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Cited by 63Telomeres, Telomerase, and SenescenceExercise and Physiological ResponsesGenetics, Aging, and Longevity in Model Organisms

Exercise Counters the Age-Related Accumulation of Senescent Cells

Open access
Zhang, Xu, Englund, Davis A., Aversa, Zaira, Jachim, Sarah K., White, Thomas A., LeBrasseur, Nathan K.·2022·Exercise and Sport Sciences Reviews
DOI 10.1249/jes.0000000000000302PMC PMC9680689
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Abstract

We propose the beneficial effects of exercise are in part mediated through the prevention and elimination of senescent cells. Exercise counters multiple forms of age-related molecular damage that initiate the senescence program and activates immune cells responsible for senescent cell clearance. Preclinical and clinical evidence for exercise as a senescence-targeting therapy and areas needing further investigation are discussed.

AI snapshot

Written from the paper’s full text.

TL;DR

The paper proposes that exercise partly mediates its health benefits by preventing age-related accumulation of senescent cells and promoting their immune clearance. It reviews preclinical and human evidence that exercise reduces senescence inducers and markers across multiple tissues, while emphasizing that evidence is preliminary and more rigorous studies are needed.

Key findings

  • Exercise is hypothesized to act as a senotherapeutic by countering molecular damage that initiates senescence—DNA/telomere damage, mitochondrial dysfunction/ROS, and inflammation/SASP—and by modulating immune cells involved in senescent cell clearance.
  • Preclinical studies cited show exercise reduces senescence markers: 8 wk treadmill running attenuated age-associated DNA damage (8-OHdG) in skeletal muscle of 30-month-old rats; 30 wk voluntary wheel running in mtDNA mutator mice reduced mtDNA mutations and accelerated aging features in skeletal muscle, heart, and brain; exercise reduced P16/P21/SASP markers in adipose, liver, brain, and skeletal muscle.
  • Human evidence: in 170 healthy participants aged 18–80 yr, >240 min/month habitual physical activity was associated with lower P16 in circulating T cells; 12 wk structured strength and endurance training reduced P16, P21, cGAS, and TNFα in peripheral blood CD3+ T cells and lowered circulating senescence-related proteins in older (~67 yr) adults; 5 months resistance training in older (~73 yr) overweight/obese women reduced P16-expressing cells in thigh adipose tissue.
  • Exercise may increase DNA repair and telomere stability: physical activity and high-intensity activity were positively associated with DNA repair in lymphocytes; marathon runners/triathletes had lower P53 and P16, greater telomerase activity and telomere length than untrained controls.

Methods

  • Narrative review/commentary; the authors propose a hypothesis and synthesize existing preclinical and clinical literature, with no new primary data.
  • Evidence base includes animal exercise studies (e.g., treadmill running, voluntary wheel running, swimming) and human cross-sectional and exercise intervention studies (e.g., 170 healthy participants aged 18–80 yr; 47 patients aged 56–81 yr; older adults ~67 yr; older ~73 yr overweight/obese women).
  • Main analysis is qualitative synthesis of exercise effects on senescence inducers, markers, and immune clearance; the authors cite a systematic review/meta-analysis noting high heterogeneity in animal studies.

Limitations

  • Stated: evidence is preliminary; limited preclinical work supports the premise; only two human exercise intervention reports were known to the authors; many studies relied on a single senescence marker; preclinical evidence derives from young and middle-aged animals, so effects in older animals need investigation; no stand-alone specific senescence marker; heterogeneity in animal studies; sex-specific differences not thoroughly studied.
  • Evident: as a narrative review, it does not conduct a systematic search, risk-of-bias assessment, or meta-analysis, so conclusions are hypothesis-generating and causal mechanisms remain unestablished.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1249/jes.0000000000000302

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 95 cited sources checked · 0 supported · 0 flagged

  • Interpretationnone given

    Exercise activates immune cells responsible for senescent cell clearance.

    “Exercise counters multiple forms of age-related molecular damage that initiate the senescence program and activates immune cells responsible for senescent cell clearance.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Cellular senescence is a driver of aging and aging-related conditions.

    “Over the past decade, mounting evidence highlights cellular senescence, a cell fate in response to diverse forms of molecular and cellular damage, as a driver of aging and aging-related conditions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Khosla S, Farr JN, Tchkonia T, Kirkland JL. The role of cellular senescence in ageing and endocrine disease. Nat. Rev. Endocrinol 2020; 16(5): 263– 75. 32161396 PMC7227781 source

      Not checked in the free run.

