Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and life span in mice

Abstract

Protein restricted (PR) diets promote health and longevity in many species. While the precise components of a PR diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of PR can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in lifespan and a reduction in frailty in male, but not female, wild-type mice when fed lifelong. Our results demonstrate that restricting dietary BCAAs can increase healthspan and longevity in mice, and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.

Caloric Restriction May Help Delay the Onset of Frailty and Support Frailty Management

“…In contrast, Richardson et al suggested that lifelong restriction of dietary BCAAs may extend lifespan and prevent frailty in aged male mice. Nonetheless, the effect of the BCAA diet on frailty remains unclear ( 87 ). Further studies are needed to examine these associations in humans.…”

Amino acid availability is not essential for lifespan extension by dietary restriction in the fly

“…In flies, restriction of Methionine extends lifespan, but only under conditions of low amino acid status 25 . In mice, EAA supplementation nullified DR’s lifespan extension 26 and restriction of particular amino-acids, namely branched-chained, can confer health but not necessarily lifespan benefits 1,7,27 .…”

The coming of age for branched-chain amino acids

“…Such a revelation is somewhat unexpected, but consistent with the observation made in liver-specific Tsc1 knockout and Gcn2 knockout mice by the authors. Yu et al [5] demonstrated that isoleucine restriction mediated beneficial effects were not affected in these mice, implicating an mTOR and Gcn2 independent mechanism, both pathways are known mediators of leucine induced signaling in cells. Instead, from transcriptome analysis in liver and adipose tissues, authors identified a significant perturbation in FGF21 expression and energy expenditure following isoleucine restriction, which was necessary for low-isoleucine diet mediated metabolic protection in mice.…”

“…However, extensive evidence suggests each of the BCAA may have unique and distinct function in metabolic regulation and nutrient signaling. In a subsequent study by the same group, Yu et al [5] further delineated the specific role of each individual BCAA in dietary impact on metabolic health.…”

“…Using a series of amino acid defined diets, Yu et al [5] systematically measured the impact of lowering individual BCAA intake on the metabolic health in mice. While lowering BCAA as a group showed potent and unique effect to improve metabolic status comparing to other essential non-BCAA amino acids, lowering individual BCAA in food intake revealed a strong effect of valine and isoleucine on glucose control, insulin resistance and hepatic gluconeogenesis.…”