The metabolic roots of senescence: mechanisms and opportunities for intervention
Open accessAbstract
Cellular senescence entails a permanent proliferative arrest, coupled to multiple phenotypic changes. Among these changes is the release of numerous biologically active molecules collectively known as the senescence-associated secretory phenotype, or SASP. A growing body of literature indicates that both senescence and the SASP are sensitive to cellular and organismal metabolic states, which in turn can drive phenotypes associated with metabolic dysfunction. Here, we review the current literature linking senescence and metabolism, with an eye toward findings at the cellular level, including both metabolic inducers of senescence and alterations in cellular metabolism associated with senescence. Additionally, we consider how interventions that target either metabolism or senescent cells might influence each other and mitigate some of the pro-aging effects of cellular senescence. We conclude that the most effective interventions will likely break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence.
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SASP composition and strength vary with senescence duration, stimulus origin, and cell type.
“The composition and strength of the SASP can vary depending on the duration of senescence, the origin of the senescence stimulus and specific cell types17,21.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [21]
Senescence is characterized by morphological and functional changes including enlarged cell size, nuclear changes, metabolic remodeling, and the SASP.
“is characterized by morphological and functional changes, including enlarged cell size,9,10 nuclear changes,11,12,13,14,15 metabolic remodeling,16 and the SASP.”
From Cellular senescence in human liver under normal aging and cancer (2026) · cites this paper as [16]
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Transient p53-Mediated Regenerative Senescence in the Injured Heart
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Suppression of p16 Induces mTORC1-Mediated Nucleotide Metabolic Reprogramming
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Mitochondrial dysfunction in cell senescence and aging
Miwa, S., Kashyap, S., Chini, E., & von Zglinicki, T. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158447 · Cited by 1,061 · see citing works
SenNet recommendations for detecting senescent cells in different tissues
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“Mitochondrial dysfunction-associated senescence is primarily driven by the accumulation of cytosolic NADH, leading to ATP depletion and AMPK activation and cell cycle arrest 21 .”
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Roadmap for alleviating the manifestations of ageing in the cardiovascular system
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Research progress on interferon and cellular senescence
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Garbarino, V. R., Palavicini, J. P., Melendez, J., Barthelemy, N. R., He, Y., Kautz, T. F., Lopez-Cruzan, M., Mathews, J. J., Xu, P., Zhang, B., et al. (2025) · Neurotherapeutics · doi:10.1016/j.neurot.2025.e00591 · Cited by 19 · see citing works
“Taken together, these results place lipids as particularly sensitive and clinically valuable markers, and are consistent with preclinical studies [91,92] (for review: [93,94]).”
Cellular Models of Aging and Senescence
Kim, B., Lee, D. I., Basisty, N., & Dai, D.-F. (2025) · Cells · doi:10.3390/cells14161278 · Cited by 16 · see citing works
Cellular senescence in human liver under normal aging and cancer
Karpova, A., Li, X., Peng, C.-W., Gallant, K. L., Rapp, D. R., Alligood, D. M., Houston, A. J., Park, A., Targino da Costa, A. L. N., Chou, W.-H., et al. (2026) · Cell Genomics · doi:10.1016/j.xgen.2025.101133 · Cited by 13 · see citing works
“4 Senescence is triggered by stressors such as telomere shortening, DNA damage, oxidative stress, and oncogenic signals 5–8 and is characterized by morphological and functional changes, including enlarged cell size, 9,10 nuclear changes, 11–15 metabolic remodeling, 16 and the SASP.”
Overview of molecular signatures of senescence and associated resources: pros and cons
Ntintas, O. A., Vagena, S., Pantelis, P., Theocharous, G., Petty, R., Evangelou, K., & Gorgoulis, V. G. (2026) · FEBS Open Bio · doi:10.1002/2211-5463.70134 · Cited by 6 · see citing works
- Authors
- Wiley, C. D., & Campisi, J.
- Affiliations
- Tufts University (US)
- Buck Institute for Research on Aging (US)
- Corresponding author
- Wiley, Christopher D.
- Venue
- Nature Metabolism
- Published
- 2021-10-18
- Volume
- 3
- Issue
- 10
- Pages
- 1290-1301
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC8889622
- OpenAlex
- W3206142581
- Cited by
- 691
- References
- 216
- Citations by year
- 2026: 144 · 2025: 191 · 2024: 163 · 2023: 121 · 2022: 69 · 2021: 2 · 2020: 1
- FWCI
- 11.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- United States Department of Agriculture | Agricultural Research Service (8050-51000-099-01S)
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG051729)
- 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 › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- cellular senescence, senescence-associated secretory phenotype, cellular metabolism, metabolic dysfunction, senescence induction, senolytics, metabolic disorders, aging, proliferative arrest
- MeSH terms
- Animals, Autophagy, Homeostasis, Humans, Hyperglycemia, Lysosomes, Metals, NAD, Cellular Senescence
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.
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