Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue
Open accessAbstract
Considerable evidence implicates cellular senescence in the biology of aging and chronic disease. Diet and exercise are determinants of healthy aging; however, the extent to which they affect the behavior and accretion of senescent cells within distinct tissues is not clear. Here we tested the hypothesis that exercise prevents premature senescent cell accumulation and systemic metabolic dysfunction induced by a fast-food diet (FFD). Using transgenic mice that express EGFP in response to activation of the senescence-associated p16INK4a promoter, we demonstrate that FFD consumption causes deleterious changes in body weight and composition as well as in measures of physical, cardiac, and metabolic health. The harmful effects of the FFD were associated with dramatic increases in several markers of senescence, including p16, EGFP, senescence-associated β-galactosidase, and the senescence-associated secretory phenotype (SASP) specifically in visceral adipose tissue. We show that exercise prevents the accumulation of senescent cells and the expression of the SASP while nullifying the damaging effects of the FFD on parameters of health. We also demonstrate that exercise initiated after long-term FFD feeding reduces senescent phenotype markers in visceral adipose tissue while attenuating physical impairments, suggesting that exercise may provide restorative benefit by mitigating accrued senescent burden. These findings highlight a novel mechanism by which exercise mediates its beneficial effects and reinforces the effect of modifiable lifestyle choices on health span.
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Exercise may delay senescent cell formation and reduce inflammation, frailty, and chronic disease onset in mice.
“Exercise may delay senescent cell formation and reduce inflammation, frailty and chronic disease onset in mice136,137.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [137]
The Results and Discussion (page numbers unavailable) report that exercise reduced diet-induced senescence markers and inflammatory signaling in the visceral fat of mice, while improving physical and metabolic measures. The paper does not show that exercise reduced frailty or delayed the onset of chronic diseases in these mice; those effects extend beyond the outcomes studied. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn mice, removing senescent cells genetically or with senolytics has generally helped across many diseases and conditions.
“Using mouse models, elimination of these cells, through either genetic means or senolytic therapies, has largely shown beneficial impacts, irrespective of the disease or condition investigated (29-31, 99, 100).”
From Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives (2018) · cites this paper as [99]
Voluntary wheel running for 4 months significantly reduced the expression of SASP factors including IL-6, CCL2, and PAI1 in adipose tissue of middle-aged high-fat diet-fed mice.
“A study from our group showed that voluntary wheel running for 4 months significantly reduced the expression of SASP factors including IL-6, CCL2, and PAI1 in adipose tissue of middle-aged high-fat diet (HFD)–fed mice (31).”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [31]
In male mice, no changes in p16 or p53 expression were observed in response to either HFD or exercise.
“but no changes in p16 or p53 expression were observed in response to either the diet or exercise (31).”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [31]
In male mice, 16 wk of voluntary wheel running prevented an HFD-induced increase in p21 expression.
“we reported that 16 wk of voluntary wheel running in male mice prevented an HFD-induced increase in p21 expression”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [31]
Sixteen weeks of voluntary wheel running started at 8 months of age in male mice significantly prevented HFD-induced increases in p21, p53, and SASP-factor expression and the percentage of SA-β-gal-positive cells in visceral adipose tissue.
“Regarding adipose tissue, work from our group showed that 16 wk of voluntary wheel running started at 8 months of age in male mice significantly prevented HFD-induced increases in p21, p53, and SASP-factor expression and the percentage of SA-β-gal–positive cells in visceral adipose tissue.”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [31]
A 14-wk running wheel intervention started in mice that already had been exposed to an HFD for 16 wk attenuated the increase in p16, Pai1, and CD68 expression in visceral adipose tissue.
“In addition, we found that when a 14-wk running wheel intervention was started in mice that already had been exposed to an HFD for 16 wk, it was able to attenuate the increase in p16, Pai1, and CD68 expression in visceral adipose tissue (31).”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [31]
The adverse effects of an unhealthy diet on senescence markers were prevented by voluntary wheel running in middle-aged mice.
“Impressively, these adverse effects of an unhealthy diet were prevented by voluntary wheel running.”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Schafer et al., 2016
Middle-aged mice fed a high-fat diet from 8 to 12 months of age exhibited markedly higher senescence markers (p16INK4a, p21, SASP components, and/or SA-βgal) in visceral adipose tissue and liver relative to mice fed a standard chow diet.
“Finally, middle-aged mice fed a high-fat diet from 8 to 12 months of age exhibited markedly higher senescence markers (p16INK4a, p21, SASP components, and/or SA-βgal) in visceral adipose tissue and liver relative to mice fed a standard chow diet (Schafer et al., 2016).”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Schafer et al., 2016
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References 52 · Cited by 267
- Authors
- Schafer, M. J., White, T. A., Evans, G., Tonne, J. M., Verzosa, G. C., Stout, M. B., Mazula, D. L., Palmer, A. K., Baker, D. J., Jensen, M. D., Torbenson, M. S., Miller, J. D., Ikeda, Y., Tchkonia, T., van Deursen, J. M., Kirkland, J. L., & LeBrasseur, N. K.
- Affiliations
- Mayo Clinic (US)
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN
- Corresponding author
- LeBrasseur, Nathan K.
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2016-03-16
- Volume
- 65
- Issue
- 6
- Pages
- 1606-1615
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC4878429
- OpenAlex
- W2304048947
- Cited by
- 267
- References
- 52
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 26 · 2023: 27 · 2022: 29 · 2021: 40 · 2020: 38 · 2019: 24 · 2018: 23 · 2017: 19 · 2016: 6
- FWCI
- 19.30
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Diabetes (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Glenn Foundation for Medical Research
- National Institute on Aging (AG-041122)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- cellular senescence, physical activity, fast food diet, visceral adipose tissue, senescence-associated secretory phenotype, p16INK4a, senescence-associated β-galactosidase, healthy aging, metabolic dysfunction, body composition, cardiac health, physical fitness, lifestyle intervention
- MeSH terms
- Adipose Tissue, Aging, Animals, beta-Galactosidase, Body Composition, Body Weight, Diet, Male, Mice, Transgenic, Physical Conditioning, Animal, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Green Fluorescent Proteins, Mice, Fast Foods
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