Theses Doctoral

Aging Actin' Up: A novel aging determinant regulates the actin cytoskeleton, nutrient sensing, and lifespan in Saccharomyces cerevisiae

Sing, Cierra Nicole

The aging process is unforgiving, targeting a decline in cellular function. Originally, the actin cytoskeleton has not been defined as a hallmark of aging biology, however, numerous studies provide evidence that actin cytoskeleton integrity is declining with age. Mammalian cells express an aged-linked decline in their actin dynamics, consequently defecting their migratory movements, immunological synapse formation, and phagocytosis. Overall, suggesting actin integrity is specifically targeted by aging. Despite the substantial evidence, the underlying mechanism remains elusive, however, current research indicates actin stability as a possible mechanistic aging target. Therefore, our research goal is to further elucidate the mechanism for actin cytoskeleton aging biology in a streamlined model organism, budding yeast, Saccharomyces cerevisiae.

Here, we use aging enrichment protocols, streptavidin affinity purification, to isolate a population of older cells to examine any changes in the actin cytoskeleton with age. With an isolated aging population, we analyzed the actin cytoskeleton by testing its stability against a destabilizing drug, Lat-A, and morphology with imaging analysis. We find significant age-associated changes in the actin cytoskeleton, which we later conclude may be a consequence of the age-linked decline in the actin stability that we identified in an aging cell. Additionally, we uncovered a perplexing finding that there is an age-linked decline in actin cable bundling. How actin stability effects actin cable bundling, remains to be determined.

However, our actin stability model was further supported by our research characterizing an open reading frame, YKL075C, as a novel actin cable regulatory protein whose deletion: increased actin cable stability, abundance, and mitochondrial quality to extend the replicative lifespan. Upon further insight into YKL075C underlying mechanism, we find YKL075C effects on actin stability and morphology is dependent on alterations in branched-chain amino acid (BCAA) metabolism. Overall, our research discovered a novel actin regulatory protein, Ykl075cp, whose actin function is dependent on BCAA homeostasis, and deleting specifically YKL075C reduces BCAA levels that subsequently increases actin cable stability and abundance to enhance mitochondrial quality and extends longevity.


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More About This Work

Academic Units
Nutritional and Metabolic Biology
Thesis Advisors
Pon, Liza A.
Ph.D., Columbia University
Published Here
January 11, 2021