A Role for Sarcosine in the Benefits of Calorie Restriction

Calorie restriction slows aging and extends life span in near all species tested to date. Unfortunately the magnitude of life extension declines as species life span increases, and in humans is probably no more than a few years. Nonetheless, the short-term beneficial changes to metabolism are quite evident in human practitioners, the practice of calorie restriction reduces the risk of suffering age-related disease, and it is still the case that for most people the only approaches likely to produce equivalent or greater reliable, sustained health benefits are exercise and the use of senolytic therapies.

Calorie restriction largely functions through upregulation of the cellular maintenance processes of autophagy. This is demonstrated by the fact that models with disabled autophagy do not exhibit extended life spans when subjected to calorie restriction. There are of course also the secondary benefits that derive from a low level of visceral fat tissue that necessarily accompanies a low calorie diet, but the autophagy is nonetheless vital. New discoveries by researcher groups involved in mapping the complex changes induced by calorie restriction are often related to autophagy, and this is the case here.

The metabolomic profile of aging has also been assessed in a number of species, including Drosophila melanogaster, naked mole rat, marmoset, and humans. Tissue-specific metabolomic signatures were reported to correlate with body mass and lifespan across a diverse number of species, and some tissue metabolites were found that discriminated long-lived rodents from controls. Although data on metabolomic shifts with aging and diet are rapidly accumulating, replication across studies has been limited, which has slowed progress toward ascertaining consensus hallmark candidates and signatures that define the aging metabolome across sex, strain, and species. Furthermore, to what extent these metabolomic shifts are merely a consequence of aging per se, as opposed to playing a causal role in the aging process, has been difficult to discern from what has largely been observational data.

Here, we have characterized changes in the metabolome with aging and dietary restriction (DR) using established techniques in a well-characterized hybrid rat model of aging. We have also interrogated the metabolome for shared changes in a set of human samples obtained from a cohort of younger and older subjects consuming a Western or DR diet. We report on some unique shifts in the metabolome, including alterations in glycerophospholipids, biogenic amines, and amino acids with diet and age. In addition, statistical analyses revealed that DR is a stronger driver of the circulating and tissue rat metabolomic phenotype than age.

When screening for metabolites with similar responses between species, we identified circulating sarcosine, a biogenic amine involved in methionine (Met), glycine, and folate metabolism, as decreased with aging per se in rodents and humans and increased by DR in both species. These shifts correlated with changes in rat liver glycine-N-methyltransferase (GNMT) content, which is a known sarcosine-generating enzyme. Long-lived Ames dwarf mice demonstrate significantly elevated sarcosine levels across age, while correlation analysis of metabolites following sarcosine refeeding in old rats prominently places this metabolite as an integral node linking amines, amino acids, glycerophospholipids, and sphingolipids. We also show that sarcosine feeding reduces Met levels in old animals and is a strong activator of macroautophagy in vitro and in vivo.

Taken together, these data identify sarcosine as a potentially important biomarker of diet and aging in mammals and suggest that this metabolite plays a previously unappreciated role in mediating at least some of the beneficial effects attributed to DR on proteostasis.

Link: https://doi.org/10.1016/j.celrep.2018.09.065

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