Autophagy extends lifespan via vacuolar acidification

Abstract

Methionine restriction (MetR) is one of the rare regimes that prolongs lifespan across species barriers. Using a yeast model, we recently demonstrated that this lifespan extension is promoted by autophagy, which in turn requires vacuolar acidification. Our study is the first to place autophagy as one of the major players required for MetR-mediated longevity. In addition, our work identifies vacuolar acidification as a key downstream element of autophagy induction under MetR, and possibly after rapamycin treatment. Unlike other amino acids, methionine plays pleiotropic roles in many metabolism-relevant pathways. For instance, methionine (i) is the N-terminal amino acid of every newly translated protein; (ii) acts as the central donor of methyl groups through S-adenosyl methionine (SAM) during methylation reactions of proteins, DNA or RNA; and (iii) provides the sulfhydryl groups for FeS-cluster formation and redox detoxification via transsulfuration to cysteine. Intriguingly, MetR causes lifespan extension, both in yeast and in rodents. We could show that in Saccharomyces cerevisiae, chronological lifespan (CLS) is increased in two specific methionine-auxotrophic strains (namely Δmet2 and Δmet15).

Keywords: acidification; autophagy; chronological lifespan; dietary restriction; longevity; lysosome; methionine restriction; vacuole.

Figure 1. FIGURE 1: Methionine restriction-induced autophagy is causal for longevity-mediating enhancement of vacuolar acidification.

Methionine restriction (MetR) specifically induces autophagy during yeast chronological aging, which in turn leads to an increased number of cells bearing acidic vacuoles and ultimately to increased chronological lifespan (CLS). Genetic inhibition of vacuolar acidification by the v-ATPase abrogates the longevity effect of MetR. Also, genetic inhibition of autophagy abrogates the MetR-induced acidification of vacuoles, as well as the MetR-induced extension of CLS.