-specific efficacy [192]. Probiotics prevent dysbiosis by enhancing bile salt hydrolase activity and gut taurine levels to reinforce tight junctions [193–195]. Additionally, certain substances can indirectly alleviate inflammation by modulating gut microbiota composition. For example, tea polyphenols improve intestinal flora composition and diversity to inhibit the hippocampal TLR4/NF-κB signaling induced by gut dysbiosis and increased gut permeability, which can trigger microglia-driven neuroinflammation and memory decline [196]. Lastly, a high-tryptophan diet reduces pro-inflammatory Acetatifactor, Enterorhabdus, and Adlercreutzia genera [197].

Improving gut dysbiosis may enhance immunotherapy efficacy, potentially countering immunosenescence. Aging patients with enterotype/aging-enriched (E/AE), namely enriched Bacteroides, Clostridiales, Bilophila and Faecalicatena exhibit heightened immunotherapy sensitivity, transplanting this enterotype into aged mice boosts anti-PD-1 response [198]. The other research found that the decreased response of fused in sarcoma (FUS) and calreticulin nanoparticles (CRT-NP) in aging mice is due to the diminished alpha diversity, which is an indicator of intestinal microbial ecosystem [199]. These findings suggest gut dysbiosis as a potential prognostic marker for immunotherapy, though its utility may vary by cancer type and therapeutic approach.

A number of recent articles have described how these features of immunosenescence play a role in older tumor patients. These features are summarized in Table 2. Based on this table, it is obvious that for some hallmarks, the relationship between them and tumor is still mysterious, and if they have treatment potential targeting tumor remains unknown.

Table 2.

Hallmarks of immunosenescence: associations with tumor risk, patient prognosis, and response to immunotherapy

Hallmarks	Correlation with tumor patients	Correlation with immunotherapy response	Mechanism
Genomic instability	/	/	/
Telomere attrition	Increased risk of tumor for T cell defects [428]	/	/
Epigenetic alterations	Accelerated tumor metastasis [429]	Resistance to anti-PD-1 immunotherapy	Upregulation of E3 ubiquitin ligase BFAR in aged CD8 + T cells, activating a deubiquitinase USP39, finally inhibiting JAK2-STAT pathway, leading to a decline of tissue resident memory T (TRM) cells
	Poor survival [430]	Limited durability of anti–PD-L1 therapy	Inducing CD8 + T cell exhaustion by Asxl1, which controls the deubiquitination of histone 2 A lysine 119
Loss of proteostasis	/	/	/
Disabled autophagy	/[431]	Short progression-free survival and overall survival after PD-1 blockade therapies	Transferring mitochondria with mtDNA mutations from cancer cells into CD8+ T cells, which don’t undergo mitophagy, thus causing CD8 + T cells dysfunction
Mitochondrial defects	Accelerated tumor metastasis [277]	/	The opening of mitochondrial permeability transition pore channels to release mtDNA and lead to the mitochondria-dependent vital NETs formation in tumor-associated aged neutrophils (Naged, CXCR4 + CD62Llow)
Cellular senescence	Poor overall survival and event-free survival [432]	/	T-cell senescence and exhaustion
	Poor progonosis [433]	/	Impairing T-cell function and facilitates tumor immune evasion
	Higher mortality [434]	Less responsive to immunotherapeutic agents	T cell senescence and down-regulation of immune checkpoint genes
Hematopoietic stem cells (HSCs) myeloid bias	/	/	/
Altered intercellular communication	Poor patient survival [300]	/	T cell senescence induced by ILT4 derived from tumor cells
Chronic inflammation	Higher recurrence and poor prognosis [435]	/	Accumulation of myeloid progenitor-like cells which promotes IL-1α
Gut dysbiosis	/	/	/

Open in a new tab

The eleven hallmarks of immunosenescence are highly interconnected rather than isolated, collectively driving immune dysfunction. Genomic instability and telomere attrition contribute to cellular senescence, which interacts with epigenetic alterations that regulate immune phenotypes and are in turn influenced by chronic inflammation, forming a vicious cycle. Loss of proteostasis, often linked to disabled autophagy, impairs immune functions like antigen presentation. Mitochondrial dysfunction amplifies inflammation through pathways such as cGAS/STING, interacting with autophagy and proteostasis mechanisms. These processes drive cellular senescence and its associated secretory phenotypes, which along with hematopoietic stem cell myeloid bias, altered intercellular communication, and gut dysbiosis, further disrupt immune signaling and cell composition. Chronic inflammation, a central feature arising from multiple hallmarks, exacerbates other dysfunctions, leading to impaired immune surveillance, reduced cytotoxic responses, and systemic immunosuppression.

Effects of aging on systemic immunity in tumor patients

Cancer incidence rises with age, likely due to heightened tumor susceptibility. An overview of how aging influences systemic immunity in tumor patients has been shown in Fig. 5. Aging promotes bladder carcinogenesis induced by the BCa carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) with increased neutrophil and monocyte infiltration, though the molecular mechanism remains unclear [200]. Aging also contributes to heightened treatment resistance of tumor. Senescent bone marrow mesenchymal stem cells induce the dormancy and the inhibited proliferation of bone-metastasized breast cancer cells (BCCs) via SASP-mediated p21 upregulation, enabling treatment evasion [201]. Tumor could also acquire resistance by reducing effector T cells, which is the target cells for some treatments. Aged mice resist PD-1 blockade therapy due to elevated CD45RB in naïve CD8 + T cells, which suppresses TCR signaling and reduces generation of the CD44lowCD62Llow (P4) subset. This subset, derived from naïve T cells and marked by high one-carbon metabolism gene expression, differentiates into effector T cells in vivo to reject tumors. Strong immune stimulation by non-self-cells reverses TCR inhibition, restoring CD8 + T cell antitumor immunity [202]. However, clinical trials show similar anti-PD-1/anti-PD-(L)1 efficacy across ages, but elderly face higher immune-related adverse events (irAEs), which may be related to a higher rate of treatment discontinuation [203, 204]. The phenomenon is reasonable, because PD-1 is expressed on many types of immune cells, such as macrophages, B cells, T cells, dendritic cells [205]. This means that when taking the treatment effect of PD-1 blockade on human into consideration, the possible influence of PD-1 blockades on other immune cells, beside T cells, should also be considered. Interestingly, although aging is generally considered a risk factor for higher cancer mortality, recent studies suggest that this may vary across different types of cancer. Immune checkpoint reduction in the microenvironment worsens outcomes in 16 cancers (e.g. breast cancer, acute myeloid leukemia) due to suppressed adaptive immunity, while in glioblastoma/rectal adenocarcinoma, this aging-related molecular characteristics and outcomes differences have not been observed [206].

Fig. 5 — Systemic immunity in aging patients with tumor results in worse prognosis. The incidence of cancer increases with age, likely due to enhanced susceptibility to tumor. Tumor in aging population also easily enters dormancy to evade treatment, it acquires resistance of, for example, PD-(L)1 treatment, by reducing effector T cells in aged mice. However, this treatment doesn’t show prognostic difference in humans. Apart from effector T cells, other T cells, including, dysfunctional T cells, pro-tumor γδ17 T cells and Treg cells also present exceptions in aging tumor patient, and obviously, they bring about immunosenescence, leading to decreased immunity. Based on this, to better predict the treatment outcomes and prognosis of aging-related cancers, prognostic models based on ARGs, senescence-related lncRNAs, aging CAF-related genes and cellular senescence and tumor microenvironment-related genes have been established in various cancers. When talking about the relationship between aging and tumor metastasis and progression, there exist different opinions. Most of the time, T cells mentioned above, as well as SMCs, DCs and NKs, work together to form immunosenescence, which leads to the pro-tumor immune environment. However, T cells activated in vivo show NK cell function, through which these T cells have increased antigen-independent cytotoxicity. This may relate to an anti-tumor immune environment in some tumor-based mice

Based on this, to better predict the treatment outcomes and prognosis of aging-related cancers, prognostic models based on aging-related genes (ARGs) have been established in various cancers, including lung cancer [207–209], melanoma [210–213], glioblastoma [214], renal cell carcinoma [215], acute myeloid leukemia (AML) [216], high-grade serous ovarian cancer [217], colorectal cancer [218, 219], breast cancer [220, 221], head and neck squamous cell carcinoma (HNSCC) [222, 223], hepatocellular carcinoma (HCC) [224], diffuse large B-cell lymphoma (DLBCL) [225], pancreatic adenocarcinoma [226], and glioma [227]. These models consistently link high-risk tumors to worse immune checkpoint inhibitor (ICI) effect despite heterogeneous ARGs. Similarly, the method of establishing prognostic models based on cell senescence-related lncRNAs has been applied in glioma [228], HNSCC [229], HCC [230], and colorectal cancer [231, 232]. Additionally, an innovative study developed a prognostic model based on aging CAF-related genes (ACAFRGs) to predict the prognosis and response to immune checkpoint blockade therapy in low-grade gliomas (LGGs) [233]. Finally, the combination of CellAge and TME scores, based on cellular senescence and tumor microenvironment-related gene expression, can serve as an independent prognostic factor and predictor for immunotherapy outcomes in hepatocellular carcinoma (HCC) [234]. In summary, the effectiveness of these different models for the same tumor type requires further comparison.

It is worth noting that the relationship between aging and tumor metastasis and progression remains inconclusive. Some studies suggest that aging may promote tumor progression by impairing the immune system. This is mainly associated with dysfunction of cytotoxic T lymphocyte (CTL) cells [235], proliferation of pro-tumor γδ17-T cells [236], and an increase in immunosuppressive Treg cells [237]. Early studies debated whether age-related CTL cytotoxicity decline stemmed from reduced cell numbers or intrinsic defects [238, 239]. However, a recent study suggests that both factors may contribute to CTL cell dysfunction. Aged mice show decreased total CD8 + T cells but increased proportions recognizing dominant/subdominant epitopes. Notably, dominant epitope-specific CD8 + T cells exhibit reduced cytotoxicity versus young mice, while subdominant-targeted cells maintain function, potentially explaining accelerated tumor progression in aging. Chemotherapy differentially affects epitope-specific T cells, suggesting therapeutic potential in expanding subdominant-targeted CD8 + T cells [240]. Additionally, senescent-like myeloid cells (SMCs) and exhausted T cells (TEXs) promote epithelial-mesenchymal transition (EMT)-mediated liver metastasis in metastatic colorectal cancer (mCRC) via angiopoietin like 4 (ANGPTL4)-syndecan 1 (SDC1)/SDC4 pathway, upregulating E-cadherin and downregulating N-cadherin and vimentin of cancer cells [241]. Moreover, aging triggers mitochondrial sphingosine kinase 2 (SphK2)/sphingosine-1-phosphate (S1P) signaling in T cells, suppressing HDAC1/2 and promoting CerS6-mediated C14 ceramide accumulation. This suppresses protein kinase A (PKA) activity, reducing dynamin-related protein 1 (Drp1)’s inhibitory S637 phosphorylation to enhance Drp1-driven mitophagy, impairing mitochondrial function and anti-tumor efficacy in activated CD8 + T cells. Elevated microtubule-associated protein 1 light chain 3 (LC3) synergizes mitophagy activation by recruiting autophagosomes, though its precise mechanism needs clarification [242]. In innate immunity, aging amplifies IL-17 in the T-cell zone of peripheral lymph nodes (pLNs), skewing γδT cells toward γδ17 subsets that activate in tumor-draining lymph nodes, infiltrate tumors, and accelerate growth—despite preserved transcriptomic and functional profiles in aged γδT cells [236]. Finally, aged lung cancer models exhibit age- and tumor-dependent splenic CD4 + CD25 + Foxp3 + Treg expansion, though underlying causes remain unclear [237].

In addition to T cells, other immune cells also contribute to the acceleration of tumor progression associated with aging. Aged DCs show impaired CD8 + T cell priming in vitro and reduced migration to lymph nodes and weaker stimulation of T cell immune responses in vivo, linked to defective CCR7-mediated chemotactic responses [243]. Moreover, combining autologous DC vaccines with anti-CD134 or anti-CD137 monoclonal antibodies rescues anti-tumor responses, implicating co-stimulatory deficits in age-related DC dysfunction [244]. Furthermore, aged macrophages exhibit suppressed tumor cell binding, cytotoxicity, and reduced expression of inducible nitric oxide synthase (iNOS), Oncostatin-M (OSM), TNF, IL-1, and nitric oxide, correlating with diminished anti-tumor activity [245, 246]. NK cells in aged mice also display functional impairments, associated with reduced output from bone marrow and compromised tumor-targeting ability [247].

While aging is frequently associated with immune dysfunction that accelerates tumors, some studies paradoxically suggest slowed tumor growth and metastasis in aged individuals. Proposed mechanisms include reduced tumor cell proliferation [248], increased apoptotic cell death [249] and impaired angiogenesis [250]. Additionally, recent research suggests that the deceleration of tumor progression associated with aging may also be related to the immune system. CD8 + T cells from aged mice, when activated in vitro, display heightened antigen-independent cytotoxicity and adopt NK-like function. This shift may stem from age-related menin downregulation, which increases enhancer binding and cytotoxic gene expression such as CD244, killer cell lectin like receptor B1c (Klrb1c), Fc fragment of IgE receptor Ig (Fcer1g), and NK-associated molecules, ultimately suppressing tumor metastasis in aged mice. Thus, aging may exert dual, context-dependent effects on tumor dynamics via divergent immune and cellular pathways [251].

In summary, while there are still many mysteries surrounding the relationship between aging, tumors, and systemic immunity, aging and young tumor patients exhibit distinct immune responses, offering opportunities for improved elderly cancer therapies. Age-targeted treatments (e.g., apoptosis-inducing agents, hydrocortisone, adriamycin, anti-angiogenic agent TNP-470, and immunomodulators like Levamisole and Bacille Calmette-Guérin (BCG)) demonstrate enhanced efficacy in aged versus young mice [252]. Additionally, new technological advancements, such as engineered fusokines, are believed to enable targeted anti-tumor therapy for the elderly. For instance, glioblastoma cell lines GL261 and CT2A transfected with the GIFT-7 molecule (a fusion of IL-7 and granulocyte-macrophage colony-stimulating factor (GM-CSF)), used as fusokine tumor vaccines and administered subcutaneously, significantly improved survival and reduced tumor volume in aged glioblastoma mice by regenerating thymic function and activating DC cells to recruit systemic T cells to the intracranial tumor site. Excitingly, cured mice developed CD4 + Th17-dominant immunity against glioma recurrence [253]. While these approaches require clinical safety validation, tailoring therapies to age-specific tumor immunology remains a highly promising frontier.

The eleven major molecular markers of systemic immunosenescence act synergistically to drive immune cell functional decline and systemic immune suppression. In cancer patients, this aging-related immune remodeling primarily manifests as abnormalities in T cell function and phenotype, ultimately leading to alterations in anti-tumor immune response efficacy, treatment resistance, and prognosis in elderly patients. Notably, these systemic aging characteristics not only affect the function of circulating immune cells but also profoundly reshape the ecological landscape of the tumor microenvironment (TME). The following sections will delve into how the aging process specifically alters the cellular composition, signaling networks, and functional state of the TME, elucidating its mechanisms of action on tumor progression through the microenvironment.

Immunosenescence-driven remodeling of the tumor microenvironment

As mentioned above, TME interacts with tumor cells closely. The differences between normal and aging TME are presented in Table 2. Recently, there has been the research proving the existence of age-dependent TME changes by single cell sequencing, which provides a cell atlas in TME in different ages [254]. In short, the aging TME is characterized by increased immunosuppressive cells [255], accumulation of pro-inflammatory SASP factors [256, 257], metabolic abnormalities [258] and matrix remodeling [259]. Importantly, these features of the aging TME are not isolated phenomena but represent the localized manifestation of systemic immunosenescence. For example, SASP which induces chronic inflammation, a hallmark of systemic immunosenescence, drives and sustains the pro-inflammatory and immunosuppressive TME in most cases [260, 261]. It is reported that in aging mice, the function of CD163 + tumor associated macrophages (TAMs) can be further divided into improving tumor growth (expressing peroxisome proliferator activated receptor gamma(PPARG)) and immunosuppression (expressing Ly-6 C) in intraocular melanoma [262]. Moreover, aging TAMs could also increase metastasis and proliferation of tumor. In aging mice, p16INK4a-expressing macrophages, namely aging macrophages, secrete numerous SASP factors including bone morphogenetic protein-2 (Bmp2), Ccl2, Ccl7, Ccl8, vascular endothelial growth factor A(VEGFA), etc [256, 257]. Apart from immune cells in aging TME, cancer cells and stromal cells also secrete SASP cytokines. Similarly, tumors exploit CXCL2 to induce aging of circulating neutrophils, directing their migration to the TME to fuel progression [263]. In addition, cancer‑associated fibroblasts (CAFs) can secrete some special cytokines and extracellular matrix, including ROS and L-lactic acid [264], CCL2 [265], growth differentiation factor 15 (GDF15) [266], IL-8 [267], secreted frizzled-related protein 1 (SFRP1) [268], SFRP2 [269, 375], that promote proliferation, metastasis, angiogenesis, and drug resistance [270]. In colorectal cancer, GDF15 from senescent CAFs drives proliferation, migration and invasion of tumor via PI3K/MAPK pathway [271]. Additionally, IL-6 from CAFs promotes malignancy in both cervical and pancreatic cancers [272–274].

Apart from SASP, immune cells and stromal cells also directly act on aging TME. Next, we will discuss in detail how these cells contribute to the features of aging TME and and be reshaped by it, as well as their complex relationship with tumors (Fig. 6).

Fig. 6 — Altered TME in aging tumor patients. TME interacts with tumor cells closely. Tumor-associated aged neutrophils (Naged, CXCR4hiCD62Llow) have NETs mainly consisting of mitochondrial DNA, leading to a function as promoted the lung metastasis of breast cancer. Tumor can express CXCL2 to cause aging of circulating neutrophils, leading aging neutrophils to migrate to TME and improve tumor progression. The antitumor activity of TAMs also decreases with the decline of effector molecules including TNF, IL-1, nitric oxide, oncostatin-M (OSM) and the defect of tumor cell binding and cytotoxicity. Besides, aging macrophages, secret numerous senescence associated secretory phenotype (SASP) factors including Bmp2, Ccl2, Ccl7, Ccl8, etc. Senescent T cells affect TME mainly by downregulating costimulatory molecules and the effector molecules, inducing adaptive Treg cells, inhibiting DCs and effector T cells. Possible mechanisms about how senescent T cells influence TME focus on ATM-associated DNA damage response and activate MAPK and STAT1/3 signaling initiated by glucose competition environment created by Treg cells’ accelerated glucose consumption, accumulation of metabolic end products (cAMP, adenosine, and lactate), tumor-derived microenvironmental inflammatory cytokines, and lipid metabolism. Moreover, the aged tumor microenvironment (TME) promotes the differentiation of CD8 + T cells into a unique dysfunctional subset termed tumor-infiltrating age-associated dysfunctional (T + + TAD) cells. This CD8 + T cell subset exhibits minimal cytotoxicity, resulting in impaired tumor control. Cancer‑associated fibroblasts (CAFs) act on aging TME mainly by SASP through p38 MAPK pathway/PI3K-AKT signaling pathway/TGF-β-CTGF pathway. GDF15 is an essential SASP factor secreted by senescent CAFs to promotes cell proliferation, migration, and invasion through PI3K and MAPK pathway. Additionally, IL-6 is secreted by CAFs in TME

Neutrophils

Tumor-associated neutrophils (TAN) in the TME secrete pro- (ROS, reactive nitrogen species (RNS)) or anti-inflammatory (Type I IFN) signals that directly and indirectly shape tumor behavior [275]. They exert anti-tumor effects via phagocytosis, degranulation, and neutrophil extracellular traps (NETs) formation. To date, TANs are broadly classified into anti-tumor N1 (pro-inflammatory) and pro-tumor N2 (anti-inflammatory) subtypes. However, with aging, the function of TANs will change in some degrees. Aged cancer patients exhibit increased polymorphonuclear leukocyte (PMNs) phagocytosis but reduced intracellular killing capacity compared to young individuals, impairing tumor control [276]. Besides, tumor-driven aged neutrophils (Naged, CXCR4hiCD62Llow) different from neither N1 nor N2 type of neutrophil form metastasis-promoting NETs rich in mitochondrial DNA via tumor-derived nicotinamide phosphoribosyl transferase (NAMPT). Blocking this pathway reduces breast cancer lung metastasis in mice [277]. Clinically, CXCR2 inhibitors show efficacy in breast cancer [278]. Finally, anti-B-cell lymphoma-extra large (Bcl-xL) compounds combined with GM-CSF selectively eliminate aged TANs in preclinical models, sparing normal neutrophils and young anti-tumor TANs [279]. However, platelet toxicity remains a challenge [280].

Natural killer (NK)

Natural killer (NK) cells primarily mediate antitumor immunity through cytolysis and secretion of cytokine and chemokine [281, 282]. Little research of the correlation between NK cell senescence and tumor were delivered, but almost all of them focused on the leukemia [283, 284], neither in the solid tissues nor the TME. That is, how NK cell senescence plays a role in TME remains a mystery.

Macrophages

Macrophages in TME, which always mean TAMs, is similar to TANs mentioned above. They can be divided also into two subsets, M1 (anti-tumor) and M2 (pro-tumor). Aging biases macrophage differentiation toward M2 via IL-8 and B cell leukemia/lymphoma 3 (Bcl3) in the TME [255]. Similar phenomenon of elevated M2-type macrophages were discovered in older breast cancer patients [285]. Besides, aged TMEs exhibit increased exhausted macrophages, contributing to elevated macrophage counts without enhanced antitumor capacity and cytotoxic T-cell responses [286–288]. Furthermore, senescent TAMs show reduced antitumor activity due to diminished TNF, IL-1, nitric oxide, OSM production, and impaired tumor binding and cytotoxicity [246, 289]. More seriously, expansion of CD11b + F4/80 + Ly6G − Siglec-F − macrophages in aged mesothelioma TMEs compromises IL2/anti-CD40 immunotherapy efficacy. Macrophage depletion may improve treatment outcomes in elderly patients, though mechanisms require clarification [290]. Sports show potential to counteract age-related macrophage dysfunction through polarization regulation, though mechanistic insights remain limited [291].

T lymphocytes

As mentioned above, senescence of responsive T cells is often accompanied by a decline in their function. Their functional decline contributes to immunosuppressive TMEs through downregulated costimulatory and effector molecules, induction of adaptive Treg cells and premature senescence in T cells, and inhibition of DCs and effector T cells. Nevertheless, molecular mechanisms remain unclear but may involve ATM-associated DNA damage response, MAPK/STAT1/3 activation via glucose competition created by Treg cells’ accelerated glucose consumption, and accumulation of metabolites (cyclic AMP (cAMP), adenosine, lactate) and tumor-derived cytokines [258]. Specifically, not only Treg cells, tumor cells promote T-cell senescence also via ATM and MAPK pathways, while blocking these pathways enhances immuno-oncology therapies in vivo [292]. In this case, lots of trials attempted to specifically inhibit the MAPK pathway in senescence T cells to reverse it, avoiding affecting MAPK pathway with normal functions in T cells [293, 294]. Apart from the direct inhibition of MAPK pathway, TLR8 activation suppresses Treg glucose metabolism via mTOR inhibition, reversing immunosuppression and T cell senescence without affecting normal T cells, offering superior targeting potential [295]. Therefore, comparing to MAPK pathway inhibitors, TLR8 may be a better therapy target. Lipid metabolism also induces senescence in responder T cells through fatty acid droplet accumulation, engaging MAPK and STAT1/3 pathways and cytosolic phospholipase A2 (cPLA2α) expression, with Treg involvement [296]. Besides, aging increases Dectin-1 activation in mice, elevating IL-1β to amplify Treg suppression [297].

Besides, recent study has also showed the influence of aging TME on T cells. The aged TME drives CD8 + T cells toward a dysfunctional subset tumor-infiltrating age-associated dysfunctional (T + + TAD) cells characterized by PD-1, thymocyte selection associated high mobility group box (Tox), and IL-7R expression, with minimal cytotoxicity, exacerbating tumor progression in aging mice. This dysfunction stems from reduced NK cells in aged TME, which impair conventional type 1 dendritic cells (cDC1) recruitment via XCL1 and antigen presentation, blunting CD8 + T cell activation and cytotoxicity. Fortunately, CD40 agonists restore cDC1 function and CD8 + cytotoxicity by boosting myeloid cell quantity and function, offering therapeutic potential [298].

Based on these results, methods on suppressing the function of Treg cells were explored. Surprisingly, vascular endothelial growth factor receptor 2 (VEGFR2) inhibition in tumors upregulates exosome miR-3200-3p, targeting Treg damage-specific DNA binding protein 1 (DDB1) to trigger senescence, offering a novel Treg-targeted therapy [299]. Notably, immunoglobulin-like transcript 4 (ILT4) blocker PIR-B disrupts MAPK-ERK1/2-driven lipid accumulation in tumors, reversing T-cell senescence and boosting antitumor responses of responder T cells, highlighting lipid metabolism as a potential immunotherapeutic strategy [300]. Moreover, extracellular ATP (eATP) as an extracellular metabolism in TME induces stress-induced premature senescence (SIPS) of T responder cells via purinergic receptor (P2 × 7) ion channel, though eATP may show opposite influence on the whole tumor and the intratumor myeloid subsets [301–303]. That is, again, specific P2 × 7 inhibitors targeting on T cells are needed.

B lymphocytes

Until now, research on B cells in the TME remains limited. Studies on senescence’s effect on B cells in tumor-bearing human and animals mainly focused on subsets of them in peripheral blood. B1 cells (CD5 + CD19+), regarded as immature and innate B cells, which decline with aging, can transform into 4-1BBL + B cells (4BL cells) upon age. These cells activate GrB + CD8 + T cells via mTNFα-TNFR2/4-1BBL, enhancing tumor cell killing at a low-threshold stimuli [304, 305]. Another B cell subset, B7-DC+ (PD-L2/CD273) B cells, significantly augment the induction of both Th1 and Th17 cells [306]. Besides, B cells in TME may contribute to the cancer metastasis [307]. Notably, these results still need to be proved in TME and vivo.

Cancer‑associated fibroblasts (CAFs)

As mentioned above, CAFs could secret cytokines which promote cancer progression. Paradoxically, CAFs can enhance drug sensitivity in some contexts [308]. Senescent CAFs create a cancer-favoring microenvironment via SASP factors through multiple pathways. p38 MAPK enhances breast cancer growth by senescent CAFs, and MAPK oral inhibitor CDD-111 can inhibit SASP expression secreted by senescent CAFs [259]. Another signaling pathway in both CAFs and breast cancer cells is TGF-β/ connective tissue growth factor (CTGF). Its activation induces HIF-1α-driven metabolic changes, promoting autophagy and senescence in cancer cells but tumor-supportive senescence and autophagy in CAFs via lactate release [309]. This phenomenon once again emphasizes the value of specific targeted therapy. Phosphoinositide 3-kinase (PI3K)/AKT (PKB, protein kinase B)signaling mediates similar protumor effects in melanoma [310]. Besides, senescent CAFs upregulate fatty acid transport protein 2 (FATP2) in melanoma cells to increase the tumor’s uptake of lipids, conferring drug resistance eventually, and this process could be reversed by FATP2 targeting [311]. Surprisingly, resveratrol counteracts senescent CAFs’ protumor effects in melanoma, providing a treatment that may induce an anti-tumor hosting microenvironment [312]. Interestingly, poly ADP-ribose polymerase inhibitor (PARPi)-induced SASP in CAFs reduces the efficacy of PARPi, an targeted drug which has already been utilized in many types of solid tumors though with drug resistance in long-term use, but combining bepotastine, a H1-antihistamine, restores sensitivity via NF-κB suppression [313]. However, senescent CAFs exhibit heterogeneity even in tumors with identical primary organ but different cell type. For instance, lung large cell carcinoma, rather than adenocarcinoma or squamous cell carcinoma, uniquely induces CAFs senescence through paracrine, leading to the aggressive behavior of tumor [314]. In short, key pathways (p38 MAPK, PI3K/AKT) and SASP factors are central to senescent CAF-driven tumor remodeling across cancers.

The relationship between aging and tumor immunotherapy

Overall, the interplay between tumor immunotherapy and aging remains unclear, influenced by complex TME and varied immunotherapy types. Current research emphasizes efficacy and safety of immunotherapy in elderly patients versus younger cohorts and underlying molecular mechanisms. PD-1 inhibitors (cemiplimab, pembrolizumab) show efficacy and safety in the treatment of elderly, immunocompromised patients with locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC) and non-small cell lung cancer (NSCLC) [315, 316], while CAR-T therapy demonstrates effectiveness and low toxicity in elderly multiple myeloma patients [317]. Additionally, the type, frequency, and severity of immune-related adverse events (irAEs) from cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) or PD-L1 inhibitors are comparable across age groups, with patients > 75 years deriving similar benefits as younger individuals [318], corroborated in melanoma studies [242]. Similar findings have been observed with other forms of immunotherapy. For instance, age also does not affect outcomes of intravesical Bacillus Calmette-Guerin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC) [319]. These findings highlight age-neutral efficacy of certain immunotherapies but underscore the need for deeper mechanistic exploration.

However, when classifying irAEs by severity and affected organ systems, differences emerge between elderly and younger patients. Elderly patients on anti-PD-(L)1 therapy for solid tumors experience higher overall incidence of grade ≥ II irAEs and multiple irAEs [203]. Moreover, combination therapies result in irAEs that differ between elderly and younger patients. In metastatic renal cell carcinoma (mRCC), elderly patients treated with nivolumab (monotherapy or combined with ipilimumab) show similar antitumor responses to younger patients but experience higher incidence of gastrointestinal irAEs [320]. Similarly, aged over 70 receiving camrelizumab combined with chemotherapy exhibit increased incidence of both all-grade and high-grade irAEs [321]. To solve this side-effect, IL-6 receptor (IL6R) blockade combined with PD-L1 inhibition was found to reduce irAEs in solid tumors [322], though the age-specific safety and effectiveness clinical data are lacking. Moreover, to balance the response and the side-effect of immunotherapy, the implementation of a dosing strategy that is tailored to the individual patient’s pharmacokinetics is also a commendable approach. Pembrolizumab administration utilizing this method has been proven to show promising clinical efficacy and manageable toxicity [323], but age-tailored trials remain pending. However, considering the complexity TME in them, it is still a strategy worth exploring. Interestingly, despite the lack of age-related differences in treatment efficacy, elderly genitourinary cancer patients over 75 years with irAEs exhibit improved survival [324], a phenomenon not reported in other cancer types, possibly reflecting the disease characteristics of genitourinary cancers. A recent study also reported lower all-grade irAE incidence in elderly solid tumor patients over 70 on anti-PD-(L)1 therapy [325]. This opposite finding has not been observed in previous studies and warrants further validation with larger sample sizes.

The efficacy of immunotherapy in elderly patients exhibits contradictions: while some studies show comparable outcomes across ages in some cancers, reduced responses are observed in others. For instance, elderly patients (> 80 years) with superficial bladder cancer respond poorly to BCG or IFN-α therapy [326]. Furthermore, anti-PD-1 therapy is less effective in elderly glioblastoma patients due to abundant PD-1-negative CD8 + CD28 − T cells with cytotoxic dysfunction [327]. Mechanistically, aged mice exhibit diminished NK cell infiltration, cytotoxicity, and maturation. This leads to impaired recruitment of dendritic cells (DCs) to tumor-draining lymph nodes (TDLNs), ultimately resulting in diminished activation of tumor antigen-specific CD8 + T cells and reduced efficacy of anti-PD-L1 therapy. Infusing young NK cells into aged mice restored immunotherapy response, enhancing T cell infiltration in TME following immunotherapy [328]. In addition to anti-PD-1/PD-L1, aging also compromises therapies including anti-CD4 mAb, endotoxin injection, anti-OX40 antibody and CTLA-4 blockade, linked to T cell exhaustion and dysfunction in TME [329–331]. Moreover, elevated Tregs in aged TME suppress CTLs, though CpG oligonucleotide (CpG-ODN) adjuvant combined with Treg depletion boosts immunity without inducing immune memory in aged mice [332]. Promisingly, L-arginine supplementation enhances PD-1 antibody efficacy in aged CT26 colon cancer models by promoting CTL infiltration, though this benefit is tumor-specific for absent in MC38 models, suggesting tumor heterogeneity, which requires further molecular investigation [333]. Nevertheless, this study provides valuable insights into mitigating the potential decline in immunotherapy efficacy due to aging.

To address age-related immunotherapy resistance, combining ICIs with epigenetic modulators to reverse immunosenescence shows preclinical promise. For example, decitabine plus anti–PD-1 sustains the activity of the activator protein-1 (AP-1) transcription factor JunD in CD8 + T cells, which usually reduces following PD-1 blockade therapy, counteracting immunosenescence and enhancing proliferation [334]. Besides, the subtype-selective HDAC inhibitor (HDACi) tucidinostat combined with anti-PD-1 suppresses NF-κB signaling in CD8 + T cells, mitigating senescence [335]. Furthermore, DNMT inhibitors (DNMTi) reduce pro-inflammatory cytokines (IL-1β, TNF-α, IFN-γ), alleviating immunosenescence and inflammation [336]. However, clinical trials evaluating these combinations are ongoing, leaving human efficacy uncertain [337]. Notably, some therapies pose age-specific risks: anti-CD40/IL-2 triggers fatal cytokine storms, consisting of TNF, IL-6, IFN-γ in aged mice via macrophages, driving liver injury, but co-administration of TNF antagonist etanercept rescues survival without compromising antitumor effects of the therapy [338].

The varied results may stem from organ/cell-specific differences in immunosuppressive molecule expression. While PD-1 inhibitors show comparable efficacy in young and aged melanoma mice, PD-L1 inhibitors perform worse in aged subjects. This could be attributed to elevated PD-L1 and CD80 levels in aged DCs, forming heterodimers that preserve CD80’s co-stimulatory role while neutralizing PD-L1’s immunosuppressive effect. Thus, PD-L1 blockade in aged mice might dissociate these heterodimers, reducing co-stimulation and paradoxically increasing immunosuppression [339].

It is encouraging to note that with the rising emphasis on the health of the elderly, a number of clinical trials about immunotherapy on the prognosis among the elderly have emerged in NSCLC [340–344], esophageal squamous cell carcinoma [345–349], mantle cell lymphoma [350, 351], myelodysplastic syndrome [352], though most remain in Phase II trials pending results. Promisingly, completed trials demonstrate positive safety and efficacy outcomes. Multicenter studies reveal elderly patients with relapsed/refractory large B-cell lymphoma (R/R LBCL) receiving CAR-T therapy achieve comparable overall remission (ORR), complete remission (CR), median overall survival (OS), and progression-free survival (PFS) to younger cohorts [353, 354].

In short, aging patients show comparable immunotherapy responses to younger counterparts, though safety varies by tumor type. Moreover, IL-6 blockade enhances ICI safety, while epigenetic drugs improve efficacy by reducing immunosenescence. Besides, adjuvant therapies (e.g., probiotics [355, 356], JAK inhibitors [357]) further augment ICIs. However, clinical validation in elderly populations remains limited.

Communications and conclusions

Immunosenescence, a complex physiological process marked by phenotypic and functional alterations in innate and adaptive immune cells and chronic low-grade inflammation [358], lacks definitive etiology. Notably, it is not exclusive to aging populations—some younger individuals exhibit immune decline predisposing them to infections or age-related disease. Besides, immunosenescence is also not universal in aging: centenarians often retain robust immune systems, suggesting healthy immunity may underpin longevity [359].

In this review, we identify key hallmarks of immunosenescence as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, autophagy defects, mitochondrial dysfunction, cellular senescence, HSCs myeloid bias, altered inter-cellular communication, chronic inflammation, and gut dysbiosis. — act as interconnected drivers of immune decline. For example, mitochondrial dysfunction promotes chronic inflammation by mtDNA leakage and ROS accumulation, which activates the cGAS-STING pathway. Besides, gender differences in immunosenescence are also mentioned in our review, with males showing higher pro-inflammatory cytokines (IL-6, TNF-α) and senescent T cells, both of which may explain why women live longer than men [360]. Notably, the development of epigenetic clocks (e.g. IntrinClock) has provided new tools for assessing biological age, but their utility in tracking immune cell changes requires refinement. While our framework prioritizes intervention-validated drivers (e.g., mitochondrial dysfunction, autophagy), we acknowledge that certain features (e.g., proteostasis loss) exhibit strong associations but require further mechanistic interrogation. Future studies combining genetic models (e.g., conditional knockouts) and age-stratified clinical trials will solidify causal links. Besides, recently there has been study indicating the interaction between altered extracellular matrix and immunosenescence [361, 362]. Considering the altered extracellular matrix has already been concluded into aging hallmarks [363], researches about the relationship between extracellular matrix and aging should also go further.

The TME has been a hot topic recent years with a raise of immunotherapy. In the past, relationship between aging and TME hasn’t received enough attention, which may lead to the therapy failure when converting animal trial results into clinical trial efficacy. That’s partly because most of the animal trials utilized young mice before, while tumor is more common in aging population with immunosenescence [15, 364]. In this review, alterations of TME brought by senescence are summarized. During the last twenty years, this field gained truly rapid development. Results show that TME in elderly provide a immunosuppressive environment to promote tumor growth, though heterogeneity of mechanism lies in almost every phase of tumor initiation and progression in elderly, which exists in different tissues and organs; reverse function of the same SASP on tumor and TME, etc [256, 309, 314, 365]. Such heterogeneity necessitates cell- or organ-specific biomarkers for targeted therapies or identification of conserved pathways, including MAPK/STAT1/3 in senescent T cells [258]. Despite progress, TME-targeting approaches remain largely preclinical [366, 367], highlighting the urgent need for elderly-inclusive clinical trials addressing age-related physiological vulnerabilities.

Besides, there are some immune cells whose function in TME when senescence hasn’t been depicted yet. Autologous NK infusion effectively alleviates T cell senescence and exhaustion and suppresses SASP components, though mechanisms remain unclear [368]. B cell senescence is under-researched due to their oncogenic potential and frequent classification under tumor cell senescence [369]. Further exploration still needs on these unexplained cells for better understanding of TME senescence and more treatment of tumor. Fortunately, although the immune system of aging tumor patients is often weakened by the presence of immunosenescence, PD-1 inhibitors show comparable efficacy in older solid tumors, but CD8 + CD28 − T-cell accumulation may drive glioma resistance. In addition, current studies still seem to be inconclusive regarding the incidence of irAEs. Debate persists regarding increased irAE incidence in elderly patients, with some studies contradicting this risk. The incidence of irAEs in elderly cancer patients may require tumor type-specific evaluation. Furthermore, combination treatment strategies (e.g., L-arginine to enhance CTL infiltration) or engineered cytokines (GIFT-7 activated DCs) in senescent patients show promise for improving outcomes.

