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 and Dudley W. Lamming ()
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Reji Babygirija: University of Wisconsin-Madison
Jessica H. Han: University of Wisconsin-Madison
Michelle M. Sonsalla: University of Wisconsin-Madison
Ryan Matoska: University of Wisconsin-Madison
Mariah F. Calubag: University of Wisconsin-Madison
Cara L. Green: University of Wisconsin-Madison
Anna Tobon: University of Wisconsin-Madison
Chung-Yang Yeh: University of Wisconsin-Madison
Diana Vertein: University of Wisconsin-Madison
Sophia Schlorf: University of Wisconsin-Madison
Julia Illiano: William S. Middleton Memorial Veterans Hospital
Yang Liu: University of Wisconsin-Madison
Isaac Grunow: University of Wisconsin-Madison
Michael J. Rigby: University of Wisconsin-Madison
Luigi Puglielli: University of Wisconsin-Madison
David A. Harris: William S. Middleton Memorial Veterans Hospital
John M. Denu: University of Wisconsin-Madison
Dudley W. Lamming: University of Wisconsin-Madison

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62416-3

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