Glycine promotes longevity inCaenorhabditis elegansin a methionine cycle-dependent fashion

Abstract

The deregulation of metabolism is a hallmark of aging. As such, changes in the expression of metabolic genes and the profiles of amino acid levels are features associated with aging animals. We previously reported that the levels of most amino acids decline with age in Caenorhabditis elegans (C. elegans). Glycine, in contrast, substantially accumulates in aging C. elegans. In this study we show that this is coupled to a decrease in gene expression of enzymes important for glycine catabolism. We further show that supplementation of glycine significantly prolongs C. elegans lifespan and ameliorates specific transcriptional changes that are associated with aging. Glycine feeds into the methionine cycle. We find that mutations in components of this cycle, methionine synthase (metr-1) and S-adenosylmethionine synthetase (sams-1), completely abrogate glycine-induced lifespan extension. Strikingly, the beneficial effects of glycine supplementation are conserved when we supplement with serine, also driving the methionine cycle. RNA sequencing of serine-and glycine-supplemented worms reveals similar transcriptional profiles including widespread gene suppression. Taken together, these data uncover a novel role of glycine in the deceleration of aging through its function in the methionine cycle.. CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/393314 doi: bioRxiv preprint first posted online Aug. 16, 2018; 3 Author summaryThere are a growing number of studies showing that amino acids function as signal metabolites that influence aging and health. Although contemporary -OMICs studies have uncovered various associations between metabolite levels and aging, in many cases the directionality of the relationships is unclear. In a recent metabolomics study, we found that glycine accumulates in aged C. elegans while other amino acids decrease. The present study shows that glycine supplementation prolongs longevity and drives a genome-wide inhibition effect on C. elegans gene expression. Glycine as a one-carbon donor fuels the methyl pool of one-carbon metabolism composed of folates and methionine cycle. We find that glycinemediated longevity effect is fully dependent on methionine cycle, and that all of these observations are conserved with supplementation of the other one-carbon amino acid, serine.

Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species

“…In addition, expression of ANMT‐1 only in dopaminergic neurons suppressed age‐dependent neurodegeneration and extended lifespan and was dependent on neuronal autophagy (Schmeisser & Parker, ). Moreover, Liu et al () showed that supplementation with glycine significantly prolongs C. elegans lifespan via feeding into the methionine cycle and that mutations in components of this cycle, methionine synthase ( metr‐1 ) and S ‐adenosylmethionine synthetase ( sams‐1 ), completely abrogate glycine‐induced lifespan extension.…”

Downregulation of the tyrosine degradation pathway extends Drosophila lifespan

“…Impairing threonine catabolism via glycine-C-acetyltransferase suppression promotes C. elegans lifespan (36). Glycine supplementation can extend lifespan in both C. elegans (37) and mice (38). Despite the accumulating evidence, the role of non-proteogenic metabolism of specific amino acids in the regulation of aging and lifespan and their mechanisms are still poorly characterized.…”

L-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans

“…Recent studies have been in line with this opinion, showing that specific amino acids could positively affect the organismal lifespan and health factors. For example, glycine extended the lifespan of C. elegans in a methionine cycle-dependent manner, and glycine supplementation extended the lifespan of male and female mice 6,7 . Additionally, branched-chain amino acids induced a central neuroendocrine response, thereby extending healthspan 8 , facilitating survival, and supporting cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice 9 .…”