S-adenosyl-L-homocysteine extends lifespan through methionine restriction effects

Abstract

Methionine restriction (MetR) can extend lifespan and delay the onset of aging-associated pathologies in most model organisms. Previously, we showed that supplementation with the metabolite S-adenosyl-L-homocysteine (SAH) extends lifespan and activates the energy sensor AMP-activated protein kinase (AMPK) in the budding yeast Saccharomyces cerevisiae. However, the mechanism involved and whether SAH can extend metazoan lifespan have remained unknown. Here, we show that SAH supplementation reduces Met levels and recapitulates many physiological and molecular effects of MetR. In yeast, SAH supplementation leads to inhibition of the target of rapamycin complex 1 (TORC1) and activation of autophagy. Furthermore, in Caenorhabditis elegans SAH treatment extends lifespan by activating AMPK and providing benefits of MetR. Therefore, we propose that SAH can be used as an intervention to lower intracellular Met and confer benefits of MetR.

Keywords: Caenorhabditis elegans; Saccharomyces cerevisiae; S-adenosyl-L-homocysteine (SAH); S-adenosyl-L-methionine (SAM); methionine restriction (MetR).

FIGURE 1

SAH reduces intracellular Met and induces MetR‐like conditions in S. cerevisiae. (a) Model for yeast longevity mediated by the stimulation of SAM synthesis by SAH. Volcano plot (b) or heat map (c) showing metabolite levels in WT cells with or without SAH supplementation. n = 3. FDR < 0.05, two‐sided unpaired t‐test. See also in Table S1. Intracellular [methyl‐¹³C]Met (d), Intracellular [methyl‐¹³C]SAM levels (e), and [methyl‐¹³C]Met levels in the medium (f) were assessed using CE‐TOFMS. Mean ± S.D, n = 3, two‐sided unpaired t‐test. The relative intensity of free GFP (g) or phosphorylated Rps6 (h) normalized to Cdc28 is shown. Mean ± SD, n = 3, two‐sided unpaired t‐test. (i) The CLS curve is indicated. (d–f, g, h) ns, not significant; ***p < 0.001. (i) Statistical analyses are shown in Table S2

FIGURE 2

SAH extends lifespan via activation of AMPK, inhibition of mTORC1, and activation of autophagy in C. elegans. Representative survival curve (a) or relative AMPK phosphorylation level (b) of N2 WT animals in C. elegans, either untreated or treated with 1, 10, 50, 100 µM SAH. Mean ± SEM, n = 3, one‐way ANOVA with Tukey's correction. (c) Quantification of HLH‐30::GFP nuclear localization. n = number of worms. Mean ± SEM, chi‐square test. (d–g) Representative survival curves. (h) Representative images of hsp‐6p::GFP. Scale bar = 100 µm. Quantification of relative GFP intensity in the intestine is shown. Mean ± SEM, n = 40, one‐way ANOVA with Tukey's correction. (a–h) ns, not significant; *p < 0.05; **p < 0.01; ***p < 0.001. (a, d–g) Statistical analyses are shown in Table S3