In the past, it was widely believed that the immunosenescent environment in aging tumor patients showed pro-tumorigenic features. However, recent studies have shown that systemic immune dysregulation due to aging presents dynamic compensatory features. Subsets of aged CD8 + T cells acquire NK-like cytotoxicity to inhibit metastasis, though their in vivo relevance remains unconfirmed. This reveals the aging immune system’s ‘double-edged sword’ effect. In short, given the impact of ageing on systemic immunity, the TME, and immunotherapy, future treatments for elderly oncology patients should aim to restore anti-tumor immune activity while suppressing chronic inflammation by targeting aging-related immunosuppressive pathways, such as the STING/cGAS pathway and SASP modulation. Meanwhile, optimizing ICIs with aging hallmarks, such as combining TLR8 agonists or metabolic regulators could enhance efficacy. Furthermore, it is imperative to ameliorate the immunosuppressive state of the ageing TME, for instance, by remodeling dendritic cell (DC) function with CD40 agonists to enhance antigen presentation and improve the cytotoxicity of tumor-infiltrating T cells. Finally, metabolic interventions (Spermidine, NMN) or dietary adjustments may reverse immune senescence and rejuvenate antitumor responses.

Recent advancements in single-cell technologies have significantly enhanced our understanding of immunosenescence and its implications for therapy. For example, a study utilizing scATAC identified chromatin regulators of PD-1 blockade therapy-responsive T cell subsets and revealed the differentiation trajectories of these subpopulations in the TME [370]. This may provide a potential therapy target on regulation of these subsets to increase the effect of immunotherapy. An integrated multi-omics database on immunosenescence, which was built using AI models to provide information on the changes associated with aging in the dynamics of immune cells and cytokine levels, as well as the single-cell sequencing, transcriptomics, and epigenomics data are expected to pinpoint therapeutic targets [371]. Furthermore, recent innovations include a single-cell immunosenescence clock using PBMC-derived myeloid and lymphoid populations, overcoming prior biases on immune cell type and improving immunosenescence prediction after vaccination. However, scaling these models with larger, more diverse datasets remains critical for robust clinical translation [372].

In the context of immunosenescence, single-cell sequencing has revealed significant alterations in T cell populations. T cells exhibit significant subpopulation differentiation and functional evolution in the spleen. Recent study not only identified 11 age-dependent dynamic subpopulations of CD8⁺ T cells but also discovered a unique pro-inflammatory aging subpopulation within CD4⁺ T cells. These cells drive immunosenescence through abnormal cytokine secretion [373–376]. Besides, a cross-organ single-cell analysis indicates that the lung is highly susceptible to aging. In lung tissue, the proportion of IL-17-expressing γδT (γδ17) cells increases with age, recruiting CD62L-low pro-tumor neutrophils. These neutrophils suppress the stemness and tumor-killing functions of CD8⁺ T cells in aged male mice [377, 378]. This organ-specific immunosenescence characteristic provides a mechanistic explanation for the increased susceptibility to respiratory infections and tumor metastasis in elderly individuals.

Single cell ATAC-seq has also been used more and more recently to connect T cell changes in immunosenescence with epigenetic alterations. A study employed ATAC-seq to ascertain that chromatin accessibility diminishes in elderly naïve CD8 + T cells due to diminished NRF1 binding, culminating in impaired respiratory chain gene transcription and oxidative phosphorylation capacity, which indicates the NRF1 may be identified as a potential target for interventions aimed at decelerating CD8 + T cell senescence and restoring function [379]. Moreover, recent thymic emigrant (RTE) T cells, decreasing because of the thymic involution during immunosenescence, are distinguished by the expression of SOX4, IKZF2, and TOX and CD38 protein, as well as surface CD38 high expression universally identifies CD8 + and CD4 + RTEs. This means CD38 ++ RTE T cells may provide insights into thymic health, thus better assessing the immunosenescence [380].

Moreover, the characterization of inflammation and oxidative stress at single-cell resolution has underscored their roles as core features of immunosenescence. Aging-related transcriptional features prevalent in the hematopoietic immune system (HIS) reveal that immune cells in the spleen and bone marrow highly express inflammatory mediators and oxidative stress genes, forming the cellular basis for chronic low-grade inflammation [381, 382]. Monocytes from severe COVID-19 patients exhibit accelerated aging, confirming the amplifying effect of infection stress on immunosenescence [383].

Interestingly, the aging process of the immune system exhibits significant gender dimorphism. At the cellular level, the proportion of plasma cells in peripheral blood is significantly higher in females than in males, while the proportion of NK cells is lower. This difference becomes more pronounced with age, directly influencing the differentiation of anti-infection and anti-tumor capabilities between the sexes [384]. In elderly females, the number of memory T cells (especially the PD-1⁺CD4⁺ subpopulation) decreases in an age-dependent manner, while males maintain relatively stable levels [385]. In animal models, aged female mice exhibit increased spleen weight but reduced spleen cell count per unit weight, revealing gender-specific degradation of the spleen microenvironment [386].

The underlying mechanisms of these cellular differences involve gender differentiation in immune signaling pathways. T cell senescence in females is closely associated with excessive IL-7 signaling and abnormal N-glycan branching, leading to accelerated T cell dysfunction [387]. Regulation of neuroimmune also exhibits gender differences. Microglia undergo specific transcriptional and epigenetic reprogramming during senescence, which affects the progression of neurodegenerative diseases [388].

Sex-specific differences in immunosenescence profoundly influence tumor immune surveillance efficacy. Male individuals experience faster tumor progression due to impaired CD8⁺ T cell effector function and stem cell-like properties, leading to weakened antitumor immune responses [389, 390]. Sex hormones mediate this process through three mechanisms: regulating immune cell infiltration in the TME, altering cytokine secretion profiles, and modulating immune checkpoint molecule expression, ultimately indirectly weakening immune surveillance [391, 392].

Although current studies have made significant progress in resolving the interaction between immunosenescence and tumors, many key scientific questions remain to be explored in depth. First, while T cell and macrophage senescence is well studied, B cell and γδ T cell dynamics in aged TME remain unclear, necessitating single-cell multi-omics for spatiotemporal resolution. Secondly, the integrated regulation of the neuro-immune-metabolic axis is another area in need of a breakthrough: how does dysregulation of the hypothalamus-thymus axis drive thymic atrophy and weaken anti-tumor immunity through hormonal signals (e.g., melatonin, CRH)? Can targeting neuroendocrine pathways reverse the immunosuppressive properties of TME? These questions require a combination of gene editing and in vivo imaging techniques for mechanistic resolution. Thirdly, with much attention on the tumor immune status of elderly patients, should people also pay attention to the influence of the patients’ own metabolic conditions and aging-related factors on both the immune system and tumor aging? In addition, current murine systems poorly replicate human immune senescence heterogeneity. Humanized senescence-tumor-like organ- or patient-derived xenograft (PDX)-based models could better mimic the pathological features and drug responses of senescent TME. Finally, the integration of artificial intelligence and multi-omics provides new opportunities for precision medicine: by integrating epigenetic, metabolomic and immunomic data through machine learning algorithms, dynamic models can be constructed to predict immunotherapy response in elderly patients, though clinical validation in large cohorts remains pivotal. These advances could decode immunosenescence mechanisms and enable targeted strategies to counteract immunosenescence, promoting both tumor control and “healthy aging.”

Acknowledgements

This work was supported by the Shanghai 2024 Science and Technology Innovation Action Plan – Rising Star Program (Sailing Special Project) Application Guidelines / Cultivation Funding: 24YF2726700; The Youth Development Program Funding at Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine: 2024PY014; The National Natural Science Foundation of China (82400768).

Author contributions

Qianwen Liu, Jingfeng Li, Xiuqiao Sun, Jiayu Lin, Zhengwei Yu, Yue Xiao, and Dan Li collected the related paper and drafted the manuscript. Yihao Liu, Haili Bao and Baofa Sun participated in the design of the review and draft the manuscript. All authors read and approved the final manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Qianwen Liu, Jingfeng Li and Xiuqiao Sun contributed equally to this work.

Contributor Information

Baofa Sun, Email: sunbf@nankai.edu.cn.

Haili Bao, Email: harryb139@gmail.com.

Yihao Liu, Email: xb88053@sjtu.edu.cn.

