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Genetic regulation of fasting-induced longevity effects
Alison Luciano1, Laura Robinson1, William H Schott1
1The Jackson Laboratory, Bar Harbor, ME, USA.
Biorxiv : the Preprint Server for Biology
|September 15, 2025
Summary
Intermittent fasting (IF) responses vary significantly based on sex and genetic background in mice. Understanding these genetic factors is crucial for safely translating IF benefits to human health and longevity.
Area of Science:
- Aging Biology
- Genetics
- Nutritional Science
Background:
- Dietary interventions like caloric restriction and intermittent fasting (IF) show promise for metabolic health and lifespan extension.
- Individual variability in response to IF impacts its safety and efficacy in humans, yet remains poorly understood.
- The Collaborative Cross (CC) mouse model offers a diverse genetic platform to study intervention response heterogeneity.
Purpose of the Study:
- To investigate the impact of genetic background and sex on physiological and lifespan responses to intermittent fasting (IF).
- To establish whether IF response is genetically determined using a diverse mouse model.
- To compare findings between inbred CC mice and outbred Diversity Outbred (DO) mice.
Main Methods:
- Implemented a two-day-per-week intermittent fasting (IF) regimen in 10 inbred strains (n=800) of Collaborative Cross (CC) mice.
- Conducted longitudinal phenotyping to assess hundreds of traits, including lifespan.
- Compared results with a parallel study using Diversity Outbred (DO) mice.
Main Results:
- Sex and genetic background significantly influenced physiological responses to IF across metabolic, hematologic, and immunologic parameters.
- The effects of IF on lifespan were found to be sex-specific and varied across different genetic backgrounds.
- Key predictors of health and lifespan were identified, with notable differences between inbred and outbred mouse models.
Conclusions:
- Intermittent fasting response is genetically determined, as demonstrated in a preclinical model with human-like physiological features.
- Genetic factors play a critical role in determining individual responses to dietary interventions like IF.
- These findings provide essential insights for the personalized translation of IF's health and longevity benefits to humans.
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