Regulators of health and lifespan extension in genetically diverse mice on dietary restriction
Open accessPreprint — published as 10.1038/s41586-024-08026-3
Abstract
Summary: Caloric restriction (CR) delays aging and extends healthy lifespan in multiple species. Alternative forms of dietary restriction (DR) such as intermittent fasting (IF) have drawn significant interest as a more sustainable regimen, but the landscape of longevity-promoting dietary interventions remains largely unexplored. Identifying the most robust, efficacious, and experimentally tractable modes of DR is key to better understanding and implementing effective longevity interventions for human healthspan. To that end, we have performed an extensive assessment of DR interventions, investigating the effects of graded levels of CR (20% and 40%) and IF (1 day and 2 days of fasting per week) on the health and survival of 960 genetically diverse female mice. All interventions extended lifespan, although only CR significantly reduced the mortality doubling time. Notably, IF did not extend lifespan in mice with high pre-intervention bodyweight. We carried out extensive phenotyping to determine the health effects of long-term DR and to better understand the mechanisms driving within-diet heterogeneity in lifespan. The top within-diet predictor of lifespan was the ability of mice to maintain bodyweight through periods of handling, an indicator of stress resilience. Additional predictors of long lifespan include specific changes in immune cells, red blood cell distribution width (RDW), and retention of adiposity in late life. We found that lifespan is heritable (h 2 = 0.24), and that genetic background has a larger influence on lifespan than dietary interventions. We identified a significant association for lifespan and RDW on chromosome 18 that explained 4.3% of the diet-adjusted variation in lifespan. Diet-induced changes on metabolic traits, although beneficial, were relatively poor predictors of lifespan, arguing against the long-standing notion that DR works by counteracting the negative effects of obesity. These findings indicate that improving health and extending lifespan are not synonymous and that metabolic parameters may be inappropriate endpoints for evaluating aging interventions in preclinical models and clinical trials.
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Schork, N. J. (2024) · Nature · doi:10.1038/d41586-024-03055-4 · Cited by 2 · see citing works
Everything everywhere all at once: Unraveling the waves of aging
Escrig-Larena, J. I., & Mittelbrunn, M. (2025) · Immunity · doi:10.1016/j.immuni.2025.01.015 · Cited by 2 · see citing works
Hill, W. G., MacIver, B., Churchill, G. A., DeOliveira, M. G., Zeidel, M. L., & Cicconet, M. (2025) · Physiological Reports · doi:10.14814/phy2.70243 · Cited by 1 · see citing works
Self-citationMullis, M. N., Lefebvre, A. E. Y. T., Sivasubramanian, K., Luo, A., Schmid, F. T., Sooknah, M., Wright, K. M., Raj, A., Zavala‐Solorio, J., Zhang, C., et al. (2026) · PLoS Genetics · doi:10.1101/2025.05.13.653808 · Cited by 1 · see citing works
Self-citationJiang, S., Kazemi, S., Stommel, M., Cheng, L. K., & Xu, W. (2025) · International Conference on Mechatronics and Machine Vision in Practice (M2VIP) · doi:10.1109/m2vip67511.2025.11165599 · Cited by 1 · see citing works
Unlocking neuronal health: leveraging C. elegans for drug repurposing studies
Gowda, S., Kumar, A., & Topf, U. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-025-02592-3 · Cited by 1 · see citing works
Kalenta, H., Marchant, E. D., Kilroe, S. P., Maroto, R., May, J. T., Bugay, V., Romsdahl, T. B., Linares, J. J., Hinojosa, M. R., Lai, Z., et al. (2026) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00730.2025 · Cited by 1 · see citing works
Ozaki, Y., Ozaki, T., & Zhang-Akiyama, Q.-M. (2026) · Yeast · doi:10.1002/yea.70016 · Cited by 1 · see citing works
- Authors
- Di Francesco, A., Deighan, A. G., Litichevskiy, L., Chen, Z., Luciano, A., Robinson, L., Garland, G., Donato, H., Schott, W., Wright, K. M., Raj, A., Prateek, G. V., Mullis, M., Hill, W., Zeidel, M., Peters, L., Harding, F., Botstein, D., Korstanje, R., Thaiss, C. A., Freund, A., & Churchill, G. A.
- Affiliations
- Jackson Laboratory (US)
- University of Pennsylvania (US)
- Calico Life Sciences (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Churchill, Gary A.
- ORCID
- Venue
- Nature
- Publisher
- openRxiv
- Published
- 2023-11-28
- Volume
- 634
- Issue
- 8034
- Pages
- 684-692
- ISSN
- 0028-0836 (ISSN-L)
- PMC
- PMC11485257
- OpenAlex
- W4403243577
- Cited by
- 194
- References
- 92
- Citations by year
- 2026: 94 · 2025: 82 · 2024: 18
- FWCI
- 23.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Nature (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (P30CA034196)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- caloric restriction, intermittent fasting, lifespan extension, aging interventions, stress resilience, immune repertoire, erythroid cells, adiposity, lean mass loss, fasting blood glucose, obesity, health and longevity
- MeSH terms
- Animals, Body Weight, Erythrocytes, Fasting, Female, Health, Longevity, Lymphocytes, Genetic Variation, Caloric Restriction, Adiposity, Mice, Resilience, Psychological
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.
Statistics and arithmetic are recomputed, not judged.
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