References

1.Wang B, Tang X, Mao B, Zhang Q, Tian F, Zhao J, et al. Anti-aging effects and mechanisms of anthocyanins and their intestinal microflora metabolites. Crit Rev Food Sci Nutr. 2024;64(8):2358–74. 10.1080/10408398.2022.2123444 [DOI] [PubMed] [Google Scholar]
2.Mogilenko DA, Shchukina I, Artyomov MN. Immune ageing at single-cell resolution. Nat Rev Immunol. 2022;22(8):484–98. 10.1038/s41577-021-00646-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Ajoolabady A, Pratico D, Tang D, Zhou S, Franceschi C, Ren J. Immunosenescence and inflammaging: mechanisms and role in diseases. Ageing Res Rev. 2024;101:102540. 10.1016/j.arr.2024.102540 [DOI] [PubMed] [Google Scholar]
4.Zhang L, Pitcher LE, Yousefzadeh MJ, Niedernhofer LJ, Robbins PD, Zhu Y. Cellular senescence: a key therapeutic target in aging and diseases. J Clin Investig. 2022;132(15). 10.1172/JCI158450 [DOI] [PMC free article] [PubMed]
5.Goyani P, Christodoulou R, Vassiliou E, Immunosenescence. Aging and immune system decline. Vaccines (Basel). 2024;12(12). 10.3390/vaccines12121314 [DOI] [PMC free article] [PubMed]
6.Hazeldine J, Withnall E, Llibre A, Duggal NA, Lord JM, Sardeli AV. Physical activity modifies the metabolic profile of CD4(+) and CD8(+) T-Cell subtypes at rest and upon activation in older adults. Aging Cell. 2025;24(7):e70104. 10.1111/acel.70104 [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Nga HT, Nguyen TL, Yi HS. T-Cell senescence in human metabolic diseases. Diabetes Metab J. 2024;48(5):864–81. 10.4093/dmj.2024.0140 [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Lewis ED, Wu D, Meydani SN. Age-associated alterations in immune function and inflammation. Prog Neuropsychopharmacol Biol Psychiatry. 2022;118:110576. 10.1016/j.pnpbp.2022.110576 [DOI] [PubMed] [Google Scholar]
9.Zhou H, Zheng Z, Fan C, Zhou Z. Mechanisms and strategies of Immunosenescence effects on non-small cell lung cancer (NSCLC) treatment: A comprehensive analysis and future directions. Sem Cancer Biol. 2025;109:44–66. 10.1016/j.semcancer.2025.01.001 [DOI] [PubMed] [Google Scholar]
10.Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al. Global Cancer Statistics. 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2021;71(3):209 – 49. 10.3322/caac.21660 [DOI] [PubMed]
11.Wang Z, Zhu D, Zhang H, Wang L, He H, Li Z, et al. Recommendations and quality of Multimorbidity guidelines: a systematic review. Ageing Res Rev. 2024;102559. 10.1016/j.arr.2024.102559 [DOI] [PubMed]
12.Zhang J, Guan X, Zhong X. Immunosenescence in digestive system cancers: mechanisms, research advances, and therapeutic strategies. Semin Cancer Biol. 2024;106–107:234–50. 10.1016/j.semcancer.2024.10.006 [DOI] [PubMed] [Google Scholar]
13.Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12(1):31–46. 10.1158/2159-8290.Cd-21-1059 [DOI] [PubMed] [Google Scholar]
14.Lee S, Schmitt CA. The dynamic nature of senescence in cancer. Nat Cell Biol. 2019;21(1):94–101. 10.1038/s41556-018-0249-2 [DOI] [PubMed] [Google Scholar]
15.Fane M, Weeraratna AT. How the ageing microenvironment influences tumour progression. Nat Rev Cancer. 2020;20(2):89–106. 10.1038/s41568-019-0222-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Dong Z, Luo Y, Yuan Z, Tian Y, Jin T, Xu F. Cellular senescence and SASP in tumor progression and therapeutic opportunities. Mol Cancer. 2024;23(1):181. 10.1186/s12943-024-02096-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Drijvers JM, Sharpe AH, Haigis MC. The effects of age and systemic metabolism on anti-tumor T cell responses. Elife. 2020;9. 10.7554/eLife.62420 [DOI] [PMC free article] [PubMed]
18.Pardoll DM. The Blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64. 10.1038/nrc3239 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348(6230):62–8. 10.1126/science.aaa4967 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Papaioannou NE, Beniata OV, Vitsos P, Tsitsilonis O, Samara P. Harnessing the immune system to improve cancer therapy. Ann Transl Med. 2016;4(14):261. 10.21037/atm.2016.04.01 [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Kaiser M, Semeraro MD, Herrmann M, Absenger G, Gerger A, Renner W. Immune aging and immunotherapy in cancer. Int J Mol Sci. 2021;22(13). 10.3390/ijms22137016 [DOI] [PMC free article] [PubMed]
22.Cho YH, Woo HD, Jang Y, Porter V, Christensen S, Hamilton RF Jr, et al. The association of LINE-1 hypomethylation with age and centromere positive micronuclei in human lymphocytes. PLoS ONE. 2015;10(7):e0133909. 10.1371/journal.pone.0133909 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Sedelnikova OA, Horikawa I, Redon C, Nakamura A, Zimonjic DB, Popescu NC, et al. Delayed kinetics of DNA double-strand break processing in normal and pathological aging. Aging Cell. 2008;7(1):89–100. 10.1111/j.1474-9726.2007.00354.x [DOI] [PubMed] [Google Scholar]
24.Neri S, Pawelec G, Facchini A, Mariani E. Microsatellite instability and compromised mismatch repair gene expression during in vitro passaging of monoclonal human T lymphocytes. Rejuvenation Res. 2007;10(2):145–56. 10.1089/rej.2006.0510 [DOI] [PubMed] [Google Scholar]
25.Neri S, Pawelec G, Facchini A, Ferrari C, Mariani E. Altered expression of mismatch repair proteins associated with acquisition of microsatellite instability in a clonal model of human T lymphocyte aging. Rejuvenation Res. 2008;11(3):565–72. 10.1089/rej.2007.0639 [DOI] [PubMed] [Google Scholar]
26.González-Sánchez M, García-Martínez V, Bravo S, Kobayashi H, Martínez de Toda I, González-Bermúdez B, et al. Mitochondrial DNA insertions into nuclear DNA affecting chromosome segregation: insights for a novel mechanism of Immunosenescence in mice. Mech Ageing Dev. 2022;207:111722. 10.1016/j.mad.2022.111722 [DOI] [PubMed] [Google Scholar]
27.De Silva NS, Siewiera J, Alkhoury C, Nader GPF, Nadalin F, de Azevedo K, et al. Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages. Nat Aging. 2023;3(10):1251–68. 10.1038/s43587-023-00488-w [DOI] [PubMed] [Google Scholar]
28.Morgan RG, Venturelli M, Gross C, Tarperi C, Schena F, Reggiani C, et al. Age-Associated ALU element instability in white blood cells is linked to lower survival in elderly adults: A preliminary cohort study. PLoS ONE. 2017;12(1):e0169628. 10.1371/journal.pone.0169628 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Zhang FF, Cardarelli R, Carroll J, Fulda KG, Kaur M, Gonzalez K, et al. Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood. Epigenetics. 2011;6(5):623–9. 10.4161/epi.6.5.15335 [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Chebly A, Khalil C, Kuzyk A, Beylot-Barry M, Chevret E. T-cell lymphocytes’ aging clock: telomeres, telomerase and aging. Biogerontology. 2024;25(2):279–88. 10.1007/s10522-023-10075-6 [DOI] [PubMed] [Google Scholar]
31.Najarro K, Nguyen H, Chen G, Xu M, Alcorta S, Yao X, et al. Telomere length as an indicator of the robustness of B- and T-Cell response to influenza in older adults. J Infect Dis. 2015;212(8):1261–9. 10.1093/infdis/jiv202 [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Yousefzadeh MJ, Flores RR, Zhu Y, Schmiechen ZC, Brooks RW, Trussoni CE, et al. An aged immune system drives senescence and ageing of solid organs. Nature. 2021;594(7861):100–5. 10.1038/s41586-021-03547-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Fyhrquist F, Saijonmaa O. Telomere length and cardiovascular aging. Ann Med. 2012;44(sup1):S138–42. 10.3109/07853890.2012.660497 [DOI] [PubMed] [Google Scholar]
34.Montpetit AJ, Alhareeri AA, Montpetit M, Starkweather AR, Elmore LW, Filler K et al. Telomere length: A review of methods for measurement. Nurs Res. 2014;63(4). 10.1097/NNR.0000000000000037 [DOI] [PMC free article] [PubMed]
35.Behravan E, Moallem SA, Kalalinia F, Ahmadimanesh M, Blain P, Jowsey P, et al. Telomere shortening associated with increased levels of oxidative stress in sulfur mustard-exposed Iranian veterans. Mutat Res Genet Toxicol Environ Mutagen. 2018;834:1–5. 10.1016/j.mrgentox.2018.06.017 [DOI] [PubMed] [Google Scholar]
36.Cohen-Manheim I, Doniger GM, Sinnreich R, Simon ES, Pinchas R, Aviv A, et al. Increased attrition of leukocyte telomere length in young adults is associated with poorer cognitive function in midlife. Eur J Epidemiol. 2016;31(2):147–57. 10.1007/s10654-015-0051-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Needham BL, Wang X, Carroll JE, Barber S, Sánchez BN, Seeman TE, et al. Sociodemographic correlates of change in leukocyte telomere length during mid- to late-life: the Multi-Ethnic study of atherosclerosis. Psychoneuroendocrinology. 2019;102:182–8. 10.1016/j.psyneuen.2018.12.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Maxwell F, McGlynn LM, Muir HC, Talwar D, Benzeval M, Robertson T, et al. Telomere attrition and decreased fetuin-A levels indicate accelerated biological aging and are implicated in the pathogenesis of colorectal cancer. Clin Cancer Res. 2011;17(17):5573–81. 10.1158/1078-0432.Ccr-10-3271 [DOI] [PubMed] [Google Scholar]
39.Zhao J, Zhu Y, Uppal K, Tran VT, Yu T, Lin J, et al. Metabolic profiles of biological aging in American indians: the strong heart family study. Aging. 2014;6(3):176–86. 10.18632/aging.100644 [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Zanet DL, Thorne A, Singer J, Maan EJ, Sattha B, Le Campion A, et al. Association between short leukocyte telomere length and HIV infection in a cohort study: no evidence of a relationship with antiretroviral therapy. Clin Infect Dis. 2014;58(9):1322–32. 10.1093/cid/ciu051 [DOI] [PubMed] [Google Scholar]
41.Dowd JB, Bosch JA, Steptoe A, Jayabalasingham B, Lin J, Yolken R, et al. Persistent herpesvirus infections and telomere attrition over 3 years in the Whitehall II cohort. J Infect Dis. 2017;216(5):565–72. 10.1093/infdis/jix255 [DOI] [PMC free article] [PubMed] [Google Scholar]
42.Cao D, Zhao J, Nguyan LN, Nguyen LNT, Khanal S, Dang X, et al. Disruption of telomere integrity and DNA repair machineries by KML001 induces T cell senescence, apoptosis, and cellular dysfunctions. Front Immunol. 2019;10:1152. 10.3389/fimmu.2019.01152 [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Hsiao C-B, Bedi H, Gomez R, Khan A, Meciszewski T, Aalinkeel R, et al. Telomere length shortening in microglia: implication for accelerated senescence and neurocognitive deficits in HIV. Vaccines. 2021;9(7):721. 10.3390/vaccines9070721 [DOI] [PMC free article] [PubMed] [Google Scholar]
44.Révész D, Milaneschi Y, Terpstra EM, Penninx BW. Baseline biopsychosocial determinants of telomere length and 6-year attrition rate. Psychoneuroendocrinology. 2016;67:153–62. 10.1016/j.psyneuen.2016.02.007 [DOI] [PubMed] [Google Scholar]
45.Shin C, Yun CH, Yoon DW, Baik I. Association between snoring and leukocyte telomere length. Sleep. 2016;39(4):767–72. 10.5665/sleep.5624 [DOI] [PMC free article] [PubMed] [Google Scholar]
46.Huzen J, Wong LS, van Veldhuisen DJ, Samani NJ, Zwinderman AH, Codd V, et al. Telomere length loss due to smoking and metabolic traits. J Intern Med. 2014;275(2):155–63. 10.1111/joim.12149 [DOI] [PubMed] [Google Scholar]
47.Davis SK, Xu R, Khan RJ, Gaye A. Modifiable mediators associated with the relationship between adiposity and leukocyte telomere length in US adults: the National health and nutrition examination survey. Prev Med. 2020;138:106133. 10.1016/j.ypmed.2020.106133 [DOI] [PMC free article] [PubMed] [Google Scholar]
48.Gedvilaite G, Vilkeviciute A, Kriauciuniene L, Banevičius M, Liutkeviciene R. The relationship between leukocyte telomere length and TERT, TRF1 single nucleotide polymorphisms in healthy people of different age groups. Biogerontology. 2020;21(1):57–67. 10.1007/s10522-019-09843-0 [DOI] [PubMed] [Google Scholar]
49.Liu B, Sun Y, Xu G, Snetselaar LG, Ludewig G, Wallace RB, et al. Association between body iron status and leukocyte telomere length, a biomarker of biological aging, in a nationally representative sample of US adults. J Acad Nutr Diet. 2019;119(4):617–25. 10.1016/j.jand.2018.09.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
50.Lewis NL, Mullaney M, Mangan KF, Klumpp T, Rogatko A, Broccoli D. Measurable immune dysfunction and telomere attrition in long-term allogeneic transplant recipients. Bone Marrow Transpl. 2004;33(1):71–8. 10.1038/sj.bmt.1704300 [DOI] [PubMed] [Google Scholar]
51.Avetyan D, Zakharyan R, Petrek M, Arakelyan A. Telomere shortening in blood leukocytes of patients with posttraumatic stress disorder. J Psychiatr Res. 2019;111:83–8. 10.1016/j.jpsychires.2019.01.018 [DOI] [PubMed] [Google Scholar]
52.Lima IM, Barros A, Rosa DV, Albuquerque M, Malloy-Diniz L, Neves FS, et al. Analysis of telomere attrition in bipolar disorder. J Affect Disord. 2015;172:43–7. 10.1016/j.jad.2014.09.043 [DOI] [PubMed] [Google Scholar]
53.Jantunen H, Wasenius NS, Guzzardi MA, Iozzo P, Kajantie E, Kautiainen H, et al. Physical activity and telomeres in old age: A longitudinal 10-Year Follow-Up study. Gerontology. 2020;66(4):315–22. 10.1159/000505603 [DOI] [PubMed] [Google Scholar]
54.Steptoe A, Hamer M, Lin J, Blackburn EH, Erusalimsky JD. The longitudinal relationship between cortisol responses to mental stress and leukocyte telomere attrition. J Clin Endocrinol Metab. 2017;102(3):962–9. 10.1210/jc.2016-3035 [DOI] [PMC free article] [PubMed] [Google Scholar]
55.Brydon L, Lin J, Butcher L, Hamer M, Erusalimsky JD, Blackburn EH, et al. Hostility and cellular aging in men from the Whitehall II cohort. Biol Psychiatry. 2012;71(9):767–73. 10.1016/j.biopsych.2011.08.020 [DOI] [PMC free article] [PubMed] [Google Scholar]
56.van Ockenburg SL, de Jonge P, van der Harst P, Ormel J, Rosmalen JG. Does neuroticism make you old? Prospective associations between neuroticism and leukocyte telomere length. Psychol Med. 2014;44(4):723–9. 10.1017/s0033291713001657 [DOI] [PubMed] [Google Scholar]
57.Cherkas LF, Aviv A, Valdes AM, Hunkin JL, Gardner JP, Surdulescu GL, et al. The effects of social status on biological aging as measured by white-blood-cell telomere length. Aging Cell. 2006;5(5):361–5. 10.1111/j.1474-9726.2006.00222.x [DOI] [PubMed] [Google Scholar]
58.Soares-Miranda L, Imamura F, Siscovick D, Jenny NS, Fitzpatrick AL, Mozaffarian D. Physical activity, physical fitness, and leukocyte telomere length: the cardiovascular health study. Med Sci Sports Exerc. 2015;47(12):2525–34. 10.1249/mss.0000000000000720 [DOI] [PMC free article] [PubMed] [Google Scholar]
59.Hang D, Nan H, Kværner AS, De Vivo I, Chan AT, Hu Z, et al. Longitudinal associations of lifetime adiposity with leukocyte telomere length and mitochondrial DNA copy number. Eur J Epidemiol. 2018;33(5):485–95. 10.1007/s10654-018-0382-z [DOI] [PMC free article] [PubMed] [Google Scholar]
60.Grun LK, Teixeira NDR Jr., Mengden LV, de Bastiani MA, Parisi MM, Bortolin R, et al. TRF1 as a major contributor for telomeres’ shortening in the context of obesity. Free Radic Biol Med. 2018;129:286–95. 10.1016/j.freeradbiomed.2018.09.039 [DOI] [PubMed] [Google Scholar]
61.Wulaningsih W, Kuh D, Wong A, Hardy R, Adiposity. Telomere length, and telomere attrition in midlife: the 1946 British birth cohort. J Gerontol Biol Sci Med Sci. 2018;73(7):966–72. 10.1093/gerona/glx151 [DOI] [PMC free article] [PubMed] [Google Scholar]
62.Cabeza de Baca T, Prather AA, Lin J, Sternfeld B, Adler N, Epel ES, et al. Chronic psychosocial and financial burden accelerates 5-year telomere shortening: findings from the coronary artery risk development in young adults study. Mol Psychiatry. 2020;25(5):1141–53. 10.1038/s41380-019-0482-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
63.Meier HCS, Hussein M, Needham B, Barber S, Lin J, Seeman T, et al. Cellular response to chronic psychosocial stress: Ten-year longitudinal changes in telomere length in the Multi-Ethnic study of atherosclerosis. Psychoneuroendocrinology. 2019;107:70–81. 10.1016/j.psyneuen.2019.04.018 [DOI] [PMC free article] [PubMed] [Google Scholar]
64.Nakashima H, Ozono R, Suyama C, Sueda T, Kambe M, Oshima T. Telomere attrition in white blood cell correlating with cardiovascular damage. Hypertens Res. 2004;27(5):319–25. 10.1291/hypres.27.319 [DOI] [PubMed] [Google Scholar]
65.Nollet E, Hoymans VY, Rodrigus IR, De Bock D, Dom M, Van Hoof VOM, et al. Accelerated cellular senescence as underlying mechanism for functionally impaired bone marrow-derived progenitor cells in ischemic heart disease. Atherosclerosis. 2017;260:138–46. 10.1016/j.atherosclerosis.2017.03.023 [DOI] [PubMed] [Google Scholar]
66.Akasheva DU, Plokhova EV, Tkacheva ON, Strazhesko ID, Dudinskaya EN, Kruglikova AS, et al. Age-Related left ventricular changes and their association with leukocyte telomere length in healthy people. PLoS ONE. 2015;10(8):e0135883. 10.1371/journal.pone.0135883 [DOI] [PMC free article] [PubMed] [Google Scholar]
67.Miner AE, Graves JS. What telomeres teach Us about MS. Mult Scler Relat Disord. 2021;54:103084. 10.1016/j.msard.2021.103084 [DOI] [PubMed] [Google Scholar]
68.van den Hoogen LL, Sims GP, van Roon JA, Fritsch-Stork RD. Aging and systemic lupus Erythematosus - Immunosenescence and beyond. Curr Aging Sci. 2015;8(2):158–77. 10.2174/1874609808666150727111904 [DOI] [PubMed] [Google Scholar]
69.Opstad TB, Kalstad AA, Pettersen A, Arnesen H, Seljeflot I. Novel biomolecules of ageing, sex differences and potential underlying mechanisms of telomere shortening in coronary artery disease. Exp Gerontol. 2019;119:53–60. 10.1016/j.exger.2019.01.020 [DOI] [PubMed] [Google Scholar]
70.Bawamia B, Spray L, Wangsaputra VK, Bennaceur K, Vahabi S, Stellos K, et al. Activation of telomerase by TA-65 enhances immunity and reduces inflammation post myocardial infarction. Geroscience. 2023;45(4):2689–705. 10.1007/s11357-023-00794-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
71.Fernández-Alvira JM, Fuster V, Dorado B, Soberón N, Flores I, Gallardo M, et al. Short telomere load, telomere length, and subclinical atherosclerosis: the PESA study. J Am Coll Cardiol. 2016;67(21):2467–76. 10.1016/j.jacc.2016.03.530 [DOI] [PubMed] [Google Scholar]
72.Fali T, Fabre-Mersseman V, Yamamoto T, Bayard C, Papagno L, Fastenackels S, et al. Elderly human hematopoietic progenitor cells express cellular senescence markers and are more susceptible to pyroptosis. JCI Insight. 2018;3(13). 10.1172/jci.insight.95319 [DOI] [PMC free article] [PubMed]
73.Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115. 10.1186/gb-2013-14-10-r115 [DOI] [PMC free article] [PubMed] [Google Scholar]
74.Cheng X, Wei Y, Wang R, Jia C, Zhang Z, An J, et al. Associations of essential trace elements with epigenetic aging indicators and the potential mediating role of inflammation. Redox Biol. 2023;67. 10.1016/j.redox.2023.102910 [DOI] [PMC free article] [PubMed]
75.Tomusiak A, Floro A, Tiwari R, Riley R, Matsui H, Andrews N, et al. Development of an epigenetic clock resistant to changes in immune cell composition. Commun Biol. 2024;7(1):934. 10.1038/s42003-024-06609-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
76.Speaker Abstracts, Alcoholism. Clin Experimental Res. 2022;46(S2):18–87. 10.1111/acer.14905 [Google Scholar]
77.Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013;49(2):359–67. 10.1016/j.molcel.2012.10.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
78.Horvath S, Oshima J, Martin GM, Lu AT, Quach A, Cohen H, et al. Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria syndrome and ex vivo studies. Aging. 2018;10(7):1758–75. 10.18632/aging.101508 [DOI] [PMC free article] [PubMed] [Google Scholar]
79.Levine ME, Lu AT, Quach A, Chen BH, Assimes TL, Bandinelli S, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging. 2018;10(4):573–91. 10.18632/aging.101414 [DOI] [PMC free article] [PubMed] [Google Scholar]
80.Zhang Z, Reynolds SR, Stolrow HG, Chen JQ, Christensen BC, Salas LA. Deciphering the role of immune cell composition in epigenetic age acceleration: insights from cell-type Deconvolution applied to human blood epigenetic clocks. Aging Cell. 2024;23(3). 10.1111/acel.14071 [DOI] [PMC free article] [PubMed]
81.Mogilenko DA, Shpynov O, Andhey PS, Arthur L, Swain A, Esaulova E, et al. Comprehensive profiling of an aging immune system reveals clonal GZMK + CD8 + T cells as conserved hallmark of inflammaging. Immunity. 2021;54(1):99–e11512. 10.1016/j.immuni.2020.11.005 [DOI] [PubMed] [Google Scholar]
82.Ohyashiki M, Ohyashiki JH, Hirota A, Kobayashi C, Ohyashiki K. Age-related decrease of miRNA-92a levels in human CD8 + T-cells correlates with a reduction of Naïve T lymphocytes. Immun Ageing. 2011;8(1):11. 10.1186/1742-4933-8-11 [DOI] [PMC free article] [PubMed] [Google Scholar]
83.Kim C, Jin J, Ye Z, Jadhav RR, Gustafson CE, Hu B, et al. Histone deficiency and accelerated replication stress in T cell aging. J Clin Invest. 2021;131(11). 10.1172/jci143632 [DOI] [PMC free article] [PubMed]
84.Brunner S, Herndler-Brandstetter D, Arnold CR, Wiegers GJ, Villunger A, Hackl M, et al. Upregulation of miR-24 is associated with a decreased DNA damage response upon Etoposide treatment in highly differentiated CD8(+) T cells sensitizing them to apoptotic cell death. Aging Cell. 2012;11(4):579–87. 10.1111/j.1474-9726.2012.00819.x [DOI] [PMC free article] [PubMed] [Google Scholar]
85.Ma F, Cao Y, Du H, Braikia FZ, Zong L, Ollikainen N, et al. Three-dimensional chromatin reorganization regulates B cell development during ageing. Nat Cell Biol. 2024;26(6):991–1002. 10.1038/s41556-024-01424-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
86.Funk MC, Gleixner JG, Heigwer F, Vonficht D, Valentini E, Aydin Z, et al. Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice. Dev Cell. 2023;58(24):2914–e297. 10.1016/j.devcel.2023.11.013 [DOI] [PubMed] [Google Scholar]
87.Harries LW, Hernandez D, Henley W, Wood AR, Holly AC, Bradley-Smith RM, et al. Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing. Aging Cell. 2011;10(5):868–78. 10.1111/j.1474-9726.2011.00726.x [DOI] [PMC free article] [PubMed] [Google Scholar]
88.Rasa SMM, Annunziata F, Krepelova A, Nunna S, Omrani O, Gebert N, et al. Inflammaging is driven by upregulation of innate immune receptors and systemic interferon signaling and is ameliorated by dietary restriction. Cell Rep. 2022;39(13). 10.1016/j.celrep.2022.111017 [DOI] [PubMed]
89.Jarrold BB, Tan CYR, Ho CY, Soon AL, Lam TT, Yang X, et al. Early onset of senescence and imbalanced epidermal homeostasis across the decades in photoexposed human skin: fingerprints of inflammaging. Exp Dermatol. 2022;31(11):1748–60. 10.1111/exd.14654 [DOI] [PubMed] [Google Scholar]
90.Oltmanns C, Liu Z, Mischke J, Tauwaldt J, Mekonnen YA, Urbanek-Quaing M, et al. Reverse inflammaging: Long-term effects of HCV cure on biological age. J Hepatol. 2023;78(1):90–8. 10.1016/j.jhep.2022.08.042 [DOI] [PubMed] [Google Scholar]
91.Durso DF, Silveira-Nunes G, Coelho MM, Camatta GC, Ventura LH, Nascimento LS, et al. Living in endemic area for infectious diseases accelerates epigenetic age. Mech Ageing Dev. 2022;207:111713. 10.1016/j.mad.2022.111713 [DOI] [PubMed] [Google Scholar]
92.Horvath S, Gurven M, Levine ME, Trumble BC, Kaplan H, Allayee H, et al. An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biol. 2016;17(1):171. 10.1186/s13059-016-1030-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
93.Verschoor CP, Vlasschaert C, Rauh MJ, Paré G. A DNA methylation based measure outperforms Circulating CRP as a marker of chronic inflammation and partly reflects the monocytic response to long-term inflammatory exposure: A Canadian longitudinal study on aging analysis. Aging Cell. 2023;22(7):e13863. 10.1111/acel.13863 [DOI] [PMC free article] [PubMed] [Google Scholar]
94.Declerck K, Vanden Berghe W. Characterization of blood surrogate immune-Methylation biomarkers for immune cell infiltration in chronic inflammaging disorders. Front Genet. 2019;10. 10.3389/fgene.2019.01229 [DOI] [PMC free article] [PubMed]
95.Yue Z, Nie L, Ji N, Sun Y, Zhu K, Zou H, et al. Hyperglycaemia aggravates periodontal inflamm-aging by promoting SETDB1-mediated LINE-1 de-repression in macrophages. J Clin Periodontol. 2023;50(12):1685–96. 10.1111/jcpe.13871 [DOI] [PubMed] [Google Scholar]
96.He M, Chiang HH, Luo H, Zheng Z, Qiao Q, Wang L, et al. An acetylation switch of the NLRP3 inflammasome regulates Aging-Associated chronic inflammation and insulin resistance. Cell Metab. 2020;31(3):580–e915. 10.1016/j.cmet.2020.01.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
97.Bradburn S, McPhee J, Bagley L, Carroll M, Slevin M, Al-Shanti N, et al. Dysregulation of C-X-C motif ligand 10 during aging and association with cognitive performance. Neurobiol Aging. 2018;63:54–64. 10.1016/j.neurobiolaging.2017.11.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
98.Cheng H, Xuan H, Green CD, Han Y, Sun N, Shen H, et al. Repression of human and mouse brain inflammaging transcriptome by broad gene-body histone hyperacetylation. Proc Natl Acad Sci USA. 2018;115(29):7611–6. 10.1073/pnas.1800656115 [DOI] [PMC free article] [PubMed] [Google Scholar]
99.Zhu M, Han Y, Gu T, Wang R, Si X, Kong D, et al. Class I HDAC inhibitors enhance antitumor efficacy and persistence of CAR-T cells by activation of the Wnt pathway. Cell Rep. 2024;43(4). 10.1016/j.celrep.2024.114065 [DOI] [PubMed]
100.López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243–78. 10.1016/j.cell.2022.11.001 [DOI] [PubMed] [Google Scholar]
101.Rabinowitz JD, White E. Autophagy and metabolism. Science. 2010;330(6009):1344–8. 10.1126/science.1193497 [DOI] [PMC free article] [PubMed] [Google Scholar]
102.Hang R, Wang J, Tian X, Wu R, Hang R, Zhao Y, et al. Resveratrol promotes osteogenesis and angiogenesis through mediating immunology of senescent macrophages. Biomed Mater. 2022;17(5):055005. 10.1088/1748-605X/ac80e3 [DOI] [PubMed] [Google Scholar]
103.Chen W, Xiao W, Liu X, Yuan P, Zhang S, Wang Y, et al. Pharmacological manipulation of macrophage autophagy effectively rejuvenates the regenerative potential of biodegrading vascular graft in aging body. Bioactive Mater. 2022;11:283–99. 10.1016/j.bioactmat.2021.09.027 [DOI] [PMC free article] [PubMed] [Google Scholar]
104.Bai L, Liu Y, Zhang X, Chen P, Hang R, Xiao Y, et al. Osteoporosis remission via an anti-inflammaging effect by Icariin activated autophagy. Biomaterials. 2023;297:122125. 10.1016/j.biomaterials.2023.122125 [DOI] [PubMed] [Google Scholar]
105.Wang Z, Wu Z, Wang H, Feng R, Wang G, Li M, et al. An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development. Cell. 2023;186(20):4454–e7119. 10.1016/j.cell.2023.08.019 [DOI] [PubMed] [Google Scholar]
106.Kong H, Xu L-M, Wang D-X. Perioperative neurocognitive disorders: A narrative review focusing on diagnosis, prevention, and treatment. CNS Neurosci Ther. 2022;28(8):1147–67. 10.1111/cns.13873 [DOI] [PMC free article] [PubMed] [Google Scholar]
107.Chen F, Bai N, Yue F, Hao Y, Wang H, He Y, et al. Effects of oral β-caryophyllene (BCP) treatment on perioperative neurocognitive disorders: Attenuation of neuroinflammation associated with microglial activation and reinforcement of autophagy activity in aged mice. Brain Res. 2023;1815:148425. 10.1016/j.brainres.2023.148425 [DOI] [PubMed] [Google Scholar]
108.Ritzel RM, Li Y, Lei Z, Carter J, He J, Choi HMC, et al. Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice. GeroScience. 2022;44(3):1407–40. 10.1007/s11357-022-00562-y [DOI] [PMC free article] [PubMed] [Google Scholar]
109.Berglund R, Cheng Y, Piket E, Adzemovic Z, Zeitelhofer M, Olsson M. The aging mouse CNS is protected by an autophagy-dependent microglia population promoted by IL-34. Nat Commun. 2024;15(1):383. 10.1038/s41467-023-44556-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
110.Jalloh A, Flowers A, Hudson C, Chaput D, Guergues J, Stevens SM, et al. Polyphenol supplementation reverses Age-Related changes in microglial signaling cascades. Int J Mol Sci. 2021;22(12):6373. 10.3390/ijms22126373 [DOI] [PMC free article] [PubMed] [Google Scholar]
111.Runyan CE, Welch LC, Lecuona E, Shigemura M, Amarelle L, Abdala-Valencia H, et al. Impaired phagocytic function in CX3CR1 + tissue-resident skeletal muscle macrophages prevents muscle recovery after influenza A virus-induced pneumonia in old mice. Aging Cell. 2020;19(9). 10.1111/acel.13180 [DOI] [PMC free article] [PubMed]
112.Cannizzo Elvira S, Clement Cristina C, Morozova K, Valdor R, Kaushik S, Almeida Larissa N, et al. Age-Related oxidative stress compromises endosomal proteostasis. Cell Rep. 2012;2(1):136–49. 10.1016/j.celrep.2012.06.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
113.Schmidt F, Dahlmann B, Janek K, Kloss A, Wacker M, Ackermann R, et al. Comprehensive quantitative proteome analysis of 20S proteasome subtypes from rat liver by isotope coded affinity Tag and 2-D gel-based approaches. Proteomics. 2006;6(16):4622–32. 10.1002/pmic.200500920 [DOI] [PubMed] [Google Scholar]
114.Gohlke S, Mishto M, Textoris-Taube K, Keller C, Giannini C, Vasuri F, et al. Molecular alterations in proteasomes of rat liver during aging result in altered proteolytic activities. AGE. 2014;36(1):57–72. 10.1007/s11357-013-9543-x [DOI] [PMC free article] [PubMed] [Google Scholar]
115.Schlie K, Westerback A, DeVorkin L, Hughson LR, Brandon JM, MacPherson S, et al. Survival of effector CD8 + T cells during influenza infection is dependent on autophagy. J Immunol. 2015;194(9):4277–86. 10.4049/jimmunol.1402571 [DOI] [PubMed] [Google Scholar]
116.Xu X, Araki K, Li S, Han JH, Ye L, Tan WG, et al. Autophagy is essential for effector CD8(+) T cell survival and memory formation. Nat Immunol. 2014;15(12):1152–61. 10.1038/ni.3025 [DOI] [PMC free article] [PubMed] [Google Scholar]
117.Alsaleh G, Panse I, Swadling L, Zhang H, Richter FC, Meyer A, et al. Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses. Elife. 2020;9. 10.7554/eLife.57950 [DOI] [PMC free article] [PubMed]
118.Zhang C, Sun Y, Li S, Shen L, Teng X, Xiao Y, et al. Autophagic flux restoration of senescent T cells improves antitumor activity of TCR-engineered T cells. Clin Translational Immunol. 2022;11(9):e1419. 10.1002/cti2.1419 [DOI] [PMC free article] [PubMed] [Google Scholar]
119.Bharath LP, Agrawal M, McCambridge G, Nicholas DA, Hasturk H, Liu J, et al. Metformin enhances autophagy and normalizes mitochondrial function to alleviate Aging-Associated inflammation. Cell Metabol. 2020;32(1):44–e556. 10.1016/j.cmet.2020.04.015 [DOI] [PMC free article] [PubMed] [Google Scholar]
120.Huda N, Khambu B, Liu G, Nakatsumi H, Yan S, Chen X, et al. Senescence connects autophagy deficiency to inflammation and tumor progression in the liver. Cell Mol Gastroenterol Hepatol. 2022;14(2):333–55. 10.1016/j.jcmgh.2022.04.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
121.Steinert EM, Vasan K, Chandel NS. Mitochondrial metabolism regulation of T Cell-Mediated immunity. Annu Rev Immunol. 2021;39:395–416. 10.1146/annurev-immunol-101819-082015 [DOI] [PMC free article] [PubMed] [Google Scholar]
122.Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, et al. T cell subset-specific susceptibility to aging. Clin Immunol. 2008;127(1):107–18. 10.1016/j.clim.2007.12.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
123.Henson SM, Lanna A, Riddell NE, Franzese O, Macaulay R, Griffiths SJ, et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8⁺ T cells. J Clin Invest. 2014;124(9):4004–16. 10.1172/jci75051 [DOI] [PMC free article] [PubMed] [Google Scholar]
124.Callender LA, Carroll EC, Bober EA, Akbar AN, Solito E, Henson SM. Mitochondrial mass governs the extent of human T cell senescence. Aging Cell. 2020;19(2). 10.1111/acel.13067 [DOI] [PMC free article] [PubMed]
125.Headley CA, Gautam S, Olmo-Fontanez A, Garcia-Vilanova A, Dwivedi V, Akhter A, et al. Extracellular delivery of functional mitochondria rescues the dysfunction of CD4 + T cells in aging. Adv Sci. 2024;11(5):2303664. 10.1002/advs.202303664 [DOI] [PMC free article] [PubMed] [Google Scholar]
126.Chen Y, Ye Y, Krauß P-L, Löwe P, Pfeiffenberger M, Damerau A et al. Age-related increase of mitochondrial content in human memory CD4 + T cells contributes to ROS-mediated increased expression of Proinflammatory cytokines. Front Immunol. 2022;13. 10.3389/fimmu.2022.911050 [DOI] [PMC free article] [PubMed]
127.Ye B, Pei Y, Wang L, Meng D, Zhang Y, Zou S, et al. NAD + supplementation prevents STING-induced senescence in CD8 + T cells by improving mitochondrial homeostasis. J Cell Biochem. 2024;125(3):e30522. 10.1002/jcb.30522 [DOI] [PubMed] [Google Scholar]
128.Bektas A, Schurman SH, Gonzalez-Freire M, Dunn CA, Singh AK, Macian F, et al. Age-associated changes in human CD4 + T cells point to mitochondrial dysfunction consequent to impaired autophagy. AGING-US. 2019;11(21):9234–63. 10.18632/aging.102438 [DOI] [PMC free article] [PubMed] [Google Scholar]
129.Qiu X, Guo H, Yang J, Ji Y, Wu C-S, Chen X. Down-regulation of guanylate binding protein 1 causes mitochondrial dysfunction and cellular senescence in macrophages. Sci Rep. 2018;8(1):1679. 10.1038/s41598-018-19828-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
130.An Y, Li Y, Hou Y, Huang S, Pei G. Alzheimer’s Amyloid- β Accelerates Cell Senescence and Suppresses the SIRT1/NRF2 Pathway in Human Microglial Cells. Oxidative Medicine and Cellular Longevity. 2022;2022. 10.1155/2022/3086010 [DOI] [PMC free article] [PubMed]
131.Dongol A, Chen X, Zheng P, Seyhan ZB, Huang XF. Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process. Biol Direct. 2023;18(1):86. 10.1186/s13062-023-00445-y [DOI] [PMC free article] [PubMed] [Google Scholar]
132.Thangaraj A, Chivero ET, Tripathi A, Singh S, Niu F, Guo M-L, et al. HIV TAT-mediated microglial senescence: role of SIRT3-dependent mitochondrial oxidative stress. Redox Biol. 2021;40:101843. 10.1016/j.redox.2020.101843 [DOI] [PMC free article] [PubMed] [Google Scholar]
133.Zhong W, Rao Z, Xu J, Sun Y, Hu H, Wang P, et al. Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation. Aging Cell. 2022;21(6). 10.1111/acel.13622 [DOI] [PMC free article] [PubMed]
134.Hussain M, Chu X, Duan Sahbaz B, Gray S, Pekhale K, Park J-H, et al. Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA. Free Radic Biol Med. 2023;203:34–44. 10.1016/j.freeradbiomed.2023.03.262 [DOI] [PMC free article] [PubMed] [Google Scholar]
135.Vizioli MG, Liu T, Miller KN, Robertson NA, Gilroy K, Lagnado AB, et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes Dev. 2020;34(5):428–45. 10.1101/gad.331272.119 [DOI] [PMC free article] [PubMed] [Google Scholar]
136.Zhang X, Wang R, Chen H, Jin C, Jin Z, Lu J, et al. Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches. Immun Ageing. 2022;19(1):34. 10.1186/s12979-022-00289-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
137.Gulen MF, Samson N, Keller A, Schwabenland M, Liu C, Glück S, et al. cGAS–STING drives ageing-related inflammation and neurodegeneration. Nature. 2023;620(7973):374–80. 10.1038/s41586-023-06373-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
138.Balter LJT, Higgs S, Aldred S, Bosch JA, Raymond JE. Inflammation mediates body weight and ageing effects on psychomotor slowing. Sci Rep. 2019;9(1):15727. 10.1038/s41598-019-52062-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
139.Chougnet CA, Thacker RI, Shehata HM, Hennies CM, Lehn MA, Lages CS, et al. Loss of phagocytic and antigen Cross-Presenting capacity in aging dendritic cells is associated with mitochondrial dysfunction. J Immunol. 2015;195(6):2624–32. 10.4049/jimmunol.1501006 [DOI] [PMC free article] [PubMed] [Google Scholar]
140.Rottenberg H, Wu S. Mitochondrial dysfunction in lymphocytes from old mice: enhanced activation of the permeability transition. Biochem Biophys Res Commun. 1997;240(1):68–74. 10.1006/bbrc.1997.7605 [DOI] [PubMed] [Google Scholar]
141.Mather MW, Rottenberg H. The Inhibition of calcium signaling in T lymphocytes from old mice results from enhanced activation of the mitochondrial permeability transition pore. Mech Ageing Dev. 2002;123(6):707–24. 10.1016/S0047-6374(01)00416-X [DOI] [PubMed] [Google Scholar]
142.Han S, Georgiev P, Ringel AE, Sharpe AH, Haigis MC. Age-associated remodeling of T cell immunity and metabolism. Cell Metabol. 2023;35(1):36–55. 10.1016/j.cmet.2022.11.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
143.Xie Z, Lin M, Xing B, Wang H, Zhang H, Cai Z, et al. Citrulline regulates macrophage metabolism and inflammation to counter aging in mice. Sci Adv. 2025;11(10):eads4957. 10.1126/sciadv.ads4957 [DOI] [PMC free article] [PubMed] [Google Scholar]
144.Sawoo R, Dey R, Ghosh R, Bishayi B. TLR4 and TNFR1 Blockade dampen M1 macrophage activation and shifts them towards an M2 phenotype. Immunol Res. 2021;69(4):334–51. 10.1007/s12026-021-09209-0 [DOI] [PubMed] [Google Scholar]
145.Ryu S, Sidorov S, Ravussin E, Artyomov M, Iwasaki A, Wang A, et al. The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging. Immunity. 2022;55(9):1609–e267. 10.1016/j.immuni.2022.07.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
146.Li C, Deng C, Wang S, Dong X, Dai B, Guo W, et al. A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization. Redox Biol. 2024;70:103059. 10.1016/j.redox.2024.103059 [DOI] [PMC free article] [PubMed] [Google Scholar]
147.Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol. 2018;28(6):436–53. 10.1016/j.tcb.2018.02.001 [DOI] [PubMed] [Google Scholar]
148.Zhang J, Li Z, Zhang Q, Ma W, Fan W, Dong J, et al. LAMA4(+) CD90(+) eCAFs provide immunosuppressive microenvironment for liver cancer through induction of CD8(+) T cell senescence. Cell Commun Signal. 2025;23(1):203. 10.1186/s12964-025-02162-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
149.Li Y, Wang L, Ma W, Wu J, Wu Q, Sun C. Paracrine signaling in cancer-associated fibroblasts: central regulators of the tumor immune microenvironment. J Translational Med. 2025;23(1):697. 10.1186/s12967-025-06744-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
150.Lv N, Zhao Y, Liu X, Ye L, Liang Z, Kang Y, et al. Dysfunctional telomeres through mitostress-induced cGAS/STING activation to aggravate immune senescence and viral pneumonia. Aging Cell. 2022;21(4):e13594. 10.1111/acel.13594 [DOI] [PMC free article] [PubMed] [Google Scholar]
151.Cho RH, Sieburg HB, Muller-Sieburg CE. A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells. Blood. 2008;111(12):5553–61. 10.1182/blood-2007-11-123547 [DOI] [PMC free article] [PubMed] [Google Scholar]
152.Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci. 2005;102(26):9194–9. 10.1073/pnas.0503280102 [DOI] [PMC free article] [PubMed] [Google Scholar]
153.Hérault L, Poplineau M, Mazuel A, Platet N, Remy É, Duprez E. Single-cell RNA-seq reveals a concomitant delay in differentiation and cell cycle of aged hematopoietic stem cells. BMC Biol. 2021;19(1):19. 10.1186/s12915-021-00955-z [DOI] [PMC free article] [PubMed] [Google Scholar]
154.Khoo MLM, Carlin SM, Lutherborrow MA, Jayaswal V, Ma DDF, Moore JJ. Gene profiling reveals association between altered Wnt signaling and loss of T-cell potential with age in human hematopoietic stem cells. Aging Cell. 2014;13(4):744–54. 10.1111/acel.12229 [DOI] [PMC free article] [PubMed] [Google Scholar]
155.Rosales-Alvarez RE, Rettkowski J, Herman JS, Dumbović G, Cabezas-Wallscheid N, Grün D. VarID2 quantifies gene expression noise dynamics and unveils functional heterogeneity of ageing hematopoietic stem cells. Genome Biol. 2023;24(1):148. 10.1186/s13059-023-02974-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
156.Yamamoto R, Wilkinson AC, Ooehara J, Lan X, Lai CY, Nakauchi Y, et al. Large-Scale clonal analysis resolves aging of the mouse hematopoietic stem cell compartment. Cell Stem Cell. 2018;22(4):600–e74. 10.1016/j.stem.2018.03.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
157.Wang Y, Zhang Z, He H, Song J, Cui Y, Chen Y, et al. Aging-induced Pseudouridine synthase 10 impairs hematopoietic stem cells. Haematologica. 2023;108(10):2677–89. 10.3324/haematol.2022.282211 [DOI] [PMC free article] [PubMed] [Google Scholar]
158.Wang J, Morita Y, Han B, Niemann S, Löffler B, Rudolph KL. Per2 induction limits lymphoid-biased Haematopoietic stem cells and lymphopoiesis in the context of DNA damage and ageing. Nat Cell Biol. 2016;18(5):480–90. 10.1038/ncb3342 [DOI] [PubMed] [Google Scholar]
159.Grover A, Sanjuan-Pla A, Thongjuea S, Carrelha J, Giustacchini A, Gambardella A, et al. Single-cell RNA sequencing reveals molecular and functional platelet bias of aged Haematopoietic stem cells. Nat Commun. 2016;7(1):11075. 10.1038/ncomms11075 [DOI] [PMC free article] [PubMed] [Google Scholar]
160.Zeng X, Li X, Shao M, Xu Y, Shan W, Wei C, et al. Integrated Single-Cell bioinformatics analysis reveals intrinsic and extrinsic biological characteristics of hematopoietic stem cell aging. Front Genet. 2021;12. 10.3389/fgene.2021.745786 [DOI] [PMC free article] [PubMed]
161.Mitchell CA, Verovskaya EV, Calero-Nieto FJ, Olson OC, Swann JW, Wang X, et al. Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of Haematopoietic ageing. Nat Cell Biol. 2023;25(1):30–41. 10.1038/s41556-022-01053-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
162.Montecino-Rodriguez E, Kong Y, Casero D, Rouault A, Dorshkind K, Pioli PD. Lymphoid-Biased hematopoietic stem cells are maintained with age and efficiently generate lymphoid progeny. Stem Cell Rep. 2019;12(3):584–96. 10.1016/j.stemcr.2019.01.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
163.Wahlestedt M, Norddahl GL, Sten G, Ugale A, Frisk M-AM, Mattsson R, et al. An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state. Blood. 2013;121(21):4257–64. 10.1182/blood-2012-11-469080 [DOI] [PubMed] [Google Scholar]
164.Bocker MT, Hellwig I, Breiling A, Eckstein V, Ho AD, Lyko F. Genome-wide promoter DNA methylation dynamics of human hematopoietic progenitor cells during differentiation and aging. Blood. 2011;117(19):e182–9. 10.1182/blood-2011-01-331926 [DOI] [PubMed] [Google Scholar]
165.Khokhar ES, Borikar S, Eudy E, Stearns T, Young K, Trowbridge JJ. Aging-associated decrease in the histone acetyltransferase KAT6B is linked to altered hematopoietic stem cell differentiation. Exp Hematol. 2020;82:43–e524. 10.1016/j.exphem.2020.01.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
166.Jang G, Contreras Castillo S, Esteva E, Upadhaya S, Feng J, Adams NM, et al. Stem cell decoupling underlies impaired lymphoid development during aging. Proc Natl Acad Sci U S A. 2023;120(22):e2302019120. 10.1073/pnas.2302019120 [DOI] [PMC free article] [PubMed] [Google Scholar]
167.Gong X, Shen H, Guo L, Huang C, Su T, Wang H, et al. Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice. Immun Ageing. 2023;20(1). 10.1186/s12979-023-00337-9 [DOI] [PMC free article] [PubMed]
168.Zeng X, Li X, Li X, Wei C, Shi C, Hu K, et al. Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation. Blood. 2023;141(14):1691–707. 10.1182/blood.2022017514 [DOI] [PMC free article] [PubMed] [Google Scholar]
169.Utsuyama M, Kobayashi S, Hirokawa K. Induction of thymic hyperplasia and suppression of Splenic T cells by lesioning of the anterior hypothalamus in aging Wistar rats. J Neuroimmunol. 1997;77(2):174–80. 10.1016/S0165-5728(97)00068-4 [DOI] [PubMed] [Google Scholar]
170.Hirokawa K, Utsuyama M, Kasai M, Kurashima C, Ishijima S, Zeng YX. Understanding the mechanism of the age-change of thymic function to promote T cell differentiation. Immunol Lett. 1994;40(3):269–77. 10.1016/0165-2478(94)00065-4 [DOI] [PubMed] [Google Scholar]
171.Lesnikov VA, Korneva EA, Dall’ara A, Pierpaoli W. The involvement of pineal gland and melatonin in immunity and aging: II. Thyrotropin-releasing hormone and melatonin forestall Involution and promote reconstitution of the thymus in anterior hypothalamic area (AHA)-lesioned mice. Int J Neurosci. 1992;62(1–2):141–53. 10.3109/00207459108999767 [DOI] [PubMed] [Google Scholar]
172.Irwin M, Hauger R, Brown M. Central corticotropin-releasing hormone activates the sympathetic nervous system and reduces immune function: increased responsivity of the aged rat. Endocrinology. 1992;131(3):1047–53. 10.1210/endo.131.3.1505449 [DOI] [PubMed] [Google Scholar]
173.Mocchegiani E, Bulian D, Santarelli L, Tibaldi A, Muzzioli M, Pierpaoli W, et al. The immuno-reconstituting effect of melatonin or pineal grafting and its relation to zinc pool in aging mice. J Neuroimmunol. 1994;53(2):189–201. 10.1016/0165-5728(94)90029-9 [DOI] [PubMed] [Google Scholar]
174.Cui K, Tang X, Hu A, Fan M, Wu P, Lu X, et al. Therapeutic benefit of melatonin in choroidal neovascularization during aging through the regulation of senescent macrophage/microglia polarization. Investig Ophthalmol Vis Sci. 2023;64(11):19–. 10.1167/iovs.64.11.19 [DOI] [PMC free article] [PubMed] [Google Scholar]
175.Mazzoccoli G, Inglese M, De Cata A, Carughi S, Dagostino MP, Marzulli N, et al. Neuroendocrine–immune interactions in healthy aging. Geriatr Gerontol Int. 2011;11(1):98–106. 10.1111/j.1447-0594.2010.00628.x [DOI] [PubMed] [Google Scholar]
176.Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576–90. 10.1038/s41574-018-0059-4 [DOI] [PubMed] [Google Scholar]
177.Koelman L, Pivovarova-Ramich O, Pfeiffer AFH, Grune T, Aleksandrova K. Cytokines for evaluation of chronic inflammatory status in ageing research: reliability and phenotypic characterisation. Immun Ageing. 2019;16(1). 10.1186/s12979-019-0151-1 [DOI] [PMC free article] [PubMed]
178.Morrisette-Thomas V, Cohen AA, Fülöp T, Riesco É, Legault V, Li Q, et al. Inflamm-aging does not simply reflect increases in pro-inflammatory markers. Mech Ageing Dev. 2014;139:49–57. 10.1016/j.mad.2014.06.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
179.Laskow T, Langdon J, Sepehri S, Davalos-Bichara M, Varadhan R, Walston J. Soluble TNFR1 has greater reproducibility than IL-6 for the assessment of chronic inflammation in older adults: the case for a new inflammatory marker in aging. GeroScience. 2024;46(2):2521–30. 10.1007/s11357-023-01006-x [DOI] [PMC free article] [PubMed] [Google Scholar]
180.Pinti M, Cevenini E, Nasi M, De Biasi S, Salvioli S, Monti D, et al. Circulating mitochondrial DNA increases with age and is a familiar trait: implications for inflamm-aging. Eur J Immunol. 2014;44(5):1552–62. 10.1002/eji.201343921 [DOI] [PubMed] [Google Scholar]
181.Seicol BJ, Lin S, Xie R. Age-Related hearing loss is accompanied by chronic inflammation in the cochlea and the cochlear nucleus. Front Aging Neurosci. 2022;14. 10.3389/fnagi.2022.846804 [DOI] [PMC free article] [PubMed]
182.Bruno MEC, Mukherjee S, Powell WL, Mori SF, Wallace FK, Balasuriya BK, et al. Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation. GeroScience. 2022;44(3):1761–78. 10.1007/s11357-022-00572-w [DOI] [PMC free article] [PubMed] [Google Scholar]
183.Ruan P, Yang M, Lv X, Shen K, Chen Y, Li H et al. Metabolic shifts during coffee consumption refresh the immune response: insight from comprehensive multiomics analysis. MedComm (2020). 2024;5(7):e617. 10.1002/mco2.617 [DOI] [PMC free article] [PubMed]
184.Robbins PD, Jurk D, Khosla S, Kirkland JL, LeBrasseur NK, Miller JD, et al. Senolytic drugs: reducing senescent cell viability to extend health span. Annu Rev Pharmacol Toxicol. 2021;61:779–803. 10.1146/annurev-pharmtox-050120-105018 [DOI] [PMC free article] [PubMed] [Google Scholar]
185.Wong CP, Magnusson KR, Sharpton TJ, Ho E. Effects of zinc status on age-related T cell dysfunction and chronic inflammation. Biometals. 2021;34(2):291–301. 10.1007/s10534-020-00279-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
186.Morita Y, Jounai K, Sakamoto A, Tomita Y, Sugihara Y, Suzuki H, et al. Long-term intake of Lactobacillus paracasei KW3110 prevents age-related chronic inflammation and retinal cell loss in physiologically aged mice. Aging. 2018;10(10):2723–40. 10.18632/aging.101583 [DOI] [PMC free article] [PubMed] [Google Scholar]
187.Matt SM, Allen JM, Lawson MA, Mailing LJ, Woods JA, Johnson RW. Butyrate and dietary soluble fiber improve neuroinflammation associated with aging in mice. Front Immunol. 2018;9. 10.3389/fimmu.2018.01832 [DOI] [PMC free article] [PubMed]
188.Oh H-J, Jin H, Lee J-Y, Lee B-Y. Silk peptide ameliorates sarcopenia through the regulation of Akt/mTOR/FoxO3a signaling pathways and the Inhibition of Low-Grade chronic inflammation in aged mice. Cells. 2023. 10.3390/cells12182257 [DOI] [PMC free article] [PubMed] [Google Scholar]
189.Koelman L, Herpich C, Norman K, Jannasch F, Börnhorst C, Schulze MB, Aleksandrova K. Adherence to healthy and sustainable dietary patterns and long-term chronic inflammation: data from the EPIC-potsdam cohort. J Nutr Health Aging. 2023;27(11):1109–17. 10.1007/s12603-023-2010-1 [DOI] [PubMed]
190.Bashir H, Singh S, Singh RP, Agrewala JN, Kumar R. Age-mediated gut microbiota dysbiosis promotes the loss of dendritic cells tolerance. Aging Cell. 2023;22(6):e13838. 10.1111/acel.13838 [DOI] [PMC free article] [PubMed] [Google Scholar]
191.Golomb SM, Guldner IH, Zhao A, Wang Q, Palakurthi B, Aleksandrovic EA, et al. Multi-modal Single-Cell analysis reveals brain immune landscape plasticity during aging and gut microbiota dysbiosis. Cell Rep. 2020;33(9). 10.1016/j.celrep.2020.108438 [DOI] [PMC free article] [PubMed]
192.Stebegg M, Silva-Cayetano A, Innocentin S, Jenkins TP, Cantacessi C, Gilbert C, et al. Heterochronic faecal transplantation boosts gut germinal centres in aged mice. Nat Commun. 2019;10(1):2443. 10.1038/s41467-019-10430-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
193.Vemuri R, Gundamaraju R, Shinde T, Perera AP, Basheer W, Southam B, et al. Lactobacillus acidophilus DDS-1 modulates intestinal-specific microbiota, short-chain fatty acid and immunological profiles in aging mice. Nutrients. 2019;11(6). 10.3390/nu11061297 [DOI] [PMC free article] [PubMed]
194.Giannos P, Prokopidis K, Isanejad M, Wright HL. Markers of immune dysregulation in response to the ageing gut: insights from aged murine gut microbiota transplants. BMC Gastroenterol. 2022;22(1). 10.1186/s12876-022-02613-2 [DOI] [PMC free article] [PubMed]
195.Ahmadi S, Wang S, Nagpal R, Wang B, Jain S, Razazan A, et al. A human-origin probiotic cocktail ameliorates aging-related leaky gut and inflammation via modulating the microbiota/taurine/tight junction axis. JCI Insight. 2020;5(9). 10.1172/jci.insight.132055 [DOI] [PMC free article] [PubMed]
196.Song C, Zhang Y, Cheng L, Shi M, Li X, Zhang L, et al. Tea polyphenols ameliorates memory decline in aging model rats by inhibiting brain TLR4/NF-κB inflammatory signaling pathway caused by intestinal flora dysbiosis. Exp Gerontol. 2021;153. 10.1016/j.exger.2021.111476 [DOI] [PubMed]
197.Yusufu I, Ding K, Smith K, Wankhade UD, Sahay B, Patterson GT, et al. Article a tryptophan-deficient diet induces gut microbiota dysbiosis and increases systemic inflammation in aged mice. Int J Mol Sci. 2021;22(9). 10.3390/ijms22095005 [DOI] [PMC free article] [PubMed]
198.Zhu X, Huang X, Hu M, Sun R, Li J, Wang H, et al. A specific enterotype derived from gut Microbiome of older individuals enables favorable responses to immune checkpoint Blockade therapy. Cell Host Microbe. 2024;32(4):489–e5055. 10.1016/j.chom.2024.03.002 [DOI] [PubMed] [Google Scholar]
199.Singh A, Chandrasekar SV, Valappil VT, Scaria J, Ranjan A. Tumor Immunomodulation by nanoparticle and focused ultrasound alters gut Microbiome in a sexually dimorphic manner. Theranostics. 2025;15(1):216–32. 10.7150/thno.99664 [DOI] [PMC free article] [PubMed] [Google Scholar]
200.Woolbright BL, Xuan H, Ahmed I, Rajendran G, Abbott E, Dennis K, et al. Aging induces changes in cancer formation and microbial content in a murine model of bladder cancer. GeroScience. 2024;46(3):3361–75. 10.1007/s11357-024-01064-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
201.Li M, Liu JX, Ma B, Liu JY, Chen J, Jin F, et al. A Senescence-Associated secretory phenotype of bone marrow mesenchymal stem cells inhibits the viability of breast cancer cells. Stem Cell Reviews Rep. 2024;20(4):1093–105. 10.1007/s12015-024-10710-w [DOI] [PubMed] [Google Scholar]
202.Nakajima Y, Chamoto K, Oura T, Honjo T. Critical role of the CD44lowCD62Llow CD8 + T cell subset in restoring antitumor immunity in aged mice. Proc Natl Acad Sci USA. 2021;118(23). 10.1073/PNAS.2103730118 [DOI] [PMC free article] [PubMed]
203.Baldini C, Martin Romano P, Voisin AL, Danlos FX, Champiat S, Laghouati S, et al. Impact of aging on immune-related adverse events generated by anti–programmed death (ligand)PD-(L)1 therapies. Eur J Cancer. 2020;129:71–9. 10.1016/j.ejca.2020.01.013 [DOI] [PubMed] [Google Scholar]
204.Herin H, Aspeslagh S, Castanon E, Dyevre V, Marabelle A, Varga A, et al. Immunotherapy phase I trials in patients older than 70 years with advanced solid tumours. Eur J Cancer. 2018;95:68–74. 10.1016/j.ejca.2018.03.002 [DOI] [PubMed] [Google Scholar]
205.Costa AC, Santos JMO, Gil da Costa RM, Medeiros R. Impact of immune cells on the hallmarks of cancer: A literature review. Crit Rev Oncol/Hematol. 2021;168:103541. 10.1016/j.critrevonc.2021.103541 [DOI] [PubMed] [Google Scholar]
206.Wu Y, Wei J, Chen X, Qin Y, Mao R, Song J, et al. Comprehensive transcriptome profiling in elderly cancer patients reveals aging-altered immune cells and immune checkpoints. Int J Cancer. 2019;144(7):1657–63. 10.1002/ijc.31875 [DOI] [PubMed] [Google Scholar]
207.Lu W, Zhou Y, Zhao R, Liu Q, Yang W, Zhu T. The integration of multi-omics analysis and machine learning for the identification of prognostic assessment and immunotherapy efficacy through aging-associated genes in lung cancer. Aging. 2024;16(2):1860–78. 10.18632/aging.205464 [DOI] [PMC free article] [PubMed] [Google Scholar]
208.Meng X, Song W, Zhou B, Liang M, Gao Y. Prognostic and immune correlation analysis of mitochondrial autophagy and aging-related genes in lung adenocarcinoma. J Cancer Res Clin Oncol. 2023;149(18):16311–35. 10.1007/s00432-023-05390-x [DOI] [PMC free article] [PubMed] [Google Scholar]
209.Zhang W, Li Y, Lyu J, Shi F, Kong Y, Sheng C, et al. An aging-related signature predicts favorable outcome and immunogenicity in lung adenocarcinoma. Cancer Sci. 2022;113(3):891–903. 10.1111/cas.15254 [DOI] [PMC free article] [PubMed] [Google Scholar]
210.He Z, Chen M, Li Q, Luo Z, Li X. Multi-omics and tumor immune microenvironment characterization of a prognostic model based on aging-related genes in melanoma. Am J Cancer Res. 2024;14(3):1052–70. 10.62347/UZGP9704 [DOI] [PMC free article] [PubMed] [Google Scholar]
211.Liang X, Lin X, Lin Z, Lin W, Peng Z, Wei S. Genes associated with cellular senescence favor melanoma prognosis by stimulating immune responses in tumor microenvironment. Comput Biol Med. 2023;158. 10.1016/j.compbiomed.2023.106850 [DOI] [PubMed]
212.Zeng N, Guo C, Wang Y, Li L, Chen X, Gao S, et al. Characterization of Aging-Related genes to predict prognosis and evaluate the tumor immune microenvironment in malignant melanoma. J Oncol. 2022;2022. 10.1155/2022/1271378 [DOI] [PMC free article] [PubMed]
213.Safi M, Jin C, Aldanakh A, Feng P, Qin H, Alradhi M, et al. Immune checkpoint inhibitor (ICI) genes and aging in malignant melanoma patients: a clinicogenomic TCGA study. BMC Cancer. 2022;22(1):978. 10.1186/s12885-022-09860-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
214.Mu J, Gong J, Shi M, Zhang Y. Analysis and validation of aging-related genes in prognosis and immune function of glioblastoma. BMC Med Genom. 2023;16(1). 10.1186/s12920-023-01538-3 [DOI] [PMC free article] [PubMed]
215.Wu Y, Li X. Senescence gene expression in clear cell renal cell carcinoma role of tumor immune microenvironment and senescence-associated survival prediction. Med (United States). 2023;102(40):E35222. 10.1097/MD.0000000000035222 [DOI] [PMC free article] [PubMed] [Google Scholar]
216.Gang D, Jiang Y, Wang X, Zhou J, Zhang X, He X, et al. Aging-related genes related to the prognosis and the immune microenvironment of acute myeloid leukemia. Clin Transl Oncol. 2023;25(10):2991–3005. 10.1007/s12094-023-03168-8 [DOI] [PubMed] [Google Scholar]
217.Liu S, Liu Y, Ma J, Lv R, Wang F. Construction of an aging-related risk signature in high-grade serous ovarian cancer for predicting survival outcome and immunogenicity. Med (United States). 2023;102(35):E34851. 10.1097/MD.0000000000034851 [DOI] [PMC free article] [PubMed] [Google Scholar]
218.Tan L, Xiaohalati X, Liu F, Liu J, Fu H, Zhang Y, et al. Identification of aging and young subtypes for predicting colorectal cancer prognosis and immunotherapy responses. Int J Mol Sci. 2023;24(2). 10.3390/ijms24021516 [DOI] [PMC free article] [PubMed]
219.Kellers F, Fernandez A, Konukiewitz B, Schindeldecker M, Tagscherer KE, Heintz A, et al. Senescence-Associated molecules and Tumor-Immune-Interactions as prognostic biomarkers in colorectal cancer. Front Med. 2022;9. 10.3389/fmed.2022.865230 [DOI] [PMC free article] [PubMed]