  • Premisecitation

    Senotherapeutics that impact the abundance or behavior of senescent cells have been shown to counter multiple conditions across multiple physiological systems in mouse models of aging and disease.

    “Moreover, candidate drugs (senotherapeutics) that impact the abundance (senolytics) or behavior (senomorphics) of senescent cells have been shown to counter multiple conditions across multiple physiological systems in mouse models of aging and disease (2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Robbins PD, Jurk D, Khosla S, Senolytic drugs: reducing senescent cell viability to extend health span. Annu. Rev. Pharmacol. Toxicol 2021; 61: 779– 803. 32997601 PMC7790861 source

      Not checked in the free run.

  • Interpretationnone given

    Exercise counters multiple forms of age-related molecular damage that initiate the senescence program.

    “Exercise counters multiple forms of age-related molecular damage that initiate the senescence program and activates immune cells responsible for senescent cell clearance.”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    The beneficial effects of exercise are in part mediated through the prevention and elimination of senescent cells.

    “We propose the beneficial effects of exercise are in part mediated through the prevention and elimination of senescent cells.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 13
  • May combine two claims. 36
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The DDR is the lynchpin of other recognized inducers of cellular senescence, including reactive oxygen species, mitochondrial dysfunction, proteotoxic stress, and exogenous stressors such as irradiation and genotoxic drugs.

    “As with replicative stress, the DDR is the lynchpin of other recognized inducers of cellular senescence, including reactive oxygen species (ROS), mitochondrial dysfunction, proteotoxic stress, and exogenous stressors such as irradiation and genotoxic drugs, which together are termed stress-induced premature senescence.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Interventions that target key hallmarks of aging potentially can prevent, delay, or even reverse age-related conditions as a group.

    “The geroscience hypothesis posits that interventions that target key hallmarks of aging potentially can prevent, delay, or even reverse age-related conditions as a group (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Kennedy BK, Berger SL, Brunet A, Geroscience: linking aging to chronic disease. Cell 2014; 159(4): 709– 13. 25417146 PMC4852871 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Telomere shortening through cell divisions triggers a DNA damage response and activates key governors of the cell cycle and senescence program.

    “Through cell divisions, telomeres, which are short repeats of DNA sequences that cap the ends and protect chromosomes, progressively shorten. Ultimately, this triggers a DNA damage response (DDR) and activates key governors of the cell cycle and senescence program (thoughtfully reviewed in (4)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Victorelli S, Passos JF. Telomeres and cell senescence—size matters not. EBioMedicine 2017; 21: 14– 20. 28347656 PMC5514392 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise is a highly effective means to counter the onset and progression of the most prevalent and disabling aging-related conditions, including heart disease, diabetes, Alzheimer disease, osteoporosis, sarcopenia, cancer, and frailty.

    “Exercise, in particular, is a highly effective means to counter the onset and progression of the most prevalent and disabling aging-related conditions, including heart disease, diabetes, Alzheimer disease, osteoporosis, sarcopenia, cancer, and frailty.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Booth et al. (13) Booth FW, Roberts CK, Laye MJ. Lack of exercise is a major cause of chronic diseases. Compr. Physiol 2012; 2(2): 1143– 211. 23798298 PMC4241367

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Senescence is a consequence of multiple forms of molecular damage that increase with advancing age, exceed the cell's capacity for repair, but are insufficient to trigger death by apoptosis.

    “Senescence is a consequence of multiple forms of molecular damage that increase with advancing age, exceed the cell’s capacity for repair, but are insufficient to trigger death by apoptosis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Telomere uncapping and DNA damage within telomeres can trigger senescence independent of changes in telomere length.

    “It also should be noted that telomere uncapping and DNA damage within telomeres can trigger senescence independent of changes in telomere length (5,6).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Anderson R, Lagnado A, Maggiorani D, Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J 2019; 38(5): e100492. 30737259 PMC6396144 source

      Not checked in the free run.

    • cites [6] Morgan RG, Ives SJ, Lesniewski LA, Age-related telomere uncapping is associated with cellular senescence and inflammation independent of telomere shortening in human arteries. Am. J. Physiol. Heart Circ. Physiol 2013; 305(2): H251– 8. 23666675 PMC3726958 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With advancing age, senescent cells accumulate and are enriched at anatomical sites of disease, where they compromise the structure and function of multiple organs.

