Regulation of metabolic health by essential dietary amino acids

Abstract

Although the beneficial effects of calorie restriction (CR) on health and aging were first observed a century ago, the specific macronutrients and molecular processes that mediate the effect of CR have been heavily debated. Recently, it has become clear that dietary protein plays a key role in regulating both metabolic health and longevity, and that both the quantity and quality - the specific amino acid composition - of dietary protein mediates metabolic health. Here, we discuss recent findings in model organisms ranging from yeast to mice and humans regarding the influence of dietary protein as well as specific amino acids on metabolic health, and the physiological and molecular mechanisms which may mediate these effects. We then discuss recent findings which suggest that the restriction of specific dietary amino acids may be a potent therapy to treat or prevent metabolic syndrome. Finally, we discuss the potential for dietary restriction of specific amino acids - or pharmaceuticals which harness these same mechanisms - to promote healthy aging.

Restriction of essential amino acids dictates the systemic response to dietary protein dilution

“…Importantly, our studies here ( Fig. 1-7), as well as previous studies of amino acid (AA) restriction 23,37 , have conclusively shown that a restriction of dietary protein/AA per se can induce the systemic metabolic response to dietary protein dilution. Even though dietary protein as a nutrient can be digested and absorbed as AA or short peptides, our data reinforce that dietary AA supply is paramount under conditions of dietary protein restriction.…”

“…So could restriction of certain AA confer this response? There are several studies showing that dietary essential amino acid (EAA) restriction are sufficient to induce many of the responses to DPD 20,37 . On the other hand, there are several lines of evidence that restriction of systemic non-EAA (NEAA) supply to the liver influences FGF21 and systemic metabolism 14,[46][47][48] .…”

“…However, whether the simultaneous increase in other non-protein/AA nutrients such as certain carbohydrates [34][35][36] are required for DPD effects, as well as which particular AA drive this process is currently debated 23,37 . On one hand, restriction of EAA such as the branched chain amino acids 21,[38][39][40][41] and sulphur-containing AAs [42][43][44][45] , have been shown to be sufficient in conferring the systemic effects of DPD.…”

Lysosome: The metabolic signaling hub

“…84 Intriguingly, the discovery of SAMTOR provides the first molecular mechanism by which methionine restriction, a potent dietary intervention that improves metabolic health and extends rodent life span, [85][86][87] may mediate mTORC1 activity. [88][89][90] This study not only provides a key link between one carbon metabolism and the mTORC1 pathway but raises the question of whether additional intermediate metabolites in amino acid catabolism are also sensed by mTORC1. For example, mTORC1 has been shown to sense α-ketoglutarate, a product of glutaminolysis.…”

“…Instead of directly sensing amino acid levels, SAMTOR binds to the metabolite S-adenosylmethionine (SAM) which disrupts its interaction with GATOR1, positioning SAMTOR as an indirect sensor of methionine 84 . Intriguingly, the discovery of SAMTOR provides the first molecular mechanism by which methionine restriction, a potent dietary intervention that improves metabolic health and extends rodent lifespan 85–87 , may mediate mTORC1 activity 88–90 . This study not only provides a key link between one carbon metabolism and the mTORC1 pathway but raises the question of whether additional intermediate metabolites in amino acid catabolism are also sensed by mTORC1.…”