220.Wang Z, Liu H, Gong Y, Cheng Y. Establishment and validation of an aging-related risk signature associated with prognosis and tumor immune microenvironment in breast cancer. Eur J Med Res. 2022;27(1). 10.1186/s40001-022-00924-4 [DOI] [PMC free article] [PubMed]
221.Yang X, Sun Y, Liu X, Jiang Z. A risk model of 10 aging-related genes for predicting survival and immune response in triple-negative breast cancer. Cancer Med. 2022;11(16):3182–93. 10.1002/cam4.4674 [DOI] [PMC free article] [PubMed] [Google Scholar]
222.Chen F, Gong X, Xia M, Yu F, Wu J, Yu C, et al. The Aging-Related prognostic signature reveals the landscape of the tumor immune microenvironment in head and neck squamous cell carcinoma. Front Oncol. 2022;12. 10.3389/fonc.2022.857994 [DOI] [PMC free article] [PubMed]
223.Yang J, Jiang Q, Liu L, Peng H, Wang Y, Li S, et al. Identification of prognostic aging-related genes associated with immunosuppression and inflammation in head and neck squamous cell carcinoma. Aging. 2020;12(24):25778–804. 10.18632/aging.104199 [DOI] [PMC free article] [PubMed] [Google Scholar]
224.Hong T, Su W, Pan Y, Tian C, Lei G. Aging-related features predict prognosis and immunotherapy efficacy in hepatocellular carcinoma. Front Immunol. 2022;13. 10.3389/fimmu.2022.951459 [DOI] [PMC free article] [PubMed]
225.Luo C, Nie H, Yu L. Identification of Aging-Related genes associated with prognostic value and immune microenvironment characteristics in diffuse large B-Cell lymphoma. Oxidative Med Cell Longev. 2022;2022. 10.1155/2022/3334522 [DOI] [PMC free article] [PubMed]
226.Xue S, Ge W, Wang K, Mao T, Zhang X, Xu H, et al. Association of aging-related genes with prognosis and immune infiltration in pancreatic adenocarcinoma. Front Cell Dev Biology. 2022;10. 10.3389/fcell.2022.942225 [DOI] [PMC free article] [PubMed]
227.Luo H, Tao C, Long X, Huang K, Zhu X. A risk signature of four aging-related genes has clinical prognostic value and is associated with a tumor immune microenvironment in glioma. Aging. 2021;13(12):16198–218. 10.18632/aging.203146 [DOI] [PMC free article] [PubMed] [Google Scholar]
228.Liu Q, Bao H, Zhang S, Song T, Li C, Sun G, et al. Identification of a cellular senescence-related-lncRNA (SRlncRNA) signature to predict the overall survival of glioma patients and the tumor immune microenvironment. Front Genet. 2023;14. 10.3389/fgene.2023.1096792 [DOI] [PMC free article] [PubMed]
229.Gao Q, Shi Y, Sun Y, Zhou S, Liu Z, Sun X, et al. Identification and verification of aging-related LncRNAs for prognosis prediction and immune microenvironment in patients with head and neck squamous carcinoma. Oncol Res. 2023;31(1):35–61. 10.32604/or.2022.028193 [DOI] [PMC free article] [PubMed] [Google Scholar]
230.Li F, Xue X. Identification and characterization of an Ageing-Associated 13-lncRNA signature that predicts prognosis and immunotherapy in hepatocellular carcinoma. J Oncol. 2023;2023. 10.1155/2023/4615297 [DOI] [PMC free article] [PubMed]
231.Huang E, Ma T, Zhou J, Ma N, Yang W, Liu C, et al. A novel senescence-associated LncRNA signature predicts the prognosis and tumor microenvironment of patients with colorectal cancer: A bioinformatics analysis. J Gastrointest Oncol. 2022;13(4):1842–63. 10.21037/jgo-22-721 [DOI] [PMC free article] [PubMed] [Google Scholar]
232.Xu C, Li F, Liu Z, Yan C, Xiao J. A novel cell senescence-related IncRNA survival model associated with the tumor immune environment in colorectal cancer. Front Immunol. 2022;13. 10.3389/fimmu.2022.1019764 [DOI] [PMC free article] [PubMed]
233.Zhou Z, Wei J, Kuang L, Zhang K, Liu Y, He Z, et al. Characterization of aging cancer-associated fibroblasts draws implications in prognosis and immunotherapy response in low-grade gliomas. Front Genet. 2022;13. 10.3389/fgene.2022.897083 [DOI] [PMC free article] [PubMed]
234.Qu C, Wu Q, Lu J, Li F. Prognostic value and potential mechanism of cellular senescence and tumor microenvironment in hepatocellular carcinoma: insights from bulk transcriptomics and single-cell sequencing analysis. Environ Toxicol. 2024;39(5):2512–27. 10.1002/tox.24121 [DOI] [PubMed] [Google Scholar]
235.Flood PM, Urban JL, Kripke ML, Schreiber H. Loss of tumor-specific and idiotype-specific immunity with age. J Exp Med. 1981;154(2):275–90. 10.1084/jem.154.2.275 [DOI] [PMC free article] [PubMed] [Google Scholar]
236.Chen HC, Eling N, Martinez-Jimenez CP, O’Brien LM, Carbonaro V, Marioni JC et al. IL‐7‐dependent compositional changes within the γδ T cell pool in lymph nodes during ageing lead to an unbalanced anti‐tumour response. EMBO reports. 2019;20(8):e47379. 10.15252/embr.201847379 [DOI] [PMC free article] [PubMed]
237.Zhu LJ, Hou PF, Wang L, Zhang GB, Xie Y, Pan XD, et al. Changes in CD4 + CD25 + foxp3 + regulatory T cells in relation to aging and lung tumor incidence. Int J Gerontol. 2012;6(3):187–91. 10.1016/j.ijge.2012.01.013 [Google Scholar]
238.Norian LA, Allen PM. No intrinsic deficiencies in CD8 + T cell-mediated antitumor immunity with aging. J Immunol. 2004;173(2):835–44. 10.4049/jimmunol.173.2.835 [DOI] [PubMed] [Google Scholar]
239.Win S, Uenaka A, Nakayama E. Immune responses against allogeneic and syngeneic tumors in aged C57BL/6 mice. Microbiol Immunol. 2002;46(7):513–9. 10.1111/j.1348-0421.2002.tb02728.x [DOI] [PubMed] [Google Scholar]
240.Jackaman C, Gardner JK, Tomay F, Spowart J, Crabb H, Dye DE, et al. CD8 + cytotoxic T cell responses to dominant tumor-associated antigens are profoundly weakened by aging yet subdominant responses retain functionality and expand in response to chemotherapy. OncoImmunology. 2019;8(4):e1564452. 10.1080/2162402X.2018.1564452 [DOI] [PMC free article] [PubMed] [Google Scholar]
241.Lin S, Ma L, Mo J, Zhao R, Li J, Yu M, et al. Immune cell senescence and exhaustion promote the occurrence of liver metastasis in colorectal cancer by regulating epithelial-mesenchymal transition. Aging. 2024;16(9):7704–32. 10.18632/aging.205778 [DOI] [PMC free article] [PubMed] [Google Scholar]
242.Vaena S, Chakraborty P, Lee HG, Janneh AH, Kassir MF, Beeson G et al. Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response. Cell Reports. 2021;35(5). 10.1016/j.celrep.2021.109076 [DOI] [PMC free article] [PubMed]
243.Grolleau-Julius A, Harning EK, Abernathy LM, Yung RL. Impaired dendritic cell function in aging leads to defective antitumor immunity. Cancer Res. 2008;68(15):6341–9. 10.1158/0008-5472.Can-07-5769 [DOI] [PMC free article] [PubMed] [Google Scholar]
244.Sharma S, Lucia Dominguez A, Lustgarten J. Aging affect the anti-tumor potential of dendritic cell vaccination, but it can be overcome by co-stimulation with anti-OX40 or anti-4-1BB. Exp Gerontol. 2006;41(1):78–84. 10.1016/j.exger.2005.10.002 [DOI] [PubMed] [Google Scholar]
245.Khare V, Sodhi A, Singh SM. Age-dependent alterations in the tumoricidal functions of tumor- associated macrophages. Tumor Biology. 1999;20(1):30–43. 10.1159/000056519 [DOI] [PubMed] [Google Scholar]
246.Wallace PK, Eisenstein TK, Meissler JJ Jr, Morahan PS. Decreases in macrophage mediated antitumor activity with aging. Mech Ageing Dev. 1995;77(3):169–84. 10.1016/0047-6374(94)01524-P [DOI] [PubMed] [Google Scholar]
247.Dussault I, Miller SC. Decline in natural killer cell-mediated immunosurveillance in aging mice - a consequence of reduced cell production and tumor binding capacity. Mech Ageing Dev. 1994;75(2):115–29. 10.1016/0047-6374(94)90080-9 [DOI] [PubMed] [Google Scholar]
248.Cameron IL. Cell proliferation and renewal in aging mice. J Gerontol. 1972;27(2):162–72. 10.1093/geronj/27.2.162 [DOI] [PubMed] [Google Scholar]
249.Itzhaki O, Kaptzan T, Skutelsky E, Sinai J, Michowitz M, Siegal A, et al. Age-adjusted antitumoral therapy based on the demonstration of increased apoptosis as a mechanism underlying the reduced malignancy of tumors in the aged. Biochim Et Biophys Acta - Mol Basis Disease. 2004;1688(2):145–59. 10.1016/j.bbadis.2003.11.009 [DOI] [PubMed] [Google Scholar]
250.Kreisle RA, Stebler BA, Ershler WB. Effect of host age on tumor-associated angiogenesis in mice. J Natl Cancer Inst. 1990;82(1):44–7. 10.1093/jnci/82.1.44 [DOI] [PubMed] [Google Scholar]
251.Kakuda T, Suzuki J, Matsuoka Y, Kikugawa T, Saika T, Yamashita M. Senescent CD8 + T cells acquire NK cell-like innate functions to promote antitumor immunity. Cancer Sci. 2023;114(7):2810–20. 10.1111/cas.15824 [DOI] [PMC free article] [PubMed] [Google Scholar]
252.Leibovici J, Itzhaki O, Kaptzan T, Skutelsky E, Sinai J, Michowitz M, et al. Designing ageing conditions in tumour microenvironment-A new possible modality for cancer treatment. Mech Ageing Dev. 2009;130(1–2):76–85. 10.1016/j.mad.2008.03.004 [DOI] [PubMed] [Google Scholar]
253.Shireman JM, Gonugunta N, Zhao L, Pattnaik A, Distler E, Her S, et al. GM-CSF and IL-7 fusion cytokine engineered tumor vaccine generates long-term Th-17 memory cells and increases overall survival in aged syngeneic mouse models of glioblastoma. Aging Cell. 2023;22(7):e13864. 10.1111/acel.13864 [DOI] [PMC free article] [PubMed] [Google Scholar]
254.Falvo P, Gruener S, Orecchioni S, Pisati F, Talarico G, Mitola G, et al. Age-dependent differences in breast tumor microenvironment: challenges and opportunities for efficacy studies in preclinical models. Cell Death Differ. 2025;32(6):1000–13. 10.1038/s41418-025-01447-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
255.Huang Y, Yang X, Meng Y, Shao C, Liao J, Li F, et al. The hepatic senescence-associated secretory phenotype promotes hepatocarcinogenesis through Bcl3-dependent activation of macrophages. Cell Bioscience. 2021;11(1):173. 10.1186/s13578-021-00683-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
256.Haston S, Gonzalez-Gualda E, Morsli S, Ge J, Reen V, Calderwood A, et al. Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer. Cancer Cell. 2023;41(7):1242–e606. 10.1016/j.ccell.2023.05.004 [DOI] [PubMed] [Google Scholar]
257.Wu S, Li X, Hong F, Chen Q, Yu Y, Guo S, et al. Integrative analysis of single-cell transcriptomics reveals age-associated immune landscape of glioblastoma. Front Immunol. 2023;14. 10.3389/fimmu.2023.1028775 [DOI] [PMC free article] [PubMed]
258.Liu X, Hoft DF, Peng G. Senescent T cells within suppressive tumor microenvironments: emerging target for tumor immunotherapy. J Clin Invest. 2020;130(3):1073–83. 10.1172/jci133679 [DOI] [PMC free article] [PubMed] [Google Scholar]
259.Alspach E, Flanagan KC, Luo X, Ruhland MK, Huang H, Pazolli E, et al. p38MAPK plays a crucial role in stromal-mediated tumorigenesis. Cancer Discov. 2014;4(6):716–29. 10.1158/2159-8290.Cd-13-0743 [DOI] [PMC free article] [PubMed] [Google Scholar]
260.Li X, Li C, Zhang W, Wang Y, Qian P, Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Therapy. 2023;8(1):239. 10.1038/s41392-023-01502-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
261.Chibaya L, Snyder J, Ruscetti M. Senescence and the tumor-immune landscape: implications for cancer immunotherapy. Semin Cancer Biol. 2022;86(Pt 3):827–45. 10.1016/j.semcancer.2022.02.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
262.Ly LV, Baghat A, Versluis M, Jordanova ES, Luyten GP, van Rooijen N, et al. In aged mice, outgrowth of intraocular melanoma depends on proangiogenic M2-type macrophages. J Immunol. 2010;185(6):3481–8. 10.4049/jimmunol.0903479 [DOI] [PubMed] [Google Scholar]
263.Mittmann LA, Haring F, Schaubächer JB, Hennel R, Smiljanov B, Zuchtriegel G, et al. Uncoupled biological and chronological aging of neutrophils in cancer promotes tumor progression. J Immunother Cancer. 2021;9(12). 10.1136/jitc-2021-003495 [DOI] [PMC free article] [PubMed]
264.Balliet RM, Capparelli C, Guido C, Pestell TG, Martinez-Outschoorn UE, Lin Z, et al. Mitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth. Cell Cycle. 2011;10(23):4065–73. 10.4161/cc.10.23.18254 [DOI] [PMC free article] [PubMed] [Google Scholar]
265.Liu Y, Pan J, Pan X, Wu L, Bian J, Lin Z, et al. Klotho-mediated targeting of CCL2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments. Mol Oncol. 2019;13(11):2460–75. 10.1002/1878-0261.12577 [DOI] [PMC free article] [PubMed] [Google Scholar]
266.Zabransky DJ, Chhabra Y, Fane ME, Kartalia E, Leatherman JM, Hüser L, et al. Fibroblasts in the aged pancreas drive pancreatic cancer progression. Cancer Res. 2024;84(8):1221–36. 10.1158/0008-5472.Can-24-0086 [DOI] [PMC free article] [PubMed] [Google Scholar]
267.Li Y, Tazawa H, Nagai Y, Fujita S, Okura T, Shoji R, et al. Senescent fibroblasts potentiate peritoneal metastasis of Diffuse-type gastric cancer cells via IL-8–mediated crosstalk. Anticancer Res. 2024;44(6):2497–509. 10.21873/anticanres.17056 [DOI] [PubMed] [Google Scholar]
268.Fane ME, Chhabra Y, Alicea GM, Maranto DA, Douglass SM, Webster MR, et al. Stromal changes in the aged lung induce an emergence from melanoma dormancy. Nature. 2022;606(7913):396–405. 10.1038/s41586-022-04774-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
269.Kaur A, Webster MR, Marchbank K, Behera R, Ndoye A, Kugel CH, et al. SFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature. 2016;532(7598):250–4. 10.1038/nature17392 [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
270.Li C, Teixeira AF, Zhu HJ, Ten Dijke P. Cancer associated-fibroblast-derived exosomes in cancer progression. Mol Cancer. 2021;20(1):154. 10.1186/s12943-021-01463-y [DOI] [PMC free article] [PubMed] [Google Scholar]
271.Guo Y, Ayers JL, Carter KT, Wang T, Maden SK, Edmond D, et al. Senescence-associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15. Aging Cell. 2019;18(6):e13013. 10.1111/acel.13013 [DOI] [PMC free article] [PubMed] [Google Scholar]
272.Yamao T, Yamashita YI, Yamamura K, Nakao Y, Tsukamoto M, Nakagawa S, et al. Cellular senescence, represented by expression of Caveolin-1, in cancer-Associated fibroblasts promotes tumor invasion in pancreatic cancer. Ann Surg Oncol. 2019;26(5):1552–9. 10.1245/s10434-019-07266-2 [DOI] [PubMed] [Google Scholar]
273.Ren C, Cheng X, Lu B, Yang G. Activation of interleukin-6/signal transducer and activator of transcription 3 by human papillomavirus early proteins 6 induces fibroblast senescence to promote cervical tumourigenesis through autocrine and paracrine pathways in tumour microenvironment. Eur J Cancer. 2013;49(18):3889–99. 10.1016/j.ejca.2013.07.140 [DOI] [PubMed] [Google Scholar]
274.Higashiguchi M, Murakami H, Akita H, Kobayashi S, Takahama S, Iwagami Y, et al. The impact of cellular senescence and senescence–associated secretory phenotype in cancer–associated fibroblasts on the malignancy of pancreatic cancer. Oncol Rep. 2023;49(5). 10.3892/or.2023.8535 [DOI] [PMC free article] [PubMed]
275.Giese MA, Hind LE, Huttenlocher A. Neutrophil plasticity in the tumor microenvironment. Blood. 2019;133(20):2159–67. 10.1182/blood-2018-11-844548 [DOI] [PMC free article] [PubMed] [Google Scholar]
276.Göçer P, Gürer ÜS, Erten N, Palandüz Ş, Rayaman E, Akarsu B, et al. Comparison of polymorphonuclear leukocyte functions in elderly patients and healthy young volunteers. Med Principles Pract. 2008;14(6):382–5. 10.1159/000088109 [DOI] [PubMed] [Google Scholar]
277.Yang C, Wang Z, Li L, Zhang Z, Jin X, Wu P, et al. Aged neutrophils form mitochondria-dependent vital NETs to promote breast cancer lung metastasis. J Immunother Cancer. 2021;9(10). 10.1136/jitc-2021-002875 [DOI] [PMC free article] [PubMed]
278.Schott AF, Goldstein LJ, Cristofanilli M, Ruffini PA, McCanna S, Reuben JM, et al. Phase Ib pilot study to evaluate reparixin in combination with weekly Paclitaxel in patients with HER-2-Negative metastatic breast cancer. Clin Cancer Res. 2017;23(18):5358–65. 10.1158/1078-0432.Ccr-16-2748 [DOI] [PMC free article] [PubMed] [Google Scholar]
279.Bodac A, Mayet A, Rana S, Pascual J, Bowler AD, Roh V, et al. Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth. EMBO Mol Med. 2024;16(1):158–84. 10.1038/s44321-023-00013-x [DOI] [PMC free article] [PubMed] [Google Scholar]
280.Debrincat MA, Pleines I, Lebois M, Lane RM, Holmes ML, Corbin J, et al. BCL-2 is dispensable for thrombopoiesis and platelet survival. Cell Death Dis. 2015;6(4):e1721. 10.1038/cddis.2015.97 [DOI] [PMC free article] [PubMed] [Google Scholar]
281.Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR, Di Gialleonardo V, et al. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood. 2009;113(15):3503–11. 10.1182/blood-2008-08-173914 [DOI] [PubMed] [Google Scholar]
282.Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nat Rev Immunol. 2001;1(1):41–9. 10.1038/35095564 [DOI] [PubMed] [Google Scholar]
283.Tarazona R, Sanchez-Correa B, Casas-Avilés I, Campos C, Pera A, Morgado S, et al. Immunosenescence: limitations of natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother. 2017;66(2):233–45. 10.1007/s00262-016-1882-x [DOI] [PMC free article] [PubMed] [Google Scholar]
284.Rodrigues-Santos P, López-Sejas N, Almeida JS, Ruzičková L, Couceiro P, Alves V, et al. Effect of age on NK cell compartment in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Front Immunol. 2018;9:2587. 10.3389/fimmu.2018.02587 [DOI] [PMC free article] [PubMed] [Google Scholar]
285.Zirbes A, Joseph J, Lopez JC, Sayaman RW, Basam M, Seewaldt VL, et al. Changes in immune cell types with age in breast are consistent with a decline in immune surveillance and increased immunosuppression. J Mammary Gland Biol Neoplasia. 2021;26(3):247–61. 10.1007/s10911-021-09495-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
286.Zhu Y, Fu D, Shi Q, Shi Z, Dong L, Yi H, et al. Oncogenic mutations and tumor microenvironment alterations of older patients with diffuse large B-Cell lymphoma. Front Immunol. 2022;13. 10.3389/fimmu.2022.842439 [DOI] [PMC free article] [PubMed]
287.Li Y, Zhao Y, Gao Y, Li Y, Liu M, Xu N, et al. Age-related macrophage alterations are associated with carcinogenesis of colorectal cancer. Carcinogenesis. 2022;43(11):1039–49. 10.1093/carcin/bgac088 [DOI] [PubMed] [Google Scholar]
288.Prieto LI, Sturmlechner I, Graves SI, Zhang C, Goplen NP, Yi ES, et al. Senescent alveolar macrophages promote early-stage lung tumorigenesis. Cancer Cell. 2023;41(7):1261. 75.e6. [DOI] [PMC free article] [PubMed] [Google Scholar]
289.Khare V, Sodhi A, Singh SM. Age-Dependent alterations in the tumoricidal functions of Tumor-Associated macrophages. Tumor Biology. 1997;20(1):30–43. 10.1159/000056519 [DOI] [PubMed] [Google Scholar]
290.Duong L, Radley-Crabb HG, Gardner JK, Tomay F, Dye DE, Grounds MD, et al. Macrophage depletion in elderly mice improves response to tumor immunotherapy, increases Anti-tumor T cell activity and reduces Treatment-Induced cachexia. Front Genet. 2018;9. 10.3389/fgene.2018.00526 [DOI] [PMC free article] [PubMed]
291.Goh J, Ladiges WC. Exercise enhances wound healing and prevents cancer progression during aging by targeting macrophage Polarity. Mech Ageing Dev. 2014;139:41–8. 10.1016/j.mad.2014.06.004 [DOI] [PubMed] [Google Scholar]
292.Liu X, Si F, Bagley D, Ma F, Zhang Y, Tao Y, et al. Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy. J Immunother Cancer. 2022;10(10):e005020. 10.1136/jitc-2022-005020 [DOI] [PMC free article] [PubMed] [Google Scholar]
293.Zhang J, He T, Xue L, Guo H. Senescent T cells: a potential biomarker and target for cancer therapy. EBioMedicine. 2021;68:103409. 10.1016/j.ebiom.2021.103409 [DOI] [PMC free article] [PubMed] [Google Scholar]
294.Liu X, Si F, Bagley D, Ma F, Zhang Y, Tao Y, et al. Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy. J Immunother Cancer. 2022;10(10). 10.1136/jitc-2022-005020 [DOI] [PMC free article] [PubMed]
295.Li L, Liu X, Sanders KL, Edwards JL, Ye J, Si F, et al. TLR8-Mediated metabolic control of human Treg function: A mechanistic target for cancer immunotherapy. Cell Metab. 2019;29(1):103–e235. 10.1016/j.cmet.2018.09.020 [DOI] [PMC free article] [PubMed] [Google Scholar]
296.Liu X, Hartman CL, Li L, Albert CJ, Si F, Gao A, et al. Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy. Sci Transl Med. 2021;13(587). 10.1126/scitranslmed.aaz6314 [DOI] [PMC free article] [PubMed]
297.Bhaskaran N, Jayaraman S, Quigley C, Mamileti P, Ghannoum M, Weinberg A, et al. The role of Dectin-1 signaling in altering tumor immune microenvironment in the context of aging. Front Oncol. 2021;11. 10.3389/fonc.2021.669066 [DOI] [PMC free article] [PubMed]
298.Chen ACY, Jaiswal S, Martinez D, Yerinde C, Ji K, Miranda V, et al. The aged tumor microenvironment limits T cell control of cancer. Nat Immunol. 2024;25(6):1033–45. 10.1038/s41590-024-01828-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
299.Hui K, Dong C, Hu C, Li J, Yan D, Jiang X. VEGFR affects miR-3200-3p-mediated regulatory T cell senescence in tumour-derived exosomes in non-small cell lung cancer. Funct Integr Genomics. 2024;24(2):31. 10.1007/s10142-024-01305-2 [DOI] [PubMed] [Google Scholar]
300.Gao A, Liu X, Lin W, Wang J, Wang S, Si F, et al. Tumor-derived ILT4 induces T cell senescence and suppresses tumor immunity. J Immunother Cancer. 2021;9(3). 10.1136/jitc-2020-001536 [DOI] [PMC free article] [PubMed]
301.Romagnani A, Rottoli E, Mazza EMC, Rezzonico-Jost T, De Ponte Conti B, Proietti M, et al. P2X7 Receptor Activity Limits Accumulation of T Cells within Tumors. Cancer Res. 2020;80(18):3906–19. 10.1158/0008-5472.Can-19-3807 [DOI] [PMC free article] [PubMed] [Google Scholar]
302.Adinolfi E, Capece M, Franceschini A, Falzoni S, Giuliani AL, Rotondo A, et al. Accelerated tumor progression in mice lacking the ATP receptor P2X7. Cancer Res. 2015;75(4):635–44. 10.1158/0008-5472.Can-14-1259 [DOI] [PubMed] [Google Scholar]
303.Li XY, Moesta AK, Xiao C, Nakamura K, Casey M, Zhang H, et al. Targeting CD39 in cancer reveals an extracellular ATP- and Inflammasome-Driven tumor immunity. Cancer Discov. 2019;9(12):1754–73. 10.1158/2159-8290.Cd-19-0541 [DOI] [PMC free article] [PubMed] [Google Scholar]
304.Lee-Chang C, Bodogai M, Moritoh K, Chen X, Wersto R, Sen R, et al. Aging converts innate B1a cells into potent CD8 + T cell inducers. J Immunol. 2016;196(8):3385–97. 10.4049/jimmunol.1502034 [DOI] [PMC free article] [PubMed] [Google Scholar]
305.Lee-Chang C, Bodogai M, Moritoh K, Olkhanud PB, Chan AC, Croft M, et al. Accumulation of 4-1BBL + B cells in the elderly induces the generation of granzyme-B + CD8 + T cells with potential antitumor activity. Blood. 2014;124(9):1450–9. 10.1182/blood-2014-03-563940 [DOI] [PMC free article] [PubMed] [Google Scholar]
306.Tomihara K, Shin T, Hurez VJ, Yagita H, Pardoll DM, Zhang B, et al. Aging-associated B7-DC + B cells enhance anti-tumor immunity via Th1 and Th17 induction. Aging Cell. 2012;11(1):128–38. 10.1111/j.1474-9726.2011.00764.x [DOI] [PMC free article] [PubMed] [Google Scholar]
307.Loughran EA, Leonard AK, Hilliard TS, Phan RC, Yemc MG, Harper E, et al. Aging increases susceptibility to ovarian cancer metastasis in murine allograft models and alters immune composition of peritoneal adipose tissue. Neoplasia (United States). 2018;20(6):621–31. 10.1016/j.neo.2018.03.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
308.Remsing Rix LL, Sumi NJ, Hu Q, Desai B, Bryant AT, Li X, et al. IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells. Sci Signal. 2022;15(747):eabj5879. 10.1126/scisignal.abj5879 [DOI] [PMC free article] [PubMed] [Google Scholar]
309.Capparelli C, Whitaker-Menezes D, Guido C, Balliet R, Pestell TG, Howell A, et al. CTGF drives autophagy, Glycolysis and senescence in cancer-associated fibroblasts via HIF1 activation, metabolically promoting tumor growth. Cell Cycle. 2012;11(12):2272–84. 10.4161/cc.20717 [DOI] [PMC free article] [PubMed] [Google Scholar]
310.Kim E, Rebecca V, Fedorenko IV, Messina JL, Mathew R, Maria-Engler SS, et al. Senescent fibroblasts in melanoma initiation and progression: an integrated theoretical, experimental, and clinical approach. Cancer Res. 2013;73(23):6874–85. 10.1158/0008-5472.Can-13-1720 [DOI] [PMC free article] [PubMed] [Google Scholar]
311.Alicea GM, Rebecca VW, Goldman AR, Fane ME, Douglass SM, Behera R, et al. Changes in aged fibroblast lipid metabolism induce Age-Dependent melanoma cell resistance to targeted therapy via the fatty acid transporter FATP2. Cancer Discov. 2020;10(9):1282–95. 10.1158/2159-8290.Cd-20-0329 [DOI] [PMC free article] [PubMed] [Google Scholar]
312.Menicacci B, Laurenzana A, Chillà A, Margheri F, Peppicelli S, Tanganelli E, et al. Chronic Resveratrol treatment inhibits MRC5 fibroblast SASP-Related protumoral effects on melanoma cells. J Gerontol Biol Sci Med Sci. 2017;72(9):1187–95. 10.1093/gerona/glw336 [DOI] [PubMed] [Google Scholar]
313.Jin P, Li X, Xia Y, Li H, Li X, Yang ZY, et al. Bepotastine sensitizes ovarian cancer to PARP inhibitors through suppressing NF-κB-Triggered SASP in cancer-Associated fibroblasts. Mol Cancer Ther. 2023;22(4):447–58. 10.1158/1535-7163.Mct-22-0396 [DOI] [PubMed] [Google Scholar]
314.Lugo R, Gabasa M, Andriani F, Puig M, Facchinetti F, Ramírez J, et al. Heterotypic paracrine signaling drives fibroblast senescence and tumor progression of large cell carcinoma of the lung. Oncotarget. 2016;7(50):82324–37. 10.18632/oncotarget.10327 [DOI] [PMC free article] [PubMed] [Google Scholar]
315.Yakobson A, Abu Jama A, Abu Saleh O, Michlin R, Shalata W. PD-1 inhibitors in elderly and immunocompromised patients with advanced or metastatic cutaneous squamous cell carcinoma. Cancers. 2023;15(16). 10.3390/cancers15164041 [DOI] [PMC free article] [PubMed]
316.Kubo T, Ichihara E, Harada D, Inoue K, Fujiwara K, Hosokawa S, et al. Efficacy of immune checkpoint inhibitor monotherapy in elderly patients with non-small-cell lung cancer. Respiratory Invest. 2023;61(5):643–50. 10.1016/j.resinv.2023.06.005 [DOI] [PubMed] [Google Scholar]
317.Kalariya N, Ferreri C, Dillard C, Hawkins M, Manasanch E, Lee H, et al. CT-511 clinical characteristics and response outcomes in older multiple myeloma patients who received Idecabtagene vicleucel: A single center study. Clin Lymphoma Myeloma Leuk. 2022;22:S446. 10.1016/S2152-2650(22)01670-6 [Google Scholar]
318.Sattar J, Kartolo A, Hopman WM, Lakoff JM, Baetz T. The efficacy and toxicity of immune checkpoint inhibitors in a real-world older patient population. J Geriatric Oncol. 2019;10(3):411–4. 10.1016/j.jgo.2018.07.015 [DOI] [PubMed] [Google Scholar]
319.Ajili F, Darouiche A, Chebil M, Boubaker S. The impact of age and clinical factors in non-muscle-invasive bladder cancer treated with Bacillus calmette Guerin therapy. Ultrastruct Pathol. 2013;37(3):191–5. 10.3109/01913123.2013.770110 [DOI] [PubMed] [Google Scholar]
320.Nemoto Y, Ishihara H, Nakamura K, Tachibana H, Fukuda H, Yoshida K, et al. Efficacy and safety of immune checkpoint inhibitors in elderly patients with metastatic renal cell carcinoma. Int Urol Nephrol. 2022;54(1):47–54. 10.1007/s11255-021-03042-y [DOI] [PubMed] [Google Scholar]
321.Zhou H, Cai LL, Lin YF, Ma JJ. Toxicity profile of camrelizumab-based immunotherapy in older adults with advanced cancer. Sci Rep. 2024;14(1):18992. 10.1038/s41598-024-69944-w [DOI] [PMC free article] [PubMed] [Google Scholar]
322.Fa’ak F, Buni M, Falohun A, Lu H, Song J, Johnson DH, et al. Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events. J Immunother Cancer. 2023;11(6). 10.1136/jitc-2023-006814 [DOI] [PMC free article] [PubMed]
323.Wang N, Zheng L, Li M, Hou X, Zhang B, Chen J, et al. Clinical efficacy and safety of individualized pembrolizumab administration based on Pharmacokinetic in advanced non-small cell lung cancer: A prospective exploratory clinical trial. Lung Cancer. 2023;178:183–90. 10.1016/j.lungcan.2023.02.009 [DOI] [PubMed] [Google Scholar]
324.Schulz GB, Rodler S, Szabados B, Graser A, Buchner A, Stief C, et al. Safety, efficacy and prognostic impact of immune checkpoint inhibitors in older patients with genitourinary cancers. J Geriatric Oncol. 2020;11(7):1061–6. 10.1016/j.jgo.2020.06.012 [DOI] [PubMed] [Google Scholar]
325.Paderi A, Fancelli S, Caliman E, Pillozzi S, Gambale E, Mela MM, et al. Safety of immune checkpoint inhibitors in elderly patients: an observational study. Curr Oncol. 2021;28(5):3259–67. 10.3390/curroncol28050283 [DOI] [PMC free article] [PubMed] [Google Scholar]
326.Joudi FN, Smith BJ, O’Donnell MA, Konety BR. The impact of age on the response of patients with superficial bladder cancer to intravesical immunotherapy. J Urol. 2006;175(5):1634–40. 10.1016/S0022-5347(05)00973-0 [DOI] [PubMed] [Google Scholar]
327.Huff WX, Bam M, Shireman JM, Kwon JH, Song L, Newman S, et al. Aging- and Tumor-Mediated increase in CD8 + CD28 – T cells might impose a strong barrier to success of immunotherapy in glioblastoma. ImmunoHorizons. 2021;5(6):395–409. 10.4049/immunohorizons.2100008 [DOI] [PMC free article] [PubMed] [Google Scholar]
328.Hou J, Xie S, Gao J, Jiang T, Zhu E, Yang X, et al. NK cell transfer overcomes resistance to PD-(L)1 therapy in aged mice. Experimental Hematol Oncol. 2024;13(1):48. 10.1186/s40164-024-00511-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
329.Dunn PL, North RJ. Effect of advanced aging on ability of mice to cause regression of an Immunogenic lymphoma in response to immunotherapy based on depletion of suppressor T cells. Cancer Immunol Immunotherapy. 1991;33(6):421–3. 10.1007/BF01741605 [DOI] [PMC free article] [PubMed] [Google Scholar]
330.Dunn PL, North RJ. Effect of advanced ageing on the ability of mice to cause tumour regression in response to immunotherapy. Immunology. 1991;74(2):355–9. [PMC free article] [PubMed] [Google Scholar]
331.Sitnikova SI, Walker JA, Prickett LB, Morrow M, Valge-Archer VE, Robinson MJ, et al. Age-induced changes in anti-tumor immunity alter the tumor immune infiltrate and impact response to immuno-oncology treatments. Front Immunol. 2023;14. 10.3389/fimmu.2023.1258291 [DOI] [PMC free article] [PubMed]
332.Dominguez AL, Lustgarten J. Implications of aging and Self-Tolerance on the generation of immune and antitumor immune responses. Cancer Res. 2008;68(13):5423–31. 10.1158/0008-5472.Can-07-6436 [DOI] [PubMed] [Google Scholar]
333.Ishitobi K, Kotani H, Iida Y, Taniura T, Notsu Y, Tajima Y, et al. A modulatory effect of L-arginine supplementation on anticancer effects of chemoimmunotherapy in colon cancer-bearing aged mice. Int Immunopharmacol. 2022;113. 10.1016/j.intimp.2022.109423 [DOI] [PubMed]
334.Li X, Li Y, Dong L, Chang Y, Zhang X, Wang C, et al. Decitabine priming increases anti-PD-1 antitumor efficacy by promoting CD8 + progenitor exhausted T cell expansion in tumor models. J Clin Invest. 2023;133(7). 10.1172/jci165673 [DOI] [PMC free article] [PubMed]
335.Zhang P, Du Y, Bai H, Wang Z, Duan J, Wang X, et al. Optimized dose selective HDAC inhibitor tucidinostat overcomes anti-PD-L1 antibody resistance in experimental solid tumors. BMC Med. 2022;20(1):435. 10.1186/s12916-022-02598-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
336.Zambuzi FA, Cardoso-Silva PM, Castro RC, Fontanari C, Emery FDS, Frantz FG. Decitabine promotes modulation in phenotype and function of monocytes and macrophages that drive immune response regulation. Cells. 2021;10(4). 10.3390/cells10040868 [DOI] [PMC free article] [PubMed]
337.Zhang H, Pang Y, Yi L, Wang X, Wei P, Wang H, et al. Epigenetic regulators combined with tumour immunotherapy: current status and perspectives. Clin Epigenetics. 2025;17(1):51. 10.1186/s13148-025-01856-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
338.Bouchlaka MN, Sckisel GD, Chen M, Mirsoian A, Zamora AE, Maverakis E, et al. Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy. J Exp Med. 2013;210(11):2223–37. 10.1084/jem.20131219 [DOI] [PMC free article] [PubMed] [Google Scholar]
339.Garcia MG, Deng Y, Murray C, Reyes RM, Padron A, Bai H, et al. Immune checkpoint expression and relationships to anti-PD-L1 immune checkpoint Blockade cancer immunotherapy efficacy in aged versus young mice. Aging Cancer. 2022;3(1):68–83. 10.1002/aac2.12045 [DOI] [PMC free article] [PubMed] [Google Scholar]
340.Prospective. Single-arm Phase II Clinical Study of Single-drug Chemotherapy Plus Immunotherapy in Metastatic Non-small Cell Lung Cancer Elderly Patients 2023. Available from: https://clinicaltrials.gov/study/NCT06032052. Accessed.
341.Phase III. Randomized Trial of Atezolizumab in Elderly Patients With Advanced Non-Small-Cell Lung Cancer and Receiving Monthly Carboplatin With Weekly Paclitaxel Chemotherapy 2019. Available from: https://clinicaltrials.gov/study/NCT03977194. Accessed.
342.Phase 2 Study to Evaluate Reduced Dose Chemotherapy in. Combination With Anti-PD-1 Therapy as First Line Treatment in Vulnerable or Older Adults (Vulnerable or Age ≥ 70) With Advanced PD-L1 TPS < 50% Non-small Cell Lung Cancer 2024. Available from: https://clinicaltrials.gov/study/NCT06731413. Accessed.
343.A Prospective Study of Comprehensive Geriatric. Assessment (CGA) in Non-Small Cell Lung Cancer Patients (NSCLC) Undergoing Treatment With Immune Checkpoint Inhibitors 2022. Available from: https://clinicaltrials.gov/study/NCT05230888. Accessed.
344.A Randomized Phase. 2 Study Comparing Immunotherapy With Chemotherapy in the Treatment of Elderly Patients With Advanced NSCLC (MILES-5) 2019. Available from: https://clinicaltrials.gov/study/NCT03975114. Accessed.
345.Toripalimab After Radiotherapy Alone in Elderly Esophageal Squamous Cell Carcinoma. A Prospective Phase II Clinical Trial 2023. Available from: https://clinicaltrials.gov/study/NCT05791136. Accessed.
346.Efficacy and Safety of Toripalimab After Concurrent. Chemoradiotherapy in Elderly Patients With Esophageal Squamous Cell Carcinoma: a Multicenter, Randomized, Phase II Trial (EC-CRT-007) 2023. Available from: https://clinicaltrials.gov/study/NCT06187597. Accessed.
347.Neoadjuvant PD-1, Blockade (Toripalimab) Monotherapy for Elderly Patients With Locally Advanced Resectable Esophageal Squamous Cell Carcinoma, editors. a Phase II Trial 2024. Available from: https://clinicaltrials.gov/study/NCT06385730. Accessed.
348.Prospective Single-arm. Phase II Study of Nab-paclitaxel Plus Carboplatin in Combination With Sintilimab for Neoadjuvant Therapy in Elderly, Locally Advanced, Resectable Esophageal Squamous Cell Carcinoma 2024. Available from: https://clinicaltrials.gov/study/NCT06403878. Accessed.
349.Tislelizumab Combined With Concurrent Chemoradiation Versus Concurrent Chemoradiation for Older Patients With Inoperable Locally. Advanced Esophageal Squamous Cell Carcinoma: a Randomized, Parallel-controlled, Multicenter Phase II Clinical Study 2023. Available from: https://clinicaltrials.gov/study/NCT06061146. Accessed.
350.Acalabrutinib. and Rituximab in Elderly Patients With Untreated Mantle Cell Lymphoma 2021. Available from: https://clinicaltrials.gov/study/NCT05214183. Accessed.
351.A Multicenter Randomized Open Label Phase II Study. Evaluating the Efficacy and the Tolerance of Immunochemotherapy and of Sequential Hypofractionated Radiotherapy in Unfit or Elderly Patients with Unresectable Stage III Non Small Cell Lung Cancer 2024. Available from: https://clinicaltrials.gov/study/NCT06656598. Accessed.
352.Randomized A. Open-label, Clinical Trial to Compare the Safety and Efficacy of Hypomemylating Agents Monotherapy and Combination With eDC Therapy for Elderly Patients With Myelodysplastic Syndrome 2021. Available from: https://clinicaltrials.gov/study/NCT04999943. Accessed.
353.Bailén R, Iacoboni G, Delgado J, López-Corral L, Hernani-Morales R, Ortiz-Maldonado V, et al. Anti-CD19 CAR-T cell therapy in elderly patients: multicentric Real-World experience from GETH-TC/GELTAMO. Transpl Cell Ther. 2024;30(10):988. 10.1016/j.jtct.2024.06.022 [DOI] [PubMed] [Google Scholar]
354.Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel CAR T-Cell therapy in refractory large B-Cell lymphoma. N Engl J Med. 2017;377(26):2531–44. 10.1056/NEJMoa1707447 [DOI] [PMC free article] [PubMed] [Google Scholar]
355.Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut Microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–7. 10.1126/science.aan3706 [DOI] [PubMed] [Google Scholar]
356.Gao G, Shen S, Zhang T, Zhang J, Huang S, Sun Z, et al. Lacticaseibacillus rhamnosus Probio-M9 enhanced the antitumor response to anti-PD-1 therapy by modulating intestinal metabolites. eBioMedicine. 2023;91. 10.1016/j.ebiom.2023.104533 [DOI] [PMC free article] [PubMed]
357.Zak J, Pratumchai I, Marro BS, Marquardt KL, Zavareh RB, Lairson LL, et al. JAK Inhibition enhances checkpoint Blockade immunotherapy in patients with hodgkin lymphoma. Science. 2024;384(6702):eade8520. 10.1126/science.ade8520 [DOI] [PMC free article] [PubMed] [Google Scholar]
358.Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA. Age and Age-Related diseases: role of inflammation triggers and cytokines. Front Immunol. 2018;9:586. 10.3389/fimmu.2018.00586 [DOI] [PMC free article] [PubMed] [Google Scholar]
359.Karagiannis TT, Dowrey TW, Villacorta-Martin C, Montano M, Reed E, Belkina AC, et al. Multi-modal profiling of peripheral blood cells across the human lifespan reveals distinct immune cell signatures of aging and longevity. EBioMedicine. 2023;90:104514. 10.1016/j.ebiom.2023.104514 [DOI] [PMC free article] [PubMed] [Google Scholar]
360.Martínez de Toda I, González-Sánchez M, Díaz-Del Cerro E, Valera G, Carracedo J, Guerra-Pérez N. Sex differences in markers of oxidation and inflammation. Implications for ageing. Mech Ageing Dev. 2023;211:111797. 10.1016/j.mad.2023.111797 [DOI] [PubMed] [Google Scholar]
361.Brown BN, Haschak MJ, Lopresti ST, Stahl EC. Effects of age-related shifts in cellular function and local microenvironment upon the innate immune response to implants. Semin Immunol. 2017;29:24–32. 10.1016/j.smim.2017.05.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
362.Furler RL, Newcombe KL, Del Rio Estrada PM, Reyes-Terán G, Uittenbogaart CH, Nixon DF. Histoarchitectural deterioration of lymphoid tissues in HIV-1 infection and in aging. AIDS Res Hum Retroviruses. 2019;35(11–12):1148–59. 10.1089/aid.2019.0156 [DOI] [PMC free article] [PubMed] [Google Scholar]
363.Kroemer G, Maier AB, Cuervo AM, Gladyshev VN, Ferrucci L, Gorbunova V, et al. From geroscience to precision geromedicine: Understanding and managing aging. Cell. 2025;188(8):2043–62. 10.1016/j.cell.2025.03.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
364.Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48. 10.3322/caac.21763 [DOI] [PubMed]
365.Wang C, Long Q, Fu Q, Xu Q, Fu D, Li Y, et al. Targeting Epiregulin in the treatment-damaged tumor microenvironment restrains therapeutic resistance. Oncogene. 2022;41(45):4941–59. 10.1038/s41388-022-02476-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
366.Liu Z, Liang Q, Ren Y, Guo C, Ge X, Wang L, et al. Immunosenescence: molecular mechanisms and diseases. Signal Transduct Target Ther. 2023;8(1):200. 10.1038/s41392-023-01451-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
367.Guarente L, Sinclair DA, Kroemer G. Human trials exploring anti-aging medicines. Cell Metabol. 2024;36(2):354–76. 10.1016/j.cmet.2023.12.007 [DOI] [PubMed] [Google Scholar]
368.Tang X, Deng B, Zang A, He X, Zhou Y, Wang D, et al. Characterization of age-related immune features after autologous NK cell infusion: protocol for an open-label and randomized controlled trial. Front Immunol. 2022;13:940577. 10.3389/fimmu.2022.940577 [DOI] [PMC free article] [PubMed] [Google Scholar]
369.López-Otín C, Pietrocola F, Roiz-Valle D, Galluzzi L, Kroemer G. Meta-hallmarks of aging and cancer. Cell Metabol. 2023;35(1):12–35. 10.1016/j.cmet.2022.11.001 [DOI] [PubMed] [Google Scholar]
370.Satpathy AT, Granja JM, Yost KE, Qi Y, Meschi F, McDermott GP, et al. Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion. Nat Biotechnol. 2019;37(8):925–36. 10.1038/s41587-019-0206-z [DOI] [PMC free article] [PubMed] [Google Scholar]
371.Li H, Zhao W, Yang F, Qiao Q, Ma S, Yang K, et al. Immunosenescence Inventory—a multi-omics database for immune aging research. Nucleic Acids Res. 2024;53(D1):D1047–54. 10.1093/nar/gkae1102 [DOI] [PMC free article] [PubMed] [Google Scholar]
372.Li W, Zhang Z, Kumar S, Botey-Bataller J, Zoodsma M, Ehsani A, et al. Single-cell immune aging clocks reveal inter-individual heterogeneity during infection and vaccination. Nat Aging. 2025. 10.1038/s43587-025-00819-z [DOI] [PMC free article] [PubMed] [Google Scholar]
373.He J, Burova E, Taduriyasas C, Ni M, Adler C, Wei Y, et al. Single cell-resolved cellular, transcriptional, and epigenetic changes in mouse T cell populations linked to age-associated immune decline. Proc Natl Acad Sci U S A. 2025;122(14):e2425992122. 10.1073/pnas.2425992122 [DOI] [PMC free article] [PubMed] [Google Scholar]
374.Wang Y, Li R, Tong R, Chen T, Sun M, Luo L, et al. Integrating single-cell RNA and T cell/b cell receptor sequencing with mass cytometry reveals dynamic trajectories of human peripheral immune cells from birth to old age. Nat Immunol. 2025;26(2):308–22. 10.1038/s41590-024-02059-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
375.Lu J, Ahmad R, Nguyen T, Cifello J, Hemani H, Li J, et al. Heterogeneity and transcriptome changes of human CD8(+) T cells across nine decades of life. Nat Commun. 2022;13(1):5128. 10.1038/s41467-022-32869-x [DOI] [PMC free article] [PubMed] [Google Scholar]
376.Soto-Heredero G, Gabandé-Rodríguez E, Carrasco E, Escrig-Larena JI, Gómez de Las Heras MM, Delgado-Pulido S, et al. KLRG1 identifies regulatory T cells with mitochondrial alterations that accumulate with aging. Nat Aging. 2025;5(5):799–815. 10.1038/s43587-025-00855-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
377.Xu Y, Li M, Hu C, Luo Y, Gao X, Li X, et al. Developing a novel aging assessment model to uncover heterogeneity in organ aging and screening of aging-related drugs. Genome Med. 2025;17(1):83. 10.1186/s13073-025-01501-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
378.Duan R, Jiang L, Wang T, Li Z, Yu X, Gao Y, et al. Aging-induced immune microenvironment remodeling fosters melanoma in male mice via γδ17-Neutrophil-CD8 axis. Nat Commun. 2024;15(1):10860. 10.1038/s41467-024-55164-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
379.Moskowitz DM, Zhang DW, Hu B, Le Saux S, Yanes RE, Ye Z, et al. Epigenomics of human CD8 T cell differentiation and aging. Sci Immunol. 2017;2(8). 10.1126/sciimmunol.aag0192 [DOI] [PMC free article] [PubMed]
380.Bohacova P, Terekhova M, Tsurinov P, Mullins R, Husarcikova K, Shchukina I, et al. Multidimensional profiling of human T cells reveals high CD38 expression, marking recent thymic emigrants and age-related Naive T cell remodeling. Immunity. 2024;57(10):2362–79.e10. 10.1016/j.immuni.2024.08.019 [DOI] [PubMed] [Google Scholar]
381.Liu X, Zhang C, Lv J, Liu Y, Gu C, Gao Y, et al. Pyrroloquinoline Quinone reprograms the Single-Cell landscape of immune aging in hematopoietic immune system. Aging Cell. 2025;24(7):e70050. 10.1111/acel.70050 [DOI] [PMC free article] [PubMed] [Google Scholar]
382.Lv J, Zhang C, Liu X, Gu C, Liu Y, Gao Y, et al. An aging-related immune landscape in the hematopoietic immune system. Immun Ageing. 2024;21(1):3. 10.1186/s12979-023-00403-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
383.Li W, Zhang Z, Kumar S, Botey-Bataller J, Zoodsma M, Ehsani A, et al. Single-cell immune aging clocks reveal inter-individual heterogeneity during infection and vaccination. Nat Aging. 2025;5(4):607–21. 10.1038/s43587-025-00819-z [DOI] [PMC free article] [PubMed] [Google Scholar]
384.Huang Z, Chen B, Liu X, Li H, Xie L, Gao Y, et al. Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis. Proc Natl Acad Sci U S A. 2021;118(33). 10.1073/pnas.2023216118 [DOI] [PMC free article] [PubMed]
385.Reitsema RD, Hid Cadena R, Nijhof SH, Abdulahad WH, Huitema MG, Paap D, et al. Effect of age and sex on immune checkpoint expression and kinetics in human T cells. Immun Ageing. 2020;17(1):32. 10.1186/s12979-020-00203-y [DOI] [PMC free article] [PubMed] [Google Scholar]
386.Menees KB, Earls RH, Chung J, Jernigan J, Filipov NM, Carpenter JM, et al. Sex- and age-dependent alterations of Splenic immune cell profile and NK cell phenotypes and function in C57BL/6J mice. Immun Ageing. 2021;18(1):3. 10.1186/s12979-021-00214-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
387.McGill CJ, Benayoun BA. Time isn’t kind to female T-cells. Nat Aging. 2022;2(3):189–91. 10.1038/s43587-022-00185-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
388.Li X, Li Y, Jin Y, Zhang Y, Wu J, Xu Z, et al. Transcriptional and epigenetic decoding of the microglial aging process. Nat Aging. 2023;3(10):1288–311. 10.1038/s43587-023-00479-x [DOI] [PMC free article] [PubMed] [Google Scholar]
389.Yang C, Jin J, Yang Y, Sun H, Wu L, Shen M, et al. Androgen receptor-mediated CD8(+) T cell stemness programs drive sex differences in antitumor immunity. Immunity. 2022;55(7):1268–e839. 10.1016/j.immuni.2022.05.012 [DOI] [PubMed] [Google Scholar]
390.Xiao T, Lee J, Gauntner TD, Velegraki M, Lathia JD, Li Z. Hallmarks of sex bias in immuno-oncology: mechanisms and therapeutic implications. Nat Rev Cancer. 2024;24(5):338–55. 10.1038/s41568-024-00680-z [DOI] [PubMed] [Google Scholar]
391.Conforti F, Pala L, Di Mitri D, Catania C, Cocorocchio E, Laszlo D, et al. Sex hormones, the anticancer immune response, and therapeutic opportunities. Cancer Cell. 2025;43(3):343–60. 10.1016/j.ccell.2025.02.013 [DOI] [PubMed] [Google Scholar]
392.Pala L, De Pas T, Catania C, Giaccone G, Mantovani A, Minucci S, et al. Sex and cancer immunotherapy: current Understanding and challenges. Cancer Cell. 2022;40(7):695–700. 10.1016/j.ccell.2022.06.005 [DOI] [PubMed] [Google Scholar]
393.Shimizu J, Murao A, Aziz M, Wang P. Extracellular cirp inhibits neutrophil apoptosis to promote its aging by upregulating serpinb2 in sepsis. Shock. 2023;60(3):450–60. 10.1097/SHK.0000000000002187 [DOI] [PMC free article] [PubMed] [Google Scholar]
394.Hu Y, Bojanowski CM, Britto CJ, Wellems D, Song K, Scull C, et al. Aberrant immune programming in neutrophils in cystic fibrosis. J Leukoc Biol. 2023;115(3):420–34. 10.1093/jleuko/qiad139 [DOI] [PMC free article] [PubMed] [Google Scholar]
395.Ou B, Liu Y, Gao Z, Xu J, Yan Y, Li Y, et al. Senescent neutrophils-derived Exosomal piRNA-17560 promotes chemoresistance and EMT of breast cancer via FTO-mediated m6A demethylation. Cell Death Dis. 2022;13(10). 10.1038/s41419-022-05317-3 [DOI] [PMC free article] [PubMed]
396.Egholm C, Özcan A, Breu D, Boyman O. Type 2 immune predisposition results in accelerated neutrophil aging causing susceptibility to bacterial infection. Sci Immunol. 2022;7(71):eabi9733. 10.1126/sciimmunol.abi9733 [DOI] [PubMed] [Google Scholar]
397.Uhl B, Vadlau Y, Zuchtriegel G, Nekolla K, Sharaf K, Gaertner F, et al. Aged neutrophils contribute to the first line of defense in the acute inflammatory response. Blood. 2016;128(19):2327–37. 10.1182/blood-2016-05-718999 [DOI] [PMC free article] [PubMed] [Google Scholar]
398.Zhang D, Chen G, Manwani D, Mortha A, Xu C, Faith JJ, et al. Neutrophil ageing is regulated by the Microbiome. Nature. 2015;525(7570):528–32. 10.1038/nature15367 [DOI] [PMC free article] [PubMed] [Google Scholar]
399.Rodriguez-Rosales YA, Langereis JD, Gorris MAJ, van den Reek JMPA, Fasse E, Netea MG, et al. Immunomodulatory aged neutrophils are augmented in blood and skin of psoriasis patients. J Allergy Clin Immunol. 2021;148(4):1030–40. 10.1016/j.jaci.2021.02.041 [DOI] [PubMed] [Google Scholar]
400.Matsudaira T, Nakano S, Konishi Y, Kawamoto S, Uemura K, Kondo T, et al. Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype. Commun Biology. 2023;6(1):665. 10.1038/s42003-023-05027-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
401.Wei L, Yang X, Wang J, Wang Z, Wang Q, Ding Y, et al. H3K18 lactylation of senescent microglia potentiates brain aging and alzheimer’s disease through the NFκB signaling pathway. J Neuroinflamm. 2023;20(1):208. 10.1186/s12974-023-02879-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
402.Luo G, Xiang L, Xiao L. Quercetin alleviates atherosclerosis by suppressing oxidized LDL-induced senescence in plaque macrophage via inhibiting the p38MAPK/p16 pathway. J Nutr Biochem. 2023;116:109314. 10.1016/j.jnutbio.2023.109314 [DOI] [PubMed] [Google Scholar]
403.Li M, Niu Y, Tian L, Zhang T, Zhou S, Wang L, et al. Astragaloside IV alleviates macrophage senescence and d-galactose-induced bone loss in mice through STING/NF-κB pathway. Int Immunopharmacol. 2024;129:111588. 10.1016/j.intimp.2024.111588 [DOI] [PubMed] [Google Scholar]
404.Cheng W, Fu Y, Lin Z, Huang M, Chen Y, Hu Y, et al. Lipoteichoic acid restrains macrophage senescence via β-catenin/FOXO1/REDD1 pathway in age-related osteoporosis. Aging Cell. 2024;23(3):e14072. 10.1111/acel.14072 [DOI] [PMC free article] [PubMed] [Google Scholar]
405.Matacchione G, Perugini J, Di Mercurio E, Sabbatinelli J, Prattichizzo F, Senzacqua M, et al. Senescent macrophages in the human adipose tissue as a source of inflammaging. GeroScience. 2022;44(4):1941–60. 10.1007/s11357-022-00536-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
406.Gautam S, Kumar R, Kumar U, Kumar S, Luthra K, Dada R. Yoga maintains Th17/Treg cell homeostasis and reduces the rate of T cell aging in rheumatoid arthritis: a randomized controlled trial. Sci Rep. 2023;13(1):14924. 10.1038/s41598-023-42231-w [DOI] [PMC free article] [PubMed] [Google Scholar]
407.Xu L, Wei C, Chen Y, Wu Y, Shou X, Chen W, et al. IL-33 induces thymic involution-associated Naive T cell aging and impairs host control of severe infection. Nat Commun. 2022;13(1):6881. 10.1038/s41467-022-34660-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
408.Pan XX, Yao KL, Yang YF, Ge Q, Zhang R, Gao PJ, et al. Senescent T cell induces brown adipose tissue whitening via secreting IFN-γ. Front Cell Dev Biology. 2021;9. 10.3389/fcell.2021.637424 [DOI] [PMC free article] [PubMed]
409.Pan XX, Wu F, Chen XH, Chen DR, Chen HJ, Kong LR, et al. T-cell senescence accelerates angiotensin II-induced target organ damage. Cardiovascular Res. 2021;117(1):271–83. 10.1093/cvr/cvaa032 [DOI] [PubMed] [Google Scholar]
410.Guo Z, Wang G, Wu B, Chou WC, Cheng L, Zhou C, et al. DCAF1 regulates Treg senescence via the ROS axis during immunological aging. J Clin Invest. 2020;130(11):5893–908. 10.1172/JCI136466 [DOI] [PMC free article] [PubMed] [Google Scholar]
411.Zou NY, Liu R, Huang M, Jiao YR, Wei J, Jiang Y, et al. Age-related secretion of Grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing. Bone Res. 2024;12(1). 10.1038/s41413-023-00309-1 [DOI] [PMC free article] [PubMed]
412.Li Y, Chen R, Wu J, Xue X, Liu T, Peng G, et al. Salvianolic acid B protects against pulmonary fibrosis by attenuating stimulating protein 1-mediated macrophage and alveolar type 2 cell senescence. Phytother Res. 2024;38(2):620–35. 10.1002/ptr.8070 [DOI] [PubMed] [Google Scholar]
413.Geng F, Xu M, Zhao L, Zhang H, Li J, Jin F, et al. Quercetin alleviates pulmonary fibrosis in mice exposed to silica by inhibiting macrophage senescence. Front Pharmacol. 2022;13. 10.3389/fphar.2022.912029 [DOI] [PMC free article] [PubMed]
414.Su L, Dong Y, Wang Y, Wang Y, Guan B, Lu Y, et al. Potential role of senescent macrophages in radiation-induced pulmonary fibrosis. Cell Death Dis. 2021;12(6). 10.1038/s41419-021-03811-8 [DOI] [PMC free article] [PubMed]
415.Wada H, Otsuka R, Germeraad WTV, Murata T, Kondo T, Seino KI. Tumor cell-induced macrophage senescence plays a pivotal role in tumor initiation followed by stable growth in immunocompetent condition. J Immunother Cancer. 2023;11(11). 10.1136/jitc-2023-006677 [DOI] [PMC free article] [PubMed]
416.Liu X, Hartman CL, Li L, Albert CJ, Si F, Gao A, et al. Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy. Sci Transl Med. 2021;13(587):eaaz6314. 10.1126/scitranslmed.aaz6314 [DOI] [PMC free article] [PubMed] [Google Scholar]
417.Gao A, Liu X, Lin W, Wang J, Wang S, Si F, et al. Tumor-derived ILT4 induces T cell senescence and suppresses tumor immunity. J Immunother Cancer. 2021;9(3):e001536. 10.1136/jitc-2020-001536 [DOI] [PMC free article] [PubMed] [Google Scholar]
418.Fukushima Y, Sakamoto K, Matsuda M, Yoshikai Y, Yagita H, Kitamura D, et al. Cis interaction of CD153 with TCR/CD3 is crucial for the pathogenic activation of senescence-associated T cells. Cell Rep. 2022;40(12). 10.1016/j.celrep.2022.111373 [DOI] [PubMed]
419.Kalim H, Wahono CS, Permana BPO, Pratama MZ, Handono K. Association between senescence of T cells and disease activity in patients with systemic lupus erythematosus. Reumatologia. 2021;59(5):292–301. 10.5114/reum.2021.110318 [DOI] [PMC free article] [PubMed] [Google Scholar]
420.Mathiasen SL, Gall-Mas L, Pateras IS, Theodorou SDP, Namini MRJ, Hansen MB et al.Bacterial genotoxins induce T cell senescence. Cell Reports. 2021;35(10). 10.1016/j.celrep.2021.109220 [DOI] [PubMed]
421.Duggal NA, Upton J, Phillips AC, Hampson P, Lord JM. NK cell immunesenescence is increased by psychological but not physical stress in older adults associated with Raised cortisol and reduced Perforin expression. AGE. 2015;37(1):11. 10.1007/s11357-015-9748-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
422.Kim C, Jadhav RR, Gustafson CE, Smithey MJ, Hirsch AJ, Uhrlaub JL, et al. Defects in antiviral T cell responses inflicted by Aging-Associated miR-181a deficiency. Cell Rep. 2019;29(8):2202–e165. 10.1016/j.celrep.2019.10.044 [DOI] [PMC free article] [PubMed] [Google Scholar]
423.Fessler J, Fasching P, Raicht A, Hammerl S, Weber J, Lackner A, et al. Lymphopenia in primary sjögren’s syndrome is associated with premature aging of Naïve CD4 + T cells. Rheumatol (United Kingdom). 2021;60(2):588–97. 10.1093/rheumatology/keaa105 [DOI] [PubMed] [Google Scholar]
424.Frasca D, Romero M, Diaz A, Blomberg BB. Obesity accelerates age defects in B cells, and weight loss improves B cell function. Immun Ageing. 2023;20(1):35. 10.1186/s12979-023-00361-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
425.Rinaldi S, Pallikkuth S, George VK, de Armas LR, Pahwa R, Sanchez CM, et al. Paradoxical aging in HIV: immune senescence of B cells is most prominent in young age. Aging. 2017;9(4):1307–25. 10.18632/aging.101229 [DOI] [PMC free article] [PubMed] [Google Scholar]
426.Kawamoto S, Uemura K, Hori N, Takayasu L, Konishi Y, Katoh K, et al. Bacterial induction of B cell senescence promotes age-related changes in the gut microbiota. Nat Cell Biol. 2023;25(6):865–76. 10.1038/s41556-023-01145-5 [DOI] [PubMed] [Google Scholar]
427.Zeng X, Liang C, Yao J. Chronic shift-lag promotes NK cell ageing and impairs immunosurveillance in mice by decreasing the expression of CD122. J Cell Mol Med. 2020;24(24):14583–95. 10.1111/jcmm.16088 [DOI] [PMC free article] [PubMed] [Google Scholar]
428.Schratz KE, Flasch DA, Atik CC, Cosner ZL, Blackford AL, Yang W, et al. T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers. Cancer Cell. 2023;41(4):807–e176. 10.1016/j.ccell.2023.03.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
429.Pei S, Deng X, Yang R, Wang H, Shi J-H, Wang X, et al. Age-related decline in CD8 + tissue resident memory T cells compromises antitumor immunity. Nat Aging. 2024;4(12):1828–44. 10.1038/s43587-024-00746-5 [DOI] [PubMed] [Google Scholar]
430.Kang TG, Lan X, Mi T, Chen H, Alli S, Lim S-E, et al. Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy. Science. 2024;386(6718):eadl4492. 10.1126/science.adl4492 [DOI] [PMC free article] [PubMed] [Google Scholar]
431.Ikeda H, Kawase K, Nishi T, Watanabe T, Takenaga K, Inozume T, et al. Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature. 2025;638(8049):225–36. 10.1038/s41586-024-08439-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
432.Tang L, Wu J, Li CG, Jiang HW, Xu M, Du M, et al. Characterization of immune dysfunction and identification of prognostic immune-Related risk factors in acute myeloid leukemia. Clin Cancer Res. 2020;26(7):1763–72. 10.1158/1078-0432.Ccr-19-3003 [DOI] [PubMed] [Google Scholar]
433.Park JV, Chandra R, Cai L, Ganguly D, Li H, Toombs JE, et al. Tumor cells modulate macrophage phenotype in a novel in vitro Co-Culture model of the NSCLC tumor microenvironment. J Thorac Oncol. 2022;17(10):1178–91. 10.1016/j.jtho.2022.06.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
434.Chen P, Yang X, Chen W, Wei W, Chen Y, Wang P, et al. Developing and experimental validating a T cell senescence-related gene signature to predict prognosis and immunotherapeutic sensitivity in non-small cell lung cancer. Gene. 2025;941:149233. 10.1016/j.gene.2025.149233 [DOI] [PubMed] [Google Scholar]
435.Park MD, Le Berichel J, Hamon P, Wilk CM, Belabed M, Yatim N, et al. Hematopoietic aging promotes cancer by fueling IL-1⍺-driven emergency myelopoiesis. Science. 2024;386(6720):eadn0327. 10.1126/science.adn0327 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Citations

