Remodeling of innate antiviral immunity in aging

Abstract

Aging increases susceptibility to severe viral infection, weakens vaccine responses, promotes chronic inflammatory disease, and alters tumor immune surveillance. These outcomes reflect not a simple loss of immune activity, but age-associated remodeling of the amplitude, kinetics, and resolution of innate immune responses. In aged tissues, nucleic acid-sensing pathways often display elevated basal inflammatory or antiviral-like signaling, whereas inducible type I interferon (IFN) and interferon-stimulated gene (ISG) responses to infection or vaccination are delayed, blunted, or poorly resolved. This review summarizes the innate antiviral signaling pathways and discusses how aging and cellular senescence narrow the range between basal and inducible responses. We emphasize senescent cells as sources of senescence-associated secretory phenotype (SASP) factors that suppress neighboring-cell antiviral IFN responses and amplify inflammatory tissue damage, and discuss strategies to restore inducible IFN competence while limiting chronic basal activation in older adults, to improve vaccine efficacy and treat aging-associated infectious diseases.

1. Introduction

Population aging is reshaping the burden of infectious, inflammatory, and malignant diseases. Older individuals are more susceptible to severe respiratory viral infection, respond less efficiently to vaccination, and experience higher rates of chronic inflammatory, cardiovascular, metabolic, neurodegenerative, and cancer-associated diseases (Kennedy et al., 2014; United Nations, 2023). These associations are often discussed under immunosenescence, but immune aging is not a uniform loss of immune function. Rather, it represents a remodeling of immune set points, signaling thresholds, cellular composition, and tissue microenvironments (Goronzy & Weyand, 2013, 2019; Nikolich-Žugich, 2018). In this context, immunosenescence refers broadly to age-associated remodeling of immune function, whereas inflammaging describes the chronic low-grade inflammatory state that accompanies aging. Cellular senescence is a distinct cell state that can contribute to inflammaging through SASP production, while trained immunity refers to persistent functional reprogramming of innate immune cells after prior stimulation.

Innate immunity is central to this remodeling. Innate immune cells and barrier tissues sense viral nucleic acids and endogenous danger signals generated by cellular damage, metabolic stress, and disrupted tissue homeostasis, leading to type I and type III IFN responses, inflammatory cytokine production, antigen presentation, natural killer cell activation, and downstream adaptive immunity (Motwani et al., 2019; Zhang & Zhang, 2025). Because these pathways respond both to pathogens and to endogenous danger signals, they are readily engaged by aging-associated stress, such as mitochondrial damage, genomic DNA damage, retroelement derepression, and proteostatic stress, all of which can activate pathways that originally evolved for host defense (Molony, Malawista, et al., 2017; Montgomery & Shaw, 2015; Shaw et al., 2013).

Innate immune aging is therefore better understood as altered response dynamics than as simple enhancement or suppression. We define the “dynamic range of innate antiviral immunity” as the capacity to move from a basal state to an appropriately timed and scaled antiviral response and then back toward homeostasis. Aging increases basal inflammatory tone, delays or blunts stimulus-induced antiviral IFN peaks, and impairs inflammatory resolution, a pattern previously described as a reduced dynamic range of innate immunity (Molony, Malawista, et al., 2017; Shaw et al., 2013). This review connects the response pattern to defined mechanisms, especially endogenous nucleic acid stress, metabolic and transcriptional control of pattern recognition receptor (PRR) signaling, and SASP-mediated suppression of antiviral IFN induction. This response pattern is summarized in Fig. 1.

Fig. 1.

Remodeled innate antiviral responses in aging.

In young hosts, innate antiviral immunity is maintained at a low resting baseline and can be rapidly induced to generate robust peak responses after viral infection, followed by timely resolution. In aged hosts, basal inflammatory priming is increased, inducible antiviral responses are blunted, and resolution is defective, resulting in a reduced dynamic range of innate antiviral immunity.

We first introduce the innate immune pathways most relevant to antiviral defense and inflammatory regulation, including the Toll-like receptor (TLR), RIG-I-like receptor (RLR), and cGAS–MITA/STING pathways. We then discuss how aging biases normally transient host-defense programs toward chronic basal activation while reducing inducible antiviral competence. We emphasize senescent cells and SASP factors as active regulators of the aged tissue microenvironment, and consider therapeutic strategies that aim to restore innate immune dynamic range rather than broadly boost or suppress immunity.

2. Innate antiviral sensing pathways

Innate antiviral defense is initiated by PRRs that sense viral molecules or endogenous signals that resemble infection. Although these pathways differ in ligand source, subcellular localization, and dominant cell-type distribution, they converge on a limited set of transcriptional outputs, especially IFNs, inflammatory cytokines, chemokines, and interferon-stimulated genes (ISGs).

Endosomal TLRs detect nucleic acids in endosomes. TLR3 recognizes double-stranded RNA, TLR7 and TLR8 recognize single-stranded RNA, and TLR9 recognizes CpG-rich DNA. These receptors signal through MyD88 and/or TRIF to activate IRF3, IRF7, and NF-κB, thereby inducing IFNs, inflammatory cytokines, and chemokines (Chen et al., 2021; Kong et al., 2008; West et al., 2011). In aging, altered TLR output is important because TLR responses help shape early antiviral defense, dendritic-cell activation, vaccine adjuvant sensing, and downstream adaptive immunity (Panda et al., 2010; Sridharan et al., 2010; Stebegg et al., 2020).

RLRs detect viral RNA in the cytosol. RIG-I preferentially senses short double-stranded RNA or RNA bearing 5′-triphosphate, whereas MDA5 recognizes long double-stranded RNA (Hornung et al., 2006; Kawai & Akira, 2006). After ligand binding, RIG-I and MDA5 signal through an adaptor protein called VISA/MAVS to activate the TBK1, IKKε, and IKK kinases, leading to activation of the transcription factors IRF3, IRF7, and NF-κB (Kato et al., 2006; Seth et al., 2005; Xu et al., 2005). This pathway is essential for early IFN-β induction and for amplification of ISG expression during infection by various RNA viruses (Fredericksen et al., 2008; Kato et al., 2006).

The cGAS-MITA/STING pathway detects cytosolic DNA. cGAS binds DNA derived from DNA viruses, bacteria, mitochondria, micronuclei, chromatin fragments, and retroelements, and catalyzes the synthesis of cGAMP from ATP and GTP (Liu & Xu, 2025). cGAMP activates MITA/STING, leading to TBK1-IRF3 activation and innate immune and inflammatory responses (Ablasser & Hur, 2020; Barber, 2015; Gao et al., 2025; Ishikawa & Barber, 2008; Sun et al., 2013; Zhong et al., 2008). This pathway is a powerful antiviral and antitumor defense system, but it also links DNA damage, mitochondrial dysfunction, cellular senescence, sterile inflammation, and tissue remodeling (Dou et al., 2017; Victorelli et al., 2023).

These sensing pathways converge on antiviral IFN programs and inflammatory cytokine programs. Effective antiviral defense requires the proper timing and magnitude of both outputs. Too little early IFN permits viral replication; excessive or prolonged inflammation damages tissues (Lazear et al., 2019). Aging disrupts this coordination by increasing basal signal while limiting the inducible IFN peak.

3. Age-associated remodeling of innate antiviral immune responses

Major antiviral innate immune signaling pathways and their aging-associated alterations are summarized in Table 1.

Table 1.

Major antiviral innate immune sensing and signaling pathways and their aging-associated alterations.

Pathway (major components)	Principal ligand(s) and output	Aging-associated alterations and context	References
Endosomal TLRs TLR3-TRIF; TLR7/8/9-MyD88	TLR3: dsRNA; TLR7/8: ssRNA; TLR9: CpG-rich DNA. Activation of IRF3/IRF7 and NF-κB induces type I IFNs and inflammatory cytokines.	Human DCs from older adults show higher basal cytokine production but weaker TLR3/7/8/9-induced cytokine and IFN-α responses; these defects correlate with poorer influenza-vaccine antibody responses. In contrast, macrophages from older adults can show defective STAT1-dependent TLR3 downregulation during WNV infection, producing excessive inflammatory signaling. Thus, the direction of change is cell- and virus-dependent.	(Kong et al., 2008; Metcalf et al., 2015; Panda et al., 2010)
RLR-VISA/MAVS RIG-I/MDA5-VISA/MAVS-TBK1/IKKε	RIG-I: short or 5′-triphosphorylated viral RNA; MDA5: long dsRNA. VISA/MAVS activates IRF3/IRF7 and NF-κB, inducing type I/III IFNs.	In monocytes from older adults, enhanced K48-linked TRAF3 degradation, reduced TBK1-IRF3/IRF7 activation, and defective IRF8-dependent amplification lower inducible IFN-β and IFN-λ production. Direct evidence for a comparable age-dependent MDA5 defect remains limited.	(Connors et al., 2022; Molony, Nguyen, et al., 2017)
cGAS-MITA/STING cGAS-cGAMP-MITA/STING-TBK1-IRF3	Cytosolic viral or endogenous DNA activates type I IFN and inflammatory programs.	mtDNA, chromatin fragments, micronuclei, and LINE-1-derived cDNA can chronically activate cGAS-MITA/STING in aged or senescent tissues, sustaining basal IFN signaling, inflammation, and the SASP. Conversely, acute agonist-induced MITA/STING-TBK1 responses can be reduced in selected DC and monocyte subsets from older adults.	(De Cecco et al., 2019; Gulen et al., 2023)
Inflammasomes NLRP3/NLRC4-ASC-caspase-1	Cellular stress, mitochondrial dysfunction, ionic flux, and microbial signals promote IL-1β/IL-18 maturation and, in some settings, pyroptosis.	NLRP3 promotes systemic sterile inflammation and functional decline in aged mice. In older adults, constitutive inflammasome modules identify a high-inflammatory subgroup with oxidative stress, hypertension, arterial stiffness, and increased mortality, indicating substantial interindividual heterogeneity.	(Furman et al., 2017; Youm et al., 2013)
IFN receptor-JAK-STAT IFNAR1/2- or IFNLR1/IL10Rβ-JAK1/TYK2-STAT1/STAT2-IRF9	Type I and III IFNs activate ISGF3-dependent ISG transcription and establish antiviral states; IFN-λ acts mainly at epithelial barriers.	Age-associated JAK–STAT alterations are context dependent rather than uniformly suppressive. Older adults can exhibit elevated basal STAT phosphorylation but reduced cytokine-induced responsiveness, including responses to IFN-α. In WNV-infected dendritic cells from older donors, IFNAR1/2 induction is preserved, whereas late STAT1 and IRF1/IRF7 responses are reduced; chronic nucleic-acid stress may instead sustain basal IFN-I/ISG activity.	(De Cecco et al., 2019; Lazear et al., 2019; Qian et al., 2011; Shen-Orr et al., 2016)

Aging-associated effects are not uniformly suppressive. Chronic basal activation may coexist with reduced stimulus-induced signaling; direction and magnitude vary by cell type, tissue, stimulus, infection stage, and senescence context.

Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD; DC, dendritic cell; dsRNA, double-stranded RNA; IFN, interferon; IFNAR, type I IFN receptor; IFNLR, type III IFN receptor; IRF, interferon regulatory factor; ISG, interferon-stimulated gene; VISA, virus-induced signaling adaptor (also known as MAVS, mitochondrial antiviral signaling protein); mtDNA, mitochondrial DNA; PRR, pattern-recognition receptor; RLR, RIG-I-like receptor; SASP, senescence-associated secretory phenotype; ssRNA, single-stranded RNA; MITA, mediator of IRF3 activation (also known as STING, stimulator of interferon genes); WNV, West Nile virus.

3.1. Endogenous nucleic acid stress and chronic basal activation

Aged tissues accumulate endogenous ligands that activate innate antiviral pathways even in the absence of infection. DNA damage, nuclear envelope instability, micronuclear rupture, and cytosolic chromatin fragments engage cGAS and promote MITA/STING-dependent SASP induction (Dou et al., 2017; Glück et al., 2017; Mackenzie et al., 2017). Mitochondrial dysfunction and defective mitophagy release mitochondrial DNA (mtDNA), including mtDNA-containing nucleoids or fragments, as well as mitochondrial double-stranded RNA which can activate cGAS-MITA/STING, TLR9-MyD88, or RLR-VISA/MAVS pathways (Gulen et al., 2023; Oka et al., 2012; Sliter et al., 2018). Retrotransposons and endogenous retroviruses also become derepressed during aging and senescence. LINE-1-derived DNA activates cGAS-MITA/STING and drives type I IFN signatures in aged tissues (De Cecco et al., 2019), whereas endogenous retrovirus-derived double-stranded RNA can activate MDA5-VISA/MAVS signaling and reinforce senescence (Di Giorgio et al., 2024). This chronic exposure to virus-like endogenous ligands contributes to inflammation. In naturally aged mice, pharmacological inhibition of MITA/STING reduces multi-tissue inflammatory and type I IFN-related gene expression and improves selected functional phenotypes (Gulen et al., 2023).

Together, these findings support a model in which aging-associated endogenous nucleic acid stress chronically engages cGAS-MITA/STING and related PRR pathways (Fig. 2(A)). This raises basal inflammatory and antiviral-like signaling, but does not guarantee efficient inducible antiviral defense.

Fig. 2.

Mechanisms linking aging-associated stress to basal inflammation and impaired inducible antiviral signaling.

(A) Aging-associated stress drives SASP generation. Aging-associated cellular stress, including nuclear damage, self-DNA leakage, mitochondrial damage, and mtDNA release, promotes activation of the cGAS-MITA/STING pathway and contributes to the generation of senescent cells and SASP factors.

(B) Aging-associated mechanisms attenuate stimulus-induced antiviral signaling. SASP mediators, including GDF15, IGF-1, IL-1α, and IL-6, further suppress innate antiviral signaling through distinct mechanisms. GDF15 and IGF-1 attenuate the TBK1-IRF3 axis through AKT/MEK-mediated inhibition of GSK3β, whereas IL-1α and IL-6 promote p52/RelB accumulation, which competitively occupies NF-κB-binding sites in the promoters of type I IFN genes and thereby suppresses transcription of type I IFN genes. Metabolic and transcriptional checkpoints also shape response amplitude. PEP restrains cGAS activation by interfering with cGAS-DNA complex formation, whereas decreased SIRT1 activity promotes IRF3/IRF7 acetylation and impairs nuclear condensate formation. Additional age-associated defects, including impaired TRAF3 stability and reduced IRF8 induction, further compromise antiviral signal amplification. Together, these mechanisms elevate basal inflammation while blunting stimulus-induced type I IFN and ISG transcription. Selected schematic illustrations and signaling pathway components were generated using OpenAI ChatGPT (GPT-5.6 Sol) and subsequently edited and assembled by the authors.

3.2. Impaired inducible antiviral IFN responses

Aged hosts can show chronic basal activation while mounting weak inducible antiviral responses. In primary human dendritic cells from older adults, myeloid DCs produce less TNF-α, IL-6, and IL-12p40 after stimulation with multiple TLR ligands, whereas plasmacytoid DCs show reduced IFN-α production after stimulation with R848 or CpG. These defects correlate with impaired antibody responses to influenza vaccination (Panda et al., 2010). In human monocytes from older adults, stimulation with 5′-triphosphate double-stranded RNA induces less IFN-β and IFN-λ. Mechanistically, aging reduces TRAF3 protein abundance through enhanced K48-linked ubiquitination and proteasomal degradation, thereby limiting TBK1 activation and IRF3/IRF7 phosphorylation. Defective IRF8 induction further weakens secondary RIG-I-dependent IFN amplification and compromises antiviral resistance to influenza A virus (IAV) (Molony, Nguyen, et al., 2017). Single-cell phospho-flow analysis further shows that cDC1s, cDC2s, and CD14^dimCD16⁺ patrolling monocytes from older adults exhibit reduced IRF7 phosphorylation after TLR7/8 or RIG-I stimulation and reduced TBK1 phosphorylation after RIG-I or cGAS-MITA/STING pathway activation, linking aging to impaired PRR-induced antiviral signaling (Connors et al., 2022). Age-associated antiviral defects may also vary among viruses because different viruses engage distinct PRRs and infect different cellular and tissue compartments; therefore, findings from influenza or SARS-CoV-2 infection should not necessarily be generalized to RSV, herpesviruses, or chronic viral infections.

In aged mice infected with IAV, early pulmonary type I IFN induction is blunted, whereas type III IFN expression is increased at 3 days post-infection; viral loads are higher, and later inflammation becomes more sustained (Wu et al., 2025). Clinical COVID-19 studies similarly show a low-type I IFN/high-inflammation pattern in severe disease, and circulating IFN-α levels can negatively correlate with age during early infection (Alidjinou et al., 2022; Hadjadj et al., 2020). Together, these studies indicate that aging commonly impairs inducible type I IFN signaling across multiple innate immune cell types and viral infection settings, whereas type III IFN responses may show distinct, context-dependent alterations; the magnitude and molecular basis of these changes vary with cell type, stimulus, tissue context, and infection model.

3.3. Downstream control of inducible antiviral IFN responses

Deregulation of aging-associated innate immunity also involves defects downstream of PRR sensing. At the nuclear level, SIRT1-mediated deacetylation of IRF3 and IRF7 supports their liquid-liquid phase separation, transcriptional condensate formation, and efficient induction of type I IFN genes. Age-associated decline in SIRT1 activity leads to IRF3/IRF7 hyperacetylation, impaired condensate formation, defective IFN transcription, and increased viral replication in aged mice. Consistently, SIRT1 agonists can partially restore IFN signaling (Qin et al., 2022). This mechanism places immune aging not only at the receptor or kinase level, but also at the level of transcriptional regulation.

Metabolic state adds another layer of control. Aging changes glucose and lipid metabolism, mitochondrial quality control, NAD⁺ availability, and intracellular energy flux, all of which influence PRR thresholds (Shaw et al., 2013). The glycolytic metabolite phosphoenolpyruvate (PEP) has recently been identified as an endogenous regulator of cGAS-MITA/STING signaling. PEP binds cGAS and disrupts cGAS-DNA complex formation, thereby limiting cGAMP production and downstream MITA/STING-TBK1-IRF3 activation (Song et al., 2026). This positions PEP as a metabolic checkpoint that restrains DNA-sensing intensity and links cellular metabolic state to cGAS-driven inflammatory aging.

Together, the SIRT1-IRF3/IRF7 and PEP-cGAS mechanisms show how aging alters both transcriptional amplification and metabolic control of innate immune signaling. Chronic endogenous ligands raise basal PRR activity, whereas impaired transcriptional organization can limit inducible antiviral IFN induction. Metabolic checkpoints such as PEP further regulate cGAS-MITA/STING activation and connect cellular metabolism with inflammatory aging.

3.4. SASP-mediated suppression of antiviral immunity

Senescent cells are a major source of aging-associated inflammatory and immunoregulatory signals. SASP produced by senescent cells includes cytokines and chemokines such as IL-6, IL-1α, IL-1β, TNF-α, CXCLs, and CCL2; growth and metabolic regulators such as GDF15, IGF-1, and TGF-β; proteases such as MMP3 and MMP9; and additional factors involved in angiogenesis, tissue remodeling, and immune regulation (Acosta et al., 2013; Basisty et al., 2020; Coppé et al., 2010; Di Micco et al., 2020; Matsuda et al., 2023; Wang et al., 2024; Wiggins et al., 2019). SASP composition varies with cell type, senescence trigger, tissue environment, and time after senescence induction.

Earlier work established that senescent cells can worsen viral disease outcomes. SARS-CoV-2 can induce senescence in epithelial and organoid models, and virus-induced senescence contributes to inflammatory pathology in severe COVID-19 (Evangelou et al., 2022; Lee et al., 2021). In old mice and aged hamsters, senolytic treatment reduces coronavirus-related mortality, lowers pulmonary viral load, dampens pulmonary and systemic SASP responses, and attenuates lung disease (Camell et al., 2021; Delval et al., 2023; Lee et al., 2021). IAV can also induce paracrine lung senescence, and senescent lung fibroblasts show increased viral load after subsequent infection (Schulz et al., 2023). However, a few studies have reported antiviral effects of cellular senescence in specific settings, including restricted VSV replication in primary and tumor senescent cells and reduced DENV infection in senescent endothelial cells (AbuBakar et al., 2014; Baz-Martínez et al., 2016). These observations suggest that the effects of senescent cells and SASP on viral infection may be context dependent and require further investigation.

A recent study further connected defined SASP factors to direct suppression of innate antiviral IFN responses (Zhang et al., 2026). In aged mice, senescent cells and SASP factors accumulate systemically and suppress innate antiviral responses induced by HSV-1 and H3N2. Mechanistically, GDF15 and IGF-1 attenuate the TBK1-IRF3 axis through AKT/MEK-mediated inactivation of GSK3β, whereas IL-1α and IL-6 promote p52 and RelB accumulation, which occupy PRDII/κB elements in the Ifnb1 promoter and suppress Ifnb1 transcription. Combined blockade of GDF15, IGF-1, IL-1α, and IL-6 enhances type I IFN and chemokine responses in aged mice and reduces HSV-1 and H3N2 viral burden and tissue damage (Zhang et al., 2026). These effects were demonstrated in specific cellular and aged-mouse infection models, and whether the same SASP factors suppress antiviral IFN responses across other viruses, tissues, and senescence contexts remains to be determined.

These findings suggest that senescent-cell accumulation and SASP signaling may provide one mechanistic link between the elevated basal inflammatory state and impaired inducible antiviral IFN responses in aged tissues. Previous studies mainly showed that senescent cells are associated with, or causally contribute to, higher viral load, inflammation, and tissue injury. These findings identify a direct paracrine mechanism by which senescent cells suppress antiviral IFN responses in neighboring cells through defined SASP factors, rather than only increasing viral burden or inflammatory damage.

SASP can also amplify inflammatory damage through mechanisms separable from IFN suppression. Recent work using clinical samples, cellular systems, and mouse models showed that senescent cells promote virus-associated inflammation and tissue injury through sustained NF-κB activation. Mechanistically, reactive oxygen species in senescent cells reduce PDLIM2, an E3 ubiquitin ligase that promotes p65 degradation, thereby sustaining p65-dependent inflammatory responses (Tian et al., 2025). Together with the SASP-mediated suppression of antiviral IFN responses described above, these findings distinguish two SASP-associated outputs: reduced antiviral IFN induction and amplified inflammatory tissue damage. The major mechanisms are summarized in Fig. 2(B).

4. Disease implications of altered innate antiviral immune dynamics

The disease consequences of altered innate antiviral immunity depend on tissue context and timing. In the lung, respiratory viruses first encounter airway and alveolar epithelial cells, but disease outcome is shaped by interactions among epithelial cells, macrophages, dendritic cells, endothelial cells, fibroblasts, and recruited myeloid cells (Lee et al., 2021; Li et al., 2025). Aging can dysregulate early epithelial and myeloid antiviral programs, including type I/III IFN and ISG responses. In aged influenza models, reduced early type I IFN activity and an altered balance between type I and III IFNs are associated with increased viral replication before an effective antiviral state is established (Wu et al., 2025). Severe COVID-19 and aged influenza models illustrate this temporal imbalance, in which deficient or delayed early IFN activity is followed by sustained cytokine and chemokine production, aberrant myeloid-cell accumulation, epithelial injury, and impaired transition to tissue repair (Blanco-Melo et al., 2020; Hadjadj et al., 2020). Senescent cells and SASP-rich lung microenvironments may further reinforce this pattern by suppressing antiviral IFN induction in neighboring cells while enhancing NF-κB-driven inflammatory damage (Tian et al., 2025; Zhang et al., 2026). Thus, the aged lung is not simply immunologically weak; it can combine insufficient early viral control with persistent inflammatory tissue injury.

In the brain and cardiovascular system, endogenous nucleic acids can engage antiviral sensing pathways even without exogenous infection. Cytosolic chromatin fragments, micronuclei, mtDNA leakage, LINE-1-derived DNA, and endogenous retroviral RNA can activate cGAS-MITA/STING, TLR9-MyD88, or RLR-VISA/MAVS pathways and maintain IFN-related inflammatory programs in aged tissues (Dou et al., 2017; Gulen et al., 2023; Mackenzie et al., 2017; Oka et al., 2012; Sliter et al., 2018; Yang et al., 2026). In the aged brain, cytosolic DNA sensing and cGAS-MITA/STING signaling in microglia and other CNS-associated cells can promote reactive microglial states, neuroinflammation, and neurodegenerative pathology (Chung et al., 2024; Gulen et al., 2023; Paul et al., 2020). In the heart, age-related LINE-1 activation engages cGAS-MITA/STING signaling in cardiomyocytes and promotes inflammatory gene expression and functional decline; inhibition of LINE-1 reverse transcription or MITA/STING alleviates aspects of cardiac aging in mice (Yang et al., 2026). These examples show how pathways that are protective during acute infection can become pathogenic when persistently activated by endogenous ligands.

Cancer provides a cautious disease context. Advanced age is a major cancer risk factor, but aging does not influence tumor biology in a simply permissive direction. Cellular senescence can suppress tumor initiation by imposing stable cell-cycle arrest on damaged or oncogene-stressed cells. Persistent senescent cells and SASP-rich microenvironments can instead promote tumor progression by sustaining inflammation, remodeling extracellular matrix, inducing growth factors and proteases, and altering immune-cell recruitment (Acosta et al., 2013; Basisty et al., 2020; Coppé et al., 2010; Di Micco et al., 2020; Matsuda et al., 2023; Wang et al., 2024; Wiggins et al., 2019). Innate immune pathways also have dual roles. Acute cGAS-MITA/STING activation in antigen-presenting cells can support antitumor immunity by inducing type I IFNs, promoting dendritic-cell activation, and facilitating effector-cell priming (Woo et al., 2014). In contrast, chronic tumor-cell-intrinsic cGAS-MITA/STING activation caused by chromosomal instability or micronuclear DNA leakage can activate noncanonical NF-κB programs and has been linked to invasion, metastasis, or therapy resistance in some contexts (Bakhoum et al., 2018). Recent cancer-immunosenescence studies further highlight myeloid bias, exhausted lymphocyte states, altered intercellular communication, and reduced responsiveness to immune checkpoint inhibitors or CAR-T therapy in older or senescence-rich settings (Liu et al., 2025; Yu et al., 2026). Aging-associated SASP may therefore contribute to an inflammatory but poorly effective antitumor immune microenvironment.

Together, these disease contexts support the same principle. Aging does not merely increase or decrease innate immunity. It changes the relationship between basal activation, inducible antiviral signaling, inflammatory amplification, and resolution. Disease phenotypes emerge when this altered response range is superimposed on tissue-specific ligand sources, repair capacity, immune-cell composition, and disease stage. Therapeutic strategies should therefore be designed to restore response dynamics in a tissue- and context-specific manner.

5. Therapeutic perspectives for aging-associated diseases linked to deregulated innate immunity

5.1. Senolytics and selective SASP modulation

Senolytics provide direct evidence that reducing senescent-cell burden can improve tissue responses to viral infection in aged hosts. In old mice, dasatinib plus quercetin or fisetin reduces coronavirus-related mortality, senescence markers, inflammatory mediators, and improves antiviral antibody responses (Camell et al., 2021; Delval et al., 2023; Lee et al., 2021). In aged hamsters infected with SARS-CoV-2, pharmacological removal of senescent cells lowers pulmonary viral load and attenuates pulmonary and systemic inflammation (Camell et al., 2021; Delval et al., 2023; Lee et al., 2021). In influenza-infected mice, genetic depletion of p16-positive cells improves epithelial repair and reduces post-influenza pulmonary sequelae, whereas the BCL-2/BCL-xL inhibitor ABT-263 (navitoclax) accelerates airway epithelial repair without functioning as a simple viral-clearance enhancer (Lipskaia et al., 2025). These examples suggest that senolytics may improve disease tolerance and tissue recovery as much as direct viral control.

Clinical translation remains early and should be framed carefully. Senescent cells are heterogeneous, and some senescence programs participate in wound repair, tissue remodeling, or tumor suppression. In chronic viral settings such as treated HIV infection, persistent inflammation, mitochondrial stress, and immune-cell dysfunction make senotherapeutics conceptually attractive, but senolytics have not yet been proven to improve antiviral control or reduce viral reservoirs in patients (Jin et al., 2025). Senolysis should therefore be presented as a strategy to remodel senescence-rich inflammatory environments, not as a general antiviral therapy.

Selective SASP modulation may be more precise than global senolysis. Defined SASP factors can suppress antiviral IFN competence. GDF15 and IGF-1 attenuate the TBK1-IRF3 axis through AKT/MEK-mediated inactivation of GSK3β, whereas IL-1α and IL-6 suppress Ifnb1 transcription through p52/RelB-dependent promoter competition (Zhang et al., 2026). Blocking these factors restores virus-induced IFN and chemokine responses in aged mice and reduces viral burden and tissue damage (Zhang et al., 2026). Other SASP-associated nodes, including IL-1α, JAK/STAT signaling, mTOR-dependent SASP translation, and PAI-1/SERPINE1, may also be therapeutically relevant because they connect senescence to cytokine production, fibrosis, thrombosis, tissue remodeling, and immune dysfunction (Abdelhakim & Miyata, 2026). This shifts the therapeutic focus from eliminating all senescent cells to disabling senescence-derived signals that impair antiviral responsiveness or amplify tissue injury. These approaches may therefore be particularly relevant in contexts characterized by a high burden of senescent cells or SASP signaling.

5.2. Limiting chronic endogenous nucleic-acid sensing

Another strategy is to reduce the source or persistence of endogenous nucleic acids that chronically activate antiviral sensors. LINE-1 is a representative example. During aging or senescence, LINE-1 derepression generates cytoplasmic cDNA that activates cGAS-MITA/STING and type I IFN-related inflammation (De Cecco et al., 2019). Reverse transcriptase inhibitors, including lamivudine and related nucleoside reverse transcriptase inhibitors, can reduce retroelement-derived immunostimulatory nucleic acids and inflammatory phenotypes in aging models (De Cecco et al., 2019; Olivieri et al., 2025). In the heart, limiting LINE-1 reverse transcription or MITA/STING activity alleviates inflammatory and functional features of cardiac aging (Yang et al., 2026). This approach targets the upstream source of chronic DNA sensing rather than blocking all downstream antiviral signaling.

Direct cGAS-MITA/STING modulation may be useful when chronic sterile activation dominates. In naturally aged mice, genetic or pharmacological MITA/STING inhibition reduces inflammatory gene expression in multiple tissues and improves selected functional phenotypes (Gulen et al., 2023). Brain and musculoskeletal studies similarly support cGAS-MITA/STING as a node linking cytosolic DNA accumulation, SASP, autophagy changes, and degenerative tissue remodeling (Chung et al., 2024; Gulen et al., 2023; Paul et al., 2020; Song et al., 2023). However, sustained MITA/STING inhibition could weaken antiviral defense and antitumor immunity. A safer strategy may require transient, tissue-selective, or disease-stage-specific inhibition, combined with preservation of inducible MITA/STING function during infection or vaccination.

Metabolic checkpoints offer a complementary way to tune innate immune thresholds. SIRT1 supports IRF3/IRF7 deacetylation, liquid-liquid phase separation, and IFN transcription, suggesting that SIRT1 or NAD-related interventions may help restore antiviral transcriptional competence in aged cells (Qin et al., 2022). The glycolytic metabolite phosphoenolpyruvate restrains cGAS activation by disrupting cGAS-DNA complex formation, linking metabolic state to DNA-sensing intensity (Song et al., 2026). Nrf2-HO-1 activation may further reduce oxidative damage, DAMP generation, and inflammatory amplification in inflammaging (O'Rourke et al., 2024). These examples support a broader therapeutic principle: metabolic repair may recalibrate innate immune responsiveness rather than acting only as general anti-aging support. These strategies may be particularly relevant when chronic endogenous nucleic-acid sensing and basal inflammatory signaling are prominent.

5.3. Vaccination and restoration of inducible antiviral programs

Vaccination is a practical setting in which the dynamic range of aged innate immunity can be therapeutically adjusted. Older adults often show impaired TLR responses in dendritic cells and monocytes, reduced IFN-α production by plasmacytoid dendritic cells, and weaker cytokine output after PRR stimulation (Connors et al., 2022; Molony, Nguyen, et al., 2017; Panda et al., 2010). Adjuvants that activate TLR7/8, TLR9, or other innate sensors may improve dendritic-cell maturation, antigen presentation, cytokine production, and T- and B-cell priming, but they must be balanced against high basal inflammatory tone (Aiello et al., 2022). The goal is not maximal PRR activation, but a sharper and more appropriately timed innate signal at vaccination.

mTOR-pathway modulation provides a clinical example. RAD001 (everolimus), an mTOR inhibitor, improves influenza vaccine responses in older adults, supporting the idea that aging biology can be targeted to enhance vaccine responsiveness (Mannick et al., 2014, 2021). RTB101, an oral inhibitor of mTOR complex 1 (mTORC1), increases IFN-induced antiviral gene expression and shows signals of reduced laboratory-confirmed respiratory infections in some studies, although later clinical outcomes are not uniformly positive (Mannick et al., 2014, 2021). IFN-based interventions require similar timing logic. In aged influenza-infected mice, intranasal IFN-β improves disease-related outcomes and reshapes inflammatory pathways, but does not function as a simple antiviral cure (Wu et al., 2026). Strategies that restore inducible antiviral programs may be more relevant when virus- or vaccine-induced IFN responses are impaired. These findings argue for immune stratification based on basal IFN tone, dendritic-cell and monocyte responsiveness, SASP burden, metabolic state, frailty, chronic viral history and comorbidities (Aaby et al., 2020; Chen et al., 2022; Mogilenko et al., 2021; Nehar-Belaid et al., 2023; Ramos, 2025).

6. Conclusions and perspectives

Aging reshapes innate immunity by narrowing the functional distance between resting and stimulated states. Endogenous nucleic acid stress, mitochondrial dysfunction, retroelement activation, senescent-cell accumulation, and persistent SASP signaling increase basal inflammation and antiviral-like signaling. At the same time, aged cells and tissues often show delayed, weakened, or poorly resolved type I IFN and ISG responses after viral infection or vaccination (Connors et al., 2022; Lazear et al., 2019; Molony, Nguyen, et al., 2017; Panda et al., 2010). This high-baseline, low-induction, poorly resolved state provides a coherent framework for understanding infection susceptibility, vaccine hyporesponsiveness, sterile tissue inflammation, and altered tumor immune surveillance in older adults.

The field is moving beyond descriptive immunosenescence toward defined molecular mechanisms. Endogenous ligands, including cytosolic chromatin, mtDNA, LINE-1-derived DNA, and endogenous retroviral RNA, help explain how antiviral sensors become chronically engaged in aged tissues (De Cecco et al., 2019; Dou et al., 2017; Victorelli et al., 2023). Regulatory checkpoints such as SIRT1-dependent deacetylation and phase separation of IRF3/IRF7 and PEP-mediated inhibition of cGAS further demonstrate that antiviral signaling competence is determined not only by PRR abundance, but also by post-translational regulation, biomolecular condensation, and cellular metabolism (Qin et al., 2022; Song et al., 2026). In parallel, defined SASP factors can directly suppress antiviral IFN induction in neighboring cells. GDF15 and IGF-1 inhibit the TBK1-IRF3 axis, whereas IL-1α and IL-6 repress transcription of type I IFN genes through p52/RelB-dependent promoter competition (Zhang et al., 2026). This positions senescent cells not only as sources of inflammation, but also as regulators of whether surrounding tissues can mount protective innate antiviral responses.

Several questions now become central. It remains unclear which cell types dominate basal activation in each aged tissue, which molecular defects most strongly limit inducible IFN responses, and whether the same SASP factors suppress antiviral competence across human tissues, viruses, and senescence triggers. Future studies should measure basal state, early IFN peaks, viral replication, inflammatory injury, immune-cell recruitment, tissue repair, and resolution kinetics in the same experimental systems. Aged animal infection models, human organoids, primary tissue cultures, single-cell and spatial profiling, and perturbation of defined SASP or nucleic-acid-sensing nodes will be especially useful.

The therapeutic implication is not that aged innate immunity should be made globally stronger. It should be more appropriately tuned. Basal signaling should be weaker when chronic sterile activation dominates, inducible responses should be stronger during early infection or vaccination, inflammatory amplification should be less damaging, and resolution should be more efficient after pathogen control. Senolytics, selective SASP blockade, LINE-1 or cGAS-MITA/STING modulation, metabolic checkpoint repair, IFN-timing strategies, and age-adapted vaccine adjuvants each address different parts of this response range. The next step is to match these interventions to tissue context, disease stage, and immune-state biomarkers for treatment of aging-associated infectious diseases.

CRediT authorship contribution statement

Xu Zhang: Writing – review & editing, Writing – original draft, Visualization, Conceptualization. Qing Yang: Writing – review & editing, Supervision.

Declaration of generative AI uses

During the preparation of this work, the authors used OpenAI ChatGPT (GPT-5.6 Sol) to generate selected schematic illustrations and signaling pathway components, including representations of cells, mitochondria, viruses, the nuclear envelope, and nucleic acid leakage. These components were subsequently edited and assembled into the figures by the authors using Microsoft PowerPoint. No experimental images or data were generated or altered using AI. The authors take full responsibility for the final content of the figures and the published article.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.