Protein and amino acid restriction, aging and disease: from yeast to humans

Abstract

Many of the effects of dietary restriction (DR) on longevity and health span in model organisms have been linked to reduced protein and amino acid (AA) intake and the stimulation of specific nutrient signaling pathways. Studies in yeast have shown that addition of serine, threonine, and valine in media promotes cellular sensitization and aging by activating different but connected pathways. Protein or essential AA restriction extends both lifespan and healthspan in rodent models. In humans, protein restriction (PR) has been associated with reduced cancer, diabetes, and overall mortality. Thus, interventions aimed at lowering the intake of proteins or specific AAs can be beneficial and have the potential to be widely adopted and effective in optimizing healthspan.

Keywords: calorie restriction; dietary intervention; fasting mimicking diet (FMD); healthspan; longevity.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Schematic of nutrient signaling pathways regulated by protein and amino acid restriction

Left: Yeast nutrient signaling pathway is directly affected by the availability of certain amino acids. In addition, production of acetyl-CoA can be modulated by branched chain amino acid Leu, together these pathways make up the pro-aging and growth pathways affecting longevity. Right: An oversimplified representation of the same evolutionary conserved pathway in flies that are affected by restriction of proteins and essential amino acids, in particular, Met. These restrictions result in reduced signaling activity of the TOR network and decreased activation of the IIS pathway.

Figure 2. Model of pro-aging nutrient signaling pathways altered by protein and amino acid restriction in mammals

Intake of high levels of protein and fats, especially from animal sources has been associated with decreased healthspan in both humans and mouse models. In contrast low levels of dietary protein, in particular protein derived from plants, show an inverse correlation to risk of cardiovascular disease (CVD), diabetes, and some types of cancers as observed in human and mouse models. Pro-aging pathways are inhibited through restriction of protein or amino acids via amino acid sensing mTOR and GCN2 pathways. Restriction of essential amino acids results in elevated uncharged tRNAs, which in turn activates the amino acid deficiency sensing GCN2 pathway yielding reduced mTOR network activity. Branched chain amino acids, Ile, Val, Leu, affect production of acetyl-CoA, which in turn plays a role in regulation of lifespan by modulating activity of autophagy response. Direct role of GH/IGF-I signaling remains to be elucidated. Cytoplasmic availability of acetyl-CoA differentially regulates autophagy and subsequently modulates longevity.