Koelman L, Herpich C, Norman K, Jannasch F, Börnhorst C, Schulze MB, Aleksandrova K. Adherence to healthy and sustainable dietary patterns and long-term chronic inflammation: data from the EPIC-potsdam cohort. J Nutr Health Aging. 2023;27(11):1109–17. 10.1007/s12603-023-2010-1 [DOI] [PubMed]

Data Availability Statement

No datasets were generated or analysed during the current study.

[CR1] 1.Wang B, Tang X, Mao B, Zhang Q, Tian F, Zhao J, et al. Anti-aging effects and mechanisms of anthocyanins and their intestinal microflora metabolites. Crit Rev Food Sci Nutr. 2024;64(8):2358–74. 10.1080/10408398.2022.2123444 [DOI] [PubMed] [Google Scholar]

[CR2] 2.Mogilenko DA, Shchukina I, Artyomov MN. Immune ageing at single-cell resolution. Nat Rev Immunol. 2022;22(8):484–98. 10.1038/s41577-021-00646-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR3] 3.Ajoolabady A, Pratico D, Tang D, Zhou S, Franceschi C, Ren J. Immunosenescence and inflammaging: mechanisms and role in diseases. Ageing Res Rev. 2024;101:102540. 10.1016/j.arr.2024.102540 [DOI] [PubMed] [Google Scholar]

[CR4] 4.Zhang L, Pitcher LE, Yousefzadeh MJ, Niedernhofer LJ, Robbins PD, Zhu Y. Cellular senescence: a key therapeutic target in aging and diseases. J Clin Investig. 2022;132(15). 10.1172/JCI158450 [DOI] [PMC free article] [PubMed]

[CR5] 5.Goyani P, Christodoulou R, Vassiliou E, Immunosenescence. Aging and immune system decline. Vaccines (Basel). 2024;12(12). 10.3390/vaccines12121314 [DOI] [PMC free article] [PubMed]

[CR6] 6.Hazeldine J, Withnall E, Llibre A, Duggal NA, Lord JM, Sardeli AV. Physical activity modifies the metabolic profile of CD4(+) and CD8(+) T-Cell subtypes at rest and upon activation in older adults. Aging Cell. 2025;24(7):e70104. 10.1111/acel.70104 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR7] 7.Nga HT, Nguyen TL, Yi HS. T-Cell senescence in human metabolic diseases. Diabetes Metab J. 2024;48(5):864–81. 10.4093/dmj.2024.0140 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR8] 8.Lewis ED, Wu D, Meydani SN. Age-associated alterations in immune function and inflammation. Prog Neuropsychopharmacol Biol Psychiatry. 2022;118:110576. 10.1016/j.pnpbp.2022.110576 [DOI] [PubMed] [Google Scholar]

[CR9] 9.Zhou H, Zheng Z, Fan C, Zhou Z. Mechanisms and strategies of Immunosenescence effects on non-small cell lung cancer (NSCLC) treatment: A comprehensive analysis and future directions. Sem Cancer Biol. 2025;109:44–66. 10.1016/j.semcancer.2025.01.001 [DOI] [PubMed] [Google Scholar]

[CR10] 10.Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al. Global Cancer Statistics. 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2021;71(3):209 – 49. 10.3322/caac.21660 [DOI] [PubMed]

[CR11] 11.Wang Z, Zhu D, Zhang H, Wang L, He H, Li Z, et al. Recommendations and quality of Multimorbidity guidelines: a systematic review. Ageing Res Rev. 2024;102559. 10.1016/j.arr.2024.102559 [DOI] [PubMed]

[CR12] 12.Zhang J, Guan X, Zhong X. Immunosenescence in digestive system cancers: mechanisms, research advances, and therapeutic strategies. Semin Cancer Biol. 2024;106–107:234–50. 10.1016/j.semcancer.2024.10.006 [DOI] [PubMed] [Google Scholar]

[CR13] 13.Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12(1):31–46. 10.1158/2159-8290.Cd-21-1059 [DOI] [PubMed] [Google Scholar]

[CR14] 14.Lee S, Schmitt CA. The dynamic nature of senescence in cancer. Nat Cell Biol. 2019;21(1):94–101. 10.1038/s41556-018-0249-2 [DOI] [PubMed] [Google Scholar]

[CR15] 15.Fane M, Weeraratna AT. How the ageing microenvironment influences tumour progression. Nat Rev Cancer. 2020;20(2):89–106. 10.1038/s41568-019-0222-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR16] 16.Dong Z, Luo Y, Yuan Z, Tian Y, Jin T, Xu F. Cellular senescence and SASP in tumor progression and therapeutic opportunities. Mol Cancer. 2024;23(1):181. 10.1186/s12943-024-02096-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR17] 17.Drijvers JM, Sharpe AH, Haigis MC. The effects of age and systemic metabolism on anti-tumor T cell responses. Elife. 2020;9. 10.7554/eLife.62420 [DOI] [PMC free article] [PubMed]

[CR18] 18.Pardoll DM. The Blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64. 10.1038/nrc3239 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR19] 19.Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348(6230):62–8. 10.1126/science.aaa4967 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR20] 20.Papaioannou NE, Beniata OV, Vitsos P, Tsitsilonis O, Samara P. Harnessing the immune system to improve cancer therapy. Ann Transl Med. 2016;4(14):261. 10.21037/atm.2016.04.01 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR21] 21.Kaiser M, Semeraro MD, Herrmann M, Absenger G, Gerger A, Renner W. Immune aging and immunotherapy in cancer. Int J Mol Sci. 2021;22(13). 10.3390/ijms22137016 [DOI] [PMC free article] [PubMed]

[CR22] 22.Cho YH, Woo HD, Jang Y, Porter V, Christensen S, Hamilton RF Jr, et al. The association of LINE-1 hypomethylation with age and centromere positive micronuclei in human lymphocytes. PLoS ONE. 2015;10(7):e0133909. 10.1371/journal.pone.0133909 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR23] 23.Sedelnikova OA, Horikawa I, Redon C, Nakamura A, Zimonjic DB, Popescu NC, et al. Delayed kinetics of DNA double-strand break processing in normal and pathological aging. Aging Cell. 2008;7(1):89–100. 10.1111/j.1474-9726.2007.00354.x [DOI] [PubMed] [Google Scholar]

[CR24] 24.Neri S, Pawelec G, Facchini A, Mariani E. Microsatellite instability and compromised mismatch repair gene expression during in vitro passaging of monoclonal human T lymphocytes. Rejuvenation Res. 2007;10(2):145–56. 10.1089/rej.2006.0510 [DOI] [PubMed] [Google Scholar]

[CR25] 25.Neri S, Pawelec G, Facchini A, Ferrari C, Mariani E. Altered expression of mismatch repair proteins associated with acquisition of microsatellite instability in a clonal model of human T lymphocyte aging. Rejuvenation Res. 2008;11(3):565–72. 10.1089/rej.2007.0639 [DOI] [PubMed] [Google Scholar]

[CR26] 26.González-Sánchez M, García-Martínez V, Bravo S, Kobayashi H, Martínez de Toda I, González-Bermúdez B, et al. Mitochondrial DNA insertions into nuclear DNA affecting chromosome segregation: insights for a novel mechanism of Immunosenescence in mice. Mech Ageing Dev. 2022;207:111722. 10.1016/j.mad.2022.111722 [DOI] [PubMed] [Google Scholar]

[CR27] 27.De Silva NS, Siewiera J, Alkhoury C, Nader GPF, Nadalin F, de Azevedo K, et al. Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages. Nat Aging. 2023;3(10):1251–68. 10.1038/s43587-023-00488-w [DOI] [PubMed] [Google Scholar]

[CR28] 28.Morgan RG, Venturelli M, Gross C, Tarperi C, Schena F, Reggiani C, et al. Age-Associated ALU element instability in white blood cells is linked to lower survival in elderly adults: A preliminary cohort study. PLoS ONE. 2017;12(1):e0169628. 10.1371/journal.pone.0169628 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR29] 29.Zhang FF, Cardarelli R, Carroll J, Fulda KG, Kaur M, Gonzalez K, et al. Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood. Epigenetics. 2011;6(5):623–9. 10.4161/epi.6.5.15335 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR30] 30.Chebly A, Khalil C, Kuzyk A, Beylot-Barry M, Chevret E. T-cell lymphocytes’ aging clock: telomeres, telomerase and aging. Biogerontology. 2024;25(2):279–88. 10.1007/s10522-023-10075-6 [DOI] [PubMed] [Google Scholar]

[CR31] 31.Najarro K, Nguyen H, Chen G, Xu M, Alcorta S, Yao X, et al. Telomere length as an indicator of the robustness of B- and T-Cell response to influenza in older adults. J Infect Dis. 2015;212(8):1261–9. 10.1093/infdis/jiv202 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR32] 32.Yousefzadeh MJ, Flores RR, Zhu Y, Schmiechen ZC, Brooks RW, Trussoni CE, et al. An aged immune system drives senescence and ageing of solid organs. Nature. 2021;594(7861):100–5. 10.1038/s41586-021-03547-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR33] 33.Fyhrquist F, Saijonmaa O. Telomere length and cardiovascular aging. Ann Med. 2012;44(sup1):S138–42. 10.3109/07853890.2012.660497 [DOI] [PubMed] [Google Scholar]

[CR34] 34.Montpetit AJ, Alhareeri AA, Montpetit M, Starkweather AR, Elmore LW, Filler K et al. Telomere length: A review of methods for measurement. Nurs Res. 2014;63(4). 10.1097/NNR.0000000000000037 [DOI] [PMC free article] [PubMed]

[CR35] 35.Behravan E, Moallem SA, Kalalinia F, Ahmadimanesh M, Blain P, Jowsey P, et al. Telomere shortening associated with increased levels of oxidative stress in sulfur mustard-exposed Iranian veterans. Mutat Res Genet Toxicol Environ Mutagen. 2018;834:1–5. 10.1016/j.mrgentox.2018.06.017 [DOI] [PubMed] [Google Scholar]

[CR36] 36.Cohen-Manheim I, Doniger GM, Sinnreich R, Simon ES, Pinchas R, Aviv A, et al. Increased attrition of leukocyte telomere length in young adults is associated with poorer cognitive function in midlife. Eur J Epidemiol. 2016;31(2):147–57. 10.1007/s10654-015-0051-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR37] 37.Needham BL, Wang X, Carroll JE, Barber S, Sánchez BN, Seeman TE, et al. Sociodemographic correlates of change in leukocyte telomere length during mid- to late-life: the Multi-Ethnic study of atherosclerosis. Psychoneuroendocrinology. 2019;102:182–8. 10.1016/j.psyneuen.2018.12.007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR38] 38.Maxwell F, McGlynn LM, Muir HC, Talwar D, Benzeval M, Robertson T, et al. Telomere attrition and decreased fetuin-A levels indicate accelerated biological aging and are implicated in the pathogenesis of colorectal cancer. Clin Cancer Res. 2011;17(17):5573–81. 10.1158/1078-0432.Ccr-10-3271 [DOI] [PubMed] [Google Scholar]

[CR39] 39.Zhao J, Zhu Y, Uppal K, Tran VT, Yu T, Lin J, et al. Metabolic profiles of biological aging in American indians: the strong heart family study. Aging. 2014;6(3):176–86. 10.18632/aging.100644 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR40] 40.Zanet DL, Thorne A, Singer J, Maan EJ, Sattha B, Le Campion A, et al. Association between short leukocyte telomere length and HIV infection in a cohort study: no evidence of a relationship with antiretroviral therapy. Clin Infect Dis. 2014;58(9):1322–32. 10.1093/cid/ciu051 [DOI] [PubMed] [Google Scholar]

[CR41] 41.Dowd JB, Bosch JA, Steptoe A, Jayabalasingham B, Lin J, Yolken R, et al. Persistent herpesvirus infections and telomere attrition over 3 years in the Whitehall II cohort. J Infect Dis. 2017;216(5):565–72. 10.1093/infdis/jix255 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR42] 42.Cao D, Zhao J, Nguyan LN, Nguyen LNT, Khanal S, Dang X, et al. Disruption of telomere integrity and DNA repair machineries by KML001 induces T cell senescence, apoptosis, and cellular dysfunctions. Front Immunol. 2019;10:1152. 10.3389/fimmu.2019.01152 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR43] 43.Hsiao C-B, Bedi H, Gomez R, Khan A, Meciszewski T, Aalinkeel R, et al. Telomere length shortening in microglia: implication for accelerated senescence and neurocognitive deficits in HIV. Vaccines. 2021;9(7):721. 10.3390/vaccines9070721 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR44] 44.Révész D, Milaneschi Y, Terpstra EM, Penninx BW. Baseline biopsychosocial determinants of telomere length and 6-year attrition rate. Psychoneuroendocrinology. 2016;67:153–62. 10.1016/j.psyneuen.2016.02.007 [DOI] [PubMed] [Google Scholar]

[CR45] 45.Shin C, Yun CH, Yoon DW, Baik I. Association between snoring and leukocyte telomere length. Sleep. 2016;39(4):767–72. 10.5665/sleep.5624 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR46] 46.Huzen J, Wong LS, van Veldhuisen DJ, Samani NJ, Zwinderman AH, Codd V, et al. Telomere length loss due to smoking and metabolic traits. J Intern Med. 2014;275(2):155–63. 10.1111/joim.12149 [DOI] [PubMed] [Google Scholar]

[CR47] 47.Davis SK, Xu R, Khan RJ, Gaye A. Modifiable mediators associated with the relationship between adiposity and leukocyte telomere length in US adults: the National health and nutrition examination survey. Prev Med. 2020;138:106133. 10.1016/j.ypmed.2020.106133 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR48] 48.Gedvilaite G, Vilkeviciute A, Kriauciuniene L, Banevičius M, Liutkeviciene R. The relationship between leukocyte telomere length and TERT, TRF1 single nucleotide polymorphisms in healthy people of different age groups. Biogerontology. 2020;21(1):57–67. 10.1007/s10522-019-09843-0 [DOI] [PubMed] [Google Scholar]

[CR49] 49.Liu B, Sun Y, Xu G, Snetselaar LG, Ludewig G, Wallace RB, et al. Association between body iron status and leukocyte telomere length, a biomarker of biological aging, in a nationally representative sample of US adults. J Acad Nutr Diet. 2019;119(4):617–25. 10.1016/j.jand.2018.09.007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR50] 50.Lewis NL, Mullaney M, Mangan KF, Klumpp T, Rogatko A, Broccoli D. Measurable immune dysfunction and telomere attrition in long-term allogeneic transplant recipients. Bone Marrow Transpl. 2004;33(1):71–8. 10.1038/sj.bmt.1704300 [DOI] [PubMed] [Google Scholar]

