dgottsch

The most prevalent non-infectious diseases are associated with increasing age. Although the causes of these diseases continue to be investigated, it is clear that their association with aging stems from an age-dependent decline in the robustness of individuals. This decline results from progressive cellular dysfunction that is conserved from yeast to humans. Although a number of attractive hypotheses have been proposed to explain age-associated cellular decline, a molecular mechanism for what actually causes aging in any organism remains elusive. We propose that to determine the cause of aging, it is necessary to identify processes that deteriorate with age at the cellular level. We can then use this information to dissect the molecular events that lead to age-associated decline. The budding yeast, Saccharomyces cerevisiae, is an optimal system for rapid identification of molecular events that lead to age-associated cellular changes because (1) it serves as a fundamental model for aging studies, (2) replicative aging in yeast is conserved with aging in higher eukaryotes, as mutations in genes that extend life span in yeast also do so in worms, flies and mice, (3) knowledge of basic cellular processes is substantial in this organism and (4) technologies pioneered in yeast permit systematic genetic, biochemical and cell biological analyses. Despite these merits, replicative aging studies in yeast have been hampered by the arduous nature of isolating replicatively-aged yeast cells. The standard method for isolating aged “mother” cells is by micromanipulation, where daughter cells are counted and removed by an experimenter after every division. To resolve this technical limitation, we have recently developed an inducible genetic system, the ‘Mother Enrichment Program’ (MEP), which permits facile isolation of replicatively aged S. cerevisiae cells for biochemical, genetic and cell biological analysis. We applied the MEP technology to analyze well-characterized cellular structures and organelles as a first step in identifying molecular mechanisms of age-associated cellular decline. By developing the MEP, we have created a powerful tool to study replicative aging in S. cerevisiae. We are now in the unique position to apply the substantial collection of cell biological, biochemical and genetic resources, and knowledge about this organism to the study of aging. By using the MEP to characterize the breakdown of cellular subsystems, we will more clearly define the aging process and develop a causal understanding of aging at the molecular level.