Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification

Abstract

Reduced supply of the amino acid methionine increases longevity across species through an as yet elusive mechanism. Here, we report that methionine restriction (MetR) extends yeast chronological lifespan in an autophagy-dependent manner. Single deletion of several genes essential for autophagy (ATG5, ATG7 or ATG8) fully abolished the longevity-enhancing capacity of MetR. While pharmacological or genetic inhibition of TOR1 increased lifespan in methionine-prototroph yeast, TOR1 suppression failed to extend the longevity of methionine-restricted yeast cells. Notably, vacuole-acidity was specifically enhanced by MetR, a phenotype that essentially required autophagy. Overexpression of vacuolar ATPase components (Vma1p or Vph2p) suffices to increase chronological lifespan of methionine-prototrophic yeast. In contrast, lifespan extension upon MetR was prevented by inhibition of vacuolar acidity upon disruption of the vacuolar ATPase. In conclusion, autophagy promotes lifespan extension upon MetR and requires the subsequent stimulation of vacuolar acidification, while it is epistatic to the equally autophagy-dependent anti-aging pathway triggered by TOR1 inhibition or deletion.

The Stationary-Phase Cells of Saccharomyces cerevisiae Display Dynamic Actin Filaments Required for Processes Extending Chronological Life Span

“…As in some other studies (9,63,64), we confirmed the activation of autophagy in the early stationary phase (2-day-old cultures). We used GFP-Atg8, which is a marker of both types of macroautophagy, selective and nonselective macroautophagy (14).…”

Essential role for autophagy in life span extension

“…Intriguingly, low protein consumption in humans and mice is associated with reduced risk for age-related diseases and mortality, probably through reduced signaling of IGF-1, which is an important negative regulator of autophagy (38). Reduced supply of the amino acid methionine increases longevity across species, possibly by activation of a CR-like state, and in yeast, methionine restriction extends life span in an autophagydependent manner (39). Unfortunately, it is not possible to investigate the causal involvement of autophagy on life span extension in mice because the constitutive inactivation of essential autophagy genes either causes lethal developmental abnormalities or a fatal defect in the adaptation from intrauterine to postnatal metabolism (40,41).…”

Genetics and Pharmacology of Longevity

“…We already know that, certains amino acids regulate life span with greater effects Piper et al, 2014). Methionine restriction extends the life span of yeast (Johnson & Johnson, 2014;Ruckenstuhl et al, 2014;Wu, Song, Liu, & Huang, 2013), flies , mice (Miller et al, 2005), and rats (Orentreich, (Bass, Grandison, et al, 2007;Mair & Dillin, 2008;Metaxakis & Partridge, 2013)). …”

“…Hence, activation of AMPK leads to inhibition of mTORC1 indirectly through TSC2 phosphorylation, and directly by inhibiting raptor . For a more detailed examination of the physiological regulation of AMPK, we recommend the following excellent reviews (Burkewitz et al, 2014;Carling et al, 2011;Hardie, 2015;McBride & Hardie, 2009;Ruderman, Carling, Prentki, & Cacicedo, 2013).…”