[CR51] 51.Avetyan D, Zakharyan R, Petrek M, Arakelyan A. Telomere shortening in blood leukocytes of patients with posttraumatic stress disorder. J Psychiatr Res. 2019;111:83–8. 10.1016/j.jpsychires.2019.01.018 [DOI] [PubMed] [Google Scholar]

[CR52] 52.Lima IM, Barros A, Rosa DV, Albuquerque M, Malloy-Diniz L, Neves FS, et al. Analysis of telomere attrition in bipolar disorder. J Affect Disord. 2015;172:43–7. 10.1016/j.jad.2014.09.043 [DOI] [PubMed] [Google Scholar]

[CR53] 53.Jantunen H, Wasenius NS, Guzzardi MA, Iozzo P, Kajantie E, Kautiainen H, et al. Physical activity and telomeres in old age: A longitudinal 10-Year Follow-Up study. Gerontology. 2020;66(4):315–22. 10.1159/000505603 [DOI] [PubMed] [Google Scholar]

[CR54] 54.Steptoe A, Hamer M, Lin J, Blackburn EH, Erusalimsky JD. The longitudinal relationship between cortisol responses to mental stress and leukocyte telomere attrition. J Clin Endocrinol Metab. 2017;102(3):962–9. 10.1210/jc.2016-3035 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR55] 55.Brydon L, Lin J, Butcher L, Hamer M, Erusalimsky JD, Blackburn EH, et al. Hostility and cellular aging in men from the Whitehall II cohort. Biol Psychiatry. 2012;71(9):767–73. 10.1016/j.biopsych.2011.08.020 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR56] 56.van Ockenburg SL, de Jonge P, van der Harst P, Ormel J, Rosmalen JG. Does neuroticism make you old? Prospective associations between neuroticism and leukocyte telomere length. Psychol Med. 2014;44(4):723–9. 10.1017/s0033291713001657 [DOI] [PubMed] [Google Scholar]

[CR57] 57.Cherkas LF, Aviv A, Valdes AM, Hunkin JL, Gardner JP, Surdulescu GL, et al. The effects of social status on biological aging as measured by white-blood-cell telomere length. Aging Cell. 2006;5(5):361–5. 10.1111/j.1474-9726.2006.00222.x [DOI] [PubMed] [Google Scholar]

[CR58] 58.Soares-Miranda L, Imamura F, Siscovick D, Jenny NS, Fitzpatrick AL, Mozaffarian D. Physical activity, physical fitness, and leukocyte telomere length: the cardiovascular health study. Med Sci Sports Exerc. 2015;47(12):2525–34. 10.1249/mss.0000000000000720 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR59] 59.Hang D, Nan H, Kværner AS, De Vivo I, Chan AT, Hu Z, et al. Longitudinal associations of lifetime adiposity with leukocyte telomere length and mitochondrial DNA copy number. Eur J Epidemiol. 2018;33(5):485–95. 10.1007/s10654-018-0382-z [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR60] 60.Grun LK, Teixeira NDR Jr., Mengden LV, de Bastiani MA, Parisi MM, Bortolin R, et al. TRF1 as a major contributor for telomeres’ shortening in the context of obesity. Free Radic Biol Med. 2018;129:286–95. 10.1016/j.freeradbiomed.2018.09.039 [DOI] [PubMed] [Google Scholar]

[CR61] 61.Wulaningsih W, Kuh D, Wong A, Hardy R, Adiposity. Telomere length, and telomere attrition in midlife: the 1946 British birth cohort. J Gerontol Biol Sci Med Sci. 2018;73(7):966–72. 10.1093/gerona/glx151 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR62] 62.Cabeza de Baca T, Prather AA, Lin J, Sternfeld B, Adler N, Epel ES, et al. Chronic psychosocial and financial burden accelerates 5-year telomere shortening: findings from the coronary artery risk development in young adults study. Mol Psychiatry. 2020;25(5):1141–53. 10.1038/s41380-019-0482-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR63] 63.Meier HCS, Hussein M, Needham B, Barber S, Lin J, Seeman T, et al. Cellular response to chronic psychosocial stress: Ten-year longitudinal changes in telomere length in the Multi-Ethnic study of atherosclerosis. Psychoneuroendocrinology. 2019;107:70–81. 10.1016/j.psyneuen.2019.04.018 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR64] 64.Nakashima H, Ozono R, Suyama C, Sueda T, Kambe M, Oshima T. Telomere attrition in white blood cell correlating with cardiovascular damage. Hypertens Res. 2004;27(5):319–25. 10.1291/hypres.27.319 [DOI] [PubMed] [Google Scholar]

[CR65] 65.Nollet E, Hoymans VY, Rodrigus IR, De Bock D, Dom M, Van Hoof VOM, et al. Accelerated cellular senescence as underlying mechanism for functionally impaired bone marrow-derived progenitor cells in ischemic heart disease. Atherosclerosis. 2017;260:138–46. 10.1016/j.atherosclerosis.2017.03.023 [DOI] [PubMed] [Google Scholar]

[CR66] 66.Akasheva DU, Plokhova EV, Tkacheva ON, Strazhesko ID, Dudinskaya EN, Kruglikova AS, et al. Age-Related left ventricular changes and their association with leukocyte telomere length in healthy people. PLoS ONE. 2015;10(8):e0135883. 10.1371/journal.pone.0135883 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR67] 67.Miner AE, Graves JS. What telomeres teach Us about MS. Mult Scler Relat Disord. 2021;54:103084. 10.1016/j.msard.2021.103084 [DOI] [PubMed] [Google Scholar]

[CR68] 68.van den Hoogen LL, Sims GP, van Roon JA, Fritsch-Stork RD. Aging and systemic lupus Erythematosus - Immunosenescence and beyond. Curr Aging Sci. 2015;8(2):158–77. 10.2174/1874609808666150727111904 [DOI] [PubMed] [Google Scholar]

[CR69] 69.Opstad TB, Kalstad AA, Pettersen A, Arnesen H, Seljeflot I. Novel biomolecules of ageing, sex differences and potential underlying mechanisms of telomere shortening in coronary artery disease. Exp Gerontol. 2019;119:53–60. 10.1016/j.exger.2019.01.020 [DOI] [PubMed] [Google Scholar]

[CR70] 70.Bawamia B, Spray L, Wangsaputra VK, Bennaceur K, Vahabi S, Stellos K, et al. Activation of telomerase by TA-65 enhances immunity and reduces inflammation post myocardial infarction. Geroscience. 2023;45(4):2689–705. 10.1007/s11357-023-00794-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR71] 71.Fernández-Alvira JM, Fuster V, Dorado B, Soberón N, Flores I, Gallardo M, et al. Short telomere load, telomere length, and subclinical atherosclerosis: the PESA study. J Am Coll Cardiol. 2016;67(21):2467–76. 10.1016/j.jacc.2016.03.530 [DOI] [PubMed] [Google Scholar]

[CR72] 72.Fali T, Fabre-Mersseman V, Yamamoto T, Bayard C, Papagno L, Fastenackels S, et al. Elderly human hematopoietic progenitor cells express cellular senescence markers and are more susceptible to pyroptosis. JCI Insight. 2018;3(13). 10.1172/jci.insight.95319 [DOI] [PMC free article] [PubMed]

[CR73] 73.Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115. 10.1186/gb-2013-14-10-r115 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR74] 74.Cheng X, Wei Y, Wang R, Jia C, Zhang Z, An J, et al. Associations of essential trace elements with epigenetic aging indicators and the potential mediating role of inflammation. Redox Biol. 2023;67. 10.1016/j.redox.2023.102910 [DOI] [PMC free article] [PubMed]

[CR75] 75.Tomusiak A, Floro A, Tiwari R, Riley R, Matsui H, Andrews N, et al. Development of an epigenetic clock resistant to changes in immune cell composition. Commun Biol. 2024;7(1):934. 10.1038/s42003-024-06609-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR76] 76.Speaker Abstracts, Alcoholism. Clin Experimental Res. 2022;46(S2):18–87. 10.1111/acer.14905 [Google Scholar]

[CR77] 77.Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013;49(2):359–67. 10.1016/j.molcel.2012.10.016 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR78] 78.Horvath S, Oshima J, Martin GM, Lu AT, Quach A, Cohen H, et al. Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria syndrome and ex vivo studies. Aging. 2018;10(7):1758–75. 10.18632/aging.101508 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR79] 79.Levine ME, Lu AT, Quach A, Chen BH, Assimes TL, Bandinelli S, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging. 2018;10(4):573–91. 10.18632/aging.101414 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR80] 80.Zhang Z, Reynolds SR, Stolrow HG, Chen JQ, Christensen BC, Salas LA. Deciphering the role of immune cell composition in epigenetic age acceleration: insights from cell-type Deconvolution applied to human blood epigenetic clocks. Aging Cell. 2024;23(3). 10.1111/acel.14071 [DOI] [PMC free article] [PubMed]

[CR81] 81.Mogilenko DA, Shpynov O, Andhey PS, Arthur L, Swain A, Esaulova E, et al. Comprehensive profiling of an aging immune system reveals clonal GZMK < sup>+ CD8 < sup>+ T cells as conserved hallmark of inflammaging. Immunity. 2021;54(1):99–e11512. 10.1016/j.immuni.2020.11.005 [DOI] [PubMed] [Google Scholar]

[CR82] 82.Ohyashiki M, Ohyashiki JH, Hirota A, Kobayashi C, Ohyashiki K. Age-related decrease of miRNA-92a levels in human CD8 + T-cells correlates with a reduction of Naïve T lymphocytes. Immun Ageing. 2011;8(1):11. 10.1186/1742-4933-8-11 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR83] 83.Kim C, Jin J, Ye Z, Jadhav RR, Gustafson CE, Hu B, et al. Histone deficiency and accelerated replication stress in T cell aging. J Clin Invest. 2021;131(11). 10.1172/jci143632 [DOI] [PMC free article] [PubMed]

[CR84] 84.Brunner S, Herndler-Brandstetter D, Arnold CR, Wiegers GJ, Villunger A, Hackl M, et al. Upregulation of miR-24 is associated with a decreased DNA damage response upon Etoposide treatment in highly differentiated CD8(+) T cells sensitizing them to apoptotic cell death. Aging Cell. 2012;11(4):579–87. 10.1111/j.1474-9726.2012.00819.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR85] 85.Ma F, Cao Y, Du H, Braikia FZ, Zong L, Ollikainen N, et al. Three-dimensional chromatin reorganization regulates B cell development during ageing. Nat Cell Biol. 2024;26(6):991–1002. 10.1038/s41556-024-01424-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR86] 86.Funk MC, Gleixner JG, Heigwer F, Vonficht D, Valentini E, Aydin Z, et al. Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice. Dev Cell. 2023;58(24):2914–e297. 10.1016/j.devcel.2023.11.013 [DOI] [PubMed] [Google Scholar]

[CR87] 87.Harries LW, Hernandez D, Henley W, Wood AR, Holly AC, Bradley-Smith RM, et al. Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing. Aging Cell. 2011;10(5):868–78. 10.1111/j.1474-9726.2011.00726.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR88] 88.Rasa SMM, Annunziata F, Krepelova A, Nunna S, Omrani O, Gebert N, et al. Inflammaging is driven by upregulation of innate immune receptors and systemic interferon signaling and is ameliorated by dietary restriction. Cell Rep. 2022;39(13). 10.1016/j.celrep.2022.111017 [DOI] [PubMed]

[CR89] 89.Jarrold BB, Tan CYR, Ho CY, Soon AL, Lam TT, Yang X, et al. Early onset of senescence and imbalanced epidermal homeostasis across the decades in photoexposed human skin: fingerprints of inflammaging. Exp Dermatol. 2022;31(11):1748–60. 10.1111/exd.14654 [DOI] [PubMed] [Google Scholar]

[CR90] 90.Oltmanns C, Liu Z, Mischke J, Tauwaldt J, Mekonnen YA, Urbanek-Quaing M, et al. Reverse inflammaging: Long-term effects of HCV cure on biological age. J Hepatol. 2023;78(1):90–8. 10.1016/j.jhep.2022.08.042 [DOI] [PubMed] [Google Scholar]

[CR91] 91.Durso DF, Silveira-Nunes G, Coelho MM, Camatta GC, Ventura LH, Nascimento LS, et al. Living in endemic area for infectious diseases accelerates epigenetic age. Mech Ageing Dev. 2022;207:111713. 10.1016/j.mad.2022.111713 [DOI] [PubMed] [Google Scholar]

[CR92] 92.Horvath S, Gurven M, Levine ME, Trumble BC, Kaplan H, Allayee H, et al. An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biol. 2016;17(1):171. 10.1186/s13059-016-1030-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR93] 93.Verschoor CP, Vlasschaert C, Rauh MJ, Paré G. A DNA methylation based measure outperforms Circulating CRP as a marker of chronic inflammation and partly reflects the monocytic response to long-term inflammatory exposure: A Canadian longitudinal study on aging analysis. Aging Cell. 2023;22(7):e13863. 10.1111/acel.13863 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR94] 94.Declerck K, Vanden Berghe W. Characterization of blood surrogate immune-Methylation biomarkers for immune cell infiltration in chronic inflammaging disorders. Front Genet. 2019;10. 10.3389/fgene.2019.01229 [DOI] [PMC free article] [PubMed]

[CR95] 95.Yue Z, Nie L, Ji N, Sun Y, Zhu K, Zou H, et al. Hyperglycaemia aggravates periodontal inflamm-aging by promoting SETDB1-mediated LINE-1 de-repression in macrophages. J Clin Periodontol. 2023;50(12):1685–96. 10.1111/jcpe.13871 [DOI] [PubMed] [Google Scholar]

[CR96] 96.He M, Chiang HH, Luo H, Zheng Z, Qiao Q, Wang L, et al. An acetylation switch of the NLRP3 inflammasome regulates Aging-Associated chronic inflammation and insulin resistance. Cell Metab. 2020;31(3):580–e915. 10.1016/j.cmet.2020.01.009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR97] 97.Bradburn S, McPhee J, Bagley L, Carroll M, Slevin M, Al-Shanti N, et al. Dysregulation of C-X-C motif ligand 10 during aging and association with cognitive performance. Neurobiol Aging. 2018;63:54–64. 10.1016/j.neurobiolaging.2017.11.009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR98] 98.Cheng H, Xuan H, Green CD, Han Y, Sun N, Shen H, et al. Repression of human and mouse brain inflammaging transcriptome by broad gene-body histone hyperacetylation. Proc Natl Acad Sci USA. 2018;115(29):7611–6. 10.1073/pnas.1800656115 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR99] 99.Zhu M, Han Y, Gu T, Wang R, Si X, Kong D, et al. Class I HDAC inhibitors enhance antitumor efficacy and persistence of CAR-T cells by activation of the Wnt pathway. Cell Rep. 2024;43(4). 10.1016/j.celrep.2024.114065 [DOI] [PubMed]

[CR100] 100.López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243–78. 10.1016/j.cell.2022.11.001 [DOI] [PubMed] [Google Scholar]

[CR101] 101.Rabinowitz JD, White E. Autophagy and metabolism. Science. 2010;330(6009):1344–8. 10.1126/science.1193497 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR102] 102.Hang R, Wang J, Tian X, Wu R, Hang R, Zhao Y, et al. Resveratrol promotes osteogenesis and angiogenesis through mediating immunology of senescent macrophages. Biomed Mater. 2022;17(5):055005. 10.1088/1748-605X/ac80e3 [DOI] [PubMed] [Google Scholar]

[CR103] 103.Chen W, Xiao W, Liu X, Yuan P, Zhang S, Wang Y, et al. Pharmacological manipulation of macrophage autophagy effectively rejuvenates the regenerative potential of biodegrading vascular graft in aging body. Bioactive Mater. 2022;11:283–99. 10.1016/j.bioactmat.2021.09.027 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR104] 104.Bai L, Liu Y, Zhang X, Chen P, Hang R, Xiao Y, et al. Osteoporosis remission via an anti-inflammaging effect by Icariin activated autophagy. Biomaterials. 2023;297:122125. 10.1016/j.biomaterials.2023.122125 [DOI] [PubMed] [Google Scholar]

[CR105] 105.Wang Z, Wu Z, Wang H, Feng R, Wang G, Li M, et al. An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development. Cell. 2023;186(20):4454–e7119. 10.1016/j.cell.2023.08.019 [DOI] [PubMed] [Google Scholar]

[CR106] 106.Kong H, Xu L-M, Wang D-X. Perioperative neurocognitive disorders: A narrative review focusing on diagnosis, prevention, and treatment. CNS Neurosci Ther. 2022;28(8):1147–67. 10.1111/cns.13873 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR107] 107.Chen F, Bai N, Yue F, Hao Y, Wang H, He Y, et al. Effects of oral β-caryophyllene (BCP) treatment on perioperative neurocognitive disorders: Attenuation of neuroinflammation associated with microglial activation and reinforcement of autophagy activity in aged mice. Brain Res. 2023;1815:148425. 10.1016/j.brainres.2023.148425 [DOI] [PubMed] [Google Scholar]

[CR108] 108.Ritzel RM, Li Y, Lei Z, Carter J, He J, Choi HMC, et al. Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice. GeroScience. 2022;44(3):1407–40. 10.1007/s11357-022-00562-y [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR109] 109.Berglund R, Cheng Y, Piket E, Adzemovic Z, Zeitelhofer M, Olsson M. The aging mouse CNS is protected by an autophagy-dependent microglia population promoted by IL-34. Nat Commun. 2024;15(1):383. 10.1038/s41467-023-44556-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR110] 110.Jalloh A, Flowers A, Hudson C, Chaput D, Guergues J, Stevens SM, et al. Polyphenol supplementation reverses Age-Related changes in microglial signaling cascades. Int J Mol Sci. 2021;22(12):6373. 10.3390/ijms22126373 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR111] 111.Runyan CE, Welch LC, Lecuona E, Shigemura M, Amarelle L, Abdala-Valencia H, et al. Impaired phagocytic function in CX3CR1 + tissue-resident skeletal muscle macrophages prevents muscle recovery after influenza A virus-induced pneumonia in old mice. Aging Cell. 2020;19(9). 10.1111/acel.13180 [DOI] [PMC free article] [PubMed]

[CR112] 112.Cannizzo Elvira S, Clement Cristina C, Morozova K, Valdor R, Kaushik S, Almeida Larissa N, et al. Age-Related oxidative stress compromises endosomal proteostasis. Cell Rep. 2012;2(1):136–49. 10.1016/j.celrep.2012.06.005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR113] 113.Schmidt F, Dahlmann B, Janek K, Kloss A, Wacker M, Ackermann R, et al. Comprehensive quantitative proteome analysis of 20S proteasome subtypes from rat liver by isotope coded affinity Tag and 2-D gel-based approaches. Proteomics. 2006;6(16):4622–32. 10.1002/pmic.200500920 [DOI] [PubMed] [Google Scholar]

[CR114] 114.Gohlke S, Mishto M, Textoris-Taube K, Keller C, Giannini C, Vasuri F, et al. Molecular alterations in proteasomes of rat liver during aging result in altered proteolytic activities. AGE. 2014;36(1):57–72. 10.1007/s11357-013-9543-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR115] 115.Schlie K, Westerback A, DeVorkin L, Hughson LR, Brandon JM, MacPherson S, et al. Survival of effector CD8 + T cells during influenza infection is dependent on autophagy. J Immunol. 2015;194(9):4277–86. 10.4049/jimmunol.1402571 [DOI] [PubMed] [Google Scholar]

[CR116] 116.Xu X, Araki K, Li S, Han JH, Ye L, Tan WG, et al. Autophagy is essential for effector CD8(+) T cell survival and memory formation. Nat Immunol. 2014;15(12):1152–61. 10.1038/ni.3025 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR117] 117.Alsaleh G, Panse I, Swadling L, Zhang H, Richter FC, Meyer A, et al. Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses. Elife. 2020;9. 10.7554/eLife.57950 [DOI] [PMC free article] [PubMed]

[CR118] 118.Zhang C, Sun Y, Li S, Shen L, Teng X, Xiao Y, et al. Autophagic flux restoration of senescent T cells improves antitumor activity of TCR-engineered T cells. Clin Translational Immunol. 2022;11(9):e1419. 10.1002/cti2.1419 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR119] 119.Bharath LP, Agrawal M, McCambridge G, Nicholas DA, Hasturk H, Liu J, et al. Metformin enhances autophagy and normalizes mitochondrial function to alleviate Aging-Associated inflammation. Cell Metabol. 2020;32(1):44–e556. 10.1016/j.cmet.2020.04.015 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR120] 120.Huda N, Khambu B, Liu G, Nakatsumi H, Yan S, Chen X, et al. Senescence connects autophagy deficiency to inflammation and tumor progression in the liver. Cell Mol Gastroenterol Hepatol. 2022;14(2):333–55. 10.1016/j.jcmgh.2022.04.003 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR121] 121.Steinert EM, Vasan K, Chandel NS. Mitochondrial metabolism regulation of T Cell-Mediated immunity. Annu Rev Immunol. 2021;39:395–416. 10.1146/annurev-immunol-101819-082015 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR122] 122.Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, et al. T cell subset-specific susceptibility to aging. Clin Immunol. 2008;127(1):107–18. 10.1016/j.clim.2007.12.002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR123] 123.Henson SM, Lanna A, Riddell NE, Franzese O, Macaulay R, Griffiths SJ, et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8⁺ T cells. J Clin Invest. 2014;124(9):4004–16. 10.1172/jci75051 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR124] 124.Callender LA, Carroll EC, Bober EA, Akbar AN, Solito E, Henson SM. Mitochondrial mass governs the extent of human T cell senescence. Aging Cell. 2020;19(2). 10.1111/acel.13067 [DOI] [PMC free article] [PubMed]

[CR125] 125.Headley CA, Gautam S, Olmo-Fontanez A, Garcia-Vilanova A, Dwivedi V, Akhter A, et al. Extracellular delivery of functional mitochondria rescues the dysfunction of CD4 + T cells in aging. Adv Sci. 2024;11(5):2303664. 10.1002/advs.202303664 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR126] 126.Chen Y, Ye Y, Krauß P-L, Löwe P, Pfeiffenberger M, Damerau A et al. Age-related increase of mitochondrial content in human memory CD4 + T cells contributes to ROS-mediated increased expression of Proinflammatory cytokines. Front Immunol. 2022;13. 10.3389/fimmu.2022.911050 [DOI] [PMC free article] [PubMed]

[CR127] 127.Ye B, Pei Y, Wang L, Meng D, Zhang Y, Zou S, et al. NAD + supplementation prevents STING-induced senescence in CD8 + T cells by improving mitochondrial homeostasis. J Cell Biochem. 2024;125(3):e30522. 10.1002/jcb.30522 [DOI] [PubMed] [Google Scholar]

[CR128] 128.Bektas A, Schurman SH, Gonzalez-Freire M, Dunn CA, Singh AK, Macian F, et al. Age-associated changes in human CD4 < SUP>+ T cells point to mitochondrial dysfunction consequent to impaired autophagy. AGING-US. 2019;11(21):9234–63. 10.18632/aging.102438 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR129] 129.Qiu X, Guo H, Yang J, Ji Y, Wu C-S, Chen X. Down-regulation of guanylate binding protein 1 causes mitochondrial dysfunction and cellular senescence in macrophages. Sci Rep. 2018;8(1):1679. 10.1038/s41598-018-19828-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR130] 130.An Y, Li Y, Hou Y, Huang S, Pei G. Alzheimer’s Amyloid- β Accelerates Cell Senescence and Suppresses the SIRT1/NRF2 Pathway in Human Microglial Cells. Oxidative Medicine and Cellular Longevity. 2022;2022. 10.1155/2022/3086010 [DOI] [PMC free article] [PubMed]

[CR131] 131.Dongol A, Chen X, Zheng P, Seyhan ZB, Huang XF. Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process. Biol Direct. 2023;18(1):86. 10.1186/s13062-023-00445-y [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR132] 132.Thangaraj A, Chivero ET, Tripathi A, Singh S, Niu F, Guo M-L, et al. HIV TAT-mediated microglial senescence: role of SIRT3-dependent mitochondrial oxidative stress. Redox Biol. 2021;40:101843. 10.1016/j.redox.2020.101843 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR133] 133.Zhong W, Rao Z, Xu J, Sun Y, Hu H, Wang P, et al. Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation. Aging Cell. 2022;21(6). 10.1111/acel.13622 [DOI] [PMC free article] [PubMed]

[CR134] 134.Hussain M, Chu X, Duan Sahbaz B, Gray S, Pekhale K, Park J-H, et al. Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA. Free Radic Biol Med. 2023;203:34–44. 10.1016/j.freeradbiomed.2023.03.262 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR135] 135.Vizioli MG, Liu T, Miller KN, Robertson NA, Gilroy K, Lagnado AB, et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes Dev. 2020;34(5):428–45. 10.1101/gad.331272.119 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR136] 136.Zhang X, Wang R, Chen H, Jin C, Jin Z, Lu J, et al. Aged microglia promote peripheral T cell infiltration by reprogramming the microenvironment of neurogenic niches. Immun Ageing. 2022;19(1):34. 10.1186/s12979-022-00289-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR137] 137.Gulen MF, Samson N, Keller A, Schwabenland M, Liu C, Glück S, et al. cGAS–STING drives ageing-related inflammation and neurodegeneration. Nature. 2023;620(7973):374–80. 10.1038/s41586-023-06373-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR138] 138.Balter LJT, Higgs S, Aldred S, Bosch JA, Raymond JE. Inflammation mediates body weight and ageing effects on psychomotor slowing. Sci Rep. 2019;9(1):15727. 10.1038/s41598-019-52062-3 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR139] 139.Chougnet CA, Thacker RI, Shehata HM, Hennies CM, Lehn MA, Lages CS, et al. Loss of phagocytic and antigen Cross-Presenting capacity in aging dendritic cells is associated with mitochondrial dysfunction. J Immunol. 2015;195(6):2624–32. 10.4049/jimmunol.1501006 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR140] 140.Rottenberg H, Wu S. Mitochondrial dysfunction in lymphocytes from old mice: enhanced activation of the permeability transition. Biochem Biophys Res Commun. 1997;240(1):68–74. 10.1006/bbrc.1997.7605 [DOI] [PubMed] [Google Scholar]

[CR141] 141.Mather MW, Rottenberg H. The Inhibition of calcium signaling in T lymphocytes from old mice results from enhanced activation of the mitochondrial permeability transition pore. Mech Ageing Dev. 2002;123(6):707–24. 10.1016/S0047-6374(01)00416-X [DOI] [PubMed] [Google Scholar]

[CR142] 142.Han S, Georgiev P, Ringel AE, Sharpe AH, Haigis MC. Age-associated remodeling of T cell immunity and metabolism. Cell Metabol. 2023;35(1):36–55. 10.1016/j.cmet.2022.11.005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR143] 143.Xie Z, Lin M, Xing B, Wang H, Zhang H, Cai Z, et al. Citrulline regulates macrophage metabolism and inflammation to counter aging in mice. Sci Adv. 2025;11(10):eads4957. 10.1126/sciadv.ads4957 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR144] 144.Sawoo R, Dey R, Ghosh R, Bishayi B. TLR4 and TNFR1 Blockade dampen M1 macrophage activation and shifts them towards an M2 phenotype. Immunol Res. 2021;69(4):334–51. 10.1007/s12026-021-09209-0 [DOI] [PubMed] [Google Scholar]

[CR145] 145.Ryu S, Sidorov S, Ravussin E, Artyomov M, Iwasaki A, Wang A, et al. The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging. Immunity. 2022;55(9):1609–e267. 10.1016/j.immuni.2022.07.007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR146] 146.Li C, Deng C, Wang S, Dong X, Dai B, Guo W, et al. A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization. Redox Biol. 2024;70:103059. 10.1016/j.redox.2024.103059 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR147] 147.Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol. 2018;28(6):436–53. 10.1016/j.tcb.2018.02.001 [DOI] [PubMed] [Google Scholar]

[CR148] 148.Zhang J, Li Z, Zhang Q, Ma W, Fan W, Dong J, et al. LAMA4(+) CD90(+) eCAFs provide immunosuppressive microenvironment for liver cancer through induction of CD8(+) T cell senescence. Cell Commun Signal. 2025;23(1):203. 10.1186/s12964-025-02162-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR149] 149.Li Y, Wang L, Ma W, Wu J, Wu Q, Sun C. Paracrine signaling in cancer-associated fibroblasts: central regulators of the tumor immune microenvironment. J Translational Med. 2025;23(1):697. 10.1186/s12967-025-06744-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR150] 150.Lv N, Zhao Y, Liu X, Ye L, Liang Z, Kang Y, et al. Dysfunctional telomeres through mitostress-induced cGAS/STING activation to aggravate immune senescence and viral pneumonia. Aging Cell. 2022;21(4):e13594. 10.1111/acel.13594 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR151] 151.Cho RH, Sieburg HB, Muller-Sieburg CE. A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells. Blood. 2008;111(12):5553–61. 10.1182/blood-2007-11-123547 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR152] 152.Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci. 2005;102(26):9194–9. 10.1073/pnas.0503280102 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR153] 153.Hérault L, Poplineau M, Mazuel A, Platet N, Remy É, Duprez E. Single-cell RNA-seq reveals a concomitant delay in differentiation and cell cycle of aged hematopoietic stem cells. BMC Biol. 2021;19(1):19. 10.1186/s12915-021-00955-z [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR154] 154.Khoo MLM, Carlin SM, Lutherborrow MA, Jayaswal V, Ma DDF, Moore JJ. Gene profiling reveals association between altered Wnt signaling and loss of T-cell potential with age in human hematopoietic stem cells. Aging Cell. 2014;13(4):744–54. 10.1111/acel.12229 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR155] 155.Rosales-Alvarez RE, Rettkowski J, Herman JS, Dumbović G, Cabezas-Wallscheid N, Grün D. VarID2 quantifies gene expression noise dynamics and unveils functional heterogeneity of ageing hematopoietic stem cells. Genome Biol. 2023;24(1):148. 10.1186/s13059-023-02974-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR156] 156.Yamamoto R, Wilkinson AC, Ooehara J, Lan X, Lai CY, Nakauchi Y, et al. Large-Scale clonal analysis resolves aging of the mouse hematopoietic stem cell compartment. Cell Stem Cell. 2018;22(4):600–e74. 10.1016/j.stem.2018.03.013 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR157] 157.Wang Y, Zhang Z, He H, Song J, Cui Y, Chen Y, et al. Aging-induced Pseudouridine synthase 10 impairs hematopoietic stem cells. Haematologica. 2023;108(10):2677–89. 10.3324/haematol.2022.282211 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR158] 158.Wang J, Morita Y, Han B, Niemann S, Löffler B, Rudolph KL. Per2 induction limits lymphoid-biased Haematopoietic stem cells and lymphopoiesis in the context of DNA damage and ageing. Nat Cell Biol. 2016;18(5):480–90. 10.1038/ncb3342 [DOI] [PubMed] [Google Scholar]

[CR159] 159.Grover A, Sanjuan-Pla A, Thongjuea S, Carrelha J, Giustacchini A, Gambardella A, et al. Single-cell RNA sequencing reveals molecular and functional platelet bias of aged Haematopoietic stem cells. Nat Commun. 2016;7(1):11075. 10.1038/ncomms11075 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR160] 160.Zeng X, Li X, Shao M, Xu Y, Shan W, Wei C, et al. Integrated Single-Cell bioinformatics analysis reveals intrinsic and extrinsic biological characteristics of hematopoietic stem cell aging. Front Genet. 2021;12. 10.3389/fgene.2021.745786 [DOI] [PMC free article] [PubMed]

[CR161] 161.Mitchell CA, Verovskaya EV, Calero-Nieto FJ, Olson OC, Swann JW, Wang X, et al. Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of Haematopoietic ageing. Nat Cell Biol. 2023;25(1):30–41. 10.1038/s41556-022-01053-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR162] 162.Montecino-Rodriguez E, Kong Y, Casero D, Rouault A, Dorshkind K, Pioli PD. Lymphoid-Biased hematopoietic stem cells are maintained with age and efficiently generate lymphoid progeny. Stem Cell Rep. 2019;12(3):584–96. 10.1016/j.stemcr.2019.01.016 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR163] 163.Wahlestedt M, Norddahl GL, Sten G, Ugale A, Frisk M-AM, Mattsson R, et al. An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state. Blood. 2013;121(21):4257–64. 10.1182/blood-2012-11-469080 [DOI] [PubMed] [Google Scholar]

[CR164] 164.Bocker MT, Hellwig I, Breiling A, Eckstein V, Ho AD, Lyko F. Genome-wide promoter DNA methylation dynamics of human hematopoietic progenitor cells during differentiation and aging. Blood. 2011;117(19):e182–9. 10.1182/blood-2011-01-331926 [DOI] [PubMed] [Google Scholar]

[CR165] 165.Khokhar ES, Borikar S, Eudy E, Stearns T, Young K, Trowbridge JJ. Aging-associated decrease in the histone acetyltransferase KAT6B is linked to altered hematopoietic stem cell differentiation. Exp Hematol. 2020;82:43–e524. 10.1016/j.exphem.2020.01.014 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR166] 166.Jang G, Contreras Castillo S, Esteva E, Upadhaya S, Feng J, Adams NM, et al. Stem cell decoupling underlies impaired lymphoid development during aging. Proc Natl Acad Sci U S A. 2023;120(22):e2302019120. 10.1073/pnas.2302019120 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR167] 167.Gong X, Shen H, Guo L, Huang C, Su T, Wang H, et al. Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice. Immun Ageing. 2023;20(1). 10.1186/s12979-023-00337-9 [DOI] [PMC free article] [PubMed]

[CR168] 168.Zeng X, Li X, Li X, Wei C, Shi C, Hu K, et al. Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation. Blood. 2023;141(14):1691–707. 10.1182/blood.2022017514 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR169] 169.Utsuyama M, Kobayashi S, Hirokawa K. Induction of thymic hyperplasia and suppression of Splenic T cells by lesioning of the anterior hypothalamus in aging Wistar rats. J Neuroimmunol. 1997;77(2):174–80. 10.1016/S0165-5728(97)00068-4 [DOI] [PubMed] [Google Scholar]

[CR170] 170.Hirokawa K, Utsuyama M, Kasai M, Kurashima C, Ishijima S, Zeng YX. Understanding the mechanism of the age-change of thymic function to promote T cell differentiation. Immunol Lett. 1994;40(3):269–77. 10.1016/0165-2478(94)00065-4 [DOI] [PubMed] [Google Scholar]

[CR171] 171.Lesnikov VA, Korneva EA, Dall’ara A, Pierpaoli W. The involvement of pineal gland and melatonin in immunity and aging: II. Thyrotropin-releasing hormone and melatonin forestall Involution and promote reconstitution of the thymus in anterior hypothalamic area (AHA)-lesioned mice. Int J Neurosci. 1992;62(1–2):141–53. 10.3109/00207459108999767 [DOI] [PubMed] [Google Scholar]

[CR172] 172.Irwin M, Hauger R, Brown M. Central corticotropin-releasing hormone activates the sympathetic nervous system and reduces immune function: increased responsivity of the aged rat. Endocrinology. 1992;131(3):1047–53. 10.1210/endo.131.3.1505449 [DOI] [PubMed] [Google Scholar]

[CR173] 173.Mocchegiani E, Bulian D, Santarelli L, Tibaldi A, Muzzioli M, Pierpaoli W, et al. The immuno-reconstituting effect of melatonin or pineal grafting and its relation to zinc pool in aging mice. J Neuroimmunol. 1994;53(2):189–201. 10.1016/0165-5728(94)90029-9 [DOI] [PubMed] [Google Scholar]

[CR174] 174.Cui K, Tang X, Hu A, Fan M, Wu P, Lu X, et al. Therapeutic benefit of melatonin in choroidal neovascularization during aging through the regulation of senescent macrophage/microglia polarization. Investig Ophthalmol Vis Sci. 2023;64(11):19–. 10.1167/iovs.64.11.19 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR175] 175.Mazzoccoli G, Inglese M, De Cata A, Carughi S, Dagostino MP, Marzulli N, et al. Neuroendocrine–immune interactions in healthy aging. Geriatr Gerontol Int. 2011;11(1):98–106. 10.1111/j.1447-0594.2010.00628.x [DOI] [PubMed] [Google Scholar]

[CR176] 176.Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576–90. 10.1038/s41574-018-0059-4 [DOI] [PubMed] [Google Scholar]

[CR177] 177.Koelman L, Pivovarova-Ramich O, Pfeiffer AFH, Grune T, Aleksandrova K. Cytokines for evaluation of chronic inflammatory status in ageing research: reliability and phenotypic characterisation. Immun Ageing. 2019;16(1). 10.1186/s12979-019-0151-1 [DOI] [PMC free article] [PubMed]

[CR178] 178.Morrisette-Thomas V, Cohen AA, Fülöp T, Riesco É, Legault V, Li Q, et al. Inflamm-aging does not simply reflect increases in pro-inflammatory markers. Mech Ageing Dev. 2014;139:49–57. 10.1016/j.mad.2014.06.005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR179] 179.Laskow T, Langdon J, Sepehri S, Davalos-Bichara M, Varadhan R, Walston J. Soluble TNFR1 has greater reproducibility than IL-6 for the assessment of chronic inflammation in older adults: the case for a new inflammatory marker in aging. GeroScience. 2024;46(2):2521–30. 10.1007/s11357-023-01006-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR180] 180.Pinti M, Cevenini E, Nasi M, De Biasi S, Salvioli S, Monti D, et al. Circulating mitochondrial DNA increases with age and is a familiar trait: implications for inflamm-aging. Eur J Immunol. 2014;44(5):1552–62. 10.1002/eji.201343921 [DOI] [PubMed] [Google Scholar]

[CR181] 181.Seicol BJ, Lin S, Xie R. Age-Related hearing loss is accompanied by chronic inflammation in the cochlea and the cochlear nucleus. Front Aging Neurosci. 2022;14. 10.3389/fnagi.2022.846804 [DOI] [PMC free article] [PubMed]

[CR182] 182.Bruno MEC, Mukherjee S, Powell WL, Mori SF, Wallace FK, Balasuriya BK, et al. Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation. GeroScience. 2022;44(3):1761–78. 10.1007/s11357-022-00572-w [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR183] 183.Ruan P, Yang M, Lv X, Shen K, Chen Y, Li H et al. Metabolic shifts during coffee consumption refresh the immune response: insight from comprehensive multiomics analysis. MedComm (2020). 2024;5(7):e617. 10.1002/mco2.617 [DOI] [PMC free article] [PubMed]

