Genetic regulation of fasting-induced longevity effects

Area of Science:

• Genetics and Aging
• Metabolic Health
• Dietary Interventions

Background:

• Dietary interventions like caloric restriction and intermittent fasting (IF) show promise for improving metabolic health and lifespan in preclinical studies.
• Individual responses to IF vary significantly, hindering effective human translation due to poorly understood physiological variations.

Purpose of the Study:

• To investigate the genetic basis of physiological and lifespan responses to intermittent fasting (IF) using a genetically diverse mouse model.
• To identify how sex and genetic background influence responses to IF across various physiological domains.

Main Methods:

• Applied a two-day-per-week IF regimen to 10 inbred strains of Collaborative Cross (CC) mice.
• Utilized longitudinal phenotyping to measure hundreds of traits, including lifespan.
• Compared findings with a parallel study in Diversity Outbred (DO) mice.

Main Results:

• Sex and genetic background significantly shape physiological responses to IF, affecting metabolic, hematologic, and immunologic traits.
• Lifespan effects of IF were sex-specific and varied considerably among different mouse strains.
• Identified shared and distinct predictors of health and lifespan responses between inbred (CC) and outbred (DO) mouse populations.

Conclusions:

• Intermittent fasting response is genetically determined in a mammalian model with human-relevant physiology.
• Genetic factors play a central role in determining outcomes of dietary interventions like IF.
• Findings inform strategies for translating IF benefits for human health and longevity, emphasizing the need for personalized approaches.