Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice

Abstract

Low protein (LP) diets promote health and longevity in diverse species. Although the precise components of an LP diet that mediate its beneficial effects have not been defined, reducing dietary levels of the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine promotes metabolic health in both sexes, and increases lifespan while reducing frailty in male, but not female, C57BL/6J mice. Each BCAA has unique metabolic effects, and we recently showed that restriction of isoleucine is both sufficient to promote metabolic health and required for the metabolic benefits of an LP diet in male C57BL/6J mice. Here, we tested the hypothesis that specifically restricting isoleucine could promote healthy aging in genetically heterogenous UM-HET3 mice. We find that a reduced isoleucine diet improves the metabolic health of both young and old HET3 mice, promoting leanness and glycemic control. Restriction of isoleucine starting in adult, 6 month old HET3 mice reprograms hepatic metabolism in a way distinct from an LP diet. Finally, we find that a reduced isoleucine diet reduces frailty and extends the lifespan of both male and female HET3 mice, but to a much greater degree in males. Our results demonstrate that restricting dietary isoleucine can increase health span and longevity in a genetically diverse population of mice, and suggests that reducing dietary levels of isoleucine may have great potential as a geroprotective intervention.

Resistance exercise protects mice from protein-induced fat accretion

“…Paradoxically though, in sedentary humans increased consumption of dietary protein is associated with cancer, cardiovascular disease, and diabetes as well as increased mortality (Lagiou et al, 2007;Levine et al, 2014;Mittendorfer et al, 2020;Sluijs et al, 2010;Zhang et al, 2020). In agreement with the potential for dietary protein to negatively impact health, low protein diets and diets with reduced levels of specific essential amino acids promote healthspan and lifespan in flies and rodents (Flores et al, 2022;Green et al, 2023;Juricic et al, 2020;Lee et al, 2014;Lees et al, 2014;Orentreich et al, 1993;Richardson et al, 2021;Solon-Biet et al, 2014), and short-term protein restriction improves the metabolic health of metabolically unhealthy adult humans (Ferraz-Bannitz et al, 2022;Fontana et al, 2016).…”

“…Dietary protein in particular has been shown to have a critical role in the regulation of metabolic health and longevity; low protein diets are associated with reduced rates of diabetes and other age related diseases in human longitudinal studies, and promote leanness and insulin sensitivity in human randomized clinical trials (Ferraz-Bannitz et al, 2022; Fontana et al, 2016; Levine et al, 2014; Sluijs et al, 2010). In mice, low protein, high carbohydrate diets promote leanness, glucose tolerance, and extend lifespan (Hill et al, 2022b; Richardson et al, 2021; Solon-Biet et al, 2014; Solon-Biet et al, 2015); many of the benefits of a low protein diet are mediated by reduced consumption of the branched-chain amino acids (BCAAs), particularly isoleucine and valine, and we have recently shown dietary histidine is also associated with increased adiposity and body mass index (BMI) (Flores et al, 2022; Green et al, 2022b; Jang et al, 2016; Yu et al, 2021).…”

Late-life isoleucine restriction promotes physiological and molecular signatures of healthy aging

“…Recent work from our laboratory and others has demonstrated that a calorie is not “just a calorie,” and that the macronutrient composition of the diet is a key regulator of human and animal health (C. L. Green, D. W. Lamming, et al, 2022).…”

“…In humans, dietary isoleucine levels, but not levels of leucine or valine, are strongly correlated with BMI (Yu et al, 2021). Finally, restriction of isoleucine in adult mice extends lifespan in both males and females (Green et al, 2023), and in humans, blood levels of isoleucine, but not of leucine or valine, are positively associated with mortality (Deelen et al, 2019).…”

“…Rather than targeting the diverse array of age-related diseases individually, addressing the aging process directly may be the most effective way to promote healthy aging. One of the most robust and affordable ways to promote healthspan and extend lifespan in diverse species is calorie restriction (CR), in which calories are restricted, with animals typically receiving 60-80% of their ad libitum caloric intake in a single meal each day (C. L. Green, D. W. Lamming, et al, 2022; Pak et al, 2021).…”