Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice
Open accessAbstract
Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions.
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- Authors
- Mitchell, S. J., Madrigal-Matute, J., Scheibye-Knudsen, M., Fang, E., Aon, M., González-Reyes, J. A., Cortassa, S., Kaushik, S., Gonzalez-Freire, M., Patel, B., Wahl, D., Ali, A., Calvo-Rubio, M., Burón, M. I., Guiterrez, V., Ward, T. M., Palacios, H. H., Cai, H., Frederick, D. W., Hine, C., Broeskamp, F., Habering, L., Dawson, J., Beasley, T. M., Wan, J., Ikeno, Y., Hubbard, G., Becker, K. G., Zhang, Y., Bohr, V. A., Longo, D. L., Navas, P., Ferrucci, L., Sinclair, D. A., Cohen, P., Egan, J. M., Mitchell, J. R., Baur, J. A., Allison, D. B., Anson, R. M., Villalba, J. M., Madeo, F., Cuervo, A. M., Pearson, K. J., Ingram, D. K., Bernier, M., & de Cabo, R.
- Affiliations
- National Institutes of Health (US)
- University of Córdoba (ES)
- Albert Einstein College of Medicine (US)
- University of Pennsylvania (US)
- Harvard University (US)
- University of Graz (AT)
- University of Alabama (US)
- University of Southern California (US)
- The University of Texas at San Antonio Health Science Center (US)
- Pennington Biomedical Research Center (US)
- ORCID
- Mitchell, Sarah J.
- Fang, Evandro
- Aon, Miguel
- González-Reyes, José A.
- Cortassa, Sonia
- Kaushik, Susmita
- Wahl, Devin
- Burón, María I.
- Palacios, Hector H.
- Cai, Huan
- Hine, Christopher
- Broeskamp, Filomena
- Dawson, John
- Beasley, T. Mark
- Wan, Junxiang
- Ikeno, Yuji
- Becker, Kevin G.
- Zhang, Yongqing
- Bohr, Vilhelm A.
- Ferrucci, Luigi
- Sinclair, David A.
- Cohen, Pinchas
- Egan, Josephine M.
- Mitchell, James R.
- Baur, Joseph A.
- Allison, David B.
- Anson, R. Michael
- Villalba, José M.
- Madeo, Frank
- Pearson, Kevin J.
- Ingram, Donald K.
- Bernier, Michel
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 23
- Issue
- 6
- Pages
- 1093-1112
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4911707
- OpenAlex
- W2421296032
- Cited by
- 451
- References
- 117
- Citations by year
- 2026: 28 · 2025: 37 · 2024: 45 · 2023: 51 · 2022: 56 · 2021: 57 · 2020: 44 · 2019: 38 · 2018: 50 · 2017: 37 · 2016: 8
- FWCI
- 23.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Deposito Digital UFV (Francisco de Vitoria University) (submittedVersion, cc-by-nc-nd)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Repository of Digital Objects for Teaching Research and Culture (University of Valencia) (submittedVersion, other-oa)
- Funders
- American Diabetes Association (1-15-MI-03)
- Austrian Science Fund (P 24381, P 27893, I1000, P29203)
- Bundesministerium für Wissenschaft, Forschung und Wirtschaft
- National Institutes of Health (AG031782, AG038072)
- National Institute on Aging (AG-04-3483, P01AG034906, R01AG043483, P01AG031782, AG031782, P30AG038072, AG038072, P30AG013319, ZIAAG000368)
- National Institute of General Medical Sciences (R01GM090311)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK041296, P30DK020541, R01DK098656, P30DK079626)
- National Institute of Environmental Health Sciences (R01ES020812, P30ES013508)
- Topics
- 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
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Keywords
- caloric restriction, aging, sex differences, mouse strains, lifespan extension, healthspan, mitochondrial function, fatty acid metabolism, mitochondrial ultrastructure, metabolomics, gene expression changes
- MeSH terms
- Aging, Animals, Autophagy, Energy Intake, Female, Gene Expression Regulation, Glucose, Homeostasis, Hydrogen Sulfide, Islets of Langerhans, Liver, Longevity, Male, Mice, Inbred Strains, Mitochondria, Phenotype, Sex Characteristics, Biomarkers, Cluster Analysis, Gene Expression Profiling, Ubiquitin, Caloric Restriction, Proteasome Endopeptidase Complex, Mice, Metabolomics, Metabolome
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