UC Berkeley

Protein aggregation, DNA damage and organelle dysfunction are hallmarks of aging and age-related diseases in metazoans. However, given the multicellular complexity of metazoans, it remains challenging to distinguish which factors cause cellular aging, versus those that arise because of aging. Budding yeast, although unicellular, exhibit similar age-associated abnormalities as metazoans. During mitosis, budding yeast mother cells accumulate cellular damage, in the form of protein aggregates, ribosomal DNA (rDNA) circles and organelle abnormalities as they continue to produce daughter cells. While age-induced damage persists in mother cells throughout mitosis, these age-associated traits are eliminated during meiotic differentiation, the developmental program that generates gametes in sexually reproducing organisms. Furthermore, gametes derived from aged diploids reset their aging clock, suggesting that the elimination of age-induced damage leads to cellular rejuvenation. Our study reveals that protein aggregate and nucleolar abnormalities that accumulate in aged cells are excluded from the gametes and illustrate that their exclusion is coupled to nuclear pore complex (NPC) disposal and nuclear remodeling that occurs naturally as part of gametogenesis. We additionally found that the gamete-excluded cellular material is subsequently degraded by a programmed cell death pathway that depends on the expression of a gamete plasma membrane proton pump and vacuolar lysis of the mother cell. We conclude that nuclear remodeling and vacuolar lysis promote the elimination of age-induced damage during budding yeast gametogenesis. Our work demonstrates natural paradigms of quality control in a developmental program and may reveal therapeutic strategies to combat cellular aging in metazoans.