    “With advancing age, senescent cells accumulate and are enriched at anatomical sites of disease, where they compromise the structure and function of multiple organs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Khosla S, Farr JN, Tchkonia T, Kirkland JL. The role of cellular senescence in ageing and endocrine disease. Nat. Rev. Endocrinol 2020; 16(5): 263– 75. 32161396 PMC7227781 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Inflammatory factors, including those produced by senescent cells, have been implicated in the initiation and spread of senescence.

    “Inflammatory factors, including those produced by senescent cells (e.g., cytokines, transforming growth factor-β family ligands, and vascular endothelial growth factor), also have been implicated in the initiation and spread of senescence (8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Acosta JC, Banito A, Wuestefeld T, A complex secretory program or- chestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol 2013; 15(8): 978– 90. 23770676 PMC3732483 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two weeks of treadmill running increased the abundance of antioxidants superoxide dismutase-1 and −2 and glutathione peroxidase and reduced ROS in the hippocampus of 12-month-old rats.

    “Indeed, just 2 wk of treadmill running has been shown to increase the abundance of antioxidants superoxide dismutase-1 and −2 and glutathione peroxidase and reduce ROS in the hippocampus of 12-month-old rats (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Marosi K, Bori Z, Hart N, Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats. Neuroscience 2012; 226: 21– 8. 22982624 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Although there is an acute and transient inflammatory response after exercise, exercise training suppresses sterile inflammation.

    “Interestingly, although there is an acute and transient inflammatory response after exercise, exercise training suppresses sterile inflammation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IL-6, CCL2 (MCP1), and TNF-α are activated acutely after exercise, partially due to oxidative stress and the DDR, but basal levels are reduced after exercise intervention.

    “For example, recognized proinflammatory SASP factors, interleukin-6 (IL-6), CCL2 (MCP1), and tumor necrosis factor α (TNF-α) are activated acutely after exercise (30), partially due to oxidative stress and the DDR, but basal levels are reduced after exercise intervention.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Kinugawa T, Kato M, Ogino K, Interleukin-6 and tumor necrosis factor-alpha levels increase in response to maximal exercise in patients with chronic heart failure. Int. J. Cardiol 2003; 87(1): 83– 90. 12468058 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Physical inactivity is a major cause of chronic diseases and a threat to human healthspan.

    “In a compelling review, Booth et al. (13) underscore physical inactivity as a major cause of chronic diseases and a threat to human healthspan and showcase exercise as a profoundly effective means to prevent or delay the onset and progression of 35 conditions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Booth et al. (13) Booth FW, Roberts CK, Laye MJ. Lack of exercise is a major cause of chronic diseases. Compr. Physiol 2012; 2(2): 1143– 211. 23798298 PMC4241367

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial DNA mutations accumulate with age, secondary to increased ROS and continuous replication, which enables mutations that impair function to potentially expand clonally.

    “Mitochondrial DNA mutations also accumulate with age, secondary to increased ROS and continuous replication, which enables mutations that impair function to, potentially, expand clonally (23).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Greaves LC, Nooteboom M, Elson JL, Clonal expansion of early to mid-life mitochondrial DNA point mutations drives mitochondrial dysfunction during human ageing. PLoS Genet 2014; 10(9): e1004620. 25232829 PMC4169240 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    DNA damage initiates cell cycle arrest through the DDR and downstream p53/p21 and p16 pathways.

    “DNA damage initiates cell cycle arrest through the DDR and downstream p53/p21 and p16 pathways (Fig. 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Aging and physical inactivity independently and synergistically diminish mitochondrial content and oxidative capacity and exacerbate mitochondrial mutations and oxidative stress.

    “Aging and physical inactivity independently and synergistically diminish mitochondrial content and oxidative capacity and exacerbate mitochondrial mutations and oxidative stress.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Exercise is a profoundly effective means to prevent or delay the onset and progression of 35 conditions.

    “In a compelling review, Booth et al. (13) underscore physical inactivity as a major cause of chronic diseases and a threat to human healthspan and showcase exercise as a profoundly effective means to prevent or delay the onset and progression of 35 conditions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Booth et al. (13) Booth FW, Roberts CK, Laye MJ. Lack of exercise is a major cause of chronic diseases. Compr. Physiol 2012; 2(2): 1143– 211. 23798298 PMC4241367

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that study, both physical activity and high-intensity physical activity (MET values ≥6) were positively associated with DNA repair in lymphocytes.

