Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice

Dietary protein has emerged as a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction (PR) are mediated by reduced consumption of dietary branched-chain amino acids (BCAAs; leucine, valine and isoleucine), and restriction of BCAAs is sufficient to extend healthspan and lifespan in mice. The metabolic benefits of BCAA restriction are mediated by isoleucine and valine, with isoleucine restriction being sufficient to extend lifespan in male mice. However, the effect of valine restriction on healthy aging remains unknown. In this study, we placed young C57BL/6J mice of both sexes on either control or valine restricted (Val-R) diets and followed them longitudinally as they aged. We found that Val-R-fed male and female mice displayed significantly improved glucose regulation and increased energy expenditure, coinciding with decreased body weight and adiposity. These benefits are independent of FGF21, and mTORC1, signaling pathways associated with metabolism and aging. Further, we performed transcriptomic analysis on the liver, muscle and brown adipose tissue, and found tissue- and sex-specific changes in response to Val-R. Lastly, Val-R reduces frailty and extends the median lifespan of male, but not female, mice by 19%. Our results demonstrate that Val-R improves multiple aspects of health in mice of both sexes and extends lifespan in males, and suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.