Reminiscent of recent work on supplementation of the amino acid taurine as a means to modestly slow aging, the authors of today's open access paper examine the role of the amino acid citrulline in age-related changes occurring in mice. As is true of taurine in mice, blood and tissue levels of citrulline decline to varied degrees with age, while long-term oral supplementation with citrulline both restores youthful levels and improves a number of measures of metabolism. This includes a reduction in age-related chronic inflammation that appears mediated by changes in the behavior of the innate immune cells known as macrophages.
Human trials of taurine supplementation have not produced clearly positive outcomes, but the researchers involved may have been looking at the wrong measures in the years prior to the commonplace use of aging clocks. Taurine touches on many areas of metabolism, and a simple self-experiment for taurine supplementation produced a modest reduction in phenotypic age driven by lower levels of circulating neutrophils, another form of innate immune cell. Increased neutrophil count in a blood sample is representative of inflammation.
Citrulline has been used in a sizable number of human clinical trials versus only the few for taurine, and has shown modestly beneficial results for a range of conditions. Since inflammation contributes to the progression of near all age-related conditions, this is much what one might expect see if it is in fact reducing the contribution of macrophages to the inflammatory environment of aged tissues. Given all of this, one might be tempted to run a similar self-experiment as for taurine, using citrulline supplementation instead, and see what results - it would be straightforward to conduct.
Citrulline regulates macrophage metabolism and inflammation to counter aging in mice
Metabolic dysregulation and altered metabolites are widely recognized as key characteristics of aging. Numerous studies have investigated the roles of endogenous metabolites, such as NAD, taurine, spermidine, and others, as drivers of the aging process. In this study, we conducted a comprehensive analysis of metabolic changes in multiple organs of mice at various ages. Our findings provide the first evidence linking citrulline deficiency to aging. We identified multiple antiaging effects of citrulline, including the reduction of cellular senescence, protection against DNA damage, prevention of cell cycle arrest, modulation of macrophage metabolism, and mitigation of inflammaging. Notably, long-term supplementation of citrulline in aged mice demonstrated significant benefits by alleviating age-associated phenotypes and increasing health span. These findings underscore the critical role of citrulline deficiency as a key driver of the aging process and highlight the potential therapeutic intervention of citrulline supplementation to counteract age-related diseases.
To explore the biological mechanism by which citrulline counteracts aging, we demonstrated that citrulline acts as an endogenous metabolite antagonist to inflammation. Macrophages are primary contributors to age-associated inflammation. Our findings unveil that the decline in endogenous citrulline levels impairs the anti-inflammatory function of macrophages, thereby enhancing susceptibility to inflammatory responses during aging. The anti-inflammatory effect of citrulline has been validated in various mouse models, and its efficacy remains intact even in the context of aging. This observation suggests that the age-dependent deficiency of citrulline, acting as an endogenous antagonist to inflammation, triggers inflammaging and accelerates the aging process. In-depth mechanistic investigations have revealed that citrulline supplementation rescues age-associated metabolic alterations in macrophage metabolism. Specifically, we have demonstrated that citrulline modulates the inflammatory responses by regulating the activities of the mTOR-HIF1α-glycolysis signaling pathway in macrophages. Collectively, these results establish that citrulline governs macrophage metabolism and inflammation as a means to counteract aging.
Our study also underscores the remarkable potential of citrulline as an endogenous metabolite inhibitor of the mTOR pathway in the context of inflammation and aging. mTOR serves as a nutrient sensor that regulates cellular metabolism and is linked to cell proliferation, growth, and survival. Extensive research has established the mTOR pathway as a negative regulator of lifespan and aging. Pharmacological inhibition of mTOR using small-molecule compounds such as rapamycin has been shown to effectively extend longevity in various animal models. However, the discovery of an endogenous metabolite that inhibits mTOR to counter aging has remained elusive. Arginine, leucine, and S-adenosylmethionine (SAM; downstream metabolite of methionine) are the known metabolites that are directly sensed by mTOR components. Restriction of methionine or the three branched-chain amino acids - leucine, isoleucine, and valine - extends lifespan in mice, but the roles of these metabolites in regulating aging and mTOR are complicated. Our metabolomics data confirmed that arginine, leucine, SAM, and methionine levels remained unchanged during aging in mice. In our study, we extensively demonstrated that citrulline inhibits the activation of the mTOR pathway in macrophages in both inflammatory and aging contexts. This finding highlights citrulline as a promising endogenous metabolite with the potential to inhibit mTOR signaling.
View the full article at FightAging