    “In humans, a cross-sectional study of approximately 100 healthy women and men aged 50–72 yr did not show an association between self-reported physical activity and DNA damage (measured via comet assay), but reported a positive association between both physical activity and high-intensity physical activity (metabolic equivalent task (MET) values ≥6) and DNA repair in lymphocytes (15).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Cash SW, Beresford SA, Vaughan TL, Recent physical activity in relation to DNA damage and repair using the comet assay. J. Phys. Act. Health 2014; 11(4): 770– 6. 25078521 PMC3844056 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effects of physical activity and structured exercise interventions on telomere length have been inconsistent, and differences in study design, duration, cell/tissue types, and measurement methods prohibit consensus.

    “In terms of telomere length, the effects of physical activity and structured exercise interventions have been inconsistent. Differences in study design, duration, cell/tissue types analyzed, and the methods used to measure telomere length prohibit consensus, as highlighted in a recent systematic review (16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Valente C, Andrade R, Alvarez L, Rebelo-Marques A, Stamatakis E, Espregueira-Mendes J. Effect of physical activity and exercise on telomere length: systematic review with meta-analysis. J. Am. Geriatr. Soc 2021; 69(11): 3285– 300. 34161613 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercised mice had increased expression of TRF1, TRF2, and Ku70 in the aorta, which has been shown to protect against telomere erosion and genome degradation.

    “In younger mice, neither 3 wk nor 6 months of voluntary wheel running affected telomere length within the aorta, although exercised mice had increased expression of telomere repeat-binding factor 1 (TRF1), TRF2, and Ku70 in the aorta, which has been shown to protect against telomere erosion and genome degradation (17).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Werner C, Furster T, Widmann T, Physical exercise prevents cellular senescence in circulating leukocytes and in the vessel wall. Circulation 2009; 120(24): 2438– 47. 19948976 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Exercise may act, in part, by preventing the accumulation and augmenting the clearance of senescent cells.

    “Considering the therapeutic effects of both exercise and senotherapeutics on the pathogenesis of many aging-associated diseases and geriatric syndromes, it is plausible that exercise may act, in part, by preventing the accumulation and augmenting the clearance of senescent cells (Fig. 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Exercise may prevent senescent cell accumulation by increasing the resilience of DNA and telomeres to damage-inducing stimuli and augmenting the capacity for DNA repair when damage occurs.

    “Collectively, these findings suggest exercise may prevent senescent cell accumulation by increasing the resilience of DNA and telomeres to damage-inducing stimuli and augmenting the capacity for DNA repair when damage occurs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Exercise training restores age-associated deficits in autophagy, which translates into effective removal of damaged and dysfunctional organelles, including mitochondria.

    “Moreover, exercise training restores age-associated deficits in autophagy (22), which translates into effective removal of damaged and dysfunctional organelles, including mitochondria.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Wohlgemuth SE, Seo AY, Marzetti E, Lees HA, Leeuwenburgh C. Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise. Exp. Gerontol 2010; 45(2): 138– 48. 19903516 PMC2829942 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise has powerful effects on mitochondrial abundance, quality, and function.

    “Exercise has powerful effects on mitochondrial abundance, quality, and function, as recently reviewed (19).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Oliveira AN, Richards BJ, Slavin M, Hood DA. Exercise is muscle mitochondrial medicine. Exerc. Sport Sci. Rev 2021; 49(2): 67– 76. 33720909 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise acutely activates ROS production, which is essential for force generation within skeletal muscle, signaling to distal tissues and activating antioxidants.

    “Exercise acutely activates ROS production, which is essential for force generation within skeletal muscle, signaling to distal tissues and activating antioxidants. This adaptation ensures homeostasis and prevention of excess oxidative stress (25).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Powers SK, Nelson WB, Hudson MB. Exercise-induced oxidative stress in humans: cause and consequences. Free Radic. Biol. Med 2011; 51(5): 942– 50. 21167935 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Senescence plays a critical role in health throughout the life course, including development and parturition, and as an essential antitumor mechanism.

