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Dietary restriction in aging and longevity

Nature Aging volume 6, pages 485–505 (2026)Cite this article

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Abstract

Different types of dietary restriction (DR) have been practiced by humans for religious and medical purposes for millennia, but only during the past three decades has the scientific study of DR at cellular and molecular levels proliferated. Here we review the evidence testing a variety of DR paradigms in the context of aging, focusing on mammalian findings. We discuss potential DR mimetics that modulate autophagy, FGF21, AMPK, mTORC1, NAD+ metabolism, SIRTs, GLP-1R and other pathways as well as organismal and cellular adaptations to DR, including the roles of fasting, hunger, changes in body temperature and fat loss. We also consider the potential negative effects of DR such as increased vulnerability to infections and impaired wound healing. Further, we discuss preclinical evidence evaluating the potential of DR to improve healthspan and treat, prevent or delay age-related diseases including cancer, cardiovascular diseases and neurodegeneration. Finally, we consider the future opportunities for translation, and the challenges inherent to this complex research field.

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Fig. 1: DR in aging.
Fig. 2: DR effects on the hallmarks of aging.
Fig. 3: Physiological and cellular effects of DR and DR mimetics.

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Acknowledgements

We thank A. Molière for assistance and comments on the content of multiple sections; A. Anisimov and A. Ferrante for their comments on early drafts; J. Teeters, B. M. Delaney and A. de Grey for helping with the facilitation of valuable materials related to the CR Society; F. Pifferi for assisting with information related to the RESTRIKAL study; the Medical Library of Akershus University Hospital for their immense help with obtaining several non-digitalized materials. E.F.F. is supported by Cure Alzheimer’s Fund (282952; 284930), HELSE SØR-ØST (2020001, 2021021, 2023093), the Research Council of Norway (262175, 334361), Molecule AG/VITADAO (282942), NordForsk Foundation (119986), the National Natural Science Foundation of China (81971327; 82574074), Akershus University Hospital (269901, 261973, 262960), the Civitan Norges Forskningsfond for Alzheimers sykdom (281931), the Czech Republic-Norway KAPPA program (with M. Vyhnálek, TO01000215), the Rosa sløyfe/Norwegian Cancer Society & Norwegian Breast Cancer Society (207819), HORIZON-TMA-MSCA-DN (101073251, with R. Houtkooper), Wellcome Leap’s Dynamic Resilience Program (jointly funded by Temasek Trust; 104617) and the Alzheimer’s Association (PTC-Gene-25-1439553). C.C. is supported by Novo Nordisk Foundation (NNF22OC0073778, NNF24OC0089508, NNF23SA0084103) and the European Research Council under the European Union’s Horizon Europe research and innovation program (grant agreement no. 101170678, PDC-MAIN). A.R. is supported by the Department of Veterans Affairs (1IK6BX005238). R.d.C. is supported by the Intramural Research Program of the NIA, NIH. Figures were designed in Adobe Illustrator. Language refinement was assisted by ChatGPT to improve readability and clarity. Survival curves were extracted from published sources using WebPlotDigitizer.

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Authors and Affiliations

  1. Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway

    Tomas Schmauck-Medina, Sofie Lautrup & Evandro F. Fang

  2. Calico Life Sciences, South San Francisco, CA, USA

    Andrea Di Francesco

  3. Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA

    Sarah J. Mitchell

  4. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Christoffer Clemmensen

  5. Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK

    Linda Partridge

  6. GeroScience and Prolongevity Technologies, Pylesville, MD, USA

    George S. Roth

  7. Department of Medicine, SMPH, University of Wisconsin, Madison, WI, USA

    Rozalyn M. Anderson

  8. GRECC, William S Middleton Memorial Veterans Hospital, Madison, WI, USA

    Rozalyn M. Anderson

  9. Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

    Julie A. Mattison & Rafael de Cabo

  10. Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

    John R. Speakman

  11. School of Biological Sciences, University of Aberdeen, Aberdeen, UK

    John R. Speakman

  12. Oklahoma City VA Medical Center, Oklahoma City, OK, USA

    Arlan Richardson

  13. Department of Biochemistry & Physiology, Oklahoma University Health Science Center, Oklahoma City, OK, USA

    Arlan Richardson

  14. Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA

    Donald K. Ingram

  15. University of Wisconsin, Madison, WI, USA

    Richard Weindruch

  16. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Mark P. Mattson

  17. The Norwegian Centre on Healthy Ageing (NO-Age) and the Norwegian National Anti-Alzheimer’s Disease (NO-AD) Networks, Oslo, Norway

    Evandro F. Fang

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Contributions

Original conceptualization: T.S.-M., E.F.F. and M.P.M.; Writing, review and editing: T.S.-M., E.F.F., M.P.M., S.L., A.D.F., S.J.M., C.A., L.P., G.S.R., R.M.A., J.A.M., R.d.C., J.R.S., A.R., D.K.I. and R.W.

Corresponding authors

Correspondence to Mark P. Mattson or Evandro F. Fang.

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Competing interests

E.F.F. is a co-owner of Fang-S Consultation AS (organization no. 931 410 717) and NO-Age AS (organization no. 933 219 127). E.F.F. has a material transfer agreement with LMITO Therapeutics (South Korea), a CRADA arrangement with ChromaDex (USA), a commercialization agreement with Molecule AG/VITADAO, and material transfer agreements with GeneHarbor (Hong Kong) Biotechnologies Limited and Hong Kong Longevity Science Laboratory (Hong Kong). E.F.F. is a consultant to MindRank AI (China), NYO3 (Norway), AgeLab (Vitality Nordic AS, Norway) and Hong Kong Longevity Science Laboratory (Hong Kong). D.K.I. and G.S.R. are founders and Chief Scientific Officers for GeroScience (USA) and Prolongevity Technologies (USA). D.K.I. is Chief Scientific Officer for Functional Longevity Labs (USA). C.C. is a cofounder of Ousia Pharma, a biotech company developing therapeutics for the treatment of obesity. M.P.M. is the author of and receives royalties from The Intermittent Fasting Revolution. A.D.F. is employed by Calico Life Sciences. The remaining authors declare no competing interests.

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Schmauck-Medina, T., Lautrup, S., Di Francesco, A. et al. Dietary restriction in aging and longevity. Nat Aging 6, 485–505 (2026). https://doi.org/10.1038/s43587-026-01091-5

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