CoChat
Sign Up
Cited by 94Telomeres, Telomerase, and SenescenceMuscle Physiology and DisordersNutrition and Health in Aging

Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions

Open access
Englund, Davis A., Zhang, Xu, Aversa, Zaira, LeBrasseur, Nathan K.·2021·Mechanisms of Ageing and Development
DOI 10.1016/j.mad.2021.111595PMC PMC8627455
Open this paper in CoChat — free account

Abstract

Cellular senescence is a state of cell cycle arrest induced by several forms of metabolic stress. Senescent cells accumulate with advancing age and have a distinctive phenotype, characterized by profound chromatin alterations and a robust senescence-associated secretory phenotype (SASP) that exerts negative effects on tissue health, both locally and systemically. In preclinical models, pharmacological agents that eliminate senescent cells (senotherapeutics) restore health and youthful properties in multiple tissues. To date, however, very little is understood about the vulnerability of terminally-differentiated skeletal muscle fibers and the resident mononuclear cells that populate the interstitial microenvironment of skeletal muscle to senescence, and their contribution to the onset and progression of skeletal muscle loss and dysfunction with aging. Scientific advances in these areas have the potential to highlight new therapeutic approaches to optimize late-life muscle health. To this end, this review highlights the current evidence and the key questions that need to be addressed to advance the field’s understanding of cellular senescence as a mediator of skeletal muscle aging and the potential for emerging senescent cell-targeting therapies to counter age-related deficits in muscle mass, strength, and function.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that cellular senescence may contribute to skeletal muscle aging, but evidence in muscle fibers and resident mononuclear cells remains limited. It summarizes preclinical senotherapeutic studies showing some functional benefits while highlighting major gaps in cell-type-specific mechanisms and direct muscle outcomes.

Key findings

  • Aged skeletal muscle from humans, monkeys, and mice shows elevated senescence-associated genes including p53, p21, and Gadd45a; RNA sequencing across mice, rats, and human muscle (22–70 years) identified cellular senescence as an aging pathway, and in 53 healthy individuals (22–83 years) CDKN2B mRNA was the top age-related transcript.
  • Satellite cells from very old mice (28–32 months) show p16INK4a upregulation and impaired regenerative capacity; p16INK4a silencing restored activation and self-renewal and reduced p15INK4b, Igfbp5, and p19ARF, while autophagy restoration prevented senescence and rescued regenerative capacity.
  • Genetic clearance in progeroid BubR1H/H;INK-ATTAC mice improved muscle fiber size and treadmill exercise time, distance, and total work; in chronologically aged mice results were mixed, with 12–18-month treatment lowering senescence markers but not improving strength, exercise capacity, or motor coordination, whereas 24-month treatment improved rotarod and forelimb hang performance.
  • Pharmacologic senotherapeutics showed functional benefits: dasatinib + quercetin in 20–24-month mice improved endurance, treadmill capacity, and grip strength; SSK1 in 20-month mice improved exercise capacity, coordination/balance, and strength; ABT263 in 21–22-month mice reduced satellite cell p16 and DNA double-strand breaks; ruxolitinib in 24-month mice improved activity, hanging endurance, and grip strength; in a DMD rat model, ABT263 reduced p16, p19, p21, and SASP factors and modestly improved fiber size.

Methods

  • Narrative review synthesizing current evidence on skeletal muscle cellular landscape, aging-related cell changes, senescence markers, senotherapeutic interventions, and physical activity.
  • No systematic review, meta-analysis, or primary data collection is described; evidence is drawn from cited preclinical models and human studies, including mice, rats, monkeys, and humans.

Limitations

  • Stated: the study of senescence in skeletal muscle is in its infancy; rigorous methods are needed to identify and characterize senescent muscle fibers and mononuclear cells, and there is no stand-alone marker for senescent cells.
  • Stated: direct evidence that clearing or altering senescent cells in skeletal muscle improves age- or disease-related muscle deficits is lacking, and many senotherapeutic studies did not assess muscle morphology or senescence markers.
  • Stated: divergent satellite cell findings may be explained by sex, age, and experimental design, and human xenotransplantation evidence was limited by one subject per age and no donor health information; evident: as a narrative review, it lacks systematic search and risk-of-bias assessment.

