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.