Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer's disease

Reji Babygirija; Jessica H Han; Michelle M Sonsalla; Ryan Matoska; Mariah F Calubag; Cara L Green; Anna Tobon; Chung-Yang Yeh; Diana Vertein; Sophia Schlorf; Julia Illiano; Yang Liu; Isaac Grunow; Michael J Rigby; Luigi Puglielli; David A Harris; John M Denu; Dudley W Lamming

doi:10.1038/s41467-025-62416-3

Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer's disease

Reji Babygirija, Jessica H Han, Michelle M Sonsalla, Ryan Matoska, Mariah F Calubag, Cara L Green, Anna Tobon, Chung-Yang Yeh, Diana Vertein, Sophia Schlorf, Julia Illiano, Yang Liu, Isaac Grunow, Michael J Rigby, Luigi Puglielli, David A Harris, John M Denu, Dudley W Lamming

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

6 Citations (SciVal)

Abstract

Caloric restriction slows or prevents Alzheimer's disease in animal models. Calorie restriction is typically implemented in rodents through feeding once per day; as the animals quickly consume their food, they are subject to a prolonged self-imposed fasting period between meals. Here, we examine the distinct contributions of fasting and reduced calories to the beneficial effects of calorie restriction on Alzheimer's disease by placing male and female 3xTg and non-transgenic control mice on a series of diet regimens enabling us to dissect the effects of calories and fasting. We find that reducing calories alone improves body weight and glucose tolerance. However, a prolonged fast between meals is necessary for many of the benefits of calorie restriction, including improved insulin sensitivity, reduced Alzheimer's pathology, improved neuroprotective signaling, and improved cognition. Overall, our results suggest that both when and how much we eat may influence the development and progression of Alzheimer's disease.

Original language	English
Article number	7147
Journal	Nature Communications
Volume	16
Issue number	1
Early online date	4 Aug 2025
DOIs	https://doi.org/10.1038/s41467-025-62416-3
Publication status	Published - 4 Aug 2025

Data Availability Statement

Source data are provided with this paper. Targeted brain metabolomics data has been deposited in MassIVE with accession code MSV000095847 [https://doi.org/10.25345/C5N873B30]. Targeted plasma metabolomics data has been deposited in MassIVE with accession code MSV000095887 [https://doi.org/10.25345/C5GF0N767]. Source data are provided with this paper.

Acknowledgements

We would like to thank Dr. Heidi Pak for her valuable insights and support. We thank all the members of the Lamming lab for their feedback. The Lamming lab is supported in part by the NIA (AG056771, AG062328, AG061635, AG081482, AG084156, and AG094153 to D.W.L.), the NIDDK (DK125859 to D.W.L. and J.M.D.), by a grant from the Alzheimer’s Association (23AARG-1029665 to D.W.L.), and by startup funds from UW-Madison. This study was supported in part by F31AG081115 (to R.B.), Supplement to Promote Diversity in Health-Related Research RF1AG056771-06S1 (to M.M.S.), Dalio Philanthropies, a Glenn Foundation for Medical Research Postdoctoral Fellowship, and by grant HF-AGE AGE-009 from the Hevolution Foundation to C.L.G.; M.F.C. was supported in part by F31 AG082504 (to M.F.C.). C.Y.Y. was supported in part by NIA F32 postdoctoral fellowship (F32AG077916 to C.Y.Y.) and a NIA K99 award (K99AG084921 to C.Y.Y.). The Puglielli lab is supported in part by the NINDS (NS094154 to L.P.), the NIGMS (GM148487 to L.P.) and the NIA (AG078794 to L.P.). The Harris lab is supported by the UW Department of Surgery, School of Medicine and Public Health, Wisconsin Alumni Research Fund, and the Office of the Vice Chancellor for Research. Additionally, the Harris lab has funding through the NIA (R03AG088813 to D.A.H.), Wisconsin Alzheimer’s Disease Research Center (P30 AG062715), and a grant from the Wisconsin Partnership Program at the UW School of Medicine and Public Health (ID 6770-2024 to D.A.H.). The Denu lab is supported in part by the NIH (GM149279 and DK125859 to J.M.D.). The authors thank the University of Wisconsin Carbone Cancer Center Experimental Animal Pathology Laboratory supported by P30 CA014520, for use of its facilities and services. L.P., D.A.H., J.M.D. and D.W.L. are members of the Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging, P30 AG092586. The Lamming lab was supported in part by the U.S. Department of Veterans Affairs (I01-BX004031 and IS1-BX005524 to D.W.L.), 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 United States Government.

Keywords

Animals
Alzheimer Disease/metabolism
Caloric Restriction
Fasting/physiology
Disease Models, Animal
Male
Mice, Transgenic
Female
Mice
Insulin Resistance
Body Weight
Humans
Cognition
Mice, Inbred C57BL

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Babygirija, R., Han, J. H., Sonsalla, M. M., Matoska, R., Calubag, M. F., Green, C. L., Tobon, A., Yeh, C.-Y., Vertein, D., Schlorf, S., Illiano, J., Liu, Y., Grunow, I., Rigby, M. J., Puglielli, L., Harris, D. A., Denu, J. M., & Lamming, D. W. (2025). Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer's disease. Nature Communications, 16(1), Article 7147. https://doi.org/10.1038/s41467-025-62416-3

Babygirija, R, Han, JH, Sonsalla, MM, Matoska, R, Calubag, MF, Green, CL, Tobon, A, Yeh, C-Y, Vertein, D, Schlorf, S, Illiano, J, Liu, Y, Grunow, I, Rigby, MJ, Puglielli, L, Harris, DA, Denu, JM & Lamming, DW 2025, 'Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer's disease', Nature Communications, vol. 16, no. 1, 7147. https://doi.org/10.1038/s41467-025-62416-3

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abstract = "Caloric restriction slows or prevents Alzheimer's disease in animal models. Calorie restriction is typically implemented in rodents through feeding once per day; as the animals quickly consume their food, they are subject to a prolonged self-imposed fasting period between meals. Here, we examine the distinct contributions of fasting and reduced calories to the beneficial effects of calorie restriction on Alzheimer's disease by placing male and female 3xTg and non-transgenic control mice on a series of diet regimens enabling us to dissect the effects of calories and fasting. We find that reducing calories alone improves body weight and glucose tolerance. However, a prolonged fast between meals is necessary for many of the benefits of calorie restriction, including improved insulin sensitivity, reduced Alzheimer's pathology, improved neuroprotective signaling, and improved cognition. Overall, our results suggest that both when and how much we eat may influence the development and progression of Alzheimer's disease.",

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Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer's disease

Abstract

Data Availability Statement

Acknowledgements

Keywords

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