    “Senescence plays a critical role in health throughout the life course, including development and parturition, and as an essential antitumor mechanism (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol 2018; 28(6): 436– 53. 29477613 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Exerkines are released into circulation after exercise and are thought to orchestrate systemic adaptations in several organs including bone, brain, and adipose tissue.

    “Several bioactive proteins and molecules, termed exerkines, are released into circulation after exercise and are thought to orchestrate systemic adaptations in several organs including bone, brain, and adipose tissue (29).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Catoire M, Kersten S. The search for exercise factors in humans. FASEB J 2015; 29(5): 1615– 28. 25593123 source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    In young male mice, 20 wk of voluntary wheel running lowered senescence markers.

    “of young male mice after 20 wk of voluntary wheel running.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Kimura M, Suzuki S, Moriya A, The effects of continuous and withdrawal voluntary wheel running exercise on the expression of senescence-related genes in the visceral adipose tissue of young mice. Int. J. Mol. Sci 2020; 22(1): 264. 33383848 PMC7794976 source

      Not checked in the free run.

    • Rests on an assumption: Senescence markers used in the cited studies reliably indicate cellular senescence.

  • May combine two claims.

    Premisecitation

    Exercise reduced the frequency of P16+/PDGFRα+ and P21+/PDGFRα+ cells in both fat depots, phosphorylated-γH2A.X expression in inguinal fat, P16 and P21 in Mac3+ macrophages and P16 in CD3+ lymphocytes in the inguinal fat, and P21 in Mac3+ macrophages in the epididymal fat.

    “Using immunofluorescence detection methods, exercise has been shown to reduce the frequency of P16+/PDGFRα+ and P21+/PDGFRα+ cells in both fat depots, phosphorylated-γH2A.X expression in inguinal fat, P16 and P21 in Mac3+ macrophages and P16 in CD3+ lymphocytes in the inguinal fat, and P21 in Mac3+ macrophages in the epididymal fat (52).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Pini M, Czibik G, Sawaki D, Adipose tissue senescence is mediated by increased ATP content after a short-term high-fat diet exposure. Aging Cell 2021; 20(8): e13421. 34278707 PMC8373332 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NK cell activity measured by an in vitro killing assay increased during each row and was elevated even the day after the last bout.

    “NK cell activity measured by an in vitro killing assay also increased during each row and was elevated even the day after the last bout (41).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Nielsen HB, Secher NH, Christensen NJ, Pedersen BK. Lymphocytes and NK cell activity during repeated bouts of maximal exercise. Am. J. Physiol 1996; 271(1 Pt 2): R222– 7. 8760224

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 4-wk-old mice, 10 wk of wheel running followed by 10 wk of sedentary behavior lowered senescence markers, suggesting a legacy effect of exercise on the senescence program.

    “These senescence markers were also lower in 4-wk-old mice that underwent 10 wk of wheel running followed by 10 wk of sedentary behavior, suggesting a legacy effect of exercise on the senescence program (53).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Kimura M, Suzuki S, Moriya A, The effects of continuous and withdrawal voluntary wheel running exercise on the expression of senescence-related genes in the visceral adipose tissue of young mice. Int. J. Mol. Sci 2020; 22(1): 264. 33383848 PMC7794976 source

      Not checked in the free run.

    • Rests on an assumption: Senescence markers used in the cited studies reliably indicate cellular senescence.

  • May combine two claims.

    Premisecitation

    Exercise reduced p21 expression in inguinal adipose tissue as well as p16 and p21 expression in epididymal fat-derived preadipocytes.

    “In addition, exercise reduced p21 expression in inguinal adipose tissue as well as p16 and p21 expression in epididymal fat–derived preadipocytes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Pini M, Czibik G, Sawaki D, Adipose tissue senescence is mediated by increased ATP content after a short-term high-fat diet exposure. Aging Cell 2021; 20(8): e13421. 34278707 PMC8373332 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aging of the immune system may hamper the efficient removal of senescent cells and contribute to their progressive accumulation.

    “Aging of the immune system may hamper the efficient removal of senescent cells and contribute to their progressive accumulation (38).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Burton DGA, Stolzing A. Cellular senescence: immunosurveillance and future immunotherapy. Ageing Res. Rev 2018; 43: 17– 25. 29427795 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When eNOS knockout mice or TERT knockout mice were subjected to the same training stimulus, the positive effects of exercise were not present, suggesting that these enzymes are crucial mediators of myocardial and aortic adaptation.

