Understanding the Healthy Aging Process (18. functional senescence; 19. Caloric restriction and aging). The yeast Saccharomyces cerevisiae is a proven model organism for investigating conserved aspects of aging and lifespan that are relevant to the human condition. To date more than 40 yeast genes with roles in lifespan have been discovered. These aging genes function in a variety of cell processes including oxidative stress response, mitochondrial function, DNA recombination, chromatin structure and transcriptional silencing, and the metabolic signaling pathways that control them. The potential role in aging of thousands of other yeast genes, many with human homologs, remains an important untapped resource. We describe a methodology that promises to facilitate the rapid screening of virtually all ~4800 nonessential yeast genes for roles in lifespan. Replicative lifespan in yeast is a measure of the number of generations a mother cell can produce daughter cells before she dies. The Death of Daughters (DEAD) method exploits the properties of a yeast strain whose daughters proliferate in galactose but die in glucose. These cultures grows linearly in glucose (daughter cells accumulate but do not divide) until the mother cells reach their replicative capacity and die. Therefore, lifespan can be directly measured as the number of cell doublings, a parameter that is simply measured by optical density. For example, the deletion of SIR2 causes these cells to stop growing in glucose at optical densities 3-4 times lower than the parental strain. This method represents a significant advance over standard replicative aging assays and makes possible large scale, high throughput screens for genes and environmental conditions that affect lifespan.
We aim to optimize the DEAD method through smaller scale targeted screens for novel aging genes, including a set of approximately 20 genes known to genetically interact with the conserved aging gene SGSI. The exciting aim of this pilot project is a genome-wide DEAD screen of entire nonessential deletion library of approximately 4800 strains for new aging genes using published genetic and robotic methods. The resulting public data set is likely to identify new aging genes that could be of considerable importance to human aging.
| Qin, Hong; Lu, Meng; Goldfarb, David S (2008) Genomic instability is associated with natural life span variation in Saccharomyces cerevisiae. PLoS One 3:e2670 |
