A role for autophagy of the ER in rejuvenation revealed by microfluidics-based lifespan profiling of yeast gametes

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 completely resets precursor cell lifespan, even for replicatively aged cells but so far, no cellular mechanism responsible for this rejuvenation has been identified. This is in part due to the existing methods to quantify replicative lifespan resetting in this context, which are limited to low-throughput and labor-intensive approaches. Here, we introduce a high-throughput microfluidic-based assay that allows systematic characterization of factors required for gametogenic rejuvenation in S. cerevisiae. With this technique, we show that we can capture a wide range of gamete replicative lifespans that are consistent with known longevity mutants. Excitingly, using this technique, we report receptors involved in selective autophagy of the ER as the first identified molecular determinants of gametogenic rejuvenation. We anticipate this novel technique will enable systematic identification of additional molecular factors that drive gametogenic rejuvenation.