Cells divide a fixed number of times, termed replicative lifespan, before they stop dividing and senesce. Acceleration of the alterations to biological macromolecules that characterize the normal replicative aging process predisposes us to shortened replicative lifespan and conditions such as progeria. Despite the fundamental importance of the replicative aging process, there are still huge gaps in our understanding of the biological changes that cause aging and the molecular basis of these changes. Given that the mechanisms of aging are highly conserved across eukaryotes, we use the unparalleled genetic power of budding yeast to gain insight into the molecular mechanisms of replicative aging in all eukaryotes. Using the Mother Enrichment Program (MEP) to isolate unprecedented quantities of old cells, we performed a systematic characterization of the replicative aging process in yeast, with the intention of transferring our discoveries to mammalian systems. Using the MEP, my laboratory has been performing a systems biology analysis of the aging process, really for the first time in any organism. Our genome-wide mapping of nucleosome positions uncovered a global loss of nucleosomes during aging, leading to transcriptional upregulation of every gene in the genome. By deep sequencing of the genome during aging we discovered a global increase in retrotransposition, chromosomal translocation, DNA amplification, rDNA instability, transfer of mitochondrial DNA into the nuclear genome and DNA breaks during aging 1. We have now performed metabolomics analysis and ribosome profiling (Ribo-seq) during aging, leading us to our current hypothesis and goal of discovering the molecular details of how protein synthesis changes with aging, the beneficial consequences, and to leverage this information to extend lifespan and healthspan.
Despite the fundamental importance of the replicative aging process, there are still huge gaps in our knowledge of the biological changes that cause aging and the molecular basis of these changes. Understanding the molecular causes of aging will better position us to intelligently design therapeutic interventions to delay these events, in order to extend lifespan. The proposed studies will fill these knowledge gaps by uncovering the molecular events that occur during amino acid depletion to influence lifespan, and will leverage these discoveries to identify targeted therapies to extend lifespan.
| Tyler, Jessica K; Johnson, Jay E (2018) The role of autophagy in the regulation of yeast life span. Ann N Y Acad Sci 1418:31-43 |
| Hu, Zheng; Xia, Bo; Postnikoff, Spike Dl et al. (2018) Ssd1 and Gcn2 suppress global translation efficiency in replicatively aged yeast while their activation extends lifespan. Elife 7: |
| Pal, Sangita; Postnikoff, Spike D; Chavez, Myrriah et al. (2018) Impaired cohesion and homologous recombination during replicative aging in budding yeast. Sci Adv 4:eaaq0236 |
| Postnikoff, Spike D L; Johnson, Jay E; Tyler, Jessica K (2017) The integrated stress response in budding yeast lifespan extension. Microb Cell 4:368-375 |
