Common Pathways of Life Span Extension in Quintessential Dietary Restriction Mimetic Mutants

By: Joe Delaney

We have discovered a number of genetic mimetics of dietary restriction in yeast: sch9, a deletion of budding yeast’s S6 kinase, tor1, a deletion mutant of yeast’s mTOR, and rpl mutants, which are deletions within large ribosomal protein subunits.  All seem to be in a pathway correlated with a reduction in translation, but that is not necessarily requisite for life span extension.  For example, the tor1 mutants has been published to have a growth rate comparable to wild type yeast.  We are interested in finding a way to extend life span without compromising health span; inhibiting translation in humans would likely result in many deleterious phenotypes.  To discover which molecular pathways are necessary and sufficient for life span extension, we are comparing transcriptomes of tor1, rpl20b, and dietary restricted cells by microarray analysis.  We hope to find upregulated genes in all long lived cases which are associated with specific transcription factors.  Then we can test if deletion of these transcription factors abrogate life span extension as well as overexpress them to see if they are sufficient to extend life span as well.  These studies will overlap with the cell cycle project and hopefully determine “safer” methods of extending life span and heathspan.