Regulation of metabolic health and aging by nutrient-sensitive signaling pathways

•Many of the benefits of calorie restriction are mediated by reduced protein.•Restriction of specific dietary amino acids promotes metabolic health.•The protein kinases mTORC1 and GCN2 respond to altered dietary amino acids.•Altering dietary macronutrients may be a translatable intervention for healthy aging.

All organisms need to be capable of adapting to changes in the availability and composition of nutrients. Over 75 years ago, researchers discovered that a calorie restricted (CR) diet could significantly extend the lifespan of rats, and since then a CR diet has been shown to increase lifespan and healthspan in model organisms ranging from yeast to non-human primates. In this review, we discuss the effects of a CR diet on metabolism and healthspan, and highlight emerging evidence that suggests that dietary composition - the precise macronutrients that compose the diet - may be just as important as caloric content. In particular, we discuss recent evidence that suggests protein quality may influence metabolic health. Finally, we discuss key metabolic pathways which may influence the response to CR diets and altered macronutrient composition. Understanding the molecular mechanisms responsible for the effects of CR and dietary composition on health and longevity may allow the design of novel therapeutic approaches to age-related diseases.