Dietary protein refers to the intake of the nine essential amino acids that cannot be synthesized by our biochemistry: valine, isoleucine, leucine, methionine, phenylalanine, tryptophan, threonine, histidine, and lysine. The single value for “protein” that regulators such as the FDA required to be provided on food packaging is derived via a complicated process that starts with one of a number of different assays used to determine essential amino acid content of a foodstuff, all of which can produce subtly different results in different foodstuffs. Those results are massaged into a single number via reference to (a) what is thought to be the optimal balance of different essential amino acids versus the actual balance in the foodstuff, (b) what is thought to be the bioavailability of the amino acids present in the foodstuff, and (c) a few other scaling factors with empirical evidence for their use. A sizable literature of ongoing experimentation and debate underlies this present approach.
Restriction of dietary protein is an approach used to trigger the beneficial metabolic changes that take place in reaction to a lack of nutrients. It can be combined with overall calorie restriction, or the diet structured such that calorie level remains constant even as protein intake is reduced. Many nutrient sensing mechanisms evolved to react to levels of specific essential amino acids, and consequently researchers have experimented with restriction of essential amino acids one by one rather than all at once. Most such animal studies have focused on the effects of restricting dietary methionine, and have demonstrated that methionine restriction reproduces a fair-sized fraction of the benefits of overall calorie restriction. In today’s open access paper, researchers instead restrict valine, and find that while it appears beneficial in both sexes, it only extends life in male mice.
Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice
Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced consumption of dietary branched-chain amino acids (BCAAs; leucine, valine and isoleucine), and restriction of the BCAAs is sufficient to extend healthspan and lifespan in mice. While the BCAAs have often been considered as a group, it has become apparent that they have distinct metabolic roles, and we recently found that restriction of isoleucine is sufficient to extend the healthspan and lifespan of male and female mice.
Here, we test the effect of lifelong restriction of the BCAA valine on healthy aging. We find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promoting leanness and glycemic control in both sexes. To investigate the molecular mechanisms engaged by Val-R with aging, we conducted multi-tissue transcriptional profiling and gene network analysis. While Val-R had a significantly greater molecular impact in the liver, muscle, and brown adipose tissue of female mice than males, there was a stronger gene enrichment with phenotypic traits in male mice. Further, we found that phenotypic changes are associated with a multi-tissue downregulation of the longevity associated PI3K–Akt signaling pathway. Val-R reduces frailty in both sexes and extends the lifespan of male by 23%, but does not extend female lifespan, corresponding with a male-specific downregulation of PI3K-Akt signaling.
Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes and extends lifespan in males, suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.
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