Exercise May Reduce Age-Related Decline in Immune Function: From How It Works to Possible Treatments

Aging is frequently characterized by glucose intolerance and hyperglycemia, which accelerate immunosenescence through multiple mechanisms: suppressing neutrophil chemotaxis and ROS generation [44], promoting pro-inflammatory M1 macrophage polarization [45], and generating advanced glycation end products (AGEs). AGEs bind to their receptor (RAGE) on immune cells, triggering a self-perpetuating "AGEs-RAGE-inflammation" loop that sustains chronic cytokine release (TNF-α, IL-6) [46,47]. Regular exercise dismantles this inflammatory machinery by fundamentally remodeling glucose handling and downstream signaling through three interconnected mechanisms.

Restoration of insulin sensitivity and glycolytic homeostasis. By enhancing skeletal muscle GLUT4 expression and glucose uptake, exercise reduces glycemic fluctuations and limits the formation of AGEs [48,49]. This metabolic stabilization restores the phagocytic and bactericidal capacity of neutrophils and macrophages, which are otherwise compromised by glucotoxicity [50,51].

Lactate as an epigenetic and signaling modulator. Beyond its role as a fuel source, exercise-derived lactate acts as a potent "lactokine" that orchestrates immune plasticity. While acute high-intensity exercise elevates lactate to 20–30 mmol/L [52], producing transient immunosuppression via pH reduction and GPR81 signaling to limit tissue damage [53,54], physiological adaptations to regular exercise are more profound. Recent evidence highlights that lactate serves as a substrate for histone lactylation (e.g., H3K18la) [55]. This epigenetic modification directly activates M2-associated gene expression, driving macrophages from a pro-aging M1 phenotype toward a reparative M2 phenotype [56,57]. Furthermore, lactate supports the oxidative phosphorylation (OXPHOS) of regulatory T cells (Tregs) and memory T cells through MCT1/LDHB, subsets critical for maintaining immune tolerance in the elderly [56,58,59].

Recalibration of the AMPK-mTOR-HIF-1α energy-sensing axis. Exercise counteracts immunosenescence by restoring the balance of cellular energy sensors that are dysregulated in aging. Exercise-induced ATP depletion activates AMPK [60], which acts as a "metabolic brake" on aging by directly inhibiting mTORC1—a complex often overactive in aging that drives pro-inflammatory glycolysis—thereby shifting immune cells towards anti-inflammatory phenotypes (e.g., Tregs, M2 macrophages) [61,62,63]. While acute hypoxia activates HIF-1α to support effector T-cell glycolysis (e.g., Th17) [64,65,66], chronic regular exercise reduces basal HIF-1α overactivation in adipose tissue macrophages, preventing excessive pro-inflammatory polarization [67,68]. These pathways form an interactive network: AMPK inhibits mTOR and modulates HIF-1α, while HIF-1α feedback inhibits mTOR via REDD1 [69,70,71]. By fine-tuning this axis, exercise orchestrates a shift from "Warburg-like" pro-inflammatory glycolysis to mitochondrial oxidative phosphorylation, a metabolic state essential for the longevity and function of memory T cells and quiescent stem cells in the aging host [42,43].

Collectively, these three mechanisms exemplify exercise as a "systems-level metabolic reprogramming intervention". Unlike pharmacological interventions that target single pathways (e.g., metformin activating only AMPK), exercise simultaneously optimizes substrate availability (glucose), generates bioactive signaling metabolites (lactate), and recalibrates the energy-sensing machinery (AMPK/mTOR/HIF-1α). This multi-pronged approach is particularly critical in aging, where isolated interventions often fail due to redundant pro-inflammatory pathways. For instance, restoring insulin sensitivity alone cannot fully reverse immunosenescence if basal HIF-1α remains elevated; conversely, inhibiting mTOR without addressing hyperglycemia may compromise nutrient-sensing adaptability. Exercise, by contrast, creates a "virtuous cycle": improved glucose handling reduces the metabolic stress that drives mTOR overactivation → suppressed mTOR enhances AMPK activity → activated AMPK promotes lactate utilization and M2 polarization → M2 macrophages further improve insulin sensitivity in adipose tissue. This self-reinforcing loop underscores why exercise remains the most effective non-pharmacological strategy for delaying immunosenescence.

Aging-associated lipid metabolism dysregulation extends far beyond simple fat accumulation, manifesting as a systemic disruption of the adipose tissue–immune cell–circulating lipid network [2,72]. Rather than viewing these components in isolation, emerging evidence positions adipose tissue as a central immunometabolic hub whose dysfunction during aging initiates cascading failures across three interconnected layers. At the tissue level, visceral adipose expansion and hypoxia create a pro-inflammatory microenvironment dominated by M1 macrophages and senescent cells. At the endocrine level, altered secretion of adipokines (adiponectin ↓, leptin ↑) shifts systemic immune tone toward chronic activation. At the metabolic level, dyslipidemia—characterized by elevated pro-inflammatory saturated fatty acids (SFAs) and triglycerides (TGs) coupled with reduced functional high-density lipoprotein (HDL)—directly impairs immune cell membrane integrity, signaling, and survival. Crucially, exercise does not merely "burn fat" but functions as a systemic reprogramming intervention that simultaneously reduces adipose inflammation, restores adipokine balance, and optimizes the circulating lipid profile. This multi-tiered approach breaks the vicious cycle of "adipose dysfunction → immune activation → metabolic deterioration → accelerated immunosenescence," creating instead a virtuous loop where improved adipose health reinforces immune resilience [72,73].

Adipose tissue remodeling and bidirectional immune–adipocyte crosstalk. The aging process is frequently accompanied by exacerbated visceral fat accumulation and adipose tissue dysfunction, characterized by adipocyte hypertrophy, hypoxia, increased cell death, and the massive infiltration and M1 polarization of immune cells, particularly macrophages [74]. However, this is not a one-way street: activated adipose tissue macrophages (ATMs) and dysfunctional adipocytes engage in bidirectional crosstalk that amplifies local and systemic inflammation. ATMs secrete pro-inflammatory cytokines (TNF-α, IL-6, MCP-1) that further impair adipocyte insulin signaling and lipolysis, while hypertrophic adipocytes release free fatty acids (FFAs) and damage-associated molecular patterns (DAMPs) that activate macrophage NLRP3 inflammasomes [75,76]. This crosstalk forms a local inflammatory microenvironment that spills into circulation, triggering systemic, chronic low-grade inflammation that accelerates immunosenescence. Recent single-cell RNA sequencing analyses reveal that aged visceral adipose tissue harbors at least 13 distinct macrophage subpopulations, with age-associated macrophages (AAMs) expressing CD38 and exhibiting heightened sensitivity to lipopolysaccharide (LPS) alongside reduced efferocytosis capacity—a phenotype that perpetuates the accumulation of dead adipocytes and inflammatory debris [72].

Long-term regular exercise, especially endurance training combined with resistance training, effectively reduces body fat, particularly visceral fat [77], decreases the total macrophage infiltration in adipose tissue, and promotes M1-to-M2 phenotype switching [78]. For example, 8 weeks of voluntary wheel running significantly reduced the proportion of F4/80+CD11c+ M1 macrophages in the epididymal adipose tissue of obese mice, increased the F4/80+CD206+ M2 proportion, and downregulated TNF-α and IL-6 mRNA expression [79]. Subcutaneous adipose tissue biopsies from obese or overweight individuals after exercise training showed the decreased expression of M1-associated genes (CD68, CD11c) and the increased expression of M2-associated genes (CD163, IL-10) [80]. Additionally, exercise alleviates adipose tissue hypoxia, thereby suppressing inflammation initiation [81]. Studies have demonstrated that moderate-intensity exercise, such as Tai Chi, effectively reduces serum inflammatory markers (IL-6, CRP) in obese middle-aged and elderly individuals, improving inflammation associated with adipose tissue dysfunction [82].

