Yu and Richardson et al. find that restriction of dietary isoleucine or valine promotes metabolic health in mice and that restriction of dietary isoleucine is required for the metabolic benefits of a low-protein diet. Furthermore, higher dietary isoleucine levels are associated with increased BMI in humans.

Protein restricted (PR) diets promote health and longevity in many species. While the precise components of a PR diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of PR can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in lifespan and a reduction in frailty in male, but not female, wild-type mice when fed lifelong. Our results demonstrate that restricting dietary BCAAs can increase healthspan and longevity in mice, and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.

Calorie restriction (CR) promotes healthy aging in diverse species. Recently, it has been shown that fasting for a portion of each day has metabolic benefits and promotes lifespan. These findings complicate the interpretation of rodent CR studies, in which animals typically eat only once per day and rapidly consume their food, which collaterally imposes fasting. Here, we show that a prolonged fast is necessary for key metabolic, molecular and geroprotective effects of a CR diet. Using a series of feeding regimens, we dissect the effects of calories and fasting, and proceed to demonstrate that fasting alone recapitulates many of the physiological and molecular effects of CR. Our results shed new light on how both when and how much we eat regulate metabolic health and longevity, and demonstrate that daily prolonged fasting, and not solely reduced calorie intake, is likely responsible for the metabolic and geroprotective benefits of a CR diet.

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The adipocyte hormone leptin plays an important part in the reproductive function and in energy homeostasis. Only single studies have addressed the relationship between leptin and the hypothalamus-pituitary-gonadal axis (HPG) in anorexia nervosa (AN). In the present study 18 female adolescents with AN were investigated during weight gain. Leptin, LH, FSH, fT3, BMI and body composition were measured in the 1(st), 3(rd), 7(th) and 11(th) week of inpatient treatment. 18 eumenorrheic age- and gender-matched controls were examined once during the early follicular phase of their menstrual cycle. Our results demonstrate a critical leptin level of 1.2 ng/ml for an increase of FSH and confirmed a leptin threshold level of 1.85 ng/ml for LH. It may be concluded that leptin represents a metabolic gate to gonadotropin secretion. Once this is exceeded other biological mechanisms seem to be important for the complete recovery of the reproductive function and the resumption of menses.

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Obesity and type 2 diabetes are increasing in prevalence around the world, and there is a clear need for new and effective strategies to promote metabolic health. A low protein (LP) diet improves metabolic health in both rodents and humans, but the mechanisms that underlie this effect remain unknown. The gut microbiome has recently emerged as a potent regulator of host metabolism and the response to diet. Here, we demonstrate that a LP diet significantly alters the taxonomic composition of the gut microbiome at the phylum level, altering the relative abundance of Actinobacteria, Bacteroidetes, and Firmicutes. Transcriptional profiling suggested that any impact of the microbiome on liver metabolism was likely independent of the microbiome-farnesoid X receptor (FXR) axis. We therefore tested the ability of a LP diet to improve metabolic health following antibiotic ablation of the gut microbiota. We found that a LP diet promotes leanness, increases energy expenditure, and improves glycemic control equally well in mice treated with antibiotics as in untreated control animals. Our results demonstrate that the beneficial effects of a LP diet on glucose homeostasis, energy balance, and body composition are unlikely to be mediated by diet-induced changes in the taxonomic composition of the gut microbiome.

Low protein (LP) diets promote health and longevity in diverse species. Although the precise components of an LP diet that mediate its beneficial effects have not been defined, reducing dietary levels of the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine promotes metabolic health in both sexes, and increases lifespan while reducing frailty in male, but not female, C57BL/6J mice. Each BCAA has unique metabolic effects, and we recently showed that restriction of isoleucine is both sufficient to promote metabolic health and required for the metabolic benefits of an LP diet in male C57BL/6J mice. Here, we tested the hypothesis that specifically restricting isoleucine could promote healthy aging in genetically heterogenous UM-HET3 mice. We find that a reduced isoleucine diet improves the metabolic health of both young and old HET3 mice, promoting leanness and glycemic control. Restriction of isoleucine starting in adult, 6 month old HET3 mice reprograms hepatic metabolism in a way distinct from an LP diet. Finally, we find that a reduced isoleucine diet reduces frailty and extends the lifespan of both male and female HET3 mice, but to a much greater degree in males. Our results demonstrate that restricting dietary isoleucine can increase health span and longevity in a genetically diverse population of mice, and suggests that reducing dietary levels of isoleucine may have great potential as a geroprotective intervention.