Glycine promotes longevity in C. elegans in a methionine cycle-dependent fashion
Yasmine J. Liu1, Rashmi Kamble1, Henk van Lenthe1, Alyson W. MacInnes1, Riekelt H. Houtkooper1* 1Laboratory Genetic Metabolic Diseases, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands *Corresponding Author: email@example.com
The deregulation of metabolism is a hallmark of aging. One mechanism demonstrated to be an effective and efficient way to slow this deleterious process is nutritional intervention. We previously found that profiles of amino acid levels follow distinct patterns with age in both mice and C. elegans. In fact, supplementations of some amino acids, such as branched-chain amino acids, can have a profound impact on lifespan in both invertebrates and mice. However, the causal effect of most other amino acids on aging is largely unknown. In this study we measured amino acid levels in parallel with gene expression analysis at various stages of the worm's lifespan. We observed that the amino acid glycine steadily and substantially accumulates in aging C. elegans. This is coupled to a decrease in the expression levels of genes involved in glycine degradation and glycine consumption. In contrast, we found the expression of genes involved in glycine synthesis remain unchanged during the course of the worm's life. To test the causal involvement of amino acids in lifespan regulation, we supplemented glycine to C. elegans. Glycine extended lifespan at molarities between 5-500 µM, but not at higher concentrations. This lifespan extension was only observed when the worms were fed UV-killed instead of live bacteria to reduce potentially confounding factors of the bacteria's metabolism of glycine. Glycine feeds into several metabolic pathways, including the methionine cycle. We therefore tested whether this pathway is mechanistically involved in the lifespan extension. Indeed, glycine supplementation increased levels of S-adenosylmethionine (SAMe), whose substrates include methionine and ATP. C. elegans strains carrying mutations in genes involved in SAMe synthesis, i.e. methionine synthetase (metr-1(ok521)) or S-adenosylmethionine synthetase (sams-1(ok3033)), do not confer the lifespan effects of glycine or changes in SAMe level. This suggests that the effects of glycine on longevity in C. elegans include driving the methionine cycle. Strikingly, the beneficial effects of glycine supplementation were conserved when we supplemented serine, which also feeds into the methionine cycle. Taken together, these data uncover the novel role of glycine to decelerate aging by altering methionine cycle metabolism in C. elegans.
Funding: Work in the Houtkooper group is financially supported by an ERC Starting grant (no. 638290).