Adipokine-mediated endocrine reprogramming and immune modulation. Exercise counteracts immunosenescence by significantly altering the circulating levels and tissue expression of key adipokines. Adiponectin, the most representative anti-inflammatory and insulin-sensitizing adipokine [83], is typically reduced in elderly and obese individuals, whereas regular exercise, particularly long-term endurance training, can elevate its circulating concentrations [84]. Adiponectin activates AMPK and PPARα/γ pathways in macrophages via receptors AdipoR1 and AdipoR2, promoting M2 polarization, suppressing endotoxin-induced TNF-α and IL-6 production, and enhancing phagocytosis and IL-10 secretion [85] while simultaneously inhibiting T-cell proliferation and activation and promoting Treg function, thereby alleviating immunosenescence [86]. Conversely, leptin, a pro-inflammatory cytokine whose levels positively correlate with body fat mass, promotes monocyte/macrophage activation and cytokine production, induces Th1 immune responses, and inhibits Treg development and function [87]. Hyperleptinemia and leptin resistance are common in obesity-associated aging states, and regular exercise, particularly when accompanied by weight loss, can reduce circulating leptin levels [88]. For instance, 12 weeks of aerobic exercise significantly decreased serum leptin in overweight/obese adults, accompanied by reductions in inflammatory markers such as CRP [89]. Importantly, the immunomodulatory capacity of adipokines is influenced not only by their circulating concentrations but also by age-related changes in post-translational modifications and receptor expression on immune cells [2,72].

Circulating lipid profile optimization and membrane-level immune cell protection. Exercise directly ameliorates aging-associated immune dysregulation by optimizing the circulating lipid profile. Dyslipidemia (elevated free fatty acids [FFAs], elevated triglycerides [TGs], and reduced high-density lipoprotein [HDL]) progressively worsens during aging and is closely associated with immune functional decline and chronic inflammation [90,91]. Regarding FFAs, different types exhibit markedly distinct immunological effects. Saturated fatty acids (SFAs, such as palmitic acid) directly activate Toll-like receptor 4 (TLR4) signaling to trigger NF-κB-mediated pro-inflammatory cytokine production [72,92]. Monounsaturated fatty acids (MUFAs, such as oleic acid) exert weaker inflammatory effects than SFAs and may reduce membrane-dependent pro-inflammatory signaling or exert limited anti-inflammatory effects by partially replacing membrane SFAs, though these effects are less pronounced than those of polyunsaturated fatty acids (PUFAs) [93]. PUFAs are categorized into n-6 (arachidonic acid is a precursor of pro-inflammatory eicosanoids, though some metabolites also possess anti-inflammatory activity) and n-3 (renowned for anti-inflammatory and pro-resolution properties via specialized pro-resolving mediators [SPMs]), which often exhibit antagonistic relationships [2]. Although acute exercise transiently elevates FFAs for energy supply, chronic regular exercise significantly enhances the tissue FFA utilization capacity, reducing fasting and postprandial FFAs, especially pro-inflammatory SFAs [94], thereby decreasing aged immune cell exposure to high pro-inflammatory FFA risk. Moreover, reducing basal FFAs through improved insulin sensitivity is critical for alleviating aging-associated chronic inflammation—studies confirm that regular exercise reduces serum FFAs in obese populations, accompanied by decreased CRP and IL-6 [95].

Regarding HDL, its multiple immune protective functions (neutralizing endotoxin to prevent TLR4 activation; inhibiting monocyte adhesion to and migration across the endothelium; directly suppressing monocyte/macrophage inflammatory responses, reducing TNF-α and promoting IL-10 release; preventing macrophage conversion to pro-inflammatory "foam cells" by promoting cholesterol efflux via ABCA1/ABCG1 [96]) are often attenuated during aging due to decreased HDL levels and impaired function. Aerobic and endurance exercise effectively elevates the levels of HDL [97] and not only increases its concentration but also improves its functional quality (e.g., enhancing the cholesterol efflux capacity [CEC] and antioxidant capacity, such as paraoxonase 1 [PON1] activity) [98], providing important support for delaying immunosenescence. Regarding TGs, hypertriglyceridemia commonly associated with aging induces lipotoxicity through uptake of TG-rich lipoproteins (very-low-density lipoprotein [VLDL] and its remnants) by innate immune cells, accompanied by oxidative stress and endothelial dysfunction, exacerbating systemic low-grade inflammation and creating an adverse microenvironment that accelerates immunosenescence. Regular aerobic exercise effectively reduces circulating TGs [68] by increasing skeletal muscle fatty acid uptake and oxidation, reducing hepatic VLDL-TG synthesis and secretion, and improving insulin sensitivity, directly alleviating the pro-inflammatory stimulation and lipotoxic stress of lipid overload on aged immune cells [99].

Collectively, these three layers exemplify adipose tissue as a "systemic immunometabolic command center" whose exercise-induced remodeling exerts pleiotropic anti-aging effects. Unlike targeted pharmacological interventions (e.g., PPARγ agonists that improve adipose insulin sensitivity but may worsen fluid retention; fibrates that lower TGs but do not restore HDL function), exercise simultaneously (1) reduces adipose tissue hypoxia and the M1 macrophage burden, (2) restores the adiponectin/leptin ratio to favor anti-inflammatory signaling, and (3) optimizes the FFA/TG/HDL profile to protect immune cell membranes and receptor function. This creates a self-reinforcing virtuous cycle: reduced visceral fat → ↓ leptin and ↑ adiponectin → M2 polarization in adipose tissue → ↓ systemic IL-6/TNF-α → improved insulin sensitivity → further reduction in lipotoxic FFAs → preserved T-cell and macrophage function [73,100]. Notably, emerging single-cell transcriptomics data reveal that aging-associated changes in adipose tissue are heterogeneous, with distinct macrophage subpopulations responding differently to metabolic challenges. These findings underscore that optimizing lipid metabolism through exercise is not merely a metabolic intervention but a cornerstone strategy for preserving immunological homeostasis and extending healthspan.

The aging process is frequently accompanied by amino acid metabolic imbalance, which disrupts immune cell function through multiple interconnected mechanisms. Beyond their classical roles as protein building blocks, specific amino acids—glutamine (Gln), arginine (Arg), and branched-chain amino acids (BCAAs: leucine, isoleucine, valine)—function as critical signaling molecules that directly influence immune cell fate and metabolic programming [101]. At the metabolic substrate level, amino acids serve as preferential fuels and biosynthetic precursors for rapidly proliferating immune cells. At the signaling level, amino acids act as mTOR pathway sensors that regulate effector versus regulatory immune cell differentiation. At the microenvironmental level, amino acid availability shapes local immunosuppressive or pro-inflammatory niches. Exercise induces systemic and local changes in amino acid metabolism, and fluctuations in the concentrations of key amino acids and alterations in metabolic pathways directly regulate immune cell function, playing a crucial role in maintaining immune cell functionality during aging [102,103].