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

Integrity signals

Registry

Crossref · 10.1016/j.mad.2021.111595

Cites

147 of 147 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 125 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Cellular senescence has emerged as a nexus between chronological aging and deficits in structure and function of multiple organs.

    “cellular senescence has emerged as the nexus between chronological aging and deficits in the structure and function of multiple organs”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Flanary et al., 2007 source

      Not checked in the free run.

    • cites Salminen et al., 2011 source

      Not checked in the free run.

    • cites Hashimoto et al., 2016 source

      Not checked in the free run.

  • Premisenone given

    In preclinical models, pharmacological agents that eliminate senescent cells restore health and youthful properties in multiple tissues.

    “In preclinical models, pharmacological agents that eliminate senescent cells (senotherapeutics) restore health and youthful properties in multiple tissues.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Reduced satellite cell regenerative ability with aging is partly caused by cell-extrinsic factors.

    “Reduced satellite cell regenerative ability with aging seems to be partly caused by cell-extrinsic factors, supported by parabiosis and hetero-grafting studies that show regenerative capacity in old mice can be restored when exposed to a young milieu”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Conboy et al., 2005 source

      Not checked in the free run.

  • Premisecitation

    In very old mice (>28 months) there is continued decline in regenerative capacity in the absence of further reductions in satellite cells.

    “In very old mice (>28-months) there is a continued decline in regenerative capacity in the absence of further reductions in satellite cells”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sousa-Victor et al., 2014 source

      Not checked in the free run.

  • Premisenone given

    Senescent cells accumulate with advancing age.

    “Senescent cells accumulate with advancing age and have a distinctive phenotype, characterized by profound chromatin alterations and a robust senescence-associated secretory phenotype (SASP) that exerts negative effects on tissue health, both locally and systemically.”
    Quote in the paperSubstantial claim
  • May combine two claims. 30
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Premisecitation

    Senescent cells have a distinctive phenotype characterized by profound chromatin alterations and a SASP that exerts negative effects on tissue health locally and systemically.

    “They have a distinctive phenotype, characterized by profound chromatin alterations and the development of a senescence-associated secretory phenotype (SASP), mainly comprised of cytokines, chemokines, matrix remodeling proteins, and growth factors, that has deleterious effects on tissue function, both locally and systemically”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Coppé et al., 2010 source

      Not checked in the free run.

    • cites Schafer et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The age-related loss of regenerative potential is partly due to reduced satellite cell content in old mice and humans but primarily driven by impaired activation and proliferation in response to damage-inducing stimuli.

    “This is partly due to reduced satellite cell content in old mice (20–24-months) (Brack et al., 2007; Chakkalakal et al., 2012) and humans (Carlson et al., 2009) but is primarily driven by impaired activation and proliferation in response to damage-inducing stimuli.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Brack et al., 2007 source

      Not checked in the free run.

    • cites Chakkalakal et al., 2012 source

      Not checked in the free run.

    • cites Carlson et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Advancing age drives aberrant signaling in FAPs that stimulates profibrotic behavior and skeletal muscle fibrosis, and compromises satellite cell function.

    “Advancing age drives aberrant signaling in FAPs that stimulates their profibrotic behavior and skeletal muscle fibrosis, and simultaneously compromises satellite cell function”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lukjanenko et al., 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Key angiogenic regulators and endothelial cell content in skeletal muscle are reduced during aging.

    “Key angiogenic regulators and endothelial cell content in skeletal muscle are reduced during aging.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Rubenstein et al., 2020 source

      Not checked in the free run.

    • cites Wang et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, skeletal muscle M1 macrophages decrease with aging while M2 macrophages increase.

    “In humans, skeletal muscle M1 macrophages decrease with aging while M2 macrophages increase”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cui et al., 2019 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Cellular senescence is a state of irreversible cell cycle arrest induced by stressful insults and certain pathophysiological processes.

    “Cellular senescence is a state of irreversible cell cycle arrest induced by stressful insults and certain pathophysiological processes including DNA damage, oncogene activation, telomere erosion, autophagy impairment, reactive oxygen species (ROS), high levels of glucose, and proteome instability”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Mijares et al., 2020

      Not checked in the free run.

    • cites Passos et al., 2010 source

      Not checked in the free run.

    • cites Passos et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reductions in proteostasis are a hallmark of skeletal muscle decline with age and a promoter of cellular senescence.

    “Reductions in proteostasis—the balance between protein synthesis, folding, and degradation—is another hallmark of skeletal muscle decline with age, and is a promoter of cellular senescence”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Montague-Cardoso, 2021 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Senescent cells display a wide range of transcriptional and proteomic heterogeneity, and there is not a stand-alone marker for their identification.

    “Senescent cells display a wide range of transcriptional and proteomic heterogeneity, and there is not a stand-alone marker for their identification”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    M1 macrophages reduce, while M2 macrophages enhance, FAP adipogenic potential.

    “Through their secretome, M1 macrophages reduce, while M2 macrophages enhance, FAP adipogenic potential”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Moratal et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Telomere length shortens progressively in human skeletal muscle with advancing age and is concomitant with increased free radical production.

    “Telomere length shortens progressively in human skeletal muscle with advancing age and is concomitant with increased free radical production”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Venturelli et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Declines in skeletal muscle perfusion may directly influence anabolic resistance and contribute to sarcopenia.

    “Corresponding declines in skeletal muscle perfusion may directly influence anabolic resistance and contribute to sarcopenia”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Rubenstein et al., 2020 source

      Not checked in the free run.

    • cites Wang et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Satellite cells isolated from very old mice (28-32 months) transplanted into injured muscles of young hosts were unable to repair the damaged muscle, indicating that the impairment in function in very old mice is intrinsic.

    “satellite cells isolated from very old mice (28–32 months) were transplanted into injured muscles of young hosts and were unable to repair the damaged muscle, indicating that the impairment in function in very old mice is intrinsic, as it is not reversed by exposure to a young milieu”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sousa-Victor et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Satellite cells are vulnerable to senescence, directly influencing their regenerative potential.

    “Sousa-Victor and colleagues provided intriguing evidence that satellite cells are vulnerable to senescence, directly influencing their regenerative potential”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Baar et al., 2018 source

      Not checked in the free run.

    • cites Sousa-Victor et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several cellular markers of senescence were evidenced within either the nuclei or muscle fiber cross-sections in aged skeletal muscle, and further analysis showed correlations between a subset of these markers and parameters of fiber atrophy.

    “several cellular markers of senescence were evidenced within either the nuclei or muscle fiber cross-sections in aged skeletal muscle, and further analysis showed correlations between a subset of these markers and parameters of fiber atrophy”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites da Silva et al., 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Regeneration is impaired 5 days following muscle graft transplantation from old (27-29 months old) mice into young hosts, but this is resolved by day 10.

    “while regeneration is impaired 5 days following muscle graft transplantation from old (27–29 months old) mice into young hosts, this is resolved by day 10”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shavlakadze et al., 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p16INK4a silencing alone enhanced proliferative ability and reduced additional markers of senescence.

    “p16INK4a silencing alone enhanced proliferative ability and also reduced additional markers of senescence, including p15INK4b, Igfbp5, and p19ARF”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sousa-Victor et al., 2014 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Senescent satellite cells may exacerbate skeletal muscle loss or dysfunction in the context of aging, disease, or injury.

    “this does not rule out the possibility that senescent satellite cells may exacerbate skeletal muscle loss or dysfunction in the context of aging, disease, or injury”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fry et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is a growing body of evidence for senescence in terminally differentiated cell types, challenging the dogma that only mitotic cell types can undergo senescence.

    “While there is a long-standing dogma in the field that only mitotic cell types can undergo senescence, there is a growing body of evidence for senescence in terminally differentiated cell types, challenging this paradigm”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sapieha and Mallette, 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle samples taken from cadavers maintained their myogenic potential after being transplanted into immunodeficient mice, with no declines in regenerative potential up to 78 years of age.

    “a recent study in humans utilized xenotransplantation to determine whether muscle samples taken from cadavers maintained their myogenic potential after being transplanted into immunodeficient mice and found no declines in regenerative potential up to 78 years of age”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Novak et al., 2021 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In this more chronic context, senescent FAPs and endothelial cells may contribute increased fibrosis and fatty infiltration and reduced capillarization.

    “they may contribute increased fibrosis and fatty infiltration and reduced capillarization, which are characteristic of aged skeletal muscle”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    In the dasatinib + quercetin study, neither muscle weights, muscle morphology (i.e., muscle fiber cross-sectional area), nor markers of senescence in skeletal muscle or resident cell populations were assessed.

