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Research Highlights

Calorie restriction and fasting improve health in female mice

Calorie restriction combined with intermittent fasting provides greater health benefits and longer lifespan in middle-aged female mice than intermittent fasting alone, according to NIA scientists. Findings from the study were published in Cell Metabolism.

Salad filling a quarter of a plate

Research from the past century suggests that calorie restriction without malnutrition may promote healthy aging and increase longevity. Since calorie restriction is difficult to maintain, alternative strategies such as intermittent fasting have become popular. Time-restricted feeding (TRF), a form of intermittent fasting, involves limiting daily access to food to an eight-to-10-hour window but does not necessarily restrict calories. Preclinical research on the health impact of TRF and calorie restriction has mostly used male mice. As previous studies point to sex differences in how mice respond to caloric restriction, the underrepresentation of female mice has impeded translation to human research.

To address this gap, NIA scientists examined the impact of TRF and calorie restriction on the health of middle-aged female mice. The mice were divided into groups and assigned different types of diets: TRF (four or eight hours of access to food per day), calorie restriction with a 20% reduction (one meal per day or two mini-meals per day), and a control group with unhindered access to food. The calorie-restricted groups also had prolonged periods of fasting with a dietary pattern similar to the four-hour TRF group. For 80 weeks, the research team measured how the diets affected body composition, metabolic health, physical performance, and lifespan.

First, the researchers examined body composition and found different diets did not significantly affect fat-to-muscle ratio in the mice at any point during the study, but the groups with restricted diets did improve compared to the control group. Next, the researchers measured fasting blood glucose, a test often used to diagnose diabetes. They found calorie restriction and TRF decreased fasting blood glucose levels after 20 weeks. The scientists then performed an oral glucose tolerance test, which is also commonly used to diagnose diabetes. The calorie-restricted mice cleared glucose from their bloodstreams at a significantly faster rate than the control mice.

After 39 weeks of the feeding schedule, mice on both the calorie-restriction and TRF diets had better physical performance than the control group. However, mice maintained on calorie-restricted diets outperformed mice on TRF diets. The scientists also used a combination of physical tests to determine the frailty of each mouse. The data suggest that calorie restriction protected the mice against frailty in old age, while TRF did not.

Both calorie restriction and TRF also resulted in small increases in lifespan, with the mice living approximately 3% longer on average. However, only calorie restriction led to a small but significant increase in both average and maximum lifespan. Calorie restriction also reduced incidence of tumors and the severity of inflammatory lung diseases.

Overall, the results suggest that a diet with prolonged periods of fasting is most beneficial when combined with calorie restriction. The authors note several limitations to their study, mainly that they only used female mice, which prevents a direct comparison of how these diets affect females and males differently. The mice were also from the same genetic background, which prevents capturing genetic differences that likely affect the effects of each diet. Future studies will address these limitations and examine whether the eating window time in TRF changes health effects.

Reference: Duregon E, et al. Prolonged fasting times reap greater geroprotective effects when combined with calorie restriction in adult female mice. Cell Metabolism. 2023;35(7):1179-1194.e5. doi: 10.1016/j.cmet.2023.05.003.

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