Biomarkers of cellular senescence predict the onset of mobility disability and are reduced by physical activity in older adults
Open accessAbstract
Studies in mice and cross-sectional studies in humans support the premise that cellular senescence is a contributing mechanism to age-associated deficits in physical function. We tested the hypotheses that circulating proteins secreted by senescent cells are (i) associated with the incidence of major mobility disability (MMD), the development of persistent mobility disability (PMMD), and decrements in physical functioning in older adults, and (ii) influenced by physical activity (PA). Using samples and data obtained longitudinally from the Lifestyle Interventions in Elders Study clinical trial, we measured a panel of 27 proteins secreted by senescent cells. Among 1 377 women and men randomized to either a structured PA intervention or a healthy aging (HA) intervention, we observed significant associations between several senescence biomarkers, most distinctly vascular endothelial growth factor A (VEGFA), tumor necrosis factor receptor 1 (TNFR1), and matrix metallopeptidase 7 (MMP7), and the onset of both MMD and PMMD. Moreover, VEGFA, GDF15, osteopontin, and other senescence biomarkers were associated with reductions in short physical performance battery scores. The change in senescence biomarkers did not differ between PA and HA participants. In the whole cohort, higher levels of PA were associated with significantly greater reductions in 10 senescence-related proteins at 12 and/or 24 months. These data reinforce cellular senescence as a contributing mechanism of age-associated functional decline and the potential for PA to attenuate this hallmark of aging. Clinical Trials Registration Number: NCT01072500
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The introduction argues that senescent cells and their SASP products contribute to deficits in cognition and mobility.
“Recent evidence suggests that the accumulation of senescent cells, which can release a variety of pro-inflammatory, apoptotic, and toxic by-products, called the senescence-associated secretory phenotype (SASP), is one of the drivers of deficits in both cognition11, 12, 13, 14, 15, 16 and mobility.7,17, 18, 19, 20, 21, 22”
From A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease (2025) · cites this paper as [19]
The Discussion links cellular senescence and SASP molecules to inflammation and impaired physical function, and reports associations between SASP biomarkers and mobility disability in older adults. The page 2 introductory passage also discusses mobility, but the passages found do not link senescence or SASP products to cognitive deficits. The claim is therefore supported for mobility, not cognition. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThere is emerging evidence that exercise increases mitochondrial biogenesis (PRT), oxidative metabolism (cycling-aerobic exercise), cellular senescence, and muscle oxidative capacity.
“However, there is emerging evidence that exercise increases mitochondrial biogenesis (PRT) [654], oxidative metabolism (cycling-aerobic exercise [655]), cellular senescence [72,73], and muscle oxidative capacity [656] (as measured by phosphocreatine recovery rate constant (kPCr) using 31 P Magnetic Resonance Spectroscopy).”
From Global consensus on optimal exercise recommendations for enhancing healthy longevity in older adults (ICFSR) (2025) · cites this paper as [72]
Exercise increases mitochondrial biogenesis (PRT), oxidative metabolism (cycling-aerobic exercise), cellular senescence, and muscle oxidative capacity.
“However, there is emerging evidence that exercise increases mitochondrial biogenesis (PRT) [654], oxidative metabolism (cycling-aerobic exercise [655]), cellular senescence [72,73], and muscle oxidative capacity [656] (as measured by phosphocreatine recovery rate constant (kPCr) using 31 P Magnetic Resonance Spectroscopy).”
From Global consensus on optimal exercise recommendations for enhancing healthy longevity in older adults (ICFSR) (2025) · cites this paper as [72]
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- Authors
- Fielding, R. A., Atkinson, E. J., Aversa, Z., White, T. A., Heeren, A. A., Mielke, M. M., Cummings, S. R., Pahor, M., Leeuwenburgh, C., & LeBrasseur, N. K.
- Affiliations
- Tufts University (US)
- Mayo Clinic (US)
- Wake Forest University Health Sciences (US)
- University of California, San Francisco (US)
- University of Florida (US)
- Corresponding author
- LeBrasseur, Nathan K
- ORCID
- Venue
- The Journals of Gerontology: Series A
- Publisher
- Oxford University Press (OUP)
- Published
- 2023-11-08
- Volume
- 79
- Issue
- 3
- ISSN
- 1079-5006 (ISSN-L)
- 1758-535X
- PMC
- PMC10851672
- OpenAlex
- W4388556609
- Cited by
- 38
- References
- 48
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 13
- FWCI
- 6.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journals of Gerontology Series A (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01 AG055529, R56 AG060907, P01 AG062413, U54 AG044170)
- Glenn Foundation for Medical Research
- Pritzker Foundation
- U.S. Department of Agriculture (58-8050-9-004)
- NIH Boston Claude D. Pepper Center (1P30AG031679)
- NIH University of Florida Claude D. Pepper Center (P30AG028740)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Geriatrics and Gerontology › Frailty in Older Adults
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular senescence, senescence-associated secretory phenotype, mobility impairment, physical activity, older adults, physical function decline, VEGF-A, TNFR1, MMP-7, GDF15, osteopontin, Short Physical Performance Battery, healthy aging interventions, biomarkers
- MeSH terms
- Aged, Animals, Cross-Sectional Studies, Exercise Therapy, Female, Humans, Life Style, Male, Biomarkers, Cellular Senescence, Vascular Endothelial Growth Factor A, Mice
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