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Cellular Senescence Biomarker p16INK4a+ Cell Burden in Thigh Adipose is Associated With Poor Physical Function in Older Women
Open accessAbstract
Background: Ample evidence implicates cellular senescence as a contributor to frailty and functional decline in rodents, but considerable effort remains to translate these findings to human aging. Methods: We quantified senescence biomarker p16INK4a-expressing cells in thigh adipose tissue obtained from older women previously enrolled in a 5-month resistance training intervention, with or without caloric restriction (RT ± CR, n = 11 baseline, 8 pre-post-intervention pairs). Women in this subsample were older (72.9 ± 3.4 y) and overweight/obese (body mass index: 30.6 ± 2.4 kg/m2). p16INK4a+ cells were identified from 12 to 20 random visual fields/sample at 20× magnification (immunohistochemical, nuclear staining) and were present in all adipose samples. Results: Cross-sectional associations were observed between p16INK4a+ cell burden and physical function, including grip strength (r = -0.74), 400-m walk time (r = 0.74), 4-m gait speed (r = -0.73), and self-perceived mobility (r = -0.78) (p ≤ .05). These relationships remained significant after independent adjustments for age and adiposity (p ≤ .05). p16INK4a+ cell abundance was lower following the intervention (pre: 5.47 ± 3.4%, post: 2.17 ± 1.1% count p16INK4a+ cells, p ≤ .05). Conclusions: These results provide proof-of-concept that p16INK4a+ cells in thigh adipose are associated with physical function, and may be sensitive to change with RT ± CR in overweight/obese older women.
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“Blood biomarkers included cytokines and chemo-attractants, matrix metalloproteinases (MMP), tissue inhibitors of MMPs (TIMPs), adhesion molecules, growth factors, and their binding proteins.20,23,29 Expression of senescence markers (e.g., ARF, p16, p21, p16INK4a)41, 42, 43, 44 in CD3 positive T lymphocytes was measured by rt-PCR.”
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 [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Other studies have shown reductions in p16INK4a in adipose tissue following senolytic treatment.20,30”
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 [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These evidence suggest that exercise can effectively reduce the appearance of age-related markers, such as p16, so as to achieve the effect of delaying aging.”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [334]
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“Correspondingly, resistance training for five months in older overweight or obese women reduced the number of P16-expressing cells in their thigh fat tissue.334”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [334]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“There is growing evidence that senescent cells and their SASPs contribute to the pathogenesis of many other age-related diseases as well”
From Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain (2020) · cites this paper as Justice et al. 2018
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“Oxidative stress and macromolecular damage in aged cells induce a complex stress response termed cellular senescence, which has been shown to cause or exacerbate aging and several age-related pathologies”
From Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain (2020) · cites this paper as Justice et al. 2018
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“Senescent cell abundance is increased in multiple age-related diseases and disorders in experimental animals and humans.30, 31, 32”
From Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans (2022) · cites this paper as [32]
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In the citing paper
“Blood biomarkers included cytokines and chemo-attractants, matrix metalloproteinases (MMP), tissue inhibitors of MMPs (TIMPs), adhesion molecules, growth factors, and their binding proteins.20,23,29”
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 [20]
Experimental — accuracy not yet measuredIn the citing paper
“Using P16-expressing cells (associated with cellular senescence), Justice et al. (2018) showed a very strong link between the abundance of senescent-like cells and IMAT, and that this was strongly and inversely associated with functional measures like gait speed and Short Physical Performance Battery (SPPB) score.”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Justice et al., 2018
In the citing paper
“IMAT in older persons can also be a source of senescent cells; as reported previously, the frequency of P16-expressing cells in IMAT was strongly and inversely associated with functional measures like gait speed and SPPB score (Justice et al., 2018).”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Justice et al., 2018
In the citing paper
“Five months of resistance training in older (~73 yr) overweight/obese women reduced P16-expressing cells in thigh adipose tissue, and P16+ cell content was negatively associated with several parameters of physical function, including grip strength and 400-m walk time (65).”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [65]
In the citing paper
“Five months of resistance training in older (~73 yr) overweight/obese women reduced P16-expressing cells in thigh adipose tissue, and P16+ cell content was negatively associated with several parameters of physical function, including grip strength and 400-m walk time (65).”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [65]
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Citations
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BackgroundSelf-citationNaturally occurring p16Ink4a-positive cells shorten healthy lifespan
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BackgroundSelf-citationReplication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes
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Cited by
Sorted by citations
Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty
Ferrucci, L., & Fabbri, E. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0064-2 · Cited by 3,690
Senolytics improve physical function and increase lifespan in old age
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Self-citationSarcopenia: Aging-Related Loss of Muscle Mass and Function
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Li, X., Li, C., Zhang, W., Wang, Y., Qian, P., & Huang, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01502-8 · Cited by 1,443
“Correspondingly, resistance training for five months in older overweight or obese women reduced the number of P16expressing cells in their thigh fat tissue.(334) These evidence suggest that exercise can effectively reduce the appearance of age-related markers, such as p16, so as to achieve the effect of delaying aging.”
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Metadata
- Authors
- Justice, J. N., Gregory, H., Tchkonia, T., LeBrasseur, N. K., Kirkland, J. L., Kritchevsky, S. B., & Nicklas, B. J.
- Affiliations
- Wake Forest University Health Sciences (US)
- Mayo Clinic (US)
- Corresponding author
- Justice, Jamie N
- ORCID
- Venue
- The Journals of Gerontology: Series A
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-06-27
- Volume
- 73
- Issue
- 7
- Pages
- 939-945
- ISSN
- 1079-5006 (ISSN-L)
- 1758-535X
- PMC
- PMC6001887
- OpenAlex
- W2731074566
- Cited by
- 129
- References
- 35
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 8 · 2023: 11 · 2022: 21 · 2021: 22 · 2020: 23 · 2019: 11 · 2018: 9
- FWCI
- 8.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journals of Gerontology Series A (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wake Forest Claude D. Pepper Older Americans Independence Center (P30-AG21332)
- National Institutes of Health (R01AG020583 [BJN], T32-AG33534 [SKB, BJN; JNJ trainee], AG52958 [NKL], R37AG13925 [JLK])
- Noaber and Glenn Foundations
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- cellular senescence, p16INK4a, senescence biomarkers, physical function, older women, resistance training, caloric restriction, frailty, grip strength, walking speed, mobility (physical function), obesity, aging
- MeSH terms
- Frailty, Physical Functional Performance, Adipose Tissue, Aged, Aging, Cross-Sectional Studies, Female, Humans, Obesity, Thigh, Biomarkers, Body Mass Index, Frail Elderly, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Caloric Restriction, Adiposity, Overweight, Resistance Training
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