[CR184] 184.Robbins PD, Jurk D, Khosla S, Kirkland JL, LeBrasseur NK, Miller JD, et al. Senolytic drugs: reducing senescent cell viability to extend health span. Annu Rev Pharmacol Toxicol. 2021;61:779–803. 10.1146/annurev-pharmtox-050120-105018 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR185] 185.Wong CP, Magnusson KR, Sharpton TJ, Ho E. Effects of zinc status on age-related T cell dysfunction and chronic inflammation. Biometals. 2021;34(2):291–301. 10.1007/s10534-020-00279-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR186] 186.Morita Y, Jounai K, Sakamoto A, Tomita Y, Sugihara Y, Suzuki H, et al. Long-term intake of Lactobacillus paracasei KW3110 prevents age-related chronic inflammation and retinal cell loss in physiologically aged mice. Aging. 2018;10(10):2723–40. 10.18632/aging.101583 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR187] 187.Matt SM, Allen JM, Lawson MA, Mailing LJ, Woods JA, Johnson RW. Butyrate and dietary soluble fiber improve neuroinflammation associated with aging in mice. Front Immunol. 2018;9. 10.3389/fimmu.2018.01832 [DOI] [PMC free article] [PubMed]

[CR188] 188.Oh H-J, Jin H, Lee J-Y, Lee B-Y. Silk peptide ameliorates sarcopenia through the regulation of Akt/mTOR/FoxO3a signaling pathways and the Inhibition of Low-Grade chronic inflammation in aged mice. Cells. 2023. 10.3390/cells12182257 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR189] 189.Koelman L, Herpich C, Norman K, Jannasch F, Börnhorst C, Schulze MB, Aleksandrova K. Adherence to healthy and sustainable dietary patterns and long-term chronic inflammation: data from the EPIC-potsdam cohort. J Nutr Health Aging. 2023;27(11):1109–17. 10.1007/s12603-023-2010-1 [DOI] [PubMed]

[CR190] 190.Bashir H, Singh S, Singh RP, Agrewala JN, Kumar R. Age-mediated gut microbiota dysbiosis promotes the loss of dendritic cells tolerance. Aging Cell. 2023;22(6):e13838. 10.1111/acel.13838 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR191] 191.Golomb SM, Guldner IH, Zhao A, Wang Q, Palakurthi B, Aleksandrovic EA, et al. Multi-modal Single-Cell analysis reveals brain immune landscape plasticity during aging and gut microbiota dysbiosis. Cell Rep. 2020;33(9). 10.1016/j.celrep.2020.108438 [DOI] [PMC free article] [PubMed]

[CR192] 192.Stebegg M, Silva-Cayetano A, Innocentin S, Jenkins TP, Cantacessi C, Gilbert C, et al. Heterochronic faecal transplantation boosts gut germinal centres in aged mice. Nat Commun. 2019;10(1):2443. 10.1038/s41467-019-10430-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR193] 193.Vemuri R, Gundamaraju R, Shinde T, Perera AP, Basheer W, Southam B, et al. Lactobacillus acidophilus DDS-1 modulates intestinal-specific microbiota, short-chain fatty acid and immunological profiles in aging mice. Nutrients. 2019;11(6). 10.3390/nu11061297 [DOI] [PMC free article] [PubMed]

[CR194] 194.Giannos P, Prokopidis K, Isanejad M, Wright HL. Markers of immune dysregulation in response to the ageing gut: insights from aged murine gut microbiota transplants. BMC Gastroenterol. 2022;22(1). 10.1186/s12876-022-02613-2 [DOI] [PMC free article] [PubMed]

[CR195] 195.Ahmadi S, Wang S, Nagpal R, Wang B, Jain S, Razazan A, et al. A human-origin probiotic cocktail ameliorates aging-related leaky gut and inflammation via modulating the microbiota/taurine/tight junction axis. JCI Insight. 2020;5(9). 10.1172/jci.insight.132055 [DOI] [PMC free article] [PubMed]

[CR196] 196.Song C, Zhang Y, Cheng L, Shi M, Li X, Zhang L, et al. Tea polyphenols ameliorates memory decline in aging model rats by inhibiting brain TLR4/NF-κB inflammatory signaling pathway caused by intestinal flora dysbiosis. Exp Gerontol. 2021;153. 10.1016/j.exger.2021.111476 [DOI] [PubMed]

[CR197] 197.Yusufu I, Ding K, Smith K, Wankhade UD, Sahay B, Patterson GT, et al. Article a tryptophan-deficient diet induces gut microbiota dysbiosis and increases systemic inflammation in aged mice. Int J Mol Sci. 2021;22(9). 10.3390/ijms22095005 [DOI] [PMC free article] [PubMed]

[CR198] 198.Zhu X, Huang X, Hu M, Sun R, Li J, Wang H, et al. A specific enterotype derived from gut Microbiome of older individuals enables favorable responses to immune checkpoint Blockade therapy. Cell Host Microbe. 2024;32(4):489–e5055. 10.1016/j.chom.2024.03.002 [DOI] [PubMed] [Google Scholar]

[CR199] 199.Singh A, Chandrasekar SV, Valappil VT, Scaria J, Ranjan A. Tumor Immunomodulation by nanoparticle and focused ultrasound alters gut Microbiome in a sexually dimorphic manner. Theranostics. 2025;15(1):216–32. 10.7150/thno.99664 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR200] 200.Woolbright BL, Xuan H, Ahmed I, Rajendran G, Abbott E, Dennis K, et al. Aging induces changes in cancer formation and microbial content in a murine model of bladder cancer. GeroScience. 2024;46(3):3361–75. 10.1007/s11357-024-01064-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR201] 201.Li M, Liu JX, Ma B, Liu JY, Chen J, Jin F, et al. A Senescence-Associated secretory phenotype of bone marrow mesenchymal stem cells inhibits the viability of breast cancer cells. Stem Cell Reviews Rep. 2024;20(4):1093–105. 10.1007/s12015-024-10710-w [DOI] [PubMed] [Google Scholar]

[CR202] 202.Nakajima Y, Chamoto K, Oura T, Honjo T. Critical role of the CD44lowCD62Llow CD8 + T cell subset in restoring antitumor immunity in aged mice. Proc Natl Acad Sci USA. 2021;118(23). 10.1073/PNAS.2103730118 [DOI] [PMC free article] [PubMed]

[CR203] 203.Baldini C, Martin Romano P, Voisin AL, Danlos FX, Champiat S, Laghouati S, et al. Impact of aging on immune-related adverse events generated by anti–programmed death (ligand)PD-(L)1 therapies. Eur J Cancer. 2020;129:71–9. 10.1016/j.ejca.2020.01.013 [DOI] [PubMed] [Google Scholar]

[CR204] 204.Herin H, Aspeslagh S, Castanon E, Dyevre V, Marabelle A, Varga A, et al. Immunotherapy phase I trials in patients older than 70 years with advanced solid tumours. Eur J Cancer. 2018;95:68–74. 10.1016/j.ejca.2018.03.002 [DOI] [PubMed] [Google Scholar]

[CR205] 205.Costa AC, Santos JMO, Gil da Costa RM, Medeiros R. Impact of immune cells on the hallmarks of cancer: A literature review. Crit Rev Oncol/Hematol. 2021;168:103541. 10.1016/j.critrevonc.2021.103541 [DOI] [PubMed] [Google Scholar]

[CR206] 206.Wu Y, Wei J, Chen X, Qin Y, Mao R, Song J, et al. Comprehensive transcriptome profiling in elderly cancer patients reveals aging-altered immune cells and immune checkpoints. Int J Cancer. 2019;144(7):1657–63. 10.1002/ijc.31875 [DOI] [PubMed] [Google Scholar]

[CR207] 207.Lu W, Zhou Y, Zhao R, Liu Q, Yang W, Zhu T. The integration of multi-omics analysis and machine learning for the identification of prognostic assessment and immunotherapy efficacy through aging-associated genes in lung cancer. Aging. 2024;16(2):1860–78. 10.18632/aging.205464 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR208] 208.Meng X, Song W, Zhou B, Liang M, Gao Y. Prognostic and immune correlation analysis of mitochondrial autophagy and aging-related genes in lung adenocarcinoma. J Cancer Res Clin Oncol. 2023;149(18):16311–35. 10.1007/s00432-023-05390-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR209] 209.Zhang W, Li Y, Lyu J, Shi F, Kong Y, Sheng C, et al. An aging-related signature predicts favorable outcome and immunogenicity in lung adenocarcinoma. Cancer Sci. 2022;113(3):891–903. 10.1111/cas.15254 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR210] 210.He Z, Chen M, Li Q, Luo Z, Li X. Multi-omics and tumor immune microenvironment characterization of a prognostic model based on aging-related genes in melanoma. Am J Cancer Res. 2024;14(3):1052–70. 10.62347/UZGP9704 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR211] 211.Liang X, Lin X, Lin Z, Lin W, Peng Z, Wei S. Genes associated with cellular senescence favor melanoma prognosis by stimulating immune responses in tumor microenvironment. Comput Biol Med. 2023;158. 10.1016/j.compbiomed.2023.106850 [DOI] [PubMed]

[CR212] 212.Zeng N, Guo C, Wang Y, Li L, Chen X, Gao S, et al. Characterization of Aging-Related genes to predict prognosis and evaluate the tumor immune microenvironment in malignant melanoma. J Oncol. 2022;2022. 10.1155/2022/1271378 [DOI] [PMC free article] [PubMed]

[CR213] 213.Safi M, Jin C, Aldanakh A, Feng P, Qin H, Alradhi M, et al. Immune checkpoint inhibitor (ICI) genes and aging in malignant melanoma patients: a clinicogenomic TCGA study. BMC Cancer. 2022;22(1):978. 10.1186/s12885-022-09860-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR214] 214.Mu J, Gong J, Shi M, Zhang Y. Analysis and validation of aging-related genes in prognosis and immune function of glioblastoma. BMC Med Genom. 2023;16(1). 10.1186/s12920-023-01538-3 [DOI] [PMC free article] [PubMed]

[CR215] 215.Wu Y, Li X. Senescence gene expression in clear cell renal cell carcinoma role of tumor immune microenvironment and senescence-associated survival prediction. Med (United States). 2023;102(40):E35222. 10.1097/MD.0000000000035222 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR216] 216.Gang D, Jiang Y, Wang X, Zhou J, Zhang X, He X, et al. Aging-related genes related to the prognosis and the immune microenvironment of acute myeloid leukemia. Clin Transl Oncol. 2023;25(10):2991–3005. 10.1007/s12094-023-03168-8 [DOI] [PubMed] [Google Scholar]

[CR217] 217.Liu S, Liu Y, Ma J, Lv R, Wang F. Construction of an aging-related risk signature in high-grade serous ovarian cancer for predicting survival outcome and immunogenicity. Med (United States). 2023;102(35):E34851. 10.1097/MD.0000000000034851 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR218] 218.Tan L, Xiaohalati X, Liu F, Liu J, Fu H, Zhang Y, et al. Identification of aging and young subtypes for predicting colorectal cancer prognosis and immunotherapy responses. Int J Mol Sci. 2023;24(2). 10.3390/ijms24021516 [DOI] [PMC free article] [PubMed]

[CR219] 219.Kellers F, Fernandez A, Konukiewitz B, Schindeldecker M, Tagscherer KE, Heintz A, et al. Senescence-Associated molecules and Tumor-Immune-Interactions as prognostic biomarkers in colorectal cancer. Front Med. 2022;9. 10.3389/fmed.2022.865230 [DOI] [PMC free article] [PubMed]

[CR220] 220.Wang Z, Liu H, Gong Y, Cheng Y. Establishment and validation of an aging-related risk signature associated with prognosis and tumor immune microenvironment in breast cancer. Eur J Med Res. 2022;27(1). 10.1186/s40001-022-00924-4 [DOI] [PMC free article] [PubMed]

[CR221] 221.Yang X, Sun Y, Liu X, Jiang Z. A risk model of 10 aging-related genes for predicting survival and immune response in triple-negative breast cancer. Cancer Med. 2022;11(16):3182–93. 10.1002/cam4.4674 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR222] 222.Chen F, Gong X, Xia M, Yu F, Wu J, Yu C, et al. The Aging-Related prognostic signature reveals the landscape of the tumor immune microenvironment in head and neck squamous cell carcinoma. Front Oncol. 2022;12. 10.3389/fonc.2022.857994 [DOI] [PMC free article] [PubMed]

[CR223] 223.Yang J, Jiang Q, Liu L, Peng H, Wang Y, Li S, et al. Identification of prognostic aging-related genes associated with immunosuppression and inflammation in head and neck squamous cell carcinoma. Aging. 2020;12(24):25778–804. 10.18632/aging.104199 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR224] 224.Hong T, Su W, Pan Y, Tian C, Lei G. Aging-related features predict prognosis and immunotherapy efficacy in hepatocellular carcinoma. Front Immunol. 2022;13. 10.3389/fimmu.2022.951459 [DOI] [PMC free article] [PubMed]

[CR225] 225.Luo C, Nie H, Yu L. Identification of Aging-Related genes associated with prognostic value and immune microenvironment characteristics in diffuse large B-Cell lymphoma. Oxidative Med Cell Longev. 2022;2022. 10.1155/2022/3334522 [DOI] [PMC free article] [PubMed]

[CR226] 226.Xue S, Ge W, Wang K, Mao T, Zhang X, Xu H, et al. Association of aging-related genes with prognosis and immune infiltration in pancreatic adenocarcinoma. Front Cell Dev Biology. 2022;10. 10.3389/fcell.2022.942225 [DOI] [PMC free article] [PubMed]

[CR227] 227.Luo H, Tao C, Long X, Huang K, Zhu X. A risk signature of four aging-related genes has clinical prognostic value and is associated with a tumor immune microenvironment in glioma. Aging. 2021;13(12):16198–218. 10.18632/aging.203146 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR228] 228.Liu Q, Bao H, Zhang S, Song T, Li C, Sun G, et al. Identification of a cellular senescence-related-lncRNA (SRlncRNA) signature to predict the overall survival of glioma patients and the tumor immune microenvironment. Front Genet. 2023;14. 10.3389/fgene.2023.1096792 [DOI] [PMC free article] [PubMed]

[CR229] 229.Gao Q, Shi Y, Sun Y, Zhou S, Liu Z, Sun X, et al. Identification and verification of aging-related LncRNAs for prognosis prediction and immune microenvironment in patients with head and neck squamous carcinoma. Oncol Res. 2023;31(1):35–61. 10.32604/or.2022.028193 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR230] 230.Li F, Xue X. Identification and characterization of an Ageing-Associated 13-lncRNA signature that predicts prognosis and immunotherapy in hepatocellular carcinoma. J Oncol. 2023;2023. 10.1155/2023/4615297 [DOI] [PMC free article] [PubMed]

[CR231] 231.Huang E, Ma T, Zhou J, Ma N, Yang W, Liu C, et al. A novel senescence-associated LncRNA signature predicts the prognosis and tumor microenvironment of patients with colorectal cancer: A bioinformatics analysis. J Gastrointest Oncol. 2022;13(4):1842–63. 10.21037/jgo-22-721 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR232] 232.Xu C, Li F, Liu Z, Yan C, Xiao J. A novel cell senescence-related IncRNA survival model associated with the tumor immune environment in colorectal cancer. Front Immunol. 2022;13. 10.3389/fimmu.2022.1019764 [DOI] [PMC free article] [PubMed]

[CR233] 233.Zhou Z, Wei J, Kuang L, Zhang K, Liu Y, He Z, et al. Characterization of aging cancer-associated fibroblasts draws implications in prognosis and immunotherapy response in low-grade gliomas. Front Genet. 2022;13. 10.3389/fgene.2022.897083 [DOI] [PMC free article] [PubMed]

[CR234] 234.Qu C, Wu Q, Lu J, Li F. Prognostic value and potential mechanism of cellular senescence and tumor microenvironment in hepatocellular carcinoma: insights from bulk transcriptomics and single-cell sequencing analysis. Environ Toxicol. 2024;39(5):2512–27. 10.1002/tox.24121 [DOI] [PubMed] [Google Scholar]

[CR235] 235.Flood PM, Urban JL, Kripke ML, Schreiber H. Loss of tumor-specific and idiotype-specific immunity with age. J Exp Med. 1981;154(2):275–90. 10.1084/jem.154.2.275 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR236] 236.Chen HC, Eling N, Martinez-Jimenez CP, O’Brien LM, Carbonaro V, Marioni JC et al. IL‐7‐dependent compositional changes within the γδ T cell pool in lymph nodes during ageing lead to an unbalanced anti‐tumour response. EMBO reports. 2019;20(8):e47379. 10.15252/embr.201847379 [DOI] [PMC free article] [PubMed]

[CR237] 237.Zhu LJ, Hou PF, Wang L, Zhang GB, Xie Y, Pan XD, et al. Changes in CD4 + CD25 + foxp3 + regulatory T cells in relation to aging and lung tumor incidence. Int J Gerontol. 2012;6(3):187–91. 10.1016/j.ijge.2012.01.013 [Google Scholar]

[CR238] 238.Norian LA, Allen PM. No intrinsic deficiencies in CD8 + T cell-mediated antitumor immunity with aging. J Immunol. 2004;173(2):835–44. 10.4049/jimmunol.173.2.835 [DOI] [PubMed] [Google Scholar]

[CR239] 239.Win S, Uenaka A, Nakayama E. Immune responses against allogeneic and syngeneic tumors in aged C57BL/6 mice. Microbiol Immunol. 2002;46(7):513–9. 10.1111/j.1348-0421.2002.tb02728.x [DOI] [PubMed] [Google Scholar]

[CR240] 240.Jackaman C, Gardner JK, Tomay F, Spowart J, Crabb H, Dye DE, et al. CD8 + cytotoxic T cell responses to dominant tumor-associated antigens are profoundly weakened by aging yet subdominant responses retain functionality and expand in response to chemotherapy. OncoImmunology. 2019;8(4):e1564452. 10.1080/2162402X.2018.1564452 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR241] 241.Lin S, Ma L, Mo J, Zhao R, Li J, Yu M, et al. Immune cell senescence and exhaustion promote the occurrence of liver metastasis in colorectal cancer by regulating epithelial-mesenchymal transition. Aging. 2024;16(9):7704–32. 10.18632/aging.205778 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR242] 242.Vaena S, Chakraborty P, Lee HG, Janneh AH, Kassir MF, Beeson G et al. Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response. Cell Reports. 2021;35(5). 10.1016/j.celrep.2021.109076 [DOI] [PMC free article] [PubMed]

[CR243] 243.Grolleau-Julius A, Harning EK, Abernathy LM, Yung RL. Impaired dendritic cell function in aging leads to defective antitumor immunity. Cancer Res. 2008;68(15):6341–9. 10.1158/0008-5472.Can-07-5769 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR244] 244.Sharma S, Lucia Dominguez A, Lustgarten J. Aging affect the anti-tumor potential of dendritic cell vaccination, but it can be overcome by co-stimulation with anti-OX40 or anti-4-1BB. Exp Gerontol. 2006;41(1):78–84. 10.1016/j.exger.2005.10.002 [DOI] [PubMed] [Google Scholar]

[CR245] 245.Khare V, Sodhi A, Singh SM. Age-dependent alterations in the tumoricidal functions of tumor- associated macrophages. Tumor Biology. 1999;20(1):30–43. 10.1159/000056519 [DOI] [PubMed] [Google Scholar]

[CR246] 246.Wallace PK, Eisenstein TK, Meissler JJ Jr, Morahan PS. Decreases in macrophage mediated antitumor activity with aging. Mech Ageing Dev. 1995;77(3):169–84. 10.1016/0047-6374(94)01524-P [DOI] [PubMed] [Google Scholar]

[CR247] 247.Dussault I, Miller SC. Decline in natural killer cell-mediated immunosurveillance in aging mice - a consequence of reduced cell production and tumor binding capacity. Mech Ageing Dev. 1994;75(2):115–29. 10.1016/0047-6374(94)90080-9 [DOI] [PubMed] [Google Scholar]

[CR248] 248.Cameron IL. Cell proliferation and renewal in aging mice. J Gerontol. 1972;27(2):162–72. 10.1093/geronj/27.2.162 [DOI] [PubMed] [Google Scholar]

[CR249] 249.Itzhaki O, Kaptzan T, Skutelsky E, Sinai J, Michowitz M, Siegal A, et al. Age-adjusted antitumoral therapy based on the demonstration of increased apoptosis as a mechanism underlying the reduced malignancy of tumors in the aged. Biochim Et Biophys Acta - Mol Basis Disease. 2004;1688(2):145–59. 10.1016/j.bbadis.2003.11.009 [DOI] [PubMed] [Google Scholar]

[CR250] 250.Kreisle RA, Stebler BA, Ershler WB. Effect of host age on tumor-associated angiogenesis in mice. J Natl Cancer Inst. 1990;82(1):44–7. 10.1093/jnci/82.1.44 [DOI] [PubMed] [Google Scholar]

[CR251] 251.Kakuda T, Suzuki J, Matsuoka Y, Kikugawa T, Saika T, Yamashita M. Senescent CD8 + T cells acquire NK cell-like innate functions to promote antitumor immunity. Cancer Sci. 2023;114(7):2810–20. 10.1111/cas.15824 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR252] 252.Leibovici J, Itzhaki O, Kaptzan T, Skutelsky E, Sinai J, Michowitz M, et al. Designing ageing conditions in tumour microenvironment-A new possible modality for cancer treatment. Mech Ageing Dev. 2009;130(1–2):76–85. 10.1016/j.mad.2008.03.004 [DOI] [PubMed] [Google Scholar]

[CR253] 253.Shireman JM, Gonugunta N, Zhao L, Pattnaik A, Distler E, Her S, et al. GM-CSF and IL-7 fusion cytokine engineered tumor vaccine generates long-term Th-17 memory cells and increases overall survival in aged syngeneic mouse models of glioblastoma. Aging Cell. 2023;22(7):e13864. 10.1111/acel.13864 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR254] 254.Falvo P, Gruener S, Orecchioni S, Pisati F, Talarico G, Mitola G, et al. Age-dependent differences in breast tumor microenvironment: challenges and opportunities for efficacy studies in preclinical models. Cell Death Differ. 2025;32(6):1000–13. 10.1038/s41418-025-01447-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR255] 255.Huang Y, Yang X, Meng Y, Shao C, Liao J, Li F, et al. The hepatic senescence-associated secretory phenotype promotes hepatocarcinogenesis through Bcl3-dependent activation of macrophages. Cell Bioscience. 2021;11(1):173. 10.1186/s13578-021-00683-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR256] 256.Haston S, Gonzalez-Gualda E, Morsli S, Ge J, Reen V, Calderwood A, et al. Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer. Cancer Cell. 2023;41(7):1242–e606. 10.1016/j.ccell.2023.05.004 [DOI] [PubMed] [Google Scholar]

[CR257] 257.Wu S, Li X, Hong F, Chen Q, Yu Y, Guo S, et al. Integrative analysis of single-cell transcriptomics reveals age-associated immune landscape of glioblastoma. Front Immunol. 2023;14. 10.3389/fimmu.2023.1028775 [DOI] [PMC free article] [PubMed]

[CR258] 258.Liu X, Hoft DF, Peng G. Senescent T cells within suppressive tumor microenvironments: emerging target for tumor immunotherapy. J Clin Invest. 2020;130(3):1073–83. 10.1172/jci133679 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR259] 259.Alspach E, Flanagan KC, Luo X, Ruhland MK, Huang H, Pazolli E, et al. p38MAPK plays a crucial role in stromal-mediated tumorigenesis. Cancer Discov. 2014;4(6):716–29. 10.1158/2159-8290.Cd-13-0743 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR260] 260.Li X, Li C, Zhang W, Wang Y, Qian P, Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Therapy. 2023;8(1):239. 10.1038/s41392-023-01502-8 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR261] 261.Chibaya L, Snyder J, Ruscetti M. Senescence and the tumor-immune landscape: implications for cancer immunotherapy. Semin Cancer Biol. 2022;86(Pt 3):827–45. 10.1016/j.semcancer.2022.02.005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR262] 262.Ly LV, Baghat A, Versluis M, Jordanova ES, Luyten GP, van Rooijen N, et al. In aged mice, outgrowth of intraocular melanoma depends on proangiogenic M2-type macrophages. J Immunol. 2010;185(6):3481–8. 10.4049/jimmunol.0903479 [DOI] [PubMed] [Google Scholar]

[CR263] 263.Mittmann LA, Haring F, Schaubächer JB, Hennel R, Smiljanov B, Zuchtriegel G, et al. Uncoupled biological and chronological aging of neutrophils in cancer promotes tumor progression. J Immunother Cancer. 2021;9(12). 10.1136/jitc-2021-003495 [DOI] [PMC free article] [PubMed]

[CR264] 264.Balliet RM, Capparelli C, Guido C, Pestell TG, Martinez-Outschoorn UE, Lin Z, et al. Mitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth. Cell Cycle. 2011;10(23):4065–73. 10.4161/cc.10.23.18254 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR265] 265.Liu Y, Pan J, Pan X, Wu L, Bian J, Lin Z, et al. Klotho-mediated targeting of CCL2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments. Mol Oncol. 2019;13(11):2460–75. 10.1002/1878-0261.12577 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR266] 266.Zabransky DJ, Chhabra Y, Fane ME, Kartalia E, Leatherman JM, Hüser L, et al. Fibroblasts in the aged pancreas drive pancreatic cancer progression. Cancer Res. 2024;84(8):1221–36. 10.1158/0008-5472.Can-24-0086 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR267] 267.Li Y, Tazawa H, Nagai Y, Fujita S, Okura T, Shoji R, et al. Senescent fibroblasts potentiate peritoneal metastasis of Diffuse-type gastric cancer cells via IL-8–mediated crosstalk. Anticancer Res. 2024;44(6):2497–509. 10.21873/anticanres.17056 [DOI] [PubMed] [Google Scholar]

[CR268] 268.Fane ME, Chhabra Y, Alicea GM, Maranto DA, Douglass SM, Webster MR, et al. Stromal changes in the aged lung induce an emergence from melanoma dormancy. Nature. 2022;606(7913):396–405. 10.1038/s41586-022-04774-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR269] 269.Kaur A, Webster MR, Marchbank K, Behera R, Ndoye A, Kugel CH, et al. SFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature. 2016;532(7598):250–4. 10.1038/nature17392 [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]

[CR270] 270.Li C, Teixeira AF, Zhu HJ, Ten Dijke P. Cancer associated-fibroblast-derived exosomes in cancer progression. Mol Cancer. 2021;20(1):154. 10.1186/s12943-021-01463-y [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR271] 271.Guo Y, Ayers JL, Carter KT, Wang T, Maden SK, Edmond D, et al. Senescence-associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15. Aging Cell. 2019;18(6):e13013. 10.1111/acel.13013 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR272] 272.Yamao T, Yamashita YI, Yamamura K, Nakao Y, Tsukamoto M, Nakagawa S, et al. Cellular senescence, represented by expression of Caveolin-1, in cancer-Associated fibroblasts promotes tumor invasion in pancreatic cancer. Ann Surg Oncol. 2019;26(5):1552–9. 10.1245/s10434-019-07266-2 [DOI] [PubMed] [Google Scholar]

[CR273] 273.Ren C, Cheng X, Lu B, Yang G. Activation of interleukin-6/signal transducer and activator of transcription 3 by human papillomavirus early proteins 6 induces fibroblast senescence to promote cervical tumourigenesis through autocrine and paracrine pathways in tumour microenvironment. Eur J Cancer. 2013;49(18):3889–99. 10.1016/j.ejca.2013.07.140 [DOI] [PubMed] [Google Scholar]

[CR274] 274.Higashiguchi M, Murakami H, Akita H, Kobayashi S, Takahama S, Iwagami Y, et al. The impact of cellular senescence and senescence–associated secretory phenotype in cancer–associated fibroblasts on the malignancy of pancreatic cancer. Oncol Rep. 2023;49(5). 10.3892/or.2023.8535 [DOI] [PMC free article] [PubMed]

[CR275] 275.Giese MA, Hind LE, Huttenlocher A. Neutrophil plasticity in the tumor microenvironment. Blood. 2019;133(20):2159–67. 10.1182/blood-2018-11-844548 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR276] 276.Göçer P, Gürer ÜS, Erten N, Palandüz Ş, Rayaman E, Akarsu B, et al. Comparison of polymorphonuclear leukocyte functions in elderly patients and healthy young volunteers. Med Principles Pract. 2008;14(6):382–5. 10.1159/000088109 [DOI] [PubMed] [Google Scholar]

[CR277] 277.Yang C, Wang Z, Li L, Zhang Z, Jin X, Wu P, et al. Aged neutrophils form mitochondria-dependent vital NETs to promote breast cancer lung metastasis. J Immunother Cancer. 2021;9(10). 10.1136/jitc-2021-002875 [DOI] [PMC free article] [PubMed]

[CR278] 278.Schott AF, Goldstein LJ, Cristofanilli M, Ruffini PA, McCanna S, Reuben JM, et al. Phase Ib pilot study to evaluate reparixin in combination with weekly Paclitaxel in patients with HER-2-Negative metastatic breast cancer. Clin Cancer Res. 2017;23(18):5358–65. 10.1158/1078-0432.Ccr-16-2748 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR279] 279.Bodac A, Mayet A, Rana S, Pascual J, Bowler AD, Roh V, et al. Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth. EMBO Mol Med. 2024;16(1):158–84. 10.1038/s44321-023-00013-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR280] 280.Debrincat MA, Pleines I, Lebois M, Lane RM, Holmes ML, Corbin J, et al. BCL-2 is dispensable for thrombopoiesis and platelet survival. Cell Death Dis. 2015;6(4):e1721. 10.1038/cddis.2015.97 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR281] 281.Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR, Di Gialleonardo V, et al. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood. 2009;113(15):3503–11. 10.1182/blood-2008-08-173914 [DOI] [PubMed] [Google Scholar]

[CR282] 282.Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nat Rev Immunol. 2001;1(1):41–9. 10.1038/35095564 [DOI] [PubMed] [Google Scholar]

[CR283] 283.Tarazona R, Sanchez-Correa B, Casas-Avilés I, Campos C, Pera A, Morgado S, et al. Immunosenescence: limitations of natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother. 2017;66(2):233–45. 10.1007/s00262-016-1882-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR284] 284.Rodrigues-Santos P, López-Sejas N, Almeida JS, Ruzičková L, Couceiro P, Alves V, et al. Effect of age on NK cell compartment in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Front Immunol. 2018;9:2587. 10.3389/fimmu.2018.02587 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR285] 285.Zirbes A, Joseph J, Lopez JC, Sayaman RW, Basam M, Seewaldt VL, et al. Changes in immune cell types with age in breast are consistent with a decline in immune surveillance and increased immunosuppression. J Mammary Gland Biol Neoplasia. 2021;26(3):247–61. 10.1007/s10911-021-09495-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR286] 286.Zhu Y, Fu D, Shi Q, Shi Z, Dong L, Yi H, et al. Oncogenic mutations and tumor microenvironment alterations of older patients with diffuse large B-Cell lymphoma. Front Immunol. 2022;13. 10.3389/fimmu.2022.842439 [DOI] [PMC free article] [PubMed]

[CR287] 287.Li Y, Zhao Y, Gao Y, Li Y, Liu M, Xu N, et al. Age-related macrophage alterations are associated with carcinogenesis of colorectal cancer. Carcinogenesis. 2022;43(11):1039–49. 10.1093/carcin/bgac088 [DOI] [PubMed] [Google Scholar]

[CR288] 288.Prieto LI, Sturmlechner I, Graves SI, Zhang C, Goplen NP, Yi ES, et al. Senescent alveolar macrophages promote early-stage lung tumorigenesis. Cancer Cell. 2023;41(7):1261. 75.e6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR289] 289.Khare V, Sodhi A, Singh SM. Age-Dependent alterations in the tumoricidal functions of Tumor-Associated macrophages. Tumor Biology. 1997;20(1):30–43. 10.1159/000056519 [DOI] [PubMed] [Google Scholar]

[CR290] 290.Duong L, Radley-Crabb HG, Gardner JK, Tomay F, Dye DE, Grounds MD, et al. Macrophage depletion in elderly mice improves response to tumor immunotherapy, increases Anti-tumor T cell activity and reduces Treatment-Induced cachexia. Front Genet. 2018;9. 10.3389/fgene.2018.00526 [DOI] [PMC free article] [PubMed]

[CR291] 291.Goh J, Ladiges WC. Exercise enhances wound healing and prevents cancer progression during aging by targeting macrophage Polarity. Mech Ageing Dev. 2014;139:41–8. 10.1016/j.mad.2014.06.004 [DOI] [PubMed] [Google Scholar]

[CR292] 292.Liu X, Si F, Bagley D, Ma F, Zhang Y, Tao Y, et al. Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy. J Immunother Cancer. 2022;10(10):e005020. 10.1136/jitc-2022-005020 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR293] 293.Zhang J, He T, Xue L, Guo H. Senescent T cells: a potential biomarker and target for cancer therapy. EBioMedicine. 2021;68:103409. 10.1016/j.ebiom.2021.103409 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR294] 294.Liu X, Si F, Bagley D, Ma F, Zhang Y, Tao Y, et al. Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy. J Immunother Cancer. 2022;10(10). 10.1136/jitc-2022-005020 [DOI] [PMC free article] [PubMed]

[CR295] 295.Li L, Liu X, Sanders KL, Edwards JL, Ye J, Si F, et al. TLR8-Mediated metabolic control of human Treg function: A mechanistic target for cancer immunotherapy. Cell Metab. 2019;29(1):103–e235. 10.1016/j.cmet.2018.09.020 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR296] 296.Liu X, Hartman CL, Li L, Albert CJ, Si F, Gao A, et al. Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy. Sci Transl Med. 2021;13(587). 10.1126/scitranslmed.aaz6314 [DOI] [PMC free article] [PubMed]

[CR297] 297.Bhaskaran N, Jayaraman S, Quigley C, Mamileti P, Ghannoum M, Weinberg A, et al. The role of Dectin-1 signaling in altering tumor immune microenvironment in the context of aging. Front Oncol. 2021;11. 10.3389/fonc.2021.669066 [DOI] [PMC free article] [PubMed]

[CR298] 298.Chen ACY, Jaiswal S, Martinez D, Yerinde C, Ji K, Miranda V, et al. The aged tumor microenvironment limits T cell control of cancer. Nat Immunol. 2024;25(6):1033–45. 10.1038/s41590-024-01828-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR299] 299.Hui K, Dong C, Hu C, Li J, Yan D, Jiang X. VEGFR affects miR-3200-3p-mediated regulatory T cell senescence in tumour-derived exosomes in non-small cell lung cancer. Funct Integr Genomics. 2024;24(2):31. 10.1007/s10142-024-01305-2 [DOI] [PubMed] [Google Scholar]

[CR300] 300.Gao A, Liu X, Lin W, Wang J, Wang S, Si F, et al. Tumor-derived ILT4 induces T cell senescence and suppresses tumor immunity. J Immunother Cancer. 2021;9(3). 10.1136/jitc-2020-001536 [DOI] [PMC free article] [PubMed]

[CR301] 301.Romagnani A, Rottoli E, Mazza EMC, Rezzonico-Jost T, De Ponte Conti B, Proietti M, et al. P2X7 Receptor Activity Limits Accumulation of T Cells within Tumors. Cancer Res. 2020;80(18):3906–19. 10.1158/0008-5472.Can-19-3807 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR302] 302.Adinolfi E, Capece M, Franceschini A, Falzoni S, Giuliani AL, Rotondo A, et al. Accelerated tumor progression in mice lacking the ATP receptor P2X7. Cancer Res. 2015;75(4):635–44. 10.1158/0008-5472.Can-14-1259 [DOI] [PubMed] [Google Scholar]

[CR303] 303.Li XY, Moesta AK, Xiao C, Nakamura K, Casey M, Zhang H, et al. Targeting CD39 in cancer reveals an extracellular ATP- and Inflammasome-Driven tumor immunity. Cancer Discov. 2019;9(12):1754–73. 10.1158/2159-8290.Cd-19-0541 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR304] 304.Lee-Chang C, Bodogai M, Moritoh K, Chen X, Wersto R, Sen R, et al. Aging converts innate B1a cells into potent CD8 + T cell inducers. J Immunol. 2016;196(8):3385–97. 10.4049/jimmunol.1502034 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR305] 305.Lee-Chang C, Bodogai M, Moritoh K, Olkhanud PB, Chan AC, Croft M, et al. Accumulation of 4-1BBL + B cells in the elderly induces the generation of granzyme-B + CD8 + T cells with potential antitumor activity. Blood. 2014;124(9):1450–9. 10.1182/blood-2014-03-563940 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR306] 306.Tomihara K, Shin T, Hurez VJ, Yagita H, Pardoll DM, Zhang B, et al. Aging-associated B7-DC + B cells enhance anti-tumor immunity via Th1 and Th17 induction. Aging Cell. 2012;11(1):128–38. 10.1111/j.1474-9726.2011.00764.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR307] 307.Loughran EA, Leonard AK, Hilliard TS, Phan RC, Yemc MG, Harper E, et al. Aging increases susceptibility to ovarian cancer metastasis in murine allograft models and alters immune composition of peritoneal adipose tissue. Neoplasia (United States). 2018;20(6):621–31. 10.1016/j.neo.2018.03.007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR308] 308.Remsing Rix LL, Sumi NJ, Hu Q, Desai B, Bryant AT, Li X, et al. IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung cancer cells. Sci Signal. 2022;15(747):eabj5879. 10.1126/scisignal.abj5879 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR309] 309.Capparelli C, Whitaker-Menezes D, Guido C, Balliet R, Pestell TG, Howell A, et al. CTGF drives autophagy, Glycolysis and senescence in cancer-associated fibroblasts via HIF1 activation, metabolically promoting tumor growth. Cell Cycle. 2012;11(12):2272–84. 10.4161/cc.20717 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR310] 310.Kim E, Rebecca V, Fedorenko IV, Messina JL, Mathew R, Maria-Engler SS, et al. Senescent fibroblasts in melanoma initiation and progression: an integrated theoretical, experimental, and clinical approach. Cancer Res. 2013;73(23):6874–85. 10.1158/0008-5472.Can-13-1720 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR311] 311.Alicea GM, Rebecca VW, Goldman AR, Fane ME, Douglass SM, Behera R, et al. Changes in aged fibroblast lipid metabolism induce Age-Dependent melanoma cell resistance to targeted therapy via the fatty acid transporter FATP2. Cancer Discov. 2020;10(9):1282–95. 10.1158/2159-8290.Cd-20-0329 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR312] 312.Menicacci B, Laurenzana A, Chillà A, Margheri F, Peppicelli S, Tanganelli E, et al. Chronic Resveratrol treatment inhibits MRC5 fibroblast SASP-Related protumoral effects on melanoma cells. J Gerontol Biol Sci Med Sci. 2017;72(9):1187–95. 10.1093/gerona/glw336 [DOI] [PubMed] [Google Scholar]

[CR313] 313.Jin P, Li X, Xia Y, Li H, Li X, Yang ZY, et al. Bepotastine sensitizes ovarian cancer to PARP inhibitors through suppressing NF-κB-Triggered SASP in cancer-Associated fibroblasts. Mol Cancer Ther. 2023;22(4):447–58. 10.1158/1535-7163.Mct-22-0396 [DOI] [PubMed] [Google Scholar]

[CR314] 314.Lugo R, Gabasa M, Andriani F, Puig M, Facchinetti F, Ramírez J, et al. Heterotypic paracrine signaling drives fibroblast senescence and tumor progression of large cell carcinoma of the lung. Oncotarget. 2016;7(50):82324–37. 10.18632/oncotarget.10327 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR315] 315.Yakobson A, Abu Jama A, Abu Saleh O, Michlin R, Shalata W. PD-1 inhibitors in elderly and immunocompromised patients with advanced or metastatic cutaneous squamous cell carcinoma. Cancers. 2023;15(16). 10.3390/cancers15164041 [DOI] [PMC free article] [PubMed]

[CR316] 316.Kubo T, Ichihara E, Harada D, Inoue K, Fujiwara K, Hosokawa S, et al. Efficacy of immune checkpoint inhibitor monotherapy in elderly patients with non-small-cell lung cancer. Respiratory Invest. 2023;61(5):643–50. 10.1016/j.resinv.2023.06.005 [DOI] [PubMed] [Google Scholar]

[CR317] 317.Kalariya N, Ferreri C, Dillard C, Hawkins M, Manasanch E, Lee H, et al. CT-511 clinical characteristics and response outcomes in older multiple myeloma patients who received Idecabtagene vicleucel: A single center study. Clin Lymphoma Myeloma Leuk. 2022;22:S446. 10.1016/S2152-2650(22)01670-6 [Google Scholar]

[CR318] 318.Sattar J, Kartolo A, Hopman WM, Lakoff JM, Baetz T. The efficacy and toxicity of immune checkpoint inhibitors in a real-world older patient population. J Geriatric Oncol. 2019;10(3):411–4. 10.1016/j.jgo.2018.07.015 [DOI] [PubMed] [Google Scholar]

[CR319] 319.Ajili F, Darouiche A, Chebil M, Boubaker S. The impact of age and clinical factors in non-muscle-invasive bladder cancer treated with Bacillus calmette Guerin therapy. Ultrastruct Pathol. 2013;37(3):191–5. 10.3109/01913123.2013.770110 [DOI] [PubMed] [Google Scholar]

[CR320] 320.Nemoto Y, Ishihara H, Nakamura K, Tachibana H, Fukuda H, Yoshida K, et al. Efficacy and safety of immune checkpoint inhibitors in elderly patients with metastatic renal cell carcinoma. Int Urol Nephrol. 2022;54(1):47–54. 10.1007/s11255-021-03042-y [DOI] [PubMed] [Google Scholar]

[CR321] 321.Zhou H, Cai LL, Lin YF, Ma JJ. Toxicity profile of camrelizumab-based immunotherapy in older adults with advanced cancer. Sci Rep. 2024;14(1):18992. 10.1038/s41598-024-69944-w [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR322] 322.Fa’ak F, Buni M, Falohun A, Lu H, Song J, Johnson DH, et al. Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events. J Immunother Cancer. 2023;11(6). 10.1136/jitc-2023-006814 [DOI] [PMC free article] [PubMed]

[CR323] 323.Wang N, Zheng L, Li M, Hou X, Zhang B, Chen J, et al. Clinical efficacy and safety of individualized pembrolizumab administration based on Pharmacokinetic in advanced non-small cell lung cancer: A prospective exploratory clinical trial. Lung Cancer. 2023;178:183–90. 10.1016/j.lungcan.2023.02.009 [DOI] [PubMed] [Google Scholar]

[CR324] 324.Schulz GB, Rodler S, Szabados B, Graser A, Buchner A, Stief C, et al. Safety, efficacy and prognostic impact of immune checkpoint inhibitors in older patients with genitourinary cancers. J Geriatric Oncol. 2020;11(7):1061–6. 10.1016/j.jgo.2020.06.012 [DOI] [PubMed] [Google Scholar]

[CR325] 325.Paderi A, Fancelli S, Caliman E, Pillozzi S, Gambale E, Mela MM, et al. Safety of immune checkpoint inhibitors in elderly patients: an observational study. Curr Oncol. 2021;28(5):3259–67. 10.3390/curroncol28050283 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR326] 326.Joudi FN, Smith BJ, O’Donnell MA, Konety BR. The impact of age on the response of patients with superficial bladder cancer to intravesical immunotherapy. J Urol. 2006;175(5):1634–40. 10.1016/S0022-5347(05)00973-0 [DOI] [PubMed] [Google Scholar]

[CR327] 327.Huff WX, Bam M, Shireman JM, Kwon JH, Song L, Newman S, et al. Aging- and Tumor-Mediated increase in CD8 + CD28 – T cells might impose a strong barrier to success of immunotherapy in glioblastoma. ImmunoHorizons. 2021;5(6):395–409. 10.4049/immunohorizons.2100008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR328] 328.Hou J, Xie S, Gao J, Jiang T, Zhu E, Yang X, et al. NK cell transfer overcomes resistance to PD-(L)1 therapy in aged mice. Experimental Hematol Oncol. 2024;13(1):48. 10.1186/s40164-024-00511-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR329] 329.Dunn PL, North RJ. Effect of advanced aging on ability of mice to cause regression of an Immunogenic lymphoma in response to immunotherapy based on depletion of suppressor T cells. Cancer Immunol Immunotherapy. 1991;33(6):421–3. 10.1007/BF01741605 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR330] 330.Dunn PL, North RJ. Effect of advanced ageing on the ability of mice to cause tumour regression in response to immunotherapy. Immunology. 1991;74(2):355–9. [PMC free article] [PubMed] [Google Scholar]

[CR331] 331.Sitnikova SI, Walker JA, Prickett LB, Morrow M, Valge-Archer VE, Robinson MJ, et al. Age-induced changes in anti-tumor immunity alter the tumor immune infiltrate and impact response to immuno-oncology treatments. Front Immunol. 2023;14. 10.3389/fimmu.2023.1258291 [DOI] [PMC free article] [PubMed]

[CR332] 332.Dominguez AL, Lustgarten J. Implications of aging and Self-Tolerance on the generation of immune and antitumor immune responses. Cancer Res. 2008;68(13):5423–31. 10.1158/0008-5472.Can-07-6436 [DOI] [PubMed] [Google Scholar]

[CR333] 333.Ishitobi K, Kotani H, Iida Y, Taniura T, Notsu Y, Tajima Y, et al. A modulatory effect of L-arginine supplementation on anticancer effects of chemoimmunotherapy in colon cancer-bearing aged mice. Int Immunopharmacol. 2022;113. 10.1016/j.intimp.2022.109423 [DOI] [PubMed]

[CR334] 334.Li X, Li Y, Dong L, Chang Y, Zhang X, Wang C, et al. Decitabine priming increases anti-PD-1 antitumor efficacy by promoting CD8 + progenitor exhausted T cell expansion in tumor models. J Clin Invest. 2023;133(7). 10.1172/jci165673 [DOI] [PMC free article] [PubMed]

[CR335] 335.Zhang P, Du Y, Bai H, Wang Z, Duan J, Wang X, et al. Optimized dose selective HDAC inhibitor tucidinostat overcomes anti-PD-L1 antibody resistance in experimental solid tumors. BMC Med. 2022;20(1):435. 10.1186/s12916-022-02598-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR336] 336.Zambuzi FA, Cardoso-Silva PM, Castro RC, Fontanari C, Emery FDS, Frantz FG. Decitabine promotes modulation in phenotype and function of monocytes and macrophages that drive immune response regulation. Cells. 2021;10(4). 10.3390/cells10040868 [DOI] [PMC free article] [PubMed]

[CR337] 337.Zhang H, Pang Y, Yi L, Wang X, Wei P, Wang H, et al. Epigenetic regulators combined with tumour immunotherapy: current status and perspectives. Clin Epigenetics. 2025;17(1):51. 10.1186/s13148-025-01856-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR338] 338.Bouchlaka MN, Sckisel GD, Chen M, Mirsoian A, Zamora AE, Maverakis E, et al. Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy. J Exp Med. 2013;210(11):2223–37. 10.1084/jem.20131219 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR339] 339.Garcia MG, Deng Y, Murray C, Reyes RM, Padron A, Bai H, et al. Immune checkpoint expression and relationships to anti-PD-L1 immune checkpoint Blockade cancer immunotherapy efficacy in aged versus young mice. Aging Cancer. 2022;3(1):68–83. 10.1002/aac2.12045 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR340] 340.Prospective. Single-arm Phase II Clinical Study of Single-drug Chemotherapy Plus Immunotherapy in Metastatic Non-small Cell Lung Cancer Elderly Patients 2023. Available from: https://clinicaltrials.gov/study/NCT06032052. Accessed.

[CR341] 341.Phase III. Randomized Trial of Atezolizumab in Elderly Patients With Advanced Non-Small-Cell Lung Cancer and Receiving Monthly Carboplatin With Weekly Paclitaxel Chemotherapy 2019. Available from: https://clinicaltrials.gov/study/NCT03977194. Accessed.

[CR342] 342.Phase 2 Study to Evaluate Reduced Dose Chemotherapy in. Combination With Anti-PD-1 Therapy as First Line Treatment in Vulnerable or Older Adults (Vulnerable or Age ≥ 70) With Advanced PD-L1 TPS < 50% Non-small Cell Lung Cancer 2024. Available from: https://clinicaltrials.gov/study/NCT06731413. Accessed.

[CR343] 343.A Prospective Study of Comprehensive Geriatric. Assessment (CGA) in Non-Small Cell Lung Cancer Patients (NSCLC) Undergoing Treatment With Immune Checkpoint Inhibitors 2022. Available from: https://clinicaltrials.gov/study/NCT05230888. Accessed.

[CR344] 344.A Randomized Phase. 2 Study Comparing Immunotherapy With Chemotherapy in the Treatment of Elderly Patients With Advanced NSCLC (MILES-5) 2019. Available from: https://clinicaltrials.gov/study/NCT03975114. Accessed.

[CR345] 345.Toripalimab After Radiotherapy Alone in Elderly Esophageal Squamous Cell Carcinoma. A Prospective Phase II Clinical Trial 2023. Available from: https://clinicaltrials.gov/study/NCT05791136. Accessed.

[CR346] 346.Efficacy and Safety of Toripalimab After Concurrent. Chemoradiotherapy in Elderly Patients With Esophageal Squamous Cell Carcinoma: a Multicenter, Randomized, Phase II Trial (EC-CRT-007) 2023. Available from: https://clinicaltrials.gov/study/NCT06187597. Accessed.

[CR347] 347.Neoadjuvant PD-1, Blockade (Toripalimab) Monotherapy for Elderly Patients With Locally Advanced Resectable Esophageal Squamous Cell Carcinoma, editors. a Phase II Trial 2024. Available from: https://clinicaltrials.gov/study/NCT06385730. Accessed.

[CR348] 348.Prospective Single-arm. Phase II Study of Nab-paclitaxel Plus Carboplatin in Combination With Sintilimab for Neoadjuvant Therapy in Elderly, Locally Advanced, Resectable Esophageal Squamous Cell Carcinoma 2024. Available from: https://clinicaltrials.gov/study/NCT06403878. Accessed.

[CR349] 349.Tislelizumab Combined With Concurrent Chemoradiation Versus Concurrent Chemoradiation for Older Patients With Inoperable Locally. Advanced Esophageal Squamous Cell Carcinoma: a Randomized, Parallel-controlled, Multicenter Phase II Clinical Study 2023. Available from: https://clinicaltrials.gov/study/NCT06061146. Accessed.

[CR350] 350.Acalabrutinib. and Rituximab in Elderly Patients With Untreated Mantle Cell Lymphoma 2021. Available from: https://clinicaltrials.gov/study/NCT05214183. Accessed.

[CR351] 351.A Multicenter Randomized Open Label Phase II Study. Evaluating the Efficacy and the Tolerance of Immunochemotherapy and of Sequential Hypofractionated Radiotherapy in Unfit or Elderly Patients with Unresectable Stage III Non Small Cell Lung Cancer 2024. Available from: https://clinicaltrials.gov/study/NCT06656598. Accessed.

[CR352] 352.Randomized A. Open-label, Clinical Trial to Compare the Safety and Efficacy of Hypomemylating Agents Monotherapy and Combination With eDC Therapy for Elderly Patients With Myelodysplastic Syndrome 2021. Available from: https://clinicaltrials.gov/study/NCT04999943. Accessed.

[CR353] 353.Bailén R, Iacoboni G, Delgado J, López-Corral L, Hernani-Morales R, Ortiz-Maldonado V, et al. Anti-CD19 CAR-T cell therapy in elderly patients: multicentric Real-World experience from GETH-TC/GELTAMO. Transpl Cell Ther. 2024;30(10):988. 10.1016/j.jtct.2024.06.022 [DOI] [PubMed] [Google Scholar]

[CR354] 354.Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel CAR T-Cell therapy in refractory large B-Cell lymphoma. N Engl J Med. 2017;377(26):2531–44. 10.1056/NEJMoa1707447 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR355] 355.Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut Microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–7. 10.1126/science.aan3706 [DOI] [PubMed] [Google Scholar]

[CR356] 356.Gao G, Shen S, Zhang T, Zhang J, Huang S, Sun Z, et al. <em > Lacticaseibacillus rhamnosus Probio-M9 enhanced the antitumor response to anti-PD-1 therapy by modulating intestinal metabolites</em >. eBioMedicine. 2023;91. 10.1016/j.ebiom.2023.104533 [DOI] [PMC free article] [PubMed]

[CR357] 357.Zak J, Pratumchai I, Marro BS, Marquardt KL, Zavareh RB, Lairson LL, et al. JAK Inhibition enhances checkpoint Blockade immunotherapy in patients with hodgkin lymphoma. Science. 2024;384(6702):eade8520. 10.1126/science.ade8520 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR358] 358.Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA. Age and Age-Related diseases: role of inflammation triggers and cytokines. Front Immunol. 2018;9:586. 10.3389/fimmu.2018.00586 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR359] 359.Karagiannis TT, Dowrey TW, Villacorta-Martin C, Montano M, Reed E, Belkina AC, et al. Multi-modal profiling of peripheral blood cells across the human lifespan reveals distinct immune cell signatures of aging and longevity. EBioMedicine. 2023;90:104514. 10.1016/j.ebiom.2023.104514 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR360] 360.Martínez de Toda I, González-Sánchez M, Díaz-Del Cerro E, Valera G, Carracedo J, Guerra-Pérez N. Sex differences in markers of oxidation and inflammation. Implications for ageing. Mech Ageing Dev. 2023;211:111797. 10.1016/j.mad.2023.111797 [DOI] [PubMed] [Google Scholar]

[CR361] 361.Brown BN, Haschak MJ, Lopresti ST, Stahl EC. Effects of age-related shifts in cellular function and local microenvironment upon the innate immune response to implants. Semin Immunol. 2017;29:24–32. 10.1016/j.smim.2017.05.001 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR362] 362.Furler RL, Newcombe KL, Del Rio Estrada PM, Reyes-Terán G, Uittenbogaart CH, Nixon DF. Histoarchitectural deterioration of lymphoid tissues in HIV-1 infection and in aging. AIDS Res Hum Retroviruses. 2019;35(11–12):1148–59. 10.1089/aid.2019.0156 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR363] 363.Kroemer G, Maier AB, Cuervo AM, Gladyshev VN, Ferrucci L, Gorbunova V, et al. From geroscience to precision geromedicine: Understanding and managing aging. Cell. 2025;188(8):2043–62. 10.1016/j.cell.2025.03.011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR364] 364.Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48. 10.3322/caac.21763 [DOI] [PubMed]

[CR365] 365.Wang C, Long Q, Fu Q, Xu Q, Fu D, Li Y, et al. Targeting Epiregulin in the treatment-damaged tumor microenvironment restrains therapeutic resistance. Oncogene. 2022;41(45):4941–59. 10.1038/s41388-022-02476-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR366] 366.Liu Z, Liang Q, Ren Y, Guo C, Ge X, Wang L, et al. Immunosenescence: molecular mechanisms and diseases. Signal Transduct Target Ther. 2023;8(1):200. 10.1038/s41392-023-01451-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR367] 367.Guarente L, Sinclair DA, Kroemer G. Human trials exploring anti-aging medicines. Cell Metabol. 2024;36(2):354–76. 10.1016/j.cmet.2023.12.007 [DOI] [PubMed] [Google Scholar]

[CR368] 368.Tang X, Deng B, Zang A, He X, Zhou Y, Wang D, et al. Characterization of age-related immune features after autologous NK cell infusion: protocol for an open-label and randomized controlled trial. Front Immunol. 2022;13:940577. 10.3389/fimmu.2022.940577 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR369] 369.López-Otín C, Pietrocola F, Roiz-Valle D, Galluzzi L, Kroemer G. Meta-hallmarks of aging and cancer. Cell Metabol. 2023;35(1):12–35. 10.1016/j.cmet.2022.11.001 [DOI] [PubMed] [Google Scholar]

[CR370] 370.Satpathy AT, Granja JM, Yost KE, Qi Y, Meschi F, McDermott GP, et al. Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion. Nat Biotechnol. 2019;37(8):925–36. 10.1038/s41587-019-0206-z [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR371] 371.Li H, Zhao W, Yang F, Qiao Q, Ma S, Yang K, et al. Immunosenescence Inventory—a multi-omics database for immune aging research. Nucleic Acids Res. 2024;53(D1):D1047–54. 10.1093/nar/gkae1102 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR372] 372.Li W, Zhang Z, Kumar S, Botey-Bataller J, Zoodsma M, Ehsani A, et al. Single-cell immune aging clocks reveal inter-individual heterogeneity during infection and vaccination. Nat Aging. 2025. 10.1038/s43587-025-00819-z [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR373] 373.He J, Burova E, Taduriyasas C, Ni M, Adler C, Wei Y, et al. Single cell-resolved cellular, transcriptional, and epigenetic changes in mouse T cell populations linked to age-associated immune decline. Proc Natl Acad Sci U S A. 2025;122(14):e2425992122. 10.1073/pnas.2425992122 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR374] 374.Wang Y, Li R, Tong R, Chen T, Sun M, Luo L, et al. Integrating single-cell RNA and T cell/b cell receptor sequencing with mass cytometry reveals dynamic trajectories of human peripheral immune cells from birth to old age. Nat Immunol. 2025;26(2):308–22. 10.1038/s41590-024-02059-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR375] 375.Lu J, Ahmad R, Nguyen T, Cifello J, Hemani H, Li J, et al. Heterogeneity and transcriptome changes of human CD8(+) T cells across nine decades of life. Nat Commun. 2022;13(1):5128. 10.1038/s41467-022-32869-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR376] 376.Soto-Heredero G, Gabandé-Rodríguez E, Carrasco E, Escrig-Larena JI, Gómez de Las Heras MM, Delgado-Pulido S, et al. KLRG1 identifies regulatory T cells with mitochondrial alterations that accumulate with aging. Nat Aging. 2025;5(5):799–815. 10.1038/s43587-025-00855-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR377] 377.Xu Y, Li M, Hu C, Luo Y, Gao X, Li X, et al. Developing a novel aging assessment model to uncover heterogeneity in organ aging and screening of aging-related drugs. Genome Med. 2025;17(1):83. 10.1186/s13073-025-01501-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR378] 378.Duan R, Jiang L, Wang T, Li Z, Yu X, Gao Y, et al. Aging-induced immune microenvironment remodeling fosters melanoma in male mice via γδ17-Neutrophil-CD8 axis. Nat Commun. 2024;15(1):10860. 10.1038/s41467-024-55164-3 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR379] 379.Moskowitz DM, Zhang DW, Hu B, Le Saux S, Yanes RE, Ye Z, et al. Epigenomics of human CD8 T cell differentiation and aging. Sci Immunol. 2017;2(8). 10.1126/sciimmunol.aag0192 [DOI] [PMC free article] [PubMed]

[CR380] 380.Bohacova P, Terekhova M, Tsurinov P, Mullins R, Husarcikova K, Shchukina I, et al. Multidimensional profiling of human T cells reveals high CD38 expression, marking recent thymic emigrants and age-related Naive T cell remodeling. Immunity. 2024;57(10):2362–79.e10. 10.1016/j.immuni.2024.08.019 [DOI] [PubMed] [Google Scholar]

[CR381] 381.Liu X, Zhang C, Lv J, Liu Y, Gu C, Gao Y, et al. Pyrroloquinoline Quinone reprograms the Single-Cell landscape of immune aging in hematopoietic immune system. Aging Cell. 2025;24(7):e70050. 10.1111/acel.70050 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR382] 382.Lv J, Zhang C, Liu X, Gu C, Liu Y, Gao Y, et al. An aging-related immune landscape in the hematopoietic immune system. Immun Ageing. 2024;21(1):3. 10.1186/s12979-023-00403-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR383] 383.Li W, Zhang Z, Kumar S, Botey-Bataller J, Zoodsma M, Ehsani A, et al. Single-cell immune aging clocks reveal inter-individual heterogeneity during infection and vaccination. Nat Aging. 2025;5(4):607–21. 10.1038/s43587-025-00819-z [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR384] 384.Huang Z, Chen B, Liu X, Li H, Xie L, Gao Y, et al. Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis. Proc Natl Acad Sci U S A. 2021;118(33). 10.1073/pnas.2023216118 [DOI] [PMC free article] [PubMed]

[CR385] 385.Reitsema RD, Hid Cadena R, Nijhof SH, Abdulahad WH, Huitema MG, Paap D, et al. Effect of age and sex on immune checkpoint expression and kinetics in human T cells. Immun Ageing. 2020;17(1):32. 10.1186/s12979-020-00203-y [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR386] 386.Menees KB, Earls RH, Chung J, Jernigan J, Filipov NM, Carpenter JM, et al. Sex- and age-dependent alterations of Splenic immune cell profile and NK cell phenotypes and function in C57BL/6J mice. Immun Ageing. 2021;18(1):3. 10.1186/s12979-021-00214-3 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR387] 387.McGill CJ, Benayoun BA. Time isn’t kind to female T-cells. Nat Aging. 2022;2(3):189–91. 10.1038/s43587-022-00185-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR388] 388.Li X, Li Y, Jin Y, Zhang Y, Wu J, Xu Z, et al. Transcriptional and epigenetic decoding of the microglial aging process. Nat Aging. 2023;3(10):1288–311. 10.1038/s43587-023-00479-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR389] 389.Yang C, Jin J, Yang Y, Sun H, Wu L, Shen M, et al. Androgen receptor-mediated CD8(+) T cell stemness programs drive sex differences in antitumor immunity. Immunity. 2022;55(7):1268–e839. 10.1016/j.immuni.2022.05.012 [DOI] [PubMed] [Google Scholar]

[CR390] 390.Xiao T, Lee J, Gauntner TD, Velegraki M, Lathia JD, Li Z. Hallmarks of sex bias in immuno-oncology: mechanisms and therapeutic implications. Nat Rev Cancer. 2024;24(5):338–55. 10.1038/s41568-024-00680-z [DOI] [PubMed] [Google Scholar]

[CR391] 391.Conforti F, Pala L, Di Mitri D, Catania C, Cocorocchio E, Laszlo D, et al. Sex hormones, the anticancer immune response, and therapeutic opportunities. Cancer Cell. 2025;43(3):343–60. 10.1016/j.ccell.2025.02.013 [DOI] [PubMed] [Google Scholar]

[CR392] 392.Pala L, De Pas T, Catania C, Giaccone G, Mantovani A, Minucci S, et al. Sex and cancer immunotherapy: current Understanding and challenges. Cancer Cell. 2022;40(7):695–700. 10.1016/j.ccell.2022.06.005 [DOI] [PubMed] [Google Scholar]

[CR393] 393.Shimizu J, Murao A, Aziz M, Wang P. Extracellular cirp inhibits neutrophil apoptosis to promote its aging by upregulating serpinb2 in sepsis. Shock. 2023;60(3):450–60. 10.1097/SHK.0000000000002187 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR394] 394.Hu Y, Bojanowski CM, Britto CJ, Wellems D, Song K, Scull C, et al. Aberrant immune programming in neutrophils in cystic fibrosis. J Leukoc Biol. 2023;115(3):420–34. 10.1093/jleuko/qiad139 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR395] 395.Ou B, Liu Y, Gao Z, Xu J, Yan Y, Li Y, et al. Senescent neutrophils-derived Exosomal piRNA-17560 promotes chemoresistance and EMT of breast cancer via FTO-mediated m6A demethylation. Cell Death Dis. 2022;13(10). 10.1038/s41419-022-05317-3 [DOI] [PMC free article] [PubMed]

[CR396] 396.Egholm C, Özcan A, Breu D, Boyman O. Type 2 immune predisposition results in accelerated neutrophil aging causing susceptibility to bacterial infection. Sci Immunol. 2022;7(71):eabi9733. 10.1126/sciimmunol.abi9733 [DOI] [PubMed] [Google Scholar]

[CR397] 397.Uhl B, Vadlau Y, Zuchtriegel G, Nekolla K, Sharaf K, Gaertner F, et al. Aged neutrophils contribute to the first line of defense in the acute inflammatory response. Blood. 2016;128(19):2327–37. 10.1182/blood-2016-05-718999 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR398] 398.Zhang D, Chen G, Manwani D, Mortha A, Xu C, Faith JJ, et al. Neutrophil ageing is regulated by the Microbiome. Nature. 2015;525(7570):528–32. 10.1038/nature15367 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR399] 399.Rodriguez-Rosales YA, Langereis JD, Gorris MAJ, van den Reek JMPA, Fasse E, Netea MG, et al. Immunomodulatory aged neutrophils are augmented in blood and skin of psoriasis patients. J Allergy Clin Immunol. 2021;148(4):1030–40. 10.1016/j.jaci.2021.02.041 [DOI] [PubMed] [Google Scholar]

[CR400] 400.Matsudaira T, Nakano S, Konishi Y, Kawamoto S, Uemura K, Kondo T, et al. Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype. Commun Biology. 2023;6(1):665. 10.1038/s42003-023-05027-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR401] 401.Wei L, Yang X, Wang J, Wang Z, Wang Q, Ding Y, et al. H3K18 lactylation of senescent microglia potentiates brain aging and alzheimer’s disease through the NFκB signaling pathway. J Neuroinflamm. 2023;20(1):208. 10.1186/s12974-023-02879-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR402] 402.Luo G, Xiang L, Xiao L. Quercetin alleviates atherosclerosis by suppressing oxidized LDL-induced senescence in plaque macrophage via inhibiting the p38MAPK/p16 pathway. J Nutr Biochem. 2023;116:109314. 10.1016/j.jnutbio.2023.109314 [DOI] [PubMed] [Google Scholar]

[CR403] 403.Li M, Niu Y, Tian L, Zhang T, Zhou S, Wang L, et al. Astragaloside IV alleviates macrophage senescence and d-galactose-induced bone loss in mice through STING/NF-κB pathway. Int Immunopharmacol. 2024;129:111588. 10.1016/j.intimp.2024.111588 [DOI] [PubMed] [Google Scholar]

[CR404] 404.Cheng W, Fu Y, Lin Z, Huang M, Chen Y, Hu Y, et al. Lipoteichoic acid restrains macrophage senescence via β-catenin/FOXO1/REDD1 pathway in age-related osteoporosis. Aging Cell. 2024;23(3):e14072. 10.1111/acel.14072 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR405] 405.Matacchione G, Perugini J, Di Mercurio E, Sabbatinelli J, Prattichizzo F, Senzacqua M, et al. Senescent macrophages in the human adipose tissue as a source of inflammaging. GeroScience. 2022;44(4):1941–60. 10.1007/s11357-022-00536-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR406] 406.Gautam S, Kumar R, Kumar U, Kumar S, Luthra K, Dada R. Yoga maintains Th17/Treg cell homeostasis and reduces the rate of T cell aging in rheumatoid arthritis: a randomized controlled trial. Sci Rep. 2023;13(1):14924. 10.1038/s41598-023-42231-w [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR407] 407.Xu L, Wei C, Chen Y, Wu Y, Shou X, Chen W, et al. IL-33 induces thymic involution-associated Naive T cell aging and impairs host control of severe infection. Nat Commun. 2022;13(1):6881. 10.1038/s41467-022-34660-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR408] 408.Pan XX, Yao KL, Yang YF, Ge Q, Zhang R, Gao PJ, et al. Senescent T cell induces brown adipose tissue whitening via secreting IFN-γ. Front Cell Dev Biology. 2021;9. 10.3389/fcell.2021.637424 [DOI] [PMC free article] [PubMed]

[CR409] 409.Pan XX, Wu F, Chen XH, Chen DR, Chen HJ, Kong LR, et al. T-cell senescence accelerates angiotensin II-induced target organ damage. Cardiovascular Res. 2021;117(1):271–83. 10.1093/cvr/cvaa032 [DOI] [PubMed] [Google Scholar]

[CR410] 410.Guo Z, Wang G, Wu B, Chou WC, Cheng L, Zhou C, et al. DCAF1 regulates Treg senescence via the ROS axis during immunological aging. J Clin Invest. 2020;130(11):5893–908. 10.1172/JCI136466 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR411] 411.Zou NY, Liu R, Huang M, Jiao YR, Wei J, Jiang Y, et al. Age-related secretion of Grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing. Bone Res. 2024;12(1). 10.1038/s41413-023-00309-1 [DOI] [PMC free article] [PubMed]

[CR412] 412.Li Y, Chen R, Wu J, Xue X, Liu T, Peng G, et al. Salvianolic acid B protects against pulmonary fibrosis by attenuating stimulating protein 1-mediated macrophage and alveolar type 2 cell senescence. Phytother Res. 2024;38(2):620–35. 10.1002/ptr.8070 [DOI] [PubMed] [Google Scholar]

[CR413] 413.Geng F, Xu M, Zhao L, Zhang H, Li J, Jin F, et al. Quercetin alleviates pulmonary fibrosis in mice exposed to silica by inhibiting macrophage senescence. Front Pharmacol. 2022;13. 10.3389/fphar.2022.912029 [DOI] [PMC free article] [PubMed]

[CR414] 414.Su L, Dong Y, Wang Y, Wang Y, Guan B, Lu Y, et al. Potential role of senescent macrophages in radiation-induced pulmonary fibrosis. Cell Death Dis. 2021;12(6). 10.1038/s41419-021-03811-8 [DOI] [PMC free article] [PubMed]

[CR415] 415.Wada H, Otsuka R, Germeraad WTV, Murata T, Kondo T, Seino KI. Tumor cell-induced macrophage senescence plays a pivotal role in tumor initiation followed by stable growth in immunocompetent condition. J Immunother Cancer. 2023;11(11). 10.1136/jitc-2023-006677 [DOI] [PMC free article] [PubMed]

[CR416] 416.Liu X, Hartman CL, Li L, Albert CJ, Si F, Gao A, et al. Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy. Sci Transl Med. 2021;13(587):eaaz6314. 10.1126/scitranslmed.aaz6314 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR417] 417.Gao A, Liu X, Lin W, Wang J, Wang S, Si F, et al. Tumor-derived ILT4 induces T cell senescence and suppresses tumor immunity. J Immunother Cancer. 2021;9(3):e001536. 10.1136/jitc-2020-001536 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR418] 418.Fukushima Y, Sakamoto K, Matsuda M, Yoshikai Y, Yagita H, Kitamura D, et al. Cis interaction of CD153 with TCR/CD3 is crucial for the pathogenic activation of senescence-associated T cells. Cell Rep. 2022;40(12). 10.1016/j.celrep.2022.111373 [DOI] [PubMed]

[CR419] 419.Kalim H, Wahono CS, Permana BPO, Pratama MZ, Handono K. Association between senescence of T cells and disease activity in patients with systemic lupus erythematosus. Reumatologia. 2021;59(5):292–301. 10.5114/reum.2021.110318 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR420] 420.Mathiasen SL, Gall-Mas L, Pateras IS, Theodorou SDP, Namini MRJ, Hansen MB et al.Bacterial genotoxins induce T cell senescence. Cell Reports. 2021;35(10). 10.1016/j.celrep.2021.109220 [DOI] [PubMed]

[CR421] 421.Duggal NA, Upton J, Phillips AC, Hampson P, Lord JM. NK cell immunesenescence is increased by psychological but not physical stress in older adults associated with Raised cortisol and reduced Perforin expression. AGE. 2015;37(1):11. 10.1007/s11357-015-9748-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR422] 422.Kim C, Jadhav RR, Gustafson CE, Smithey MJ, Hirsch AJ, Uhrlaub JL, et al. Defects in antiviral T cell responses inflicted by Aging-Associated miR-181a deficiency. Cell Rep. 2019;29(8):2202–e165. 10.1016/j.celrep.2019.10.044 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR423] 423.Fessler J, Fasching P, Raicht A, Hammerl S, Weber J, Lackner A, et al. Lymphopenia in primary sjögren’s syndrome is associated with premature aging of Naïve CD4 + T cells. Rheumatol (United Kingdom). 2021;60(2):588–97. 10.1093/rheumatology/keaa105 [DOI] [PubMed] [Google Scholar]

[CR424] 424.Frasca D, Romero M, Diaz A, Blomberg BB. Obesity accelerates age defects in B cells, and weight loss improves B cell function. Immun Ageing. 2023;20(1):35. 10.1186/s12979-023-00361-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR425] 425.Rinaldi S, Pallikkuth S, George VK, de Armas LR, Pahwa R, Sanchez CM, et al. Paradoxical aging in HIV: immune senescence of B cells is most prominent in young age. Aging. 2017;9(4):1307–25. 10.18632/aging.101229 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR426] 426.Kawamoto S, Uemura K, Hori N, Takayasu L, Konishi Y, Katoh K, et al. Bacterial induction of B cell senescence promotes age-related changes in the gut microbiota. Nat Cell Biol. 2023;25(6):865–76. 10.1038/s41556-023-01145-5 [DOI] [PubMed] [Google Scholar]

[CR427] 427.Zeng X, Liang C, Yao J. Chronic shift-lag promotes NK cell ageing and impairs immunosurveillance in mice by decreasing the expression of CD122. J Cell Mol Med. 2020;24(24):14583–95. 10.1111/jcmm.16088 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR428] 428.Schratz KE, Flasch DA, Atik CC, Cosner ZL, Blackford AL, Yang W, et al. T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers. Cancer Cell. 2023;41(4):807–e176. 10.1016/j.ccell.2023.03.005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR429] 429.Pei S, Deng X, Yang R, Wang H, Shi J-H, Wang X, et al. Age-related decline in CD8 + tissue resident memory T cells compromises antitumor immunity. Nat Aging. 2024;4(12):1828–44. 10.1038/s43587-024-00746-5 [DOI] [PubMed] [Google Scholar]

[CR430] 430.Kang TG, Lan X, Mi T, Chen H, Alli S, Lim S-E, et al. Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy. Science. 2024;386(6718):eadl4492. 10.1126/science.adl4492 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR431] 431.Ikeda H, Kawase K, Nishi T, Watanabe T, Takenaga K, Inozume T, et al. Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature. 2025;638(8049):225–36. 10.1038/s41586-024-08439-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR432] 432.Tang L, Wu J, Li CG, Jiang HW, Xu M, Du M, et al. Characterization of immune dysfunction and identification of prognostic immune-Related risk factors in acute myeloid leukemia. Clin Cancer Res. 2020;26(7):1763–72. 10.1158/1078-0432.Ccr-19-3003 [DOI] [PubMed] [Google Scholar]

[CR433] 433.Park JV, Chandra R, Cai L, Ganguly D, Li H, Toombs JE, et al. Tumor cells modulate macrophage phenotype in a novel in vitro Co-Culture model of the NSCLC tumor microenvironment. J Thorac Oncol. 2022;17(10):1178–91. 10.1016/j.jtho.2022.06.011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR434] 434.Chen P, Yang X, Chen W, Wei W, Chen Y, Wang P, et al. Developing and experimental validating a T cell senescence-related gene signature to predict prognosis and immunotherapeutic sensitivity in non-small cell lung cancer. Gene. 2025;941:149233. 10.1016/j.gene.2025.149233 [DOI] [PubMed] [Google Scholar]

[CR435] 435.Park MD, Le Berichel J, Hamon P, Wilk CM, Belabed M, Yatim N, et al. Hematopoietic aging promotes cancer by fueling IL-1⍺-driven emergency myelopoiesis. Science. 2024;386(6720):eadn0327. 10.1126/science.adn0327 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Immunosenescence and cancer: molecular hallmarks, tumor microenvironment remodeling, and age-specific immunotherapy challenges

Qianwen Liu

Jingfeng Li

Xiuqiao Sun

Jiayu Lin

Zhengwei Yu

Yue Xiao

Dan Li

Baofa Sun

Haili Bao

Yihao Liu

Abstract

Introduction

Hallmarks of Immunosenescence

Genomic instability

Telomere attrition

Epigenetic alterations

Fig. 1.

Loss of proteostasis

Disabled autophagy

Fig. 2.

Mitochondrial defects

Cellular senescence

Table 1.

Hematopoietic stem cells (HSCs) myeloid bias

Altered intercellular communication

Fig. 3.

Chronic inflammation

Gut dysbiosis

Fig. 4.

Table 2.

Effects of aging on systemic immunity in tumor patients

Fig. 5.

Immunosenescence-driven remodeling of the tumor microenvironment

Fig. 6.

Neutrophils

Natural killer (NK)

Macrophages

T lymphocytes

B lymphocytes

Cancer‑associated fibroblasts (CAFs)

The relationship between aging and tumor immunotherapy

Communications and conclusions

Acknowledgements

Author contributions

Data availability

Declarations

Competing interests

Footnotes

Contributor Information

References

Associated Data

Data Citations

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases