Inflammation and aging-related disease: A transdisciplinary inflammaging framework

Abstract

Inflammaging, a state of chronic, progressive low-grade inflammation during aging, is associated with several adverse clinical outcomes, including frailty, disability, and death. Chronic inflammation is a hallmark of aging and is linked to the pathogenesis of many aging-related diseases. Anti-inflammatory therapies are also increasingly being studied as potential anti-aging treatments, and clinical trials have shown benefits in selected aging-related diseases. Despite promising advances, significant gaps remain in defining, measuring, treating, and integrating inflammaging into clinical geroscience research. The Clin-STAR Inflammation Research Interest Group was formed by a group of transdisciplinary clinician-scientists with the goal of advancing inflammaging-related clinical research and improving patient-centered care for older adults. Here, we integrate insights from nine medical subspecialties to illustrate the widespread impact of inflammaging on diseases linked to aging, highlighting the extensive opportunities for targeted interventions. We then propose a transdisciplinary approach to enhance understanding and treatment of inflammaging that aims to improve comprehensive care for our aging patients.

Introduction

First described over 20 years ago, the term inflammaging (or inflamm-aging) refers to a state of chronic, progressive low-grade inflammation associated with aging [1–3]. Inflammaging is defined by elevated circulating inflammatory markers in older compared to younger individuals [1]. The pro-inflammatory state of inflammaging is characterized by specific immune system changes that occur with aging and an imbalance of pro-inflammatory and immunoregulatory molecules.

Inflammaging occurs in parallel to biological immune aging and immunosenescence [4]. Cellular senescence refers to the process of cell cycle arrest caused by cellular stress or damage and is closely linked to chronic inflammation [5]. Classification of cellular senescence differs by tissue, where—as opposed to classically defined cellular senescence—immunosenescence describes the state of cellular exhaustion and associated immune dysfunction. Immunosenescence is also hallmarked by a loss of immune cell proliferative capacity resulting in the accumulation of effector and memory T cells with an accompanying reduction in naïve T cells and T-cell receptor repertoire [6, 7].

Senescent cells—including senescent immune cells—are associated with a pro-inflammatory milieu called the senescence-associated secretory phenotype (SASP), highlighting how inflammaging is intertwined with the broader biology of aging [8]. The term inflammaging is most commonly applied when alterations in immune parameters are associated with adverse health outcomes, although it can also occur in the context of healthy aging [9]. The drive to understand the role of inflammaging in the biology of aging, chronic diseases, and health has contributed to the burgeoning interdisciplinary field of geroscience [10].

The Clinician-Scientists Transdisciplinary Aging Research (Clin-STAR) Inflammation Research Group was formed in 2021 as a group of multidisciplinary clinician-scientists with a specific career interest in studying the intersections of geroscience and inflammation. The primary intent of the group is to learn from and integrate unique perspectives on inflammaging from various medical subspecialties. By breaking down silos of specialty care, the ultimate goals of the group are to advance inflammaging-related clinical research and improve patient-centered care for older adults.

In this expert commentary and narrative review, the Clin-STAR Inflammation Research Group aims to provide a roadmap to how to better integrate the science of inflammaging into clinical care and research. We recognize the pivotal role inflammaging plays in the onset and progression of many age-associated chronic diseases and acute illnesses. Thus, each group member has dedicated considerable effort to reviewing the available research related to inflammation and geroscience within the context of individual subspecialty and research interests.

Here, we first discuss the gaps and challenges of integrating the concept of inflammaging into the framework of clinical geroscience research (“Challenges in defining, measuring, and managing inflammation in aging” section). We then summarize inflammaging’s unique roles through illustrative (i.e., not comprehensive by design) clinical examples across nine medical subspecialties: endocrinology, rheumatology, gastroenterology, dermatology, oncology, nephrology, neurology, critical care, and infectious disease (“Disease-specific manifestations of inflammaging” section). For each disease-specific manifestation of inflammaging, we present a structured overview based on available evidence for the following sub-topics: (1) a description of the condition and pertinence of older age to its natural history, (2) a description of known pathologic mechanisms related to inflammaging and hallmarks of aging OR novel reframing of the condition in the context of inflammaging, and (3) recommendations for future therapeutic interventions or trial designs based upon inflammaging principles and/or description of contemporaneous efforts to target inflammaging. We decided to focus on both chronic and acute diseases linked to aging given the group consensus for the relevance of inflammaging to acute conditions and our goal to expand the discussion with the scientific community for the role of inflammaging beyond classic associations (e.g., cardiovascular disease and cognitive decline). Finally, in the “What we can learn from harmonizing research on inflammatory diseases of aging: shared pathways, shared interventions, and a transdisciplinary approach to clinical care” section, we propose a transdisciplinary inflammaging framework to advance our understanding of the biology underlying age-dependent disease states and ultimately enhance the lives of older adults (Fig. 1).

Fig. 1.

Connecting inflammaging pathways and treatment strategies in aging-related disease

Challenges in defining, measuring, and managing inflammation in aging

Defining the biology of inflammation in aging remains a significant challenge, hindering the translation of the concept of inflammaging into clinical practice [10]. To date, there are no universally accepted criteria (e.g., a unique panel of biomarkers or immune cell abnormalities) to clinically define this process. Traditional biomarkers for inflammaging include acute phase reactants such as C-reactive protein (CRP), plasma concentrations of cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF), cytomegalovirus (CMV) seropositivity, and myeloid cell subsets such as CD28-CD57 + KLRG1 + terminally differentiated T cells [4, 11]. Given the complexities and interconnectedness between inflammation, immunosenescence, and immune aging, each traditional biomarker is individually limited in its utility as a measure of inflammaging. As an example, CRP has been extensively studied in cross-section as a purported biomarker for inflammaging, but its levels may not accurately capture inflammaging-related changes [12]. To improve upon the shortcomings of individual biomarkers as measures of inflammaging, composite metrics such as the IMM-AGE score combine cytokine responses, immune phenotypes, and transcriptomic analyses [13]. Still, it remains unclear whether the application of multi-omic biomarker panels or objective scoring systems akin to the IMM-AGE score to individual patients will be feasible and/or clinically useful to improve health [14]. Until gold-standard biomarkers are determined, future work in this area should include longitudinal evaluation of multiple measures of inflammaging in patients with multimorbidity within both cohort studies and clinical trials.

Inflammaging is a key geroscience concept that is linked to chronic diseases of aging, disability, frailty, and death [1]. As one of the 12 “hallmarks” of aging, inflammaging is likely triggered by derangements stemming from other aging hallmarks and may be a common final pathway of biologic aging for many individuals [15]. Thus, therapies targeting inflammaging hold significant promise for the management of many acute and chronic illnesses linked to inflammation and for potentially extending the human lifespan, though the current evidence is limited [1]. Both non-specific and targeted anti-inflammatory therapies, like glucocorticoids and TNF inhibitors, respectively, have long been the mainstay of disease-specific management for many chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. Despite their widespread application in chronic inflammatory diseases, older age has often been an exclusion criterion to enrollment in randomized controlled trials of these agents [16]. Furthermore, there are few longitudinal preclinical studies of geriatric animal models (e.g., mice 28 months and older) that comprehensively and non-invasively quantify healthspan and frailty, limiting our understanding of therapies to mitigate inflammaging. Additional anti-inflammatory medications—such as colchicine and biologic drugs targeting IL-1β and IL-6—may have broader utility, as they have recently shown promise for the management and prevention of cardiovascular disease [17]. Observed beneficial effects of non-pharmacologic interventions on lifespan [18, 19]—such as exercise, diet, and other lifestyle interventions—may also be partially mediated by reductions in inflammaging [20].