    “However, neither muscle weights, muscle morphology (i.e., muscle fiber cross-sectional area), nor markers of senescence in skeletal muscle or resident cell populations were assessed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xu et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Compared to vehicle-treated mice, mice that received ruxolitinib for 10 weeks had lower circulating concentrations of several pro-inflammatory cytokines and chemokines and better performance in measures of habitual physical activity, hanging endurance, and grip strength.

    “Compared to vehicle-treated mice, mice that received ruxolitinib for 10 weeks had lower circulating concentrations of several pro-inflammatory cytokines and chemokines and better performance in measures of habitual physical activity, hanging endurance, and grip strength (Xu et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xu et al., 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle fiber size and treadmill exercise time, distance, and total work to exhaustion were significantly greater in AP20187 treated BubR1 H/H;INK-ATTAC mice.

    “Further, muscle fiber size and treadmill exercise time, distance, and total work to exhaustion were significantly greater in AP20187 treated BubR1 H/H;INK-ATTAC mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Baker et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The percentage of isolated satellite cells positive for p16 by immunostaining and the number of DNA double-strand breaks per satellite cell were lower from mice treated with ABT263 compared to vehicle.

    “The percentage of isolated satellite cells positive for p16 by immunostaining and the number of DNA double-strand breaks per satellite cell were lower from mice treated with ABT263 compared to vehicle (Chang et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chang et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    20-month-old mice treated for 8 weeks with SSK1 exhibited greater exercise capacity, coordination and balance, and muscle strength compared to vehicle-treated mice.

    “Similarly, 20-month-old mice treated for 8 weeks with an innovative SA-βgal-responsive prodrug, senescence-specific killing compound 1 (SSK1), which takes advantage of the heightened activity of this lysosomal enzyme in many senescent cell to promote drug specificity, exhibited greater exercise capacity, coordination and balance, and muscle strength compared to vehicle-treated mice (Cai et al., 2”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cai et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Compared to vehicle treated mice, mice receiving AP20187 twice a week from 12 to 18 months of age had lower expression of several senescence markers in the gastrocnemius muscle, but no differences in muscle strength, exercise capacity, or motor coordination and balance were observed.

    “Compared to vehicle treated mice, mice receiving AP20187 twice a week from 12 to 18 months of age had lower expression of several senescence markers in the gastrocnemius muscle, but no differences in muscle strength, exercise capacity, or motor coordination and balance, were observed (Baker et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Baker et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Accumulation of inflammatory macrophages and age-related declines in interferon-gamma signaling delay muscle repair following injury.

    “Previous work has shown that the accumulation of inflammatory macrophages and age-related declines in interferon-gamma signaling delay muscle repair following injury”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mann et al., 2011 source

      Not checked in the free run.

    • cites Zhang et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 4-month old mice following exposure of one hindlimb to irradiation to elicit relatively focal DNA damage, a single dose of dasatinib + quercetin reduced senescence marker p16 expression in quadriceps muscle and improved treadmill performance at both 5 days and seven months following treatment relative to vehicle.

    “In 4-month old mice following exposure of one hindlimb to irradiation to elicit relatively focal DNA damage, a single dose of dasatinib + quercetin reduced senescence marker p16 expression in quadriceps muscle and improved treadmill performance at both 5 days and seven months following treatment relative to vehicle (Zhu et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhu et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In summary, these findings suggest exercise may prevent the accumulation and/or promote the clearance of senescent cells.

    “In summary, these findings suggest exercise may prevent the accumulation and/or promote the clearance of senescent cells.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Similar approaches are emerging for the elimination of p21-expresing cells.

    “Similar approaches are emerging for the elimination of p21-expresing cells (Wang et al., 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wang et al., 2021 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 20-month-old mice, 3-weeks of voluntary wheel running rejuvenated satellite cell function and regenerative capacity through restoration of Cyclin D1, a mechanism that may offset senescence initiation through regulation of TGFβ-Smad3 signaling.

    “In 20-month-old mice, 3-weeks of voluntary wheel running rejuvenated satellite cell function and regenerative capacity through restoration of Cyclin D1, a mechanism that may offset senescence initiation through regulation of TGFβ-Smad3 signaling (Brett et al., 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Brett et al., 2020 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Thus far, there has not been a focused screen for senolytic or senomorphic compounds that target the unique features of senescent compared to non-senescent skeletal muscle fibers or the resident mononuclear cell populations.

