Caloric restriction extends healthy lifespan in multiple species1. Intermittent fasting, an alternative form of dietary restriction, is potentially mo

Dietary restriction impacts health and lifespan of genetically diverse mice

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2024-10-10 03:30:05

Caloric restriction extends healthy lifespan in multiple species1. Intermittent fasting, an alternative form of dietary restriction, is potentially more sustainable in humans, but its effectiveness remains largely unexplored2,3,4,5,6,7,8. Identifying the most efficacious forms of dietary restriction is key for developing interventions to improve human health and longevity9. Here we performed an extensive assessment of graded levels of caloric restriction (20% and 40%) and intermittent fasting (1 and 2 days fasting per week) on the health and survival of 960 genetically diverse female mice. We show that caloric restriction and intermittent fasting both resulted in lifespan extension in proportion to the degree of restriction. Lifespan was heritable and genetics had a larger influence on lifespan than dietary restriction. The strongest trait associations with lifespan included retention of body weight through periods of handling—an indicator of stress resilience, high lymphocyte proportion, low red blood cell distribution width and high adiposity in late life. Health effects differed between interventions and exhibited inconsistent relationships with lifespan extension. 40% caloric restriction had the strongest lifespan extension effect but led to a loss of lean mass and changes in the immune repertoire that could confer susceptibility to infections. Intermittent fasting did not extend the lifespan of mice with high pre-intervention body weight, and two-day intermittent fasting was associated with disruption of erythroid cell populations. Metabolic responses to dietary restriction, including reduced adiposity and lower fasting glucose, were not associated with increased lifespan, suggesting that dietary restriction does more than just counteract the negative effects of obesity. Our findings indicate that improving health and extending lifespan are not synonymous and raise questions about which end points are the most relevant for evaluating aging interventions in preclinical models and clinical trials.

Caloric restriction (CR) delays the onset of age-related diseases and extends lifespan in multiple species1. In humans, compliance with CR is challenging, and interest has shifted to more permissive forms of dietary restriction (DR), such as time-restricted feeding and intermittent fasting (IF) that have proven to be effective in promoting organismal health2,3,4,5. In mice, regular periods of fasting can convey considerable benefits without reduction in overall energy intake6. Mice on CR also experience prolonged periods of daily fasting, and the health benefits of CR can be optimized by feeding at a specific time of the day, suggesting that both caloric intake and timing of feeding contribute to physiological response and lifespan extension5,6,7,8. Despite the importance of these observations, limited information is available regarding the differences between CR and IF in relation to healthy ageing and longevity9.