Glutamine metabolic remodeling: balancing fuel supply and redox homeostasis. As the most abundant free amino acid in blood [104], Gln serves as a preferentially utilized key fuel (via glutaminolysis for energy supply) and biosynthetic precursor (providing nitrogen/carbon for nucleotide synthesis) for rapidly proliferating or highly activated immune cells, such as lymphocytes and macrophages [105]. Additionally, Gln is an essential substrate for synthesizing the critical antioxidant glutathione (GSH), which is vital for maintaining redox homeostasis and function in aged immune cells, particularly given the significant increase in oxidative stress during aging [106]. Following prolonged or exhaustive exercise, plasma Gln concentrations often decline significantly (by 20–30%), creating a "post-exercise glutamine depletion window" [107,108]. This reduction in Gln levels can transiently limit the proliferative capacity and function of immune cells such as lymphocytes, which is associated with the transient immunosuppression (e.g., increased susceptibility to upper respiratory tract infections) observed during high-intensity training periods in athletes [109].

Arginine metabolic remodeling: macrophage polarization and T-cell suppression pathways. Its metabolism in immune cells determines functional phenotypes. In the pro-inflammatory pathway, stimulated by IFN-γ and LPS, inducible nitric oxide synthase (iNOS) is highly expressed and utilizes Arg to produce large amounts of cytotoxic nitric oxide (NO) [110]. In the anti-inflammatory/suppressive pathway, stimulated by IL-4/IL-10, arginase 1 (Arg1) is highly expressed and catabolizes Arg into ornithine [111]. More importantly, Arg1 exerts immunosuppressive effects by depleting local arginine required by T cells, thereby inhibiting T-cell proliferation and function via suppression of the T-cell receptor ζ-chain (CD3ζ) and cell cycle arrest [112]. This arginine depletion by Arg1-expressing cells (myeloid-derived suppressor cells [MDSCs], M2 macrophages) is a recognized feature of aging-associated immune dysfunction, where accumulated dysfunctional myeloid populations create arginine-depleted microenvironments that impair T-cell responses.

Acute intense exercise can induce immunosuppression through Arg1 upregulation, whereas long-term, regular, moderate-intensity exercise tends to shape an anti-inflammatory environment [113], improving the overall immune regulatory capacity and T-cell function through mechanisms such as optimizing the Arg1/iNOS balance and reducing myeloid-derived suppressor cell (MDSC) suppressive effects—particularly important for maintaining T-cell function during aging [114]. Importantly, recent evidence reveals that arginine metabolism intersects with tryptophan catabolism (via indoleamine 2,3-dioxygenase 1 [IDO1]) in macrophages: both pathways converge on mTOR and aryl hydrocarbon receptor (AhR) signaling to coordinately regulate macrophage polarization and immune responses [110].

Branched-chain amino acid metabolic remodeling: mTOR-mediated T-cell differentiation and memory formation. Comprising leucine (Leu), isoleucine (Ile), and valine (Val), BCAAs are not only fundamental building blocks for protein synthesis but also important signaling molecules and energy substrates that directly participate in immune cell functional regulation. Leu plays a pivotal role in T-cell fate determination by activating mTORC1 [115]; elevated mTORC1 activity drives effector T-cell (Th1, Th17) differentiation and function, while moderate inhibition favors Treg and memory T-cell formation, which is crucial for maintaining immune homeostasis during aging [116]. Ile and Val serve as important alternative energy sources during the rapid proliferation of activated lymphocytes and can act as precursors for synthesizing key metabolites such as glutamine [104]. Adequate Val supply is a prerequisite for the effective proliferation of aged T cells [102], while Ile participates in regulating B-cell antibody production and maintaining aged macrophage function [117].

Critically, BCAAs modulate immune inflammation not only through mTOR activation but also via AMPK-mediated counter-regulation [101]. Regular exercise, particularly endurance training, significantly upregulates the expression and activity of key BCAA catabolic enzymes (branched-chain aminotransferase [BCAT] and branched-chain α-ketoacid dehydrogenase [BCKDH]) in tissues such as skeletal muscle [118], enhancing the body's overall capacity to catabolize and utilize BCAAs. This leads to adaptive changes in their circulating concentrations, tissue distribution, and metabolic flux, thereby modulating immune function and delaying immunosenescence.

Collectively, these three amino acids exemplify a nutrient-sensing regulatory system that exercise modulates to support immune function during aging. At the substrate level, exercise optimizes amino acid availability through enhanced tissue utilization and metabolic efficiency. At the signaling level, exercise influences the mTOR-AMPK axis through modulation of BCAA metabolism and availability. At the microenvironmental level, exercise impacts the balance of amino acid-dependent immunosuppressive and pro-inflammatory signals. This creates a coordinated response: exercise-enhanced amino acid metabolism → optimized substrate availability → balanced mTOR/AMPK signaling → preserved immune cell function → delayed immunosenescence [101,117]. Unlike pharmacological mTOR inhibitors (e.g., rapamycin), which globally suppress immune function, exercise achieves metabolic modulation through physiological adaptation that maintains the capacity for protective immune responses while reducing chronic inflammation. These findings underscore that amino acid metabolism represents an important mechanism through which exercise maintains immune homeostasis during aging.

Contracting skeletal muscle functions as an endocrine organ that synthesizes and secretes a diverse array of signaling molecules, collectively termed myokines, which constitute a critical bridge for muscle–immune communication and form an immune regulatory network with synergistic effects [119,120]. The muscle–immune relationship is not unidirectional but represents a dynamic, bidirectional crosstalk: while exercise-induced myokines (including heat shock proteins, interleukins, and metabolic regulators) reprogram immune cell phenotypes and suppress inflammaging, immune-derived inflammatory cytokines (TNF-α, IL-6, IL-1β) conversely drive muscle wasting in aging, creating a vicious cycle that accelerates sarcopenia and immunosenescence [17,121]. Understanding this bidirectional axis reveals why breaking the cycle through exercise—which simultaneously reduces immune-derived catabolic signals while enhancing muscle-derived protective myokines—is uniquely effective at delaying aging. This section integrates the muscle-to-immune (anabolic) and immune-to-muscle (catabolic) pathways, highlighting how exercise-induced molecular chaperones (heat shock proteins) and myokines (IL-6, IL-15, irisin, FGF21) act as a unified "stress response–endocrine network" that recalibrates this axis to favor healthy aging.

Exercise-induced stress response and immune modulation: the HSP–myokine continuum. The aging process is frequently accompanied by protein homeostasis dysregulation. Acute exercise, especially high-intensity or eccentric exercise, induces increased protein degradation and structural damage in skeletal muscle tissue, triggering a stress response that leads to the upregulated expression and potential release of molecular chaperones such as heat shock proteins (HSPs). As intracellular molecular chaperones, HSPs are responsible for the proper protein folding, transport, repair, and degradation of damaged proteins to maintain protein homeostasis, which is crucial for counteracting aging-associated protein misfolding and aggregation [122]. Following a single bout of exhaustive or high-intensity exercise, HSP70 mRNA and protein levels are significantly elevated in human peripheral blood mononuclear cells (PBMCs) and skeletal muscle [123]. This adaptive response helps protect cells from damage and maintain function, which is particularly important for the survival and function of aged lymphocytes under stress conditions [124].