    “Thus far, there has not been a focused screen for senolytic or senomorphic compounds that target the unique features of senescent compared to non-senescent skeletal muscle fibers or the resident mononuclear cell populations.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Each senescent cell type may have unique features that enable drug targeting.

    “As detailed by Zhang et al. (Zhang et al., 2021) each senescent cell type may have unique features that enable drug targeting.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhang et al., 2021 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Twelve-weeks of structured strength and endurance training reduced expression of key markers of the senescence program including p16, p21, cGAS, and TNFα in peripheral blood CD3+ T cells and lowered the circulating concentrations of several senescence-related proteins in older adults.

    “In line with this finding, twelve-weeks of structured strength and endurance training reduced expression of key markers of the senescence program including p16, p21, cGAS, and TNFα in peripheral blood CD3+ T cells and lowered the circulating concentrations of several senescence-related proteins in older adults (Englund et al., 2021).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Englund et al., 2021 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    As senescent cells can take 2-6 weeks to reaccumulate, it reasons that senolytics have therapeutic effects even when given intermittently at intervals longer than the drug's half-life.

    “As senescent cells can take 2–6 weeks to reaccumulate, it reasons that senolytics have therapeutic effects even when given intermittently at intervals longer than the drug’s half-life.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Senescent cells can take 2–6 weeks to reaccumulate.
35 of 35

  • The paper relies on this without support.

    The susceptibility of skeletal muscle cell populations—both postmitotic and mitotically-competent—to senesce and their impact on late-life skeletal muscle mass, strength, and function has not been rigorously explored.

    “the susceptibility of skeletal muscle cell populations—both postmitotic and mitotically-competent—to senesce and their impact on late-life skeletal muscle mass, strength, and function has not been rigorously explored”

  • The paper relies on this without support.

    The biological mechanisms that cause age-related changes in skeletal muscle remain poorly understood.

    “the biological mechanisms that cause age-related changes in skeletal muscle remain poorly understood”

  • The paper relies on this without support.

    There are no effective or approved pharmacological therapies for age-related muscle loss.

    “To date, there are no effective or approved pharmacological therapies.”

  • The paper relies on this without support.

    The role of macrophages in sarcopenia is poorly understood.

    “Currently, the role of macrophages in sarcopenia is poorly understood.”

  • The authors state this as an assumption.

    p16INK4a-expressing cells are senescent.

    “systemic removal of p16Ink4a-expressing cells, that are presumably senescent”

  • The paper relies on this without support.

    Senescent cells can take 2–6 weeks to reaccumulate.

    “As senescent cells can take 2–6 weeks to reaccumulate, it reasons that senolytics have therapeutic effects even when given intermittently at intervals longer than the drug’s half-life.”
6 of 6

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?

  • 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).”

    From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [56]

Cites

Flagged first, then by citations

1 of the 148 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Englund, D. A., Zhang, X., Aversa, Z., & LeBrasseur, N. K.
Affiliations
Mayo Clinic (US)
Corresponding author
LeBrasseur, Nathan K.
ORCID
Venue
Mechanisms of Ageing and Development
Publisher
Elsevier BV
Published
2021-12
Volume
200
Pages
111595
ISSN
0047-6374 (ISSN-L)
DOI
10.1016/j.mad.2021.111595
PMC
PMC8627455
OpenAlex
W3208275331
Semantic Scholar
03a5e6379c29188e8686e351b6972aac5eb8b322
Cited by
94
References
148
Citations by year
2026: 21 · 2025: 28 · 2024: 17 · 2023: 21 · 2022: 7
FWCI
1.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Mechanisms of Ageing and Development (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • Glenn Foundation for Medical Research
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
Keywords
skeletal muscle aging, cellular senescence, senotherapeutics, senolytics, senescence-associated secretory phenotype, senescent cell accumulation, muscle fiber differentiation, mononuclear cells, muscle microenvironment, sarcopenia, muscle strength, senolytic therapy
MeSH terms
Senescence-Associated Secretory Phenotype, Senotherapeutics, Humans, Cellular Senescence, Muscle, Skeletal, Sarcopenia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review