    “When endothelial nitric oxide synthase (eNOS) knockout mice or TERT knockout mice (8-wk-old) were subjected to the same training stimulus, the positive effects of exercise were not present, suggesting that these enzymes are crucial mediators of myocardial and aortic adaptation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Werner C, Hanhoun M, Widmann T, Effects of physical exercise on myocardial telomere-regulating proteins, survival pathways, and apoptosis. J. Am. Coll. Cardiol 2008; 52(6): 470– 82. 18672169 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There is compelling, although modest, evidence that exercise counters inducers and activates clearance of senescent cells.

    “There is compelling, although modest, evidence that exercise counters inducers and activates clearance of senescent cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    The acute response to exercise and the adaptations to long-term training can influence the immune cells recruited by skeletal muscle and mobilized in the peripheral blood.

    “The acute response to exercise and the adaptations to long-term training can influence the immune cells recruited by skeletal muscle and mobilized in the peripheral blood.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A recent review on the senolytic effects of exercise noted high heterogeneity in animal studies and the need for additional investigations.

    “They noted the high heterogeneity observed in animal studies and the need for additional investigations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Chen XK, Yi ZN, Wong GT, Is exercise a senolytic medicine? A systematic review. Aging Cell 2021; 20(1): e13294. 33378138 PMC7811843 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Senescence markers are predictive of levels of physical function and even the responsiveness to intervention.

    “Interestingly, senescence markers are predictive of levels of physical function and even the responsiveness to intervention.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Senescence markers used in the cited studies reliably indicate cellular senescence.

  • May combine two claims.

    Interpretationreasoning

    The literature summarized suggests exercise both counters diverse forms of molecular damage that cause cellular senescence and potentially promotes immune-mediated senescent cell clearance.

    “The literature summarized herein suggests exercise both counters diverse forms of molecular damage that cause cellular senescence and potentially promotes immune-mediated senescent cell clearance.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Senescence markers used in the cited studies reliably indicate cellular senescence.

  • May combine two claims.

    Premisecitation

    Reduced P21 was associated with a reduction in TAF-positive hepatocytes and lower levels of 4HNE staining in the liver.

    “Reduced P21 was associated with a reduction in TAF-positive hepatocytes and lower levels of 4HNE staining, which is a lipid peroxidation marker (54).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Bianchi A, Marchetti L, Hall Z, Moderate exercise inhibits age-related inflammation, liver steatosis, senescence, and tumorigenesis. J. Immunol 2021; 206(4): 904– 16. 33441438 PMC7851741 source

      Not checked in the free run.

    • Rests on an assumption: Senescence markers used in the cited studies reliably indicate cellular senescence.

  • May combine two claims.

    Interpretationcitation

    In the cohort of 47 patients undergoing coronary artery bypass surgery, self-reported physical activity levels were relatively low and potentially below a threshold required for therapeutic effect.

    “Notably, self-reported physical activity levels were relatively low in this cohort and, potentially, below a threshold required for therapeutic effect.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Self-reported physical activity is a valid measure of habitual physical activity.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Based on the current state of the literature, sex-specific differences in response to exercise, as it pertains to its effects as a senotherapeutic, are not apparent.

    “Based on the current state of the literature, sex-specific differences in response to exercise, as it pertains to its effects as a senotherapeutic, are not apparent.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Senescence markers used in the cited studies reliably indicate cellular senescence.

  • May combine two claims.

    Interpretationreasoning

    High levels of physical activity may increase the resilience of DNA and telomeres to diverse forms of stress, including ROS, inflammation, and protein aggregates, and in turn reduce the induction of CDKIs and other governors of the senescence program.

    “High levels of physical activity may increase the resilience of DNA and telomeres to diverse forms of stress, including ROS, inflammation, and protein aggregates, and in turn reduce the induction of CDKIs and other governors of the senescence program.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Senescence markers used in the cited studies reliably indicate cellular senescence.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Skeletal muscle is highly responsive to exercise, understudied in the context of senescence, and serves as a noteworthy example.

    “Skeletal muscle, a tissue that is composed of terminally differentiated multinucleated muscle fibers and several mitotically competent mononuclear cell populations, is highly responsive to exercise, understudied in the context of senescence, and serves as a noteworthy example (56).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Englund DA, Zhang X, Aversa Z, LeBrasseur NK. Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions. Mech. Ageing Dev 2021; 200: 111595. 34742751 PMC8627455 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An acute bout of 14 d of downhill running promoted a senescent phenotype in skeletal muscle fibroadipogenic progenitors from young wild-type mice but not from mice with chronic inflammatory myopathy.

    “In a recent study, an acute bout of 14 d of downhill running promoted a senescent phenotype in skeletal muscle fibroadipogenic progenitors from young wild-type mice but not from mice with chronic inflammatory myopathy (58).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Saito Y, Chikenji TS, Matsumura T, Nakano M, Fujimiya M. Exercise enhances skeletal muscle regeneration by promoting senescence in fibro-adipogenic progenitors. Nat. Commun 2020; 11(1): 889. 32060352 PMC7021787 source

      Not checked in the free run.

    • Rests on an assumption: Senescence markers used in the cited studies reliably indicate cellular senescence.
44 of 44

  • The paper relies on this without support.

    Senescence markers used in the cited studies reliably indicate cellular senescence.

    “A comprehensive and rigorous approach is needed to overcome the challenges posed by i) the absence of a specific, stand-alone marker of senescence, and ii) misinterpretation of acute responses to exercise (e.g., ROS, inflammation, CDKI expression in response to cell proliferation and differentiation) as indicators of cellular senescence.”

  • The paper relies on this without support.

    Findings from animal models of exercise and senescence translate to humans.

    “Although more comprehensive and confirmatory studies are needed, the senotherapeutic effects of exercise have been demonstrated in multiple tissues in both preclinical models and humans.”

  • The paper relies on this without support.

    Exercise benefits nearly all tissues.

    “It is remarkable to note that exercise benefits nearly all tissues.”

  • The paper relies on this without support.

    Many circulating biomarkers studied to date are not unique to senescent cells.

    “This task is challenged by the fact that many of the circulating biomarkers studied to date (i.e., circulating proteins, miRNAs, or mtDNA) are not unique to senescent cells.”

  • The paper relies on this without support.

    Several other studies investigating exercise and cellular senescence relied on a single senescence marker, limiting interpretation.

    “Several other studies have investigated the impact of exercise on cellular senescence but relied on a single senescence marker (e.g., SA-β-gal or p16 expression), limiting the interpretation of these findings.”

  • The paper relies on this without support.

    Current preclinical evidence supporting exercise as a strategy to prevent or clear senescent cells is derived from young and middle-aged animals.

    “Moreover, the current preclinical evidence that supports exercise as a strategy to prevent or clear senescent cells is derived from young and middle-aged animals.”

  • The paper relies on this without support.

    Self-reported physical activity is a valid measure of habitual physical activity.

    “Early work examining the relation between cellular senescence and exercise in humans primarily relied on measures of self-reported physical activity and their cross-sectional associations with senescence markers in circulating immune cells.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Exercise is an efficient strategy for delaying aging through mechanisms such as DNA damage and oxidative stress.

    “Exercise is an efficient strategy for delaying aging330 through various mechanisms, such as DNA damage331 and oxidative stress.332”

    From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [330]

The citation lists haven’t been fetched yet

References 71 · Cited by 63

Authors
Zhang, X., Englund, D. A., Aversa, Z., Jachim, S. K., White, T. A., & LeBrasseur, N. K.
Affiliations
  • Mayo Clinic (US)
  • Robert and Arlene Kogod Center on Aging
Corresponding author
LeBrasseur, Nathan K.
ORCID
Venue
Exercise and Sport Sciences Reviews
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2022-07-01
Volume
50
Issue
4
Pages
213-221
ISSN
  • 0091-6331 (ISSN-L)
  • 1538-3008
DOI
10.1249/jes.0000000000000302
PMC
PMC9680689
OpenAlex
W4283770658
Semantic Scholar
34abedaece9af8147b9b51f1f3e3c841d8e0add7
Cited by
63
References
71
Citations by year
2026: 18 · 2025: 24 · 2024: 9 · 2023: 9 · 2022: 3
FWCI
6.97
Type
journal article
Language
en
Open access
Locations
  • Exercise and Sport Sciences Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R01AG053832, T32AG049672, P01AG062413, R01AG055529)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR056950)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
physical activity, cellular senescence, senescent cell accumulation, senolytics, aging
MeSH terms
Aging, Humans, Exercise, Cellular Senescence

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

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