β-hydroxy-β-methylbutyrate Improves Health and Slightly Extends Life Span in Flies

It is always interesting to see data on life span in short lived species for an intervention with a fair amount of human data for health benefits. The broad pattern is that short-lived species exhibit a much greater extension of life in response to interventions, but on the other hand near all of the data is focused on only a few different ways to alter metabolism, such as the upregulation of stress responses and increased cell maintenance observed in calorie restriction. Supplementation with β-hydroxy-β-methylbutyrate is yet another way to manipulate the systems of regulation linking nutrient availability and cell maintenance, in an attempt to capture some fraction of the benefits of exercise and calorie restriction.

Two lifestyle interventions that may improve muscle function and attenuate the negative physical outcomes of the aging process include exercise and dietary protein and amino acid supplementation. At the molecular level, leucine serves as a direct substrate for muscle protein synthesis as well as an activator of protein synthesis through the multi-protein complex mechanistic Target of Rapamycin Complex 1 (mTORC1). Branched-chain amino acid aminotransferase transaminase (BCAT) converts leucine to keto-isocaproic acid (KIC), which is then reduced to 𝛽-hydroxy-𝛽-methylbutyrate (HMB). Dietary HMB supplementation has been shown to have a positive effect on muscle function in several rodent studies and human trials.

A growing body of evidence suggests that HMB supplementation improves lean body mass composition and muscle function in older subjects, and can mitigate loss of lean mass in elderly subjects during periods of bed rest. Several mechanisms of HMB action on muscle have been described, including both an anabolic mechanism through an up-regulation of protein synthesis via the mTOR pathway, and an anti-catabolic mechanism through a down-regulation of muscle protein breakdown via the ubiquitin-proteasome proteolytic pathway.

We investigated the feasibility of utilizing Drosophila as a model organism to study the biological effects of HMB on aging muscle when consumed throughout adult life. Using flight ability as an index of flight muscle function, we found that HMB attenuates the age-dependent decline in flight ability. Male and female flies fed a diet supplemented with 10 mg/mL HMB had significantly higher flight scores from median age until the onset of flight senescence than control flies fed a standard diet. HMB supplementation also resulted in improved flight scores in males before median age and delayed the onset of flight senescence in females. Notably, the consumption of HMB throughout adult life increased the rate of survival and extended lifespan. The effect on lifespan did not result from changes in food consumption or body weight. Old flies on the HMB-supplemented diet retained a higher proportion of flight muscle mitochondria whose morphology resembled that of young flies than the control diet group. Together, these results suggest that HMB attenuates the age-dependent decline in flight ability and prolongs lifespan by enhancing muscle health.