Under specific conditions, such as cell necrosis or stress, HSPs can be released extracellularly [125]. Extracellular HSPs (eHSPs), particularly eHSP70 and eHSP60, act as damage-associated molecular patterns or "alarmins," activating innate immunity by binding to receptors on immune cell surfaces (TLR2, TLR4, CD91, LOX-1, etc.) [126,127]. For example, eHSP70 stimulates monocytes/macrophages and dendritic cells (DCs) to produce pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and chemokines while promoting DC maturation and antigen presentation [128], facilitating clearance of cellular debris generated by exercise-induced damage and initiating tissue repair. Critically, this transient pro-inflammatory signal serves a distinct purpose from chronic inflammaging: it activates repair programs and primes immune cells for enhanced pathogen responses [129]. However, excessive or sustained eHSP signaling may exacerbate aging-associated inflammation [130]. Long-term regular exercise training enhances stress tolerance in aged cells by elevating basal intracellular HSP levels and stress-inducible capacity while modulating eHSP release patterns or downstream signaling pathways to control post-exercise inflammatory responses and promote effective pathogen responses in aging organisms [131,132]. Notably, resistance exercise is associated with concurrent elevations in serum HSP70 and anti-inflammatory cytokine IL-10, suggesting coordinated stress-responsive anti-inflammatory signaling [132]. Long-term Tai Chi practice can increase serum HSP70 levels in elderly individuals and is associated with improved immune function, providing protein homeostasis support for delaying immunosenescence.

Myokine-mediated immune reprogramming: a multi-target network. Beyond HSPs, skeletal muscle simultaneously secretes a constellation of myokines that collectively shape anti-aging immune balance through direct immunomodulation (polarizing macrophages and T cells), metabolic regulation (optimizing glucose/lipid metabolism to reduce metabolic stress on immune cells), and systemic anti-inflammatory signaling (suppressing NF-κB and NLRP3 pathways) [119,120].

IL-6: context-dependent master regulator. IL-6 is the most extensively studied myokine. Exercise-induced IL-6 primarily originates from contracting muscle fibers, and its plasma concentration can increase dramatically during prolonged exercise (up to >100-fold above baseline), typically independent of or preceding elevations in pro-inflammatory markers such as TNF-α [133]. Crucially, this exercise-induced IL-6 exhibits an anti-inflammatory profile that is fundamentally distinct from the chronically elevated IL-6 observed in aging and obesity [120]. Exercise-induced IL-6 significantly induces the production of anti-inflammatory cytokines (IL-10) and inhibitors (IL-1ra) while suppressing the synthesis of key pro-inflammatory cytokines (TNF-α) [134], serving as a central molecule that limits potential exercise-induced inflammation and mediates systemic anti-inflammatory effects, thereby helping to alleviate aging-associated, chronic low-grade inflammation. This context dependency is critical: genetic studies confirm that muscle-derived IL-6 is indispensable for mediating benefits such as adipose tissue lipolysis and anti-inflammatory signaling, contrasting sharply with the pathological effects of chronic, systemic IL-6 elevation [120].

IL-15: NK cell and T-cell survival factor. IL-15 is stably expressed in muscle and is critical for the development, survival, and functional maintenance of natural killer (NK) cells and CD8+ T cells (key anti-tumor and antiviral immune cells), whose function gradually declines during aging [135,136]. By synergistically enhancing NK cell cytotoxicity and trafficking alongside exercise-induced IL-6 [120], IL-15 provides essential cellular support for immune surveillance in aging organisms. Additionally, IL-15 improves skeletal muscle oxidative metabolism and glucose uptake, creating a metabolic environment that favors immune cell function.

Irisin (generated by FNDC5 cleavage, with exercise being its primary inducer), beyond its metabolic regulatory effects (promoting adipose browning), also possesses direct anti-inflammatory activity. It suppresses aging-associated excessive macrophage activation by promoting M2 polarization [119]. Furthermore, irisin enhances the transcriptional activity and suppressive function of regulatory T cells (Tregs) by upregulating Foxp3 expression [120], which is crucial for maintaining immune tolerance in aging. Notably, irisin also alleviates oxidative stress-induced endoplasmic reticulum stress (ERS) and apoptosis in macrophages, protecting these cells from age-related dysfunction [137].

FGF21 and BDNF: convergent anti-inflammatory pathways. The exercise-induced skeletal muscle production of fibroblast growth factor 21 (FGF21) acts directly on macrophages through specific receptor pathways (FGFR1-Klotho-STAT5), inhibiting the NF-κB signaling pathway and reducing pro-inflammatory cytokine (IL-6 and TNF-α) secretion while promoting anti-inflammatory cytokine (IL-10) expression [138]. This direct targeting of the NF-κB pathway represents a convergent node where multiple myokines coordinate to suppress the master regulator of inflammaging. Brain-derived neurotrophic factor (BDNF), with skeletal muscle being one source of its exercise-induced release, in addition to neuroprotective and energy metabolic effects, can also modulate aging-associated inflammatory processes by influencing immune cell function or metabolic status [139]. BDNF promotes fatty acid oxidation and maintains mitochondrial quality control in aged muscle, which indirectly supports immune cell metabolism [120].

Immune-derived cytokines drive muscle wasting in aging. While the above discussion highlights the beneficial effects of muscle-derived signals on immunity, the reverse pathway—immune-to-muscle—represents a major driver of sarcopenia and functional decline in aging [17,121]. Chronic low-grade inflammation (inflammaging), characterized by elevated circulating levels of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β), directly induces muscle catabolism through multiple mechanisms: (1) Ubiquitin–proteasome pathway activation: Elevated IL-6 and TNF-α upregulate ubiquitin ligases (e.g., MuRF1, atrogin-1) and proteasome activity, leading to accelerated muscle protein degradation [121]. Clinical studies have shown that increased ubiquitin protein and mRNA levels are linked to elevated IL-6 expression in sarcopenic individuals. (2) NF-κB-mediated muscle atrophy: pro-inflammatory cytokines activate the NF-κB pathway, which drives the expression of atrophy-related genes (atrogenes) and contributes to progressive muscle loss and functional decline with aging [17,121]. (3) Cortisol amplification: IL-6 and TNF-α induce the age-related upregulation of 11βHSD1 (based on in vitro investigations), thereby amplifying the synthesis of cortisol and contributing to muscle catabolism in sarcopenia [17,121]. (4) Macrophage-mediated muscle damage: Aged muscle exhibits the increased infiltration of pro-inflammatory M1 macrophages, which produce TNF-α and IL-6 locally. Single-cell RNA sequencing reveals that aged muscle macrophages express elevated pro-inflammatory and senescence-related markers, impairing their capacity to support satellite cell activation and muscle regeneration [17,121]. Resistance training can shift this balance: a total of 14 weeks of progressive heavy resistance training increases anti-inflammatory M2 macrophages (CD11b+/CD206+) in the skeletal muscle of older individuals, promoting repair over destruction. (5) T-cell dysfunction: Age-related decreases in regulatory T cells (Tregs) in muscle are associated with impaired muscle regeneration. Deficiency in IL6Rα on T cells exhibits deficiencies in muscle Tregs during exercise, resulting in a more pronounced decline in muscle mass [17,121].

This bidirectional framework reveals a self-amplifying pathological loop in aging: chronic inflammation (↑ TNF-α, IL-6 from immune cells) → muscle wasting (↓ muscle mass ↓ myokine secretion) → further immune dysfunction (↓ Tregs ↑ M1 macrophages) → exacerbated inflammation. Exercise uniquely disrupts this cycle at multiple nodes simultaneously:

Muscle-to-immune: ↑ exercise-induced IL-6, IL-15, irisin, FGF21 → M2 macrophage polarization, Treg enhancement, NK cell activation → ↓ systemic TNF-α, IL-1β.

Immune-to-muscle: ↓ chronic IL-6/TNF-α → ↓ ubiquitin–proteasome activity ↓ NF-κB activation → preserved muscle mass → sustained myokine production.

Metabolic recalibration: ↑ irisin, BDNF → adipose browning ↑ insulin sensitivity → ↓ metabolic stress on immune cells → ↓ inflammaging.

Notably, resistance training is particularly effective at reducing inflammatory cytokine levels (specifically IL-6) in sarcopenic participants [17], demonstrating that this exercise modality can be tailored to target specific populations.

By simultaneously enhancing muscle-derived protective myokines and suppressing immune-derived catabolic cytokines, exercise transforms the muscle–immune axis from a vicious cycle (inflammation → sarcopenia → immunosenescence) into a virtuous cycle (myokine secretion → immune rejuvenation → muscle preservation) [119,121]. These coordinated actions are crucial for delaying immunosenescence, maintaining immune homeostasis, and promoting adaptive immunity. Furthermore, emerging evidence suggests that the efficacy of this bidirectional recalibration may depend on the exercise modality: resistance training preferentially targets macrophage polarization and reduces local muscle inflammation, while endurance training enhances systemic myokine release and metabolic benefits.

As the "second genome" of the human body, the gut microbiota establishes a bidirectional communication network with the immune system through its structural composition and metabolic products, playing a critical role in regulating immune homeostasis. However, this relationship is not unidirectional: while gut dysbiosis drives immune dysfunction and inflammaging, immune-derived inflammatory mediators conversely disrupt intestinal barrier integrity and exacerbate microbial imbalance, creating a self-amplifying pathological loop [140,141]. With advancing age, alterations in the gut microbiota structure not only lead to chronic low-grade inflammation (inflammaging) but also accelerate immunosenescence by affecting immune cell differentiation, activation, and function.

Aging-associated gut dysbiosis and immune abnormalities. Aging-associated studies have shown that gut microbiota α-diversity is significantly reduced with an increased abundance of pro-inflammatory Proteobacteria (major members of Gram-negative bacteria) and a decreased abundance of beneficial bacterial groups with anti-inflammatory effects, including Firmicutes, Clostridiaceae, and Lachnospiraceae [142]. This microbial dysbiosis induces immune abnormalities and triggers peripheral chronic inflammatory responses. Gut microbiota disruption leads to intestinal barrier dysfunction, resulting in "leaky gut". The intestinal barrier, composed of the mucus layer, intestinal epithelium, and lamina propria, is crucial for maintaining immune homeostasis. Pathogenic bacteria (such as Bacteroides fragilis, Escherichia coli, and Salmonella) can disrupt tight junction proteins and increase intestinal permeability [143,144]. Leaky gut not only causes gut microbiota translocation and leakage of harmful metabolites (such as lipopolysaccharide [LPS] and bacteria-derived amyloid) but also leads to polymorphonuclear leukocyte migration from systemic circulation to the intestinal mucosa, inducing inflammatory responses [145]. Gut-derived pro-inflammatory factors can enter the circulatory system and promote systemic inflammatory responses [146].

The gut microbiota regulates systemic immune function through multiple mechanisms. Research demonstrates that the gut microbiota not only regulates peripheral immune cells but also influences the development and function of central lymphoid organs [147], suggesting its important role in immune regulation. Intestinal inflammation can enhance the migratory capacity of peripheral immune cells, promoting their recruitment to tissues with elevated oxidative stress and affecting systemic immune function through cascade effects [148]. More importantly, sustained antigenic stimulation and inflammatory signals resulting from gut dysbiosis can promote the excessive depletion of naive T cells, accelerate their conversion to aging-associated effector/memory phenotypes, and upregulate the expression of inhibitory receptors such as PD-1, exacerbating T-cell exhaustion [149]. The gut microbiota and its metabolites can directly or indirectly influence dendritic cells and macrophages through epithelial cell intervention, with regulation occurring via epigenetic mechanisms [150,151,152]. Regulatory T cells (Tregs) can also be induced by gut microbiota metabolites [153,154]. The gut microbiota can also induce the maturation of B cells and alter their immunoglobulin subtypes [155,156]. Therefore, gut microbiota dysbiosis induces immune abnormalities and triggers peripheral inflammatory responses, thereby affecting systemic immune function.

Immune-derived mediators disrupt gut homeostasis in aging. While the above discussion highlights how gut dysbiosis impairs immunity, the reverse pathway—immune-to-gut—represents a major driver of intestinal barrier dysfunction and accelerates the progression of aging-associated gut pathology [141,157]. Aging is associated with the chronic elevation of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, IL-6) that directly compromise intestinal epithelial barrier function through multiple mechanisms [140,141]: (1) Tight junction disruption by IFN-γ and TNF-α: Age-related increases in circulating and mucosal IFN-γ directly downregulate tight junction proteins (claudins, occludin, ZO-1), increasing intestinal permeability [141]. Studies in aged mice demonstrate that IFN-γ-mediated barrier dysfunction facilitates bacterial translocation and the systemic dissemination of microbial products, perpetuating inflammaging [141]. TNF-α synergistically amplifies this effect by activating myosin light chain kinase (MLCK), which phosphorylates tight junction proteins and disrupts their structural integrity [158]. (2) TNF-driven intestinal inflammation: Aging is characterized by elevated intestinal TNF production, which drives local inflammation and epithelial cell apoptosis [140]. Importantly, the genetic or pharmacological ablation of TNF signaling in aged mice restores intestinal barrier integrity and reduces systemic inflammation, demonstrating a direct causal role of immune-derived TNF in age-related gut dysfunction [140]. (3) IL-1β-mediated barrier dysfunction: The age-related activation of the NLRP3 inflammasome in intestinal macrophages leads to excessive IL-1β production, which impairs epithelial tight junction assembly and promotes intestinal permeability [157]. This process is partially microbiota-independent, as aged germ-free mice still exhibit elevated IL-1β levels and barrier dysfunction [157]. (4) Treg dysfunction and loss of immune tolerance: Age-related decreases in colonic regulatory T cells (Tregs) result in the inadequate suppression of effector T-cell responses and reduced IL-10 production, failing to counterbalance pro-inflammatory cytokines [159]. This loss of mucosal immune tolerance perpetuates epithelial damage and creates a permissive environment for pathobiont expansion [159]. (5) Feed-forward loop: immune-mediated dysbiosis: critically, this immune-driven barrier dysfunction subsequently alters the microbiota composition, enriching pro-inflammatory taxa (Proteobacteria) and depleting SCFA-producing bacteria (Firmicutes, Lachnospiraceae), which further exacerbates inflammation and creates a self-amplifying vicious cycle [140,141].

Breaking the vicious cycle through exercise. This bidirectional framework reveals a self-amplifying pathological loop in aging: gut dysbiosis (↓ SCFA-producing bacteria ↑ LPS) → systemic inflammation (↑ TNF-α, IFN-γ, IL-1β) → intestinal barrier dysfunction (↓ tight junctions, ↑ permeability) → microbial translocation and dysbiosis → exacerbated inflammation [140,141,157]. Exercise uniquely disrupts this cycle at multiple nodes simultaneously [160]:

Gut-to-immune: ↑ SCFA-producing bacteria (Firmicutes, butyrate-producers) → ↓ LPS ↑ Tregs, ↓ systemic TNF-α/IL-6.

Immune-to-gut: ↓ pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β) → ↑ tight junction protein expression ↓ intestinal permeability → ↓ bacterial translocation.

