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

Abstract

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.

Keywords: Aging; Branched-chain amino acids; Calorie restriction; GCN2; Protein quality; Protein restriction; mTOR.

Figure 1. Protein quality may contribute to the effects of calorie restriction

CR usually involves the restriction of all macronutrients, including dietary protein. We and others have found that the specific amino acid composition of the diet (protein quality) regulates metabolism, health, and longevity, and partially mimics the effects of a CR diet. Restriction of dietary branched chain amino acids (BCAAs) promotes leanness and glucose tolerance, while restriction of dietary methionine promotes leanness, insulin sensitivity, and lifespan. We propose that the beneficial effects of a CR diet on metabolic health and aging is mediated not simply by a reduction in caloric intake, but by the restriction of specific macronutrients, including BCAAs and methionine.

Figure 2. Model for the recruitment and activation of mTORC1 activity by amino acids

Both amino acids and growth factor (e.g., insulin) signaling are required to activate mTORC1. Activation of mTORC1 requires the co-localization of mTORC1 with Rheb-GTP. A) In the absence of amino acids and insulin, neither mTORC1 or Rheb localize to the lysosome. B) Amino acids promote the localization of mTORC1 to the lysosome, in part by relieving the inhibition of Sestrin1/2 and CASTOR1 on GATOR2, which permits GATOR2 to inhibit the GAP activity of GATOR1. Amino acids also promote the lysosomal recruitment of Rheb by MCRS1. TSC, which is localized to the lysosome under conditions of stress, continues to inhibit Rheb, and thus mTORC1 remains inactive. C) Insulin induces TSC to leave the lysosome, permitting Rheb to bind GTP; mTORC1 can then interact with GTP-bound Rheb and becomes active. Adapted from Kennedy and Lamming, 2016, Cell Metabolism, with permission.

Figure 3. Amino acids regulate multiple, interacting nutrient sensing pathways

Amino acid availability is sensed by multiple kinases, including mTORC1, GCN2, and AMPK. The high integration and feedback signaling between these pathways has made understanding the molecular basis for the physiological effects of protein quality infeasible until recently.