Analogous to therapies and lifestyle interventions known to modulate inflammatory cascades, senotherapeutics are interventions that target cellular senescence, which can act by selectively eliminating senescent cells (“senolytics”) or inhibiting the SASP (“senomorphics”), and have been associated with reductions in inflammatory markers in phase I clinical trials [21, 22]. While promising, the use of therapies to directly target inflammaging or immunosenescence independent from individual diseases remains experimental and has not been integrated into clinical practice. Thus, further understanding of the shared biological pathways, clinical phenotypes, and treatment strategies for inflammatory diseases of aging promises to improve both the measurement and management of inflammaging across the entire clinical spectrum.

Disease-specific manifestations of inflammaging

Chronic conditions

Diabetes mellitus

Type 2 diabetes (T2D) is a complex metabolic disorder that leads to chronic hyperglycemia and affects nearly 25% of adults aged 65 and older in the USA [23]. T2D is a clinical manifestation of several hallmarks of aging including, but not limited to, chronic inflammation, deregulated nutrient-sensing, cellular senescence, and epigenetic changes [15]. There is increasing evidence for mechanistic interactions between these two hallmarks of aging—together, called “immunometabolism” [24]. T2D, as a chronic inflammatory state [25], in combination with chronic hyperglycemia contributes to the long-term complications associated with diabetes, including non-alcoholic fatty liver disease [24], cardiovascular disease [26], retinopathy [27, 28], and nephropathy [29], and may contribute to the association of T2D with other age-related conditions such as Alzheimer’s disease [30] and rheumatoid arthritis [31]. Cytokines that have been associated with these long-term complications include IL-1β, IL-8, and TNF [24]. Strong evidence now also supports that increased glucose metabolism characteristic of T2D influences the inflammatory response and can contribute to a pro-inflammatory state. Glucose metabolism can influence inflammatory responses through effects on NADH:NAD + ratio and the NADH-sensitive transcriptional co-repressor CtBP, HDAC4 protein levels, NLRP3 inflammasome formation, and activation of RAGE [32–34].

Metabolic influence on the immune system is long-lasting. Hyperglycemia augments glucose utilization and increases flux through glycolysis, a process that persists in patients with T2DM even after restoration of normal circulating glucose levels with available therapies. This unrelenting, diffuse induction of glycolysis—a phenomenon known as “metabolic memory” [35–37]—leads to chronic immune activation and may partially explain why inflammation increases over time with advancing age in adults with T2D [2]. Conversely, reduction of glycolysis through dietary restriction has generally been found to decrease inflammation, which may delay age-related diseases and increase lifespan in humans and other species [38–41].

Some current non-pharmacologic and pharmacologic therapeutic approaches to T2D, in addition to their primary mechanisms of action, have significant anti-inflammatory effects. Non-pharmacological therapies, such as regular exercise, are associated with lower circulating CRP and IL-6 over time and improve cardiovascular and all-cause mortality [42]. Interestingly, long-term benefits of exercise have been observed despite profound transient increases in both pro- and anti-inflammatory cytokines released during an acute bout of exercise and in the immediate recovery phase[43, 44], which highlights the need to further elucidate and disentangle the complex interplay between intermittent acute immune activation and inflammaging. Like exercise, anti-diabetic agents, including insulin, metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium–glucose cotransporter-2 inhibitors, have intrinsic anti-inflammatory effects associated with their primary mechanisms of action and are associated with reductions in inflammatory markers such as NF-kappaB [45]. An improved understanding of the mechanisms linking inflammation to dysregulated metabolism has stimulated interest in directly targeting inflammatory pathways as a strategy to prevent or treat metabolic diseases in older adults [46–48].

Rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by symmetric chronic inflammatory arthritis particularly affecting small joints. RA most frequently occurs in middle-aged women, although the incidence of RA increases with age and one-third of older adults with RA are diagnosed after the age of 65 [49]. The pathogenesis and perpetuation of chronic inflammation in RA involves a complex interplay between genetics, sex hormones, and environmental and behavioral risk factors (e.g., infectious agents, cigarette smoking) [50]. Extra-articular involvement (e.g., pulmonary) and complications likely secondary to chronic systemic inflammation (e.g., increased risk of cardiovascular disease, cognitive impairment) are commonly observed in individuals with RA. RA is an autoimmune disease in which immune aging plays a critical role in disease development; in addition, accelerated immunosenescence has also been observed in individuals with RA. Several important contributions to date shed light on mechanisms by which the immune aging process shapes the immune system and contribute to the development of RA in predisposed individuals [51, 52]. These features include autoantibody production, accumulations of age-associated B cells (ABCs), accumulation of end-differentiated T cells (TEMRAs), SASP production from immune and non-immune cells, clonal hematopoiesis, and altered metabolism/mitochondrial dysfunction [53]. Inflammatory markers commonly associated with aging and age-related syndromes (e.g., frailty, cognitive impairment), such as CRP, IL-6, IL-1, and TNF, are part of the pathogenesis of multiple autoimmune diseases including RA and have proven to be highly effective therapeutic targets.

All 12 hallmarks of aging [10] have been observed in individuals with RA. Notably, these hallmarks may even exist in patients with RA at younger ages. These different cellular and molecular mechanisms lead to the transformation of immune effector cells into auto-aggressive facilitators. Patients with RA, regardless of age, have reduced T-cell receptor diversity, loss of expression of CD28 costimulatory molecules, and shortened telomeres [54]. Senescent T cells (late-stage differentiated) in RA, which are key mediators of the disease, also acquire inflammatory and cytotoxic functions and express the chemokine receptor CX3CR1. This T-cell sub-population has been implicated in the premature development of osteoporosis, cardiovascular disease, and cognitive impairment in individuals with RA.

Accelerated vascular aging, manifesting as increased vascular stiffness, is also observed in individuals with RA due to immunosenescence and chronic inflammation. A high prevalence of cardiovascular disease has been reported in individuals with RA, even after adjusting for traditional risk factors [55]. Studies have also highlighted a higher prevalence of dementia in individuals with RA [56, 57]. Interestingly, treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) (e.g., TNF inhibitors, IL-6 inhibitors) has been found to reduce excess risk of both cardiovascular disease and dementia [58, 59]. However, despite potential common pathways in the pathophysiology of such age-related conditions and RA, these benefits are possibly more related to disease control than to these therapies directly impacting these associated conditions [60]. In contrast to their beneficial effects on cardiovascular disease and dementia, bDMARDs have not shown any effect on muscle mass [61]. In contrast to current pharmacologic therapies, lifestyle interventions—including exercise training and dietary modification—may improve RA-associated sarcopenia, inflammation, and cardiovascular disease risk [62, 63]. Emerging therapies for RA—including personalized lifestyle prescription and novel pharmacotherapies targeting microRNAs, small molecules, and bioenergetic metabolism (e.g., lactate dehydrogenase, glutaminase, and AMP-activated protein kinase)—hold promise to not only modulate pro-inflammatory immune pathways but also aid in comprehensive care for RA, RA-associated comorbidities, and RA accelerated biologic aging [63–65]. Although further work is needed to better understand the connection between improved disease control and its impact on accelerated aging and associated outcomes, these results highlight the potential multiorgan benefits of treatment strategies that result in a general reduction in systemic inflammation.

Inflammatory bowel diseases

Inflammatory bowel diseases (IBDs)—including Crohn’s disease and ulcerative colitis—are chronic, remitting, relapsing, immune-mediated inflammatory conditions primarily affecting the luminal gastrointestinal tract and are associated with several extra-intestinal manifestations. They are most often diagnosed in young adults; however, IBD has a bimodal distribution of incidence with a second, smaller, peak in the fifth and sixth decades of life. In addition to older-onset IBD, patients with IBD now have a longer life expectancy resulting from improved treatment options, which has led to a dramatically increased prevalence in older adults worldwide; in the USA, one-third of people living with IBD are 60 years and older [66, 67]. While not traditionally considered a disease of aging, IBD may be a model disease that provides key insights into chronic immune stimulation and dysbiosis with advancing age.

Historically IBD was thought to become milder with advancing age due to processes such as thymic involution and immunosenescence. However, recent cohorts have established that disease behaviors and activity are remarkably similar between older and younger people and that older adults may have a higher likelihood of developing immunologic responses to IBD-related treatments [68, 69]. Furthermore, increasing evidence suggests that patients with IBD are more likely to have geriatric syndromes, like frailty, as well as experience geriatric syndromes at younger ages [70, 71]. Currently, there are no clinical, molecular, or microbial predictors to determine which older adults have IBD that will “burn out” with advancing age and which older adults are prone to active and progressive disease or flares of disease with advancing age. Thus, it is increasingly important to understand how ongoing dysbiosis and inflammation may accelerate biological aging and, conversely, whether treatment targeting IBD-related inflammation can mitigate the risk of accelerating age.

Unlike the systemic immune system, the mucosal immune system is tasked with both protection against pathogens and tolerance for commensal microbes critical for maintaining intestinal homeostasis. However, in IBD, dysbiosis disrupts the mucosal intestinal barrier allowing for increased microbial exposure, resulting in a dysregulated immune response [72]. This leads to activation of the innate immune response, with macrophages releasing TNF, IL-6, IL-12, and IL-23, as well as neutrophil degranulation, and ultimately activation of the adaptive immune system through dendritic cell antigen presentation to T cells. Similar to inflammaging, activation of the adaptive immune system through T effector cells (both regulatory and memory) is thought to be the predominant driver of inflammation in IBD. More specifically, T helper 1 (Th1) and Th17 effector cells have been implicated in the pathogenesis of IBD by further increasing concentrations of interferon-γ, macrophages, neutrophils, natural killer cells, and CD8 T cells [72]. This has been replicated in murine colitis models and overlaps with the biology of immunosenescence, in which T cells undergo remodeling and reprogramming toward Th17 and other SASP-producing phenotypes [73]. In the absence of early effective immune-targeted treatment, this results in chronic immune stimulation, which is postulated as a putative mediator of inflammaging [74]. This is clinically evident, as patients with long-standing IBD frequently exhibit premature geriatric syndromes, such as multimorbidity, disability, dementia, and frailty at younger ages [75]. Accordingly, IBD is a promising candidate for a prototypical disease that can offer significant biological insight into inflammaging, which may facilitate the discovery of reversible components of this complex process.

Dysbiosis, a microbial imbalance, is a hallmark of IBD that can be seen with advancing age. In various animal models, advancing age-related changes to the gut microbiota have been associated with intestinal barrier dysfunction and higher circulating levels of TNF [76]. Furthermore, reducing these circulating TNF levels with a TNF inhibitor agent, adalimumab, has been shown to reverse age-related changes in the microbiota [77]. While this has not been clearly demonstrated in humans, this is a clear example of how dysbiosis associated with aging may lead to a later peak of older-onset IBD. Microbial-based therapies, including microbial modulation, are thus of significant interest as a treatment strategy for IBD [78]. In parallel, understanding the most efficacious methodologies to modulate the human gut microbiome may help advance the treatment of dysbiotic aging as well.

Cellular senescence is a hallmark of aging, and it is well accepted that chronic inflammation can contribute to cellular senescence [79]. However, the relationship between IBD and cellular senescence has not been explored in depth. IBD has been described to have a SASP that may be perpetuating chronic inflammation [80]. Perhaps as the complex role of the macrophage in IBD is better understood, the relationship between cellular senescence and IBD will be elucidated [81].

Initial treatment of IBD focuses on the control of inflammation through either medications or surgery. As part of the Th1 and Th17 pathways, the majority of medical therapies focus on reducing T-cell activation (JAK inhibitors, IL-23 inhibitors) or lymphocyte trafficking (S1P receptor modulators, α4β7 inhibitors) or on reducing circulating levels of TNF (TNF inhibitors) [82]. There is also interest in boosting IL-2 levels as a treatment option—with the goal of increasing T regulatory cells and decreasing T effector cells—a treatment strategy that may be pertinent to other aging-related conditions as lower IL-2 levels have been linked to inflammaging [83]. While these therapies target overlapping inflammatory pathways associated with aging, it is unknown whether targeted treatment specifically mitigates premature aging seen in patients with IBD. One small retrospective clinical study suggested that response to effective IBD treatment may reverse frailty-related diagnoses [84], underscoring the need for further investigation. Future research is therefore needed to understand the impact of IBD-related inflammation on biological aging and whether early and effective treatment of IBD with immune-acting agents such as biologics and small molecules can reduce or even reverse the risk of accelerated biological aging [85, 86].

Inflammatory skin disease

Chronic inflammatory skin diseases, also known as immune-mediated inflammatory skin diseases, represent a disease spectrum with distinct pathologies and clinical presentations [87]. The incidence of many inflammatory skin diseases, including atopic dermatitis, psoriasis, chronic urticaria, and bullous pemphigoid, has been increasing over the past 2–3 decades, especially among older adults [88–90]. Atopic dermatitis (also known as eczema) is the most common of the inflammatory skin diseases and is characterized by an episodic course of itchy skin plaques, skin barrier dysfunction, and elevations in both skin and circulating inflammatory markers [91–93]. Although classically considered a pediatric skin condition, it is now recognized as a systemic inflammatory disorder that can present at any age [94, 95]. Atopic dermatitis is one of the most burdensome skin diseases, impacting up to 20% of children, 3–10% of adults, and > 10% of older adults, for whom it is often more active and more severe [94, 96]. Patients with atopic dermatitis have increases in blood levels of inflammatory markers and inflammatory changes in both lesional skin and normal-appearing non-lesional skin [97–99]. Additionally, moderate-to-severe atopic dermatitis is associated with an increased risk of mortality and multiple age-related conditions including cardiovascular disease, osteoporosis and fractures, and cognitive decline [100–105].

It has been hypothesized that immunosenescence contributes to an increased susceptibility to inflammatory skin disease in older adults, and multiple studies have identified differences in the inflammatory profiles of older adults with immune-mediated skin diseases as compared to younger individuals, but direct evidence is lacking [106, 107]. For example, the inflammatory profile of atopic dermatitis is heterogeneous but can generally be characterized as an initial type 2 inflammatory response followed by a widening of the immune response with the involvement of Th22, Th17, and Th1 cells. One study evaluating age-related skin changes in over 300 adults found increases in inflammation and Th2, Th22, Th1, and Th17 immune axes and dendritic cell markers with age [108]. Notably, despite the more Th2-dominant cytokine profile seen with normal aging, a concomitant reduction in serum IgE level was observed that may be due to a reduction in B-cell repertoire available to respond to antigenic stimuli [108, 109]. Comparing patients with atopic dermatitis to healthy controls, there were decreases in both skin and blood in the Th2/Th22 axes, parallel increases with age in the Th1/Th17 axes, and more pronounced barrier defects [108]. Although immune aging has been linked to atopic dermatitis and other inflammatory skin conditions, most studies that measure markers of cellular senescence or expression of SASP have focused on the role of ultraviolet (UV) radiation, tumorigenesis or wound healing, and additional research on the role of these factors in inflammatory diseases are needed [110].

Age-associated declines in skin barrier function may also contribute to systemic inflammaging. Multiple age-associated changes in the skin barrier can increase exposure to microbes and environmental toxins and reduce resilience to minor injury, which can trigger epidermal cytokine cascades [111, 112]. Beginning at age 50, skin barrier decline is caused by decreased sodium-hydrogen antiporter activity and impaired stratum corneum acidification, and after age 70, lipid production in the epidermal barrier is also impaired [113]. Experimental evidence supports the relevance of skin barrier function for inflammaging: acute barrier disruption in young mice induces keratinocyte-derived cytokine expression of TNF, IL-1a, IL-1b, and IL-6 in the skin and circulation, and correction of the epidermal barrier with moisturizers results in a significant reduction in serum levels of inflammatory markers in both mice [114] and humans [88]. Notably, the relationship between barrier function and inflammation may be cyclical as it has been shown that type 2 inflammation impacts the expression of genes relevant to barrier function[115].

Treatment strategies for inflammatory skin disease often include skin barrier restoration with topical moisturizers and immunomodulatory strategies. While historically treated with broadly immunosuppressive medications like glucocorticoids and methotrexate, the availability of new, targeted small molecules and biologics have revolutionized the treatment landscape in recent years. Modulators of the IL-4/IL-13 pathway (e.g., dupilumab and tralokinumab) and of the JAK/STAT pathway (e.g., upadacitinib, abrocitinib, and topical ruxolitinib) are now approved for atopic dermatitis and are undergoing clinical testing in other inflammatory skin diseases [116, 117]. Animal studies show that JAK inhibitors may suppress SASP expression [118], but studies of patients with inflammatory skin disease have not included this outcome. Additional research is needed on the potential impact of inflammaging and on the safety and efficacy of these new treatments as older adults are often under-represented in clinical trials in skin disease [119].

Treatments like metformin and senolytics have not been widely studied in inflammatory skin diseases, though topical formulations have shown some benefit in reducing senescent cells in photodamaged skin [106, 120]. Additional research is needed to understand the impact of anti-inflammatory, senolytic, and skin barrier function–directed treatments on accelerated aging in atopic dermatitis and other inflammatory skin diseases and the role of declining skin barrier function on accelerated aging more generally.

Multiple myeloma

The risk of developing any form of invasive cancer after the age of 70 exceeds 25% [121]. While age-related accumulation of DNA damage contributes to this disproportionate age-related disease burden, low-grade chronic inflammation in older adults may also contribute to both the development of cancer from precursor states and resistance to treatments [122]. Development and progression of multiple myeloma, a blood malignancy primarily affecting older adults, with a median age of 65 at diagnosis and a peak incidence around 80 years of age, is a prime example of this inflammation-centric oncologic disease conceptualization [123].

Multiple myeloma follows a trajectory from asymptomatic to symptomatic stages, marked by a series of critical transformations affecting the tumor and the bone marrow immune environment. From a tumor perspective, one working hypothesis is that an abnormal immune response, either to self-proteins or to infectious pathogens, increases the risk of genetic alteration and malignant transformation. Indeed, chronic inflammation is established as causal in sporadic cases of monoclonal gammopathy of undetermined significance (MGUS), the main precursor of myeloma, and specific subsets of myeloma such as those occurring in Gaucher’s disease, where long-term immune activation by lysolipids may underlie disease initiation [124]. Long-term antigenic stimulation may also promote genomic instability in myeloma by engaging cytidine deaminases, a process that may cause the progression from asymptomatic to overt myeloma [125]. Low-grade inflammation is seen early in the disease course [126] and associated with an immunosenescent state characterized by depletion of B cells, an accumulation of TEMRAs, and a shift toward a myeloid state, all of which further contribute to the generation of a pro-inflammatory state [127]. This phenomenon aligns with the concept of inflammaging and leads to the development of a hostile inflammatory milieu that is less amenable to immune regulation and contributes to tumor growth [128]. From a therapeutic perspective, this is likely to affect response to immunotherapies such as CAR-T and T-cell engagers that have recently been FDA-approved in myeloma. It has been shown that older age at diagnosis correlates with factors influencing immunotherapy response, including increased tumor mutational burden and altered immune signaling, alongside markers of immunosuppression, potentially affecting immunotherapy outcomes in older patients [129].

The interplay between aging, immune system dysregulation, and myeloma pathogenesis underscores the need for innovative therapeutic approaches that consider the unique challenges imposed by inflammaging. Such tailored approaches could contribute to optimizing anti-tumor response and healing by modulating inflammation, especially in the context of immunotherapies. These findings apply to many cancers, particularly those associated with inflammatory disorders such as colorectal cancer with IBD [130] or hepatocellular carcinoma with chronic hepatitis B viral infection [131]. Another noteworthy context which has sparked some interest in recent years has been the impact of immune aging on the effectiveness of cellular immunotherapy, such as chimeric antigen receptor T or NK cells that are primed in vitro for their inflammatory potential. A deeper understanding of these complex immune dynamics may pave the way for more targeted and effective interventions to improve the prognosis and quality of life for both oncology patients and older adults.

Chronic and end-stage kidney disease

Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) are associated with both premature and accelerated aging [132]. The mechanisms that underpin accelerated aging in kidney disease are diverse and include the impaired renal clearance of uremic toxins, telomere shortening [133], oxidative stress [134], cellular senescence and mitochondrial dysfunction, systemic inflammation [135, 136], and accumulation of advanced glycation end-products [137]. Acute kidney injury (AKI) is associated with both intrarenal and systemic inflammation [138]. As a result of AKI, chemokines and adhesion molecules in the endothelium of blood vessels in the kidney are upregulated [139] causing a homing of lymphocytes, neutrophils, and macrophages from the circulation into the kidney interstitium [140]. During this acute response, inflammatory mediators are released from kidney proximal tubules into the tubular lumen and produce vasoconstrictors that may further worsen tubular injury [141]. However, inflammatory mediators and the immune response play a key role in repair after AKI [142]. For example, M2 macrophages have anti-inflammatory functions and promote tubular regeneration after injury [143]. Furthermore, mouse models of ischemia–reperfusion injury demonstrate that depletion of CD4 + and CD25 + T regulatory cells prior to injury results in increased renal cell necrosis after ischemia, whereas repletion of T regulatory cells results in attenuated renal injury, suggesting a role for these cells in AKI recovery [141]. However, if the initial inflammatory response is heightened or unresolved, this process of repair is disrupted; after AKI, cytokines implicated in the development of kidney fibrosis, such as interleukin-13 and transforming growth factor-ß1, rise, propagating kidney dysfunction [140], which can lead to the development of irreversible CKD. These inflammatory processes can lead to multi-system morbidity in addition to kidney disease [136]. For example, CKD is a known risk factor for cardiovascular disease, in part because the associated inflammatory milieu contributes to vascular calcification [144] and direct systemic endothelial damage [145] and may even promote atrial fibrillation directly via an inflammasome-mediated pathway [146], such that patients with more advanced stages of CKD are at higher risk of cardiovascular disease mortality and morbidity even at earlier chronological ages [147].

Inflammation in kidney disease is associated with several manifestations of advanced physiologic aging. The inflammatory milieu associated with CKD can result in protein-energy wasting that results in sarcopenia and a loss of muscle mass and strength, which can contribute to the development of physical frailty [148]. Development of physical frailty is in part mediated by the elevation of fibroblast growth factor-23 (FGF-23), a bone-derived hormone involved in vitamin D and phosphate regulation, and by the suppression of Klotho, which regulates mineral and energy metabolism [149]. Elevated FGF-23 in turn leads to the upregulation of pro-inflammatory cytokines, whose effects include anemia and dysregulated iron metabolism [150]. Suppression of Klotho may also lead to reduced protection of cells from oxidative stress [151]. The cumulative effect is a hypercatabolic state that can lead to cachexia and sarcopenia [148]. Other potential contributors toward protein-energy wasting include increased sedentarism [152], loss of satellite cell function [153], and chronic metabolic acidosis [154]. Inflammation in kidney disease can also manifest as a malnutrition-inflammation complex resulting from a loss of appetite from uremic toxin build-up, which may also result in sarcopenia and has further deleterious consequences on bone and cardiovascular health [155, 156]. Furthermore, both CKD and ESKD are associated with increased cancer risk through the dysregulated activation of progressive inflammatory and fibrotic processes [157]. Lastly, inflammation in kidney disease is associated with cognitive dysfunction. Among older (≥ 55 years) adults with chronic kidney disease, high levels of CRP, fibrinogen, and IL-1β are independently associated with impaired attention on cognitive testing at follow-up [158]. Excess FGF-23 is also associated with impaired cognition, particularly among those treated with dialysis [159].

Although it is known that aging is associated with a decline in nephron mass and renal function [160], less is known about how precisely the hallmarks of aging contribute to the development and progression of CKD. It is thought that the progressive loss of nephron mass and glomerulosclerosis seen in the aging kidney may be a result of oxidative stress and telomere attrition, which contribute to the senescence of cells vital to kidney repair [161]. Accordingly, senescence and genomic damage in renal tubular epithelial cells are associated with a more rapid progression of renal fibrosis and with early vascular aging [162, 163]. Other ways in which aging may contribute to the progression of CKD include decreased renal oxygen levels, more generalized mitochondrial dysfunction, and general inflammation (as opposed to renal-specific pathways) [164].

Several of these pathways represent a potential target for intervention to arrest or ameliorate the detrimental effects of CKD or ESKD as patients age [142, 165–167]. For example, such interventions may include the development of drugs targeting specific cytokines (e.g., IL-4 or IL-6), utilizing anti-inflammatory properties of existing drugs (e.g., losartan), or drugs blocking specific inflammatory pathways (e.g., the NLRP3 inflammasome or NF-ĸB signaling) [168–172]. Readily available interventions including exercise [173] and dietary modification are promising [148, 174], and large-scale clinical trials to test their efficacy in dampening systemic inflammation and accelerated aging are needed. Further research is also needed to understand the effects of targeted anti-inflammatory therapies on the evolution of AKI and in harnessing the immune system to avoid maladaptive repair and promote kidney regeneration after injury [140, 142].

Acute conditions

Traumatic brain injury

Older adults suffer the highest incidence of traumatic brain injury (TBI) of any age group in the USA [175]. Compared with younger patients, older adults also experience higher morbidity and mortality and, on average, suffer from worse functional and cognitive outcomes [176]. Even so-called “mild” TBI can lead to long-term neurological symptoms, including increased risk for neurodegenerative diseases such as Alzheimer’s disease [177]. The pathophysiological mechanisms that lead TBI to act as an aging “accelerant” are unclear, yet a common thread is heightened inflammation via direct mechanical stress, excitotoxicity, oxidative stress, and/or DNA damage, all of which may contribute to cellular senescence and propagate inflammaging [178]. Importantly, the interaction between inflammation and age-related processes, such as the accumulation of senescent cells, may contribute to the worse outcomes seen in older adults suffering from TBI. Advanced age is associated with altered meningeal and brain tissue immune responses, including astrocytes and microglia with exaggerated pro-inflammatory responses, senescent microglia with impaired phagocytosis, and more pronounced and widespread reactive astrogliosis over time [179, 180]. Identification of age-related factors contributing to poor recoveries, such as inflammaging and senescence, would inform therapies targeting the unique pathophysiology of older adults.

While inflammation is implicated in the acute effects of head injury, its role is nuanced. In the MRC CRASH trial, 10,008 adults with TBI were randomized to receive glucocorticoids within 8 h of injury; this study was stopped early as the risk of death from all causes within 2 weeks was higher in the glucocorticoid group, regardless of injury severity or timing of glucocorticoids [181]. This mortality difference persisted at 6-month follow-up [182]. An alternative to the blunt instrument of glucocorticoids is to specifically target senescent cells, though the role of cellular senescence is similarly nuanced. Cellular senescence is implicated in regulating several crucial physiological processes, such as wound healing and suppressing tumorigenesis, yet can also be a maladaptive, pathological process that contributes to aging [183]. In mouse models of TBI, increased expression of senescent markers in microglia in the injured cortex has been found within 72 h of injury [179]. This finding is exaggerated in aged compared with young mice following TBI, and some studies suggest key sex differences in these markers [184]. In a post-mortem study that included the brains of both professional athletes with a history of repeated mild TBI and controls without TBI, cases demonstrated a significant increase in hallmark features of DNA damage, cellular senescence, and expression of SASP [185]. Senescence may also play a role in the association between TBI and subsequent dementia risk. In both preclinical animal models and post-mortem human brain tissue, neurons with tau-containing neurofibrillary tangles express a senescence-like phenotype [186].

Several senolytic drugs are currently under study in preclinical animal models of TBI [178]. One mouse model of TBI found that acute treatment with the senolytic drug ABT263 reduced markers of senescence, but only in male mice [184]. Whether senolytics have a role in addressing chronic inflammation associated with TBI is similarly under investigation. In a recent preclinical murine study of TBI, intermittent administration of the senolytic drugs dasatinib and quercetin, beginning 1 month after TBI, demonstrated a reduction in senescent cells in brain tissue and improved behavioral testing [187]. In parallel fields, the first phase 1 feasibility trial of oral senolytic therapy—combined dasatinib and quercetin—in mild Alzheimer’s disease demonstrated central nervous system penetration of dasatinib—but not quercetin—as well as general safety, tolerability, and feasibility [188].

The importance of TBI acutely and its downstream impact of a heightened risk for long-term neurodegeneration will only increase as the number of older adults in the population continues to rise. How hallmarks of aging, such as immunosenescence and inflammaging, may be targeted to modify these risks and the role of sex-based differences are critical areas of inquiry.

Acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure associated with high mortality, particularly in older adults [189]. While ARDS is clinically defined by the acute onset of diffuse lung injury with accompanying hypoxia, extrapulmonary organ injury due to systemic inflammation frequently occurs in affected patients. In fact, mortality from ARDS is generally due to multiorgan dysfunction (including acute kidney injury and cardiovascular collapse) rather than refractory hypoxia. Although ARDS was originally described in 1967 in a cohort of relatively young patients (all < 50 years old) [190], increasing age has since been identified as a major non-modifiable risk factor for both the incidence and severity of ARDS [191–194]. Incidence has been found to be 20–30 fold higher in older compared to younger patients and risk of mortality increases by as much as 30% per decade of life, with ARDS patients age > 60 having an approximately 60% risk of death [192, 194–196]. Given this link with increased age, inflammaging and immunosenescence may be contributing factors to multiorgan failure and death in ARDS. Due to the acute nature of ARDS, its relationship to inflammaging and immunosenescence is necessarily distinct from chronic conditions. Whereas inflammaging and immunosenescence can lead to the development of chronic conditions like RA and DM, in ARDS, these processes may predispose to a dysregulated immune response that contributes to multiorgan dysfunction and risk of death. Supporting this relationship, the risk of mortality from COVID-19 infection, a common cause of ARDS, has been strongly associated with (1) extreme elevations in circulating factors that characterize inflammaging including CRP and IL-6 [197] and (2) increased biologic age as measured by validated aging metrics like PhenoAge [198, 199]. Furthermore, patients that survive ARDS may experience accelerated inflammaging [200], which could subsequently contribute to the development and/or worsening of chronic diseases like DM or CKD.

ARDS is a heterogenous clinical syndrome that can be triggered by a range of insults including direct aspiration of gastric contents or indirect inflammation from systemic insults like non-pulmonary sepsis or pancreatitis. Despite a diversity of triggers, extensive work in the last decade has suggested that ARDS can be divided into sub-phenotypes defined by clinical characteristics and blood biomarkers [201]. These subtypes were discovered through retrospective, secondary analyses of large clinical trials. These studies have consistently revealed two general molecular ARDS sub-phenotypes: hypo- and hyper-inflammatory. Notably, heterogeneity of treatment effects between phenotypes has been found, supporting the validity of this novel framework [202–204]. Thus, inflammation has a key role in ARDS, by predisposing to its incidence and potentially mediating responsiveness to targeted treatments.

Due to the central role that inflammation plays in ARDS, it follows that inflammaging and immunosenescence are also likely to influence outcomes in ARDS. However, age alone is only weakly predictive of ARDS sub-phenotype classification, which suggests that more specific measures of these phenomena are necessary to determine their roles in ARDS. Indeed, two older individuals of equal chronologic age will have had distinct acute and chronic exposures, live in different environments, and possess differential genetic susceptibilities that influence inflammation [2, 3, 15, 205]. These factors are expected to lead to differential resilience to ARDS and potentially differential responsiveness to therapies. Furthermore, a scientific perspective that considers the hallmarks of aging suggests that variability in inflammatory markers that define sub-phenotype classification should be expected, as they represent the confluence of patient, environment, and pathogen-derived factors that individually contribute to ARDS pathogenesis [206]. Thus, future studies of ARDS employing sub-phenotypes could be specifically designed to consider the contributions of the hallmarks of aging including inflammaging and immunosenescence to differential outcomes and treatment responsiveness.

Studies of ARDS sub-phenotypes to date have generally only included easily accessible variables such as patient demographics, vital signs, clinically collected laboratory variables, and a small subset of inflammatory markers measurable with simple immunoassays (e.g., CRP, IL-6). The application of inflammaging to ARDS sub-phenotyping suggests that the inclusion of pre-existing patient characteristics should be considered in future studies. Due to the disproportionate impact of ARDS and other forms of critical illness on older patients, the development of risk profiles for healthy older adults integrating the many hallmarks of aging (e.g., cellular senescence, epigenetic alterations, dysbiosis) may facilitate personalized therapeutic approaches when caring for older patients with acute illnesses like ARDS. As has been accomplished for cardiovascular disease through large, population-based studies (e.g., Framingham Heart Study) [207], similar efforts focused on the development and clinical application of inflammaging-centric risk scores in ARDS may improve outcomes for older patients.

Sepsis

Sepsis is a clinical syndrome defined by an inciting infection followed by the development of multi-system organ dysfunction (i.e., indirect organ injury) that is often life-threatening [208]. One of the fundamental aging-associated medical unknowns is the pathophysiology underlying the increased incidence and severity of sepsis in older adults [209–211]. While sepsis is characterized by substantial patient-level heterogeneity, it has been consistently recognized that the aging population suffers a disproportionate burden from its effects [212–215]. Epidemiologic studies demonstrate a two-fold increase in case fatality rate and a 13-fold increase in sepsis incidence when comparing older adults (65 years of age or older) to their younger counterparts [212]. The mechanisms underlying this heightened susceptibility are incompletely understood, although two of the most prominently studied explanations are inflammaging and immunosenescence [209].

The rationale underlying the intersection of inflammaging, immunosenescence, [3] and the impact of sepsis on the geriatric population is based upon our understanding of sepsis pathogenesis at large. The “cytokine storm” hypothesis—the theory that initial infection leads to a hyper-inflammatory and deleterious host immune response—has long been investigated as the mechanistic underpinning of indirect organ injury that characterizes sepsis, as well as common symptoms such as delirium [216, 217]. Based upon this concept, it is logical to expect that older individuals would experience worsened sepsis outcomes due to baseline chronic inflammation (inflammaging). However, the contemporaneous process of immunosenescence adds another pathophysiologic layer of complexity specific to the aging population. Immunosenescence is associated with impaired and ineffective immune responses to infectious stimuli and has also been investigated as a causative factor in sepsis severity and the development of septic organ injury [218]. It is important to consider that inflammaging is not a homogeneous process in older adults. Rather, an individual’s inflammatory response is mediated by a multitude of factors with biologic age being only one variable. Conceptually, it may be beneficial to consider aging-associated susceptibility to sepsis incidence, severity of illness, and response to various treatment strategies on a “personalized” basis.

This framework is based upon the observation that sepsis interventions targeting the host inflammatory response have demonstrated inconsistent results [216, 217]. Critically, the etiology of sepsis-inducing infection (bacterial versus viral) appears to be a key predictor of treatment response. In clinical trials predominantly enrolling sepsis patients of bacterial origin, pharmacologic glucocorticoids have yielded conflicting results [219, 220] while TNF inhibitors [221], toll-like receptor antagonists [222], and activated protein C [223] have shown no benefit in any age group. Conversely, clinical experience with sepsis secondary to viral infections such as COVID-19 suggests that inflammation-modulating therapeutics (i.e., glucocorticoids and anti-cytokine therapies such as IL-6 inhibitors) are effective pharmacologic interventions in selected patients [224, 225]. These studies challenge the conceptual framework of hyper-inflammation as the primary mediator of disease severity and have led to a therapeutic nihilism regarding the treatment of older adults with sepsis. It is plausible that comprehensive, data-driven individual assessment of inflammatory status in older adults may identify sub-groups of patients who will benefit from targeted intervention.

An additional consideration is the possibility of underappreciated mediating factors impacting the relationship between inflammation and aging-associated sepsis severity. For instance, the gut microbiome has been demonstrated to be associated with aging [226], inflammatory state [227], and sepsis outcomes [228, 229]. Further investigation into this complex multi-directional relationship may delineate the pathophysiology underlying age-associated sepsis susceptibility and lead to novel, effective therapeutic strategies for older adults with sepsis.

What we can learn from harmonizing research on inflammatory diseases of aging: Shared pathways, shared interventions, and a transdisciplinary approach to clinical care

Growing evidence supports that age-related immune dysregulation plays a significant role in the development and progression of diseases in older adults. In this review, a multidisciplinary team of specialists selected examples of organ-specific and systemic aging-related diseases to showcase how inflammaging may lead to more severe or treatment-refractory disease phenotypes. Furthermore, this review highlights how chronic inflammatory diseases can lead to both premature aging-associated conditions and accelerated physiological aging, which is driven by ongoing chronic inflammation and the emergence of immunosenescent phenotypes. Although these examples do not encompass every disease process affected by the aging immune system, they provide a sampling of the diverse multiorgan manifestations of inflammaging. In Table 1, we summarize key considerations shared across multiple specialties to help conceptualize the roles of inflammaging and immunosenescence in age-related diseases.

Table 1.

Shared observations regarding inflammaging and aging-related diseases

The prevalence of inflammation-related and -mediated conditions in older adults is increasing

Inflammaging (i.e., aging-related immune dysregulation) has been implicated in the pathogenesis of aging-related diseases and subsequent increases in the risk of developing multimorbidity and/or geriatric syndromes

Much of current research targeting inflammaging is conducted in the context of single organ and/or single disease perspectives

Numerous serum inflammatory markers exist, but most have not consistently captured the complex, chronic nature of inflammaging across aging-related diseases

Interventions targeting inflammaging may include senolytics to eliminate senescent cells and inhibitors of pro-inflammatory cytokines

Sub-phenotypes of inflammaging may account for differential responses to treatment and/or clinical outcomes among aging-related diseases

In contrast to research on disease-specific processes, geroscience seeks to elucidate shared mechanisms in the pathogenesis of age-related diseases [230]. A framework based on the geroscience hypothesis, which posits that targeting aging physiology will prevent or mitigate multiple age-related chronic diseases, presents a unifying approach to treating multimorbidity in older adults. Across multiple organ systems, the effects of chronic low-grade inflammation from immune dysregulation and SASP mediators converge with the pillars of aging to promote and exacerbate disease. Inflammaging is closely entwined with immunosenescence, characterized by clonal expansion of effector T and B lymphocytes, loss of immunoregulatory molecules, and an increase in pro-inflammatory mediators [231]. Widely measured circulating inflammatory biomarkers such as the pro-inflammatory cytokines IL-1, IL-6, CRP, and TNF are associated with geriatric syndromes including frailty, functional and cognitive decline, and mood disorders [232, 233]. However, these markers neither provide information about the cause of their release nor predict the onset of transition into geriatric syndromes. Further, fluctuations in inflammatory cytokines during infectious and neoplastic states create additional confounders. Thus, the clinical value of using inflammatory biomarkers in routine clinical screening to identify patients who are at higher risk for developing frailty, multimorbidity, or worsening of existing conditions has yet to be defined [234].

Differences in disease severity and disability among people of the same chronological age have led to increased interest in markers of biological aging. These markers may help identify individuals at high risk for accelerated aging and severe manifestations of acute illnesses. Biomarkers that measure aging phenotypes including cellular senescence, DNA methylation, and mitochondrial dysfunction—along with composite biomarker scores and other immune panels—indicate that chronic diseases can accelerate aging processes [235]. Evidence of accelerated aging occurs in the many immune-mediated and age-related disorders highlighted in this paper, along with other conditions including cardiovascular disease [236], human immunodeficiency virus (HIV) [237], idiopathic pulmonary fibrosis [238], cancer treated with chemotherapy [239], multiple sclerosis [240], and COVID-19 [241]. The varying pace of aging has also led to studies of senotherapeutics targeting the removal or modulation of senescent cells—associated with heightened inflammation and tissue dysfunction—to delay or prevent chronic disease of aging and disability accumulation [242]. Currently, multiple early-phase clinical trials of drugs with senolytic or senomorphic properties are underway to treat specific diseases [21, 22]. Additionally, the use of anti-inflammatory drugs targeting central immunological processes or specific sub-components of the immune system has shown potential for improving the health of multiple organ systems [243]. For example, the use of an IL-1β inhibitor led to a significantly lower rate of cardiovascular events in patients with a previous history of myocardial infarction [244]. Interestingly, a post hoc analysis of this trial also showed that the use of an IL-1β inhibitor did not lower the risk of incident frailty over 5 years of follow-up, which may point to the challenges of using a targeted drug against a multifactorial syndrome that affects multiple organ systems and a broader range of biological processes [245]. Similarly in acute conditions, senolytic trials are underway for sepsis (ClinicalTrials.gov NCT05758246), and preclinical studies have demonstrated potential benefits in animal models of TBI [246]. Despite progress in the study of senotherapeutics and drugs targeting inflammaging, methods to define their success must be refined through ongoing work to develop aging biomarkers with high diagnostic and prognostic value as well as refined, patient-centered outcome measurements.

Interdisciplinary collaboration between clinicians and geroscientists is essential for creating a transdisciplinary framework for the design, implementation, and interpretation of studies in inflammaging and immunosenescence. Additionally, there is an urgent need to advocate for geroscience education and awareness in medical specialties lacking formal training in geriatrics, such as neurology, psychiatry, and physical medicine and rehabilitation, whose providers are increasingly involved in the care of older adults [15, 206]. Key processes of aging, such as inflammaging, should be incorporated in both benchside studies and bedside discussions of geriatric conditions. Additionally, support and expansions of platforms and collaborative networks such as the Translational Geroscience Network, the Clinician-Scientists Transdisciplinary Aging Research (Clin-STAR) Coordinating Center, the Research Centers Coordinating Network, Claude D. Pepper Older Americans Independence Centers, and Nathan Shock Centers of Excellence in the Basic Biology of Aging play a critical role in facilitating interdisciplinary research and translating geroscience findings into clinical practice.

Conclusions

Older adults are particularly vulnerable to both chronic and acute conditions and often experience worse outcomes. The concepts of inflammaging and immunosenescence offer a lens through which we may understand the inherent complexities of caring for an aging population. In this paper, we—as an interdisciplinary team of clinician-scientists—summarized the critical role of inflammaging and immunosenescence in the health trajectories of older adults. We have also compiled evidence and knowledge gaps in the use of therapies to target these processes to inform future research agendas (Table 2). While there is presently no standardized, evidence-based definition of inflammaging, studies measuring biomarkers such as CRP and IL-6 in vivo and in vitro have shown that downstream neurodegeneration, multi-system morbidity, and geriatric syndromes are more common among older adults with a greater burden of inflammation. As we identify the biological underpinnings and clinical manifestations of these processes, it becomes increasingly clear that addressing them through targeted therapies could revolutionize the management of age-related diseases. Transdisciplinary research is essential to refine our understanding and develop more effective interventions, offering a future where the burdens of age-associated conditions are significantly mitigated.

Table 2.

Knowledge gaps and future research agenda on inflammaging

Knowledge gaps	Rationale	Next steps
System-based approach to inflammaging	Existing inflammaging research largely conducted in the context of single organ/disease	- Support interdisciplinary collaboration between clinicians and geroscientists to foster transdisciplinary research - Design, implement, and interpret studies with outcome measures that address the potential role of inflammaging in other tissues and across disease processes
Impact of inflammaging on disease progression and outcomes	Older adults are under-represented in clinical trials	- Include more older adults in clinical trials - Design clinical trials targeting older adults specifically - Understand aging-related changes in pharmacokinetics and pharmacodynamics of therapies
Serologic biomarker-based definition of inflammaging	No gold-standard measure to aid clinical decision-making	- Move beyond chronologic age with or without single biomarkers to measure inflammaging (e.g., account for pre-existing patient characteristics, gene-environmental interactions) - Establish validity and utility of multi-omic biomarkers for inflammaging - Understand the correlation between the degree of inflammaging and outcomes
Sub-phenotypes of inflammaging and/or aging-related diseases	Aging-related diseases are differentially impacted by inflammaging and managed by anti-inflammatory therapies	- Identify inflammaging sub-phenotypes to aid management and outcome prediction - Develop a precision medicine approach to identify older adults with varying “resilience” to aging-related disease outcomes and/or responses to treatment
Reversible components of inflammaging	Identification of mechanisms that may reverse inflammaging can inform treatment targets and pathways	- Conduct preclinical studies (e.g., using geriatric mice) to identify reversible components of inflammaging - Conduct clinical trials with biomarkers of inflammaging as key outcomes - Include robust mechanistic/translational studies within clinical trials - Include patients with multiple aging-related diseases in clinical trials (i.e., as opposed to disease-specific focus)
Utility of therapies targeting inflammaging and/or age-related diseases	Potential therapies targeting inflammaging are understudied	- Identify the range and magnitude of pharmacotherapy effects on inflammaging (e.g., anti-inflammatories, senotherapeutics) - Identify the range and magnitude of non-pharmacologic therapy effects on inflammaging (e.g., dietary modification, caloric restriction, exercise training)

Funding

National Institute on Aging Clin-STAR Coordinating Center grant award U24AG065204.

BJA: National Institutes of Health National Institute on Aging R03AG067949, P30AG0287163.

JAH: National Institutes of Health National Heart Lung and Blood Institute K08HL159353, National Institutes of Health National Institute on Aging R03AG074056.

RL: National Institutes of Health National Institute on Aging R03AG078953-01, Alzheimer’s Association 23AACSF-1029536.

SES: Bristol Myers Squibb Foundation Robert A. Winn Diversity in Clinical Trials Career Development Award, a Rheumatology Research Foundation Investigator Award, and by the National Institutes on Health National Institute on Aging (R03AG082983).

NS: National Institutes of Health National Institute on Aging K23AR079588, R03AG082857.

ASF: National Institutes of Health National Institute on Aging R03AG078927, American College of Gastroenterology, Crohn’s and Colitis Foundation.

DN: National Institute of Diabetes and Digestive and Kidney Diseases K23DK129774.

BK: National Institutes of Health National Institute on Aging R03AG074059, K76AG083309, Crohn’s and Colitis Foundation.

JFC: National Institutes of Health National Institute on Aging K08AG061144.

MJD: National Institutes of Health National Institute on Aging R03AG067976, Foundation for Anesthesia Education and Research, Merck Investigator Studies Program, National Alzheimer’s Coordinating Center, Duke/UNC Alzheimer’s Disease Research Center.

YZ: National Institutes of Health National Institute on Aging R03AG078946.

JL: National Institutes of Health National Institute on Aging K23AG082727.

AS: National Institutes of Health National Institute on Aging R03AG067981, NCATS/NIH KL2TR001870.

SCL: National Institutes of Health National Institute on Aging R03AG074035, Larry L. Hillblom Foundation, Doris Duke Foundation, UCSF Bakar Aging Research Institute, UCSF Pepper Center.

Declarations

Competing interests

Sebastian E. Sattui: research funding from AstraZeneca and GlaxoSmithKline (clinical trials), consulting and advisory boards for Sanofi and Amgen (funds applied for research support), and speaker fees from Fresenius Kabi (funds applied for research support). Bharati Kochar: advisory boards for Pfizer, Inc. and Bristol Meyers Squibb. Adam S. Faye: consulting honoraria from Bristol Meyers Squibb, Abbvie, and Takeda. Michael J. Devinney: research funding from Merck Sharp & Dohme LLC (clinical trials). Sara C. LaHue: speaker honoraria from American Academy of Neurology and Medscape.