Protein restriction and branched-chain amino acid restriction promote geroprotective shifts in metabolism

Abstract

The proportion of humans suffering from age-related diseases is increasing around the world, and creative solutions are needed to promote healthy longevity. Recent work has clearly shown that a calorie is not just a calorie-and that low protein diets are associated with reduced mortality in humans and promote metabolic health and extended lifespan in rodents. Many of the benefits of protein restriction on metabolism and aging are the result of decreased consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we discuss the emerging evidence that BCAAs are critical modulators of healthy metabolism and longevity in rodents and humans, as well as the physiological and molecular mechanisms that may drive the benefits of BCAA restriction. Our results illustrate that protein quality-the specific composition of dietary protein-may be a previously unappreciated driver of metabolic dysfunction and that reducing dietary BCAAs may be a promising new approach to delay and prevent diseases of aging.

Keywords: FGF21; amino acids; branched-chain amino acids; isoleucine; lifespan; mTOR.

FIGURE 1

BCAA catabolism. Simplified outline of the process of BCAA catabolism into their respective ketogenic or glucogenic substrates by the skeletal muscle, though the first catabolic step, deamination, can also occur in many other tissues (but not in liver hepatocytes). KIC, α‐ketoisocaproate; KIV, α‐ketoisovalerate; KMV, α‐keto‐methylvalerate

FIGURE 2

BCAA restriction improves health and extends lifespan. Visual summary of the effects of restricting dietary BCAAs on molecular signaling, healthspan, and longevity

FIGURE 3

FGF21 in PR. PR induces hepatic FGF21 resulting in metabolic and physiological effects in many tissues. Note: FGF21 also acts through autocrine and paracrine means not illustrated here