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

Mol Cell Endocrinol. 2017 Nov 5;455:13-22. doi: 10.1016/j.mce.2016.11.014. Epub 2016 Nov 22.


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.

Publication types

  • Review

MeSH terms

  • Aging / genetics
  • Aging / metabolism*
  • Amino Acids, Branched-Chain / chemistry
  • Amino Acids, Branched-Chain / metabolism*
  • Animals
  • Caloric Restriction*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Diet / methods
  • Dietary Proteins / chemistry
  • Dietary Proteins / metabolism*
  • Gene Expression Regulation
  • Healthy Aging / genetics
  • Healthy Aging / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Ras Homolog Enriched in Brain Protein / genetics
  • Ras Homolog Enriched in Brain Protein / metabolism
  • Signal Transduction


  • Amino Acids, Branched-Chain
  • CASTOR1 protein, human
  • Carrier Proteins
  • Dietary Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ras Homolog Enriched in Brain Protein
  • EIF2AK4 protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases