Discovering how autophagy is sufficient to extend yeast replicative lifespan

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Summary Abstract Metazoan organismal lifespan is determined by a combination of chronological lifespan (the length of time a cell exists in a non-dividing state before dying) and replicative lifespan (the number of times a cell divides before irreversibly arresting; most accurately studied in budding yeast [Saccharomyces cerevisiae]). Many chemical, dietary and genetic interventions can extend lifespan. These are usually first discovered in budding yeast, and subsequently shown to apply in metazoans. However, there is still little understanding of their underlying molecular mechanisms for lifespan extension. A variety of interventions, including medications, genetic manipulations, and calorie restriction (CR), have been demonstrated to extend the lifespan of several species. However, there is a significant knowledge gap as to the identity of the ultimate molecular changes enacted by these antiaging interventions to extend lifespan. We recently showed that overexpression of Gcn4, the yeast counterpart of the metazoan ATF4 protein that induces multiple stress response pathways, extended the yeast replicative lifespan (RLS) (the number of times a cell divides before irreversibly arresting) in a manner dependent on autophagy. This finding inspired us to ask whether autophagy is required for other antiaging interventions to extend the yeast RLS. Our preliminary findings indicate that interventions that extend lifespan in many organisms, including rapamycin, metformin, ribosome depletion, CR, and increased sirtuin activity, extend the yeast RLS in an autophagy-dependent manner. Furthermore, we find that induction of autophagy is sufficient to extend the yeast RLS. Given that autophagy induction is also sufficient to extend lifespan in metazoans, we will use the yeast model to seek ultimate molecular targets of autophagy that promote antiaging.