A role for selective ER autophagy in gametogenic rejuvenation revealed by high-throughput lifespan profiling

Abstract During mitotic growth, Saccharomyces cerevisiae cells age by dividing asymmetrically, producing young daughter cells while retaining age-associated damage in the mother cell, which will eventually become senescent. Gametogenesis naturally and fully resets precursor cell lifespan, even for replicatively aged cells. However, the mechanisms responsible for gametogenic rejuvenation have remained mysterious. This is partly due to the existing methods to quantify lifespan resetting in this context, which are limited to low-throughput and labor-intensive approaches. Here, we introduce a high-throughput assay that allows systematic characterization of factors required for gametogenic rejuvenation. With this approach, we show that we can sensitively measure a wide range of gamete replicative lifespans that are consistent with established mutants. Excitingly, we also discover that Atg39 and Atg40, receptors involved in selective autophagy of the ER, are molecular determinants of gametogenic rejuvenation. This technique will enable systematic identification of the molecular factors that drive gametogenic rejuvenation.