Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice

Heidi H Pak; Spencer A Haws; Cara L Green; Mikaela Koller; Mitchell T Lavarias; Nicole E Richardson; Shany E Yang; Sabrina N Dumas; Michelle Sonsalla; Lindsey Bray; Michelle Johnson; Stephen Barnes; Victor Darley-Usmar; Jianhua Zhang; Chi-Liang Eric Yen; John M Denu; Dudley W Lamming

doi:10.1038/s42255-021-00466-9

Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice

Heidi H Pak
, Spencer A Haws
, Cara L Green
, Mikaela Koller
, Mitchell T Lavarias
, Nicole E Richardson
, Shany E Yang
, Sabrina N Dumas
, Michelle Sonsalla
, Lindsey Bray
, Michelle Johnson
, Stephen Barnes
, Victor Darley-Usmar
, Jianhua Zhang
, Chi-Liang Eric Yen
, John M Denu
, Dudley W Lamming

Department for Health

University of Wisconsin-Madison
Department of Medicine
William S. Middleton Memorial Veterans Hospital
University of Alabama

Research output: Contribution to journal › Article › peer-review

143 Citations (SciVal)

Abstract

Calorie restriction (CR) promotes healthy ageing in diverse species. Recently, it has been shown that fasting for a portion of each day has metabolic benefits and promotes lifespan. These findings complicate the interpretation of rodent CR studies, in which animals typically eat only once per day and rapidly consume their food, which collaterally imposes fasting. Here we show that a prolonged fast is necessary for key metabolic, molecular and geroprotective effects of a CR diet. Using a series of feeding regimens, we dissect the effects of calories and fasting, and proceed to demonstrate that fasting alone recapitulates many of the physiological and molecular effects of CR. Our results shed new light on how both when and how much we eat regulate metabolic health and longevity, and demonstrate that daily prolonged fasting, and not solely reduced caloric intake, is likely responsible for the metabolic and geroprotective benefits of a CR diet.

Original language	English
Pages (from-to)	1327-1341
Number of pages	15
Journal	Nature Metabolism
Volume	3
Issue number	10
Early online date	18 Oct 2021
DOIs	https://doi.org/10.1038/s42255-021-00466-9
Publication status	Published - 31 Oct 2021

Data Availability Statement

RNA-sequencing data have been deposited with the Gene Expression Omnibus and are available under accession number GSE168262. Source data are provided with this paper. Other data that support the plots and findings of this study are available from the corresponding author upon reasonable request.

Acknowledgements

We thank all members of the laboratory of D.W.L., as well as J. Simcox and R. Jain, for their valuable insights and comments. We thank S. Simpson and S. Solon-Biet for advice regarding animal care. We thank T. Herfel (Envigo) for assistance with the formulation of the Diluted AL diet. We thank M. Schaid for critical reading of the manuscript.

Funding

The laboratory of D.W.L. is supported in part by the National Institutes of Health (NIH)/NIA (AG050135, AG051974, AG056771, AG062328 and AG061635 to D.W.L.), NIH/National Institute of Diabetes and Digestive and Kidney Diseases (DK125859 to D.W.L and J.M.D.) and start-up funds from the UW School of Medicine and Public Health and Department of Medicine (to D.W.L.). Metabolomic and histone proteomic analysis was supported in part by a grant from the NIH (R37GM059785 to J.M.D.) and a UAB Nathan Shock Center of Excellence in the Basic Biology of Aging (P30AG050886) Core Services Pilot Award (to D.W.L.). Bomb calorimetry was supported by S10OD028739 (to C.-L.E.Y.), and gut integrity analysis was supported in part by DK124696 (to C.-L.E.Y.). H.H.P. is supported in part by a NIA F31 pre-doctoral fellowship (AG066311). C.L.G. is supported by a Glenn Foundation for Medical Research Postdoctoral Fellowship and was supported in part by a generous gift from D. Philanthropies. N.E.R. was supported in part by a training grant from the UW Institute on Aging (NIA T32 AG000213). S.A.H. was supported in part by a training grant from the UW Metabolism and Nutrition Training Program (T32 DK007665). Support for this research was provided by the UW Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation. This work was supported in part by the US Department of Veterans Affairs (I01-BX004031), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work does not represent the views of the Department of Veterans Affairs or the US Government.

Keywords

Aging/metabolism
Animals
Caloric Restriction
Longevity/physiology
Mice

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Pak, H. H., Haws, S. A., Green, C. L., Koller, M., Lavarias, M. T., Richardson, N. E., Yang, S. E., Dumas, S. N., Sonsalla, M., Bray, L., Johnson, M., Barnes, S., Darley-Usmar, V., Zhang, J., Yen, C.-L. E., Denu, J. M., & Lamming, D. W. (2021). Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice. Nature Metabolism, 3(10), 1327-1341. https://doi.org/10.1038/s42255-021-00466-9

Pak, HH, Haws, SA, Green, CL, Koller, M, Lavarias, MT, Richardson, NE, Yang, SE, Dumas, SN, Sonsalla, M, Bray, L, Johnson, M, Barnes, S, Darley-Usmar, V, Zhang, J, Yen, C-LE, Denu, JM & Lamming, DW 2021, 'Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice', Nature Metabolism, vol. 3, no. 10, pp. 1327-1341. https://doi.org/10.1038/s42255-021-00466-9

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Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice

Abstract

Data Availability Statement

Acknowledgements

Funding

Keywords

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