Both calorie restriction and intermittent fasting slow aging and extend life in short-lived mammals. In the short term, many measures of health are improved. In long-lived mammals such as our own species, the short term effects are very similar, but effects on life span are much smaller. The reasons why this is the case remain to be determined. Cellular biochemistry is enormously complex and calorie restriction and fasting produce sweeping changes in near every aspect of the operation of metabolism. Researchers can point to improvements in autophagy as the likely primary mechanism for benefits, but do not have an understanding as to why improved autophagy affects life span so differently in short-lived versus long-lived mammals.
Studies conducted separately to assess the effects of calorie restriction and intermittent fasting in rodents have generally indicated that calorie restriction has a larger effect on aging and longevity. Today’s open access paper reports on a direct comparison between the two strategies in the same study, and comes to much the same conclusion. One novel aspect of the research is the use of genetically diverse mice known as diversity outbred mice, a model more representative of the differences in a natural population of mammals than is the case for the usual lineages with carefully cultivated similar genetics between individuals. This led to some interesting insights into differential effects of low calorie intake between mice with different characteristics.
Dietary restriction impacts health and lifespan of genetically diverse mice
Caloric restriction extends healthy lifespan in multiple species. Intermittent fasting, an alternative form of dietary restriction, is potentially more sustainable in humans, but its effectiveness remains largely unexplored. Identifying the most efficacious forms of dietary restriction is key for developing interventions to improve human health and longevity. 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.
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