Metabolic recalibration: ↑ SCFAs (butyrate, acetate) → GPR43/GPR109A activation → NF-κB and NLRP3 suppression → ↓ intestinal inflammation.

Exercise reshapes the gut microbiota structure. Studies have confirmed that exercise of varying intensities can reshape the gut microbiota structure. Four weeks of moderate-intensity treadmill exercise significantly reversed the reduction in the Firmicutes abundance and the increase in the Bacteroidetes abundance, decreasing the Bacteroidetes/Firmicutes ratio [161]. Sixteen weeks of voluntary wheel running significantly reduced the abundance of pro-inflammatory bacterial groups, such as Proteobacteria and Tenericutes, while increasing the abundance of beneficial bacteria, such as Allobaculum [162]. High-intensity interval exercise significantly increased the relative abundance of butyrate-producing bacterial groups, including Eubacterium, Roseburia, and Clostridium, while suppressing Bacteroides fragilis, which damages intestinal mucosal health [162]. Butyrate-producing bacterial groups such as Butyrivibrio proteoclasticus, Marvinbryantia formatexigens, and Roseburia spp. were significantly increased. Importantly, exercise-induced shifts in microbiota composition are associated with increased microbial diversity and the enhanced production of beneficial metabolites, which collectively contribute to improved gut barrier function and reduced systemic inflammation in older adults.

Exercise protects intestinal barrier integrity. Scientific and rational physical activity can prevent intestinal inflammatory diseases. Studies have shown that voluntary wheel running attenuates inflammatory gene expression in the distal colon, significantly reduces the levels of pro-inflammatory cytokines, including IL-1β and TNF-α, decreases diarrhea incidence, and inhibits secondary infection by Escherichia coli, conferring protective effects against experimental colitis [163,164,165]. Swimming for 30 min/day enhances the intestinal antimicrobial capacity and alleviates chronic stress-induced intestinal barrier dysfunction by increasing the tissue expression of the α/β-defensins and RegIIIβ/γ genes and antimicrobial peptide production [166]. Four weeks of moderate-intensity treadmill exercise can also elevate intestinal tight junction protein expression levels, improve intestinal barrier damage, and reduce the serum LPS content [167]. Mechanistically, exercise reduces circulating levels of barrier-disrupting cytokines (TNF-α, IFN-γ) while promoting the expression of tight junction proteins (ZO-1, occludin, claudins), thereby restoring barrier integrity [160]. Even single bouts and short-term acute exercise promote the expression of anti-inflammatory cytokines IL-6 and IL-10 in intestinal lymphocytes [168,169].

Exercise regulates gut microbiota metabolites. Exercise improves peripheral chronic inflammatory responses by regulating the gut microbiota metabolite kynurenine (Kyn). Its secondary metabolite kynurenic acid (Kyna) can suppress LPS-induced inflammatory responses in monocytes and macrophages and control cytokine release from invariant natural killer T (iNKT) cells [170]. Simultaneously, Kyna can activate the aryl hydrocarbon receptor (AhR) on immune cells, promoting immune tolerance [171]. Eight weeks of voluntary wheel running can activate skeletal muscle peroxisome proliferator-activated receptor γ coactivator 1α1 (PGC-1α1), increase kynurenine aminotransferase (KAT) gene expression, and promote Kyn-Kyna conversion, thereby inhibiting Kyn accumulation and improving inflammatory responses [172].

Short-chain fatty acids (SCFAs) are among the most important metabolites of the gut microbiota and play critical roles in immune cell development and functional regulation. Acetate is essential for immune cell maturation and maintenance of metabolic homeostasis; germ-free mice or lower gut microbiota diversity can lead to immune cell developmental defects, resulting in impaired immune responses [147]. Butyrate functions as an anti-inflammatory agent through its role as a histone deacetylase inhibitor. Six weeks of voluntary wheel running effectively increased the butyrate/acetate ratio in the mouse intestine [173]. Compared to sedentary populations, professional rugby players showed significantly elevated fecal SCFAs, including acetate and butyrate [174]. Exercise interventions in older adults have been shown to increase the abundance of SCFA-producing bacteria and elevate circulating SCFA levels, which contribute to improved metabolic health and reduced systemic inflammation [175]. Different exercise intensities and modalities exhibit distinct effects on SCFA regulation. Rats subjected to combined aerobic and resistance exercise intervention showed decreased fecal acetate levels with no significant change in butyrate [176], whereas exhaustive exercise in rats decreased the intestinal acetate proportion while increasing the butyrate proportion [177]. This suggests that scientific and rational exercise can optimize the SCFA composition (e.g., by increasing the relative proportion of butyrate), thereby enhancing anti-inflammatory effects while maintaining the metabolic requirements for immune cell function.

Exercise improves local intestinal immune function. Additionally, exercise can improve the microbiota structure by regulating local intestinal immune function. Compared to sedentary control mice, mice undergoing long-term moderate-intensity exercise showed elevated intestinal IgA levels, the upregulated gene expression of TGF-β, IL-6, TNF-α, IL-4, and IL-10, downregulated IL-2 gene expression, and reduced numbers of B cells and CD4+ T cells. The exercise-induced elevation of intestinal IgA levels can enhance immune function, improve resistance to intestinal pathogen infection, enhance discrimination of commensal microbiota and protection of their colonization, and improve the microbiota structure [178,179]. Comprehensive studies demonstrate that 12 weeks of moderate-intensity treadmill exercise effectively increases gut microbiota α-diversity, enhances enrichment of beneficial bacterial groups, improves intestinal barrier permeability, suppresses intestinal inflammation, reverses intestinal pathology, and reduces systemic inflammatory responses [180].

By simultaneously enhancing gut-derived protective metabolites (SCFAs, Kyna) and suppressing immune-derived barrier-disrupting cytokines (TNF-α, IFN-γ, IL-1β), exercise transforms the gut–immune axis from a vicious cycle (dysbiosis → inflammation → barrier dysfunction → microbial translocation → exacerbated inflammation) into a virtuous cycle (microbial diversity → SCFA production → immune tolerance → barrier integrity → reduced systemic inflammation) [140,160]. This indicates that exercise can improve immune function and suppress dysbiosis-induced inflammatory responses from three aspects—the gut microbiota, the peripheral immune system, and systemic immune regulation—by improving the gut microbiota structure and metabolic products via both microbiota-dependent and microbiota-independent immune pathways, thereby ameliorating the occurrence and progression of immunosenescence-associated pathology.

The aging of the innate immune system is primarily characterized by "inflammaging" and the functional decline in neutrophils, macrophages, and natural killer (NK) cells. Research indicates that exercise can improve innate immune function by remodeling the inflammatory environment in the elderly. Specifically, moderate-intensity aerobic exercise has been shown to significantly reduce C-reactive protein (CRP) levels and enhance the respiratory burst capacity of neutrophils, thereby improving their bactericidal activity [181]. Intervention studies in older adults further confirm that regular exercise regulates oxidative stress and inflammatory pathways by upregulating superoxide dismutase (SOD) and reducing malondialdehyde (MDA) levels. This is manifested as a decrease in pro-inflammatory cytokines such as TNF-α and IL-6, thereby delaying the progression of immunosenescence [182,183]. However, the exercise intensity represents a critical variable, as high-intensity exercise may induce oxidative stress and inflammatory imbalance [184], underscoring the importance of moderate exercise.

At the cellular level, moderate exercise also exerts a significant enhancing effect on macrophages and NK cells. Mcfarlin et al. confirmed that long-term resistance training increases resting NK cell activity in elderly women, effectively counteracting the age-related decline in immune surveillance capabilities against tumors and infections [185]. Nevertheless, the risk of overtraining warrants attention; Kawada et al. noted that high-frequency, high-intensity resistance training might conversely reduce NK cell activity and accelerate immunosenescence [186], highlighting the necessity of scientifically monitoring exercise loads.

Furthermore, the amelioration of innate immunity by exercise involves regulation at deeper molecular levels. A 16-week combined exercise (aerobic + resistance) study in the elderly showed that exercise not only downregulated TNF-α and upregulated the anti-inflammatory cytokine IL-10 but also involved the activation of the AMPK signaling pathway and epigenetic regulatory mechanisms [187]. Simultaneously, exercise intervention can effectively reverse the exacerbated expression of immunosenescence markers associated with obesity in middle-aged individuals [187]. Some resistance training studies have also observed increases in IL-2 and IFN-γ levels alongside improvements in systemic immune status [188], suggesting that exercise provides a crucial pathway for delaying overall immunosenescence by improving the innate immune environment and the function of key immune cells.

The decline in T-cell immune function, characterized by the contraction and dysfunction of the T-cell repertoire, is a hallmark of immunosenescence. With advancing age, lymphoid progenitors exhibit differentiation defects, leading to a dual decline in both the quantity and quality of T cells. This is primarily manifested as the depletion of the naive T-cell reserve and the accumulation of immunosenescent, terminally differentiated T cells [189]. Exercise remodels conventional T cells through a coordinated process involving mobilization, selective apoptosis, and regeneration. The core mechanism is hypothesized to be the "vacating space" theory: exercise induces the apoptosis of terminally differentiated senescent T cells, thereby creating immunological space for the output of naive T cells from the bone marrow and thymus [190,191,192]. This mechanism of cellular renewal not only restores the diversity of the peripheral T-cell repertoire but also enhances the immune response to vaccination [193,194]. Furthermore, it is considered a potential mechanism by which exercise improves anti-tumor immune surveillance [195].

Thymic involution is a fundamental cause of T-cell immunosenescence. Research indicates that long-term moderate-intensity exercise can delay thymic atrophy and may even partially restore thymic hematopoiesis [196]. A landmark study by Duggal et al. demonstrated that maintaining high levels of physical activity throughout adulthood or lifelong can ameliorate reduced thymic output, a key feature of immunosenescence [190].

Several potential mechanisms may underlie the exercise-induced enhancement of thymic T-cell output. First, exercise may modulate systemic and local growth factors critical for thymic function, including insulin-like growth factor-1 (IGF-1) and interleukin-7 (IL-7), both of which promote thymocyte proliferation, survival, and differentiation [197]. Second, exercise-induced reduction in chronic low-grade inflammation may protect thymic epithelial cells (TECs) from inflammaging-associated damage, thereby preserving their capacity to support T-cell development and positive/negative selection [190]. Third, regular physical activity may enhance thymic vascularization and oxygen delivery, counteracting age-related thymic adipose involution and improving the microenvironmental niche for hematopoietic progenitor seeding and T-cell maturation. Fourth, exercise may reduce thymic fat infiltration, a hallmark of age-related thymic degeneration, thereby restoring the functional thymic tissue volume [190]. Exercise improves the thymic microenvironment, thereby enhancing the production of naive T cells and increasing the efficiency of their export into the peripheral circulation [160]. Such adaptive changes induced by regular exercise help rebalance the immune regulatory network in the aging organism and maintain the regenerative capacity of the immune system [198].

Beyond regulating cell numbers and proportions, exercise significantly improves the functional quality of T cells. Chronic exercise training has been shown to significantly increase the proportion of activated CD4+ T cells in peripheral blood and restore their proliferative capacity in vitro [199]. Regarding CD8+ T cells, exercise not only promotes their expansion in vitro but also enhances their sensitivity in recognizing tumor or viral antigen peptides. Additionally, exercise increases T-cell receptor (TCR) repertoire diversity, thereby elevating the specific immune response capability against novel pathogens [200,201,202,203]. The mechanism underlying the exercise-induced enhancement of TCR diversity appears to involve both the augmented thymic output of newly generated naive T cells—each carrying unique, randomly recombined TCR sequences generated through VDJ recombination—and the selective apoptotic clearance of clonally expanded, terminally differentiated senescent T cells that dominate the aged TCR repertoire [191,204]. By simultaneously increasing the influx of diverse naive T cells and reducing the oligoclonal expansion of exhausted effector T cells, exercise effectively "resets" the peripheral TCR landscape toward a more polyclonal, youthful configuration. This dual mechanism—thymic rejuvenation and peripheral editing—collectively restores immune repertoire breadth and enhances the capacity to recognize novel antigens [205,206].

Current evidence suggests that exercise-induced T-cell modulation is intensity- and time-dependent. Regarding chronic effects, Spielmann et al. found that higher aerobic fitness (VO_2max) is significantly associated with a lower proportion of senescent T cells (CD28−/CD57+) in human peripheral blood [191]. Similarly, Minuzzi et al. confirmed that long-term training improves the mobilization capacity and response efficiency of aging lymphocytes [192]. Regarding acute effects and intensity differences, Kruger et al. noted that acute high-intensity interval exercise (HIIT) induces a significant redistribution of T-cell subsets in peripheral blood: a dramatic increase in CD3+, CD4+, and CD8+ T-cell counts immediately post-exercise (lymphocytosis), followed by a decline to below baseline levels 3 h post-exercise (lymphocytopenia). Notably, this process is accompanied by the preferential apoptosis of highly differentiated (terminally differentiated) T cells [196,207], acting as a mechanism for the selective clearance of dysfunctional cells.

The preferential clearance of senescent T cells mentioned above involves multiple convergent apoptotic pathways that selectively target highly differentiated cells while preserving functional lymphocytes [196,207,208]. Understanding these mechanisms is critical for optimizing exercise interventions.

(1) The Fas/FasL-mediated extrinsic pathway. Evidence suggests that terminally differentiated senescent T cells (CD28⁻CD57⁺) express elevated levels of the Fas (CD95) death receptor. Exercise may acutely increase circulating Fas ligand (FasL) levels and, through catecholamine-mediated β2-adrenergic signaling [184], potentially enhance apoptotic susceptibility in senescent cells.

(2) Oxidative stress and mitochondrial pathways. High-intensity exercise transiently increases reactive oxygen species (ROS) production [209]. Senescent T cells exhibit accumulated mitochondrial dysfunction and reduced antioxidant capacity, making them more vulnerable to oxidative stress-induced apoptosis. In contrast, naive and functional memory T cells are protected by the higher expression of anti-apoptotic proteins (such as Bcl-2) and more robust antioxidant defenses [196,207,208].

(3) Glucocorticoid-mediated apoptosis. Exercise acutely elevates circulating glucocorticoids (cortisol), which can induce lymphocyte apoptosis through the transcriptional regulation of pro-apoptotic and anti-apoptotic genes. Senescent T cells may exhibit differential sensitivity to this pathway, contributing to the post-exercise lymphocytopenia observed several hours after high-intensity exercise [196,207,208].

(4) Activation-induced cell death (AICD). Exercise-induced activation signals may trigger AICD in senescent cells that have exhausted their replicative potential and possess shortened telomeres, acting as a quality control mechanism [196,207,208].

Through these selective mechanisms, exercise reduces the homeostatic burden on the T-cell compartment, potentially allowing for the expansion of newly generated naive T cells from the thymus [190,191,192].

Understanding immune aging requires integrating both conventional αβ T cells and unconventional T cells (including γδ T cells, iNKT cells, and MAIT cells). These cells bridge innate and adaptive immunity, recognizing non-peptide antigens and exhibiting rapid "innate-like" responses [210]. Collectively, they comprise approximately 10–30% of the T-cell compartment in adults, particularly at barrier sites like the gut and liver:

(1) γδ T cells. Aging leads to a progressive decline in "innate-like" Vγ9Vδ2⁺ γδ T cells, while "adaptive-like" Vδ1⁺ cells may expand due to CMV infection [210]. Exercise mobilizes γδ T cells to blood via β2-adrenergic receptor signaling. Specifically, acute graded exercise preferentially mobilizes effector Vγ9Vδ2⁺ cells with enhanced cytotoxic phenotypes, which may represent a mechanism for improved anti-tumor surveillance [211].

(2) iNKT cells. These cells (invariant natural killer T cells) exhibit age-related functional shifts from Th1 to Th2 cytokine profiles and gender-dependent declines in frequency [210]. While specific exercise data is emerging, the potential for exercise to modulate the circulating pool of these cells remains an important area for future research.

(3) MAIT cells. Mucosal-associated invariant T (MAIT) cells are highly responsive to exercise. Acute moderate-intensity aerobic exercise substantially increases circulating MAIT cell counts, with the preferential mobilization of CD8⁺ subsets expressing chemokine receptors CCR4, CCR5, and CCR6. Critically, exercise-mobilized MAIT cells exhibit enhanced functional capacity, showing increased TNFα and IFN-γ expression upon stimulation. Long-term training may help rescue age-related impairments in MAIT cell mobilization [212].

Exercise promotes adaptive immune rejuvenation through a unified framework: it mobilizes highly differentiated effector cells (both conventional and innate-like) for immediate defense, selectively induces apoptosis in senescent cells to create space, and supports thymic output. This integrated remodeling transforms the aging T-cell compartment into a more rejuvenated and responsive repertoire.

A core hallmark of immunosenescence is chronic low-grade inflammation, termed "inflammaging". Elevated levels of circulating mitochondrial DNA (cf-mtDNA), a potent damage-associated molecular pattern (DAMP), are closely linked to aging-associated pathology by triggering sterile inflammation. Regular exercise has been proven to effectively lower circulating mtDNA levels, thereby ameliorating chronic inflammation. Research indicates that professional male volleyball players exhibit significantly lower resting plasma cf-mtDNA compared to that of sedentary controls [213], suggesting an association between high-level physical activity and reduced inflammatory triggers. Acute exercise also demonstrates immediate benefits: a single bout of aerobic exercise (60% VO_2max) significantly reduced plasma cf-mtDNA levels at 54 and 90 min post-exercise [214].

Beyond direct clearance, chronic aerobic exercise remodels the gene expression profile of peripheral leukocytes, downregulating pro-inflammatory genes while upregulating anti-inflammatory genes [215,216]. This process involves multiple pathways, including reducing the count of pro-inflammatory monocyte subsets, downregulating the TLR4 expression on monocytes, and stimulating the release of anti-inflammatory myokines from skeletal muscle [217]. Mechanistically, it has been shown that 6 weeks of voluntary wheel running reduces leptin secretion from adipose tissue, which, in turn, increases the CXCL12 expression in bone marrow stromal cells (LepR+). This suppresses the proliferation of hematopoietic stem and progenitor cells (LSKs), leading to a reduction in pro-inflammatory leukocyte output. Notably, this reduction did not compromise immunity; rather, it enhanced anti-infection capabilities in mice by minimizing inflammation-induced tissue damage [218]. However, the intensity of exercise acts as a "double-edged sword"; short-term high-intensity exercise can induce mitochondrial dysfunction in peripheral leukocytes, accompanied by increased apoptosis and elevated pro-inflammatory mediators [219], underscoring the critical role of moderate intensity in managing immunosenescence.

During aging, autophagic flux in immune cells is impaired, leading to the accumulation of damaged organelles and protein aggregates. Exercise serves as a potent physiological stressor that activates the autophagy system, acting as a "quality control" mechanism. Regardless of the intensity, acute exercise enhances mitophagy in both skeletal muscle and immune cells [220]. This mechanism is directly linked to the reduction in circulating mtDNA: by activating mitophagy, exercise facilitates the timely clearance of damaged mitochondria, preventing mtDNA leakage [214,220]. In models of high-intensity exhaustive exercise, the compensatory activation of mitophagy clears damaged mitochondria and reduces mtDNA release, thereby attenuating the activation of the cGAS-STING pathway and subsequent interferon/inflammatory signaling cascades.

At the molecular level, exercise regulates the autophagy network primarily through the energy sensor AMPK. AMPK phosphorylates ULK1 (at Ser555) and inhibits mTORC1 activity, thereby initiating the autophagy complex [221]. Subsequently, the Beclin-1/VPS34 complex mediates phagophore formation, while LC3-I is converted to lipidated LC3-II via ATG7/3, participating in autophagosome elongation [222]. This cascade is pivotal for clearing oxidative damage products accumulated in senescent immune cells and restoring cellular homeostasis.

Dysregulated "immunometabolism", characterized by declined oxidative phosphorylation (OXPHOS) capacity and excessive ROS production, is a key feature of immunosenescence. Exercise reverses this aging phenotype by promoting mitochondrial biogenesis and metabolic reprogramming. Specifically, exercise upregulates PGC-1α expression via the CaMKKβ and AMPK signaling pathways [223]. As the master regulator, PGC-1α binds with Nuclear Respiratory Factors 1/2 (NRF1/2) to promote Mitochondrial Transcription Factor A (TFAM) expression, driving mtDNA transcription and replication to enhance OXPHOS capacity [224].

Furthermore, exercise-enhanced mitochondrial metabolism supports the transition of immune cells (such as macrophages) towards an anti-inflammatory M2 phenotype and suppresses excessive ROS production [225]. Crucially, enhanced mitochondrial biogenesis [226] and autophagy (e.g., increased LC3 expression) [227] via the PGC-1α/TFAM axis effectively clear damaged mitochondria. This prevents mtDNA leakage into the cytosol, thereby blocking the aberrant activation of the NLRP3 inflammasome.

Immunosenescence is accompanied by cumulative alterations in the epigenetic landscape, resulting in the sustained activation of pro-inflammatory genes and the silencing of immune function genes. Exercise can delay or reverse this process through epigenetic reprogramming. First, by modulating metabolite availability (e.g., Acetyl-CoA) and reducing DAMP release, exercise induces "Trained Immunity." This mechanism enables senescent innate immune cells to regain a rapid and robust response to pathogens via specific epigenetic modifications [228].

Second, exercise directly regulates DNA methylation and non-coding RNA networks. Regarding DNA methylation, exercise alters the methylation status of key immune gene promoters (e.g., TLR4, IL-1β) by downregulating DNA methyltransferase (DNMT) activity or modulating Ten-Eleven Translocation (TET) enzymes [229]. For instance, endurance exercise significantly reduces TLR4 expression in monocytes, an anti-inflammatory adaptation closely tied to specific histone modifications and DNA methylation patterns. Additionally, exercise regulates the expression of immune-related microRNAs (e.g., miR-155, miR-21) [222,230], providing fine-tuned post-transcriptional regulation of immune signaling pathways to reverse aging-associated epigenetic anomalies (Figure 2).