Introduction

1. A systematicscreen for lifespan-extending gene deletions in S. cerevisiaereveals multiple new conserved pathways linked to longevity Mark A. McCormick1, Mitsuhiro Tsuchiya1,Scott Tsuchiyama1,Juniper Pennypacker1, Joe Delaney2, Stephan Guyenet2, Hillary A. Miller2, Rick M. Moller2, Diana N. Pak2, Brett Robison1, Jennifer Schleit2, Marc K.Ting1, Matt Kaeberlein2,3, Brian K. Kennedy1,3 1 Buck Institute for Age Research, Novato, CA, 94945, 2University of Washington, Pathology, Seattle, WA, 98195, 3Aging Research Institute, Guangdong Medical College, Dongguan 523808, Guangdong, P.R.China Introduction Single gene deletions and mutations have been repeatedly shown to have large effects on lifespan and aging in disparate model organisms from yeast to mice. Many of the same genes that affect replicative lifespan in the budding yeast S. cerevisiae have also been shown to affect lifespan and aging in other model organisms such as C. elegans and mice. We performed a systematic screen for yeast replicative lifespan, using a set of viable deletions of S. cerevisiae ORFs. This screen revealed many knownand novel categories of genes affecting yeast replicative lifespan, including ribosomal proteins, the SAGA chromatin remodeling complex, mannosyltransferase genes, and genes involved in tricarboxylic acid cycle metabolism, among others. These show a highly statistically significant overlap with genes that extend lifespan when perturbed in C. elegans. This suggests quantitatively that some of the novel genes and pathways we have identified are likely to have broadly conserved effects, and could shed light on the fundamental mechanisms of regulation of aging and healthspan in humans. How significant are these findings outside of yeast? What are these genes? We asked this by compiling a list of all published worm gene hypomorphs, knockdowns, or deletions which extend lifespan, and comparing known orthology groups between this list and the results of our yeast screen. Design An example of one of these pathways in more detail p=4.40E-11 Acetyltransferase Future Directions We are constructing 2,400 double deletions strains and measuring their replicative lifespan, for phenotypic epistasis analysis, see e.g. Science. 2010 Jan 22;327(5964):425-31 Deubiquitinase Structure of the data Spt-Ada-Gcn5-Acetyltransferase Complex Both the SAGA complex and the individual proteins Ubp8, Sgf11, and Sgf73 are conserved through humans. Analysis of our Affyarray data and published ChIP-SEQ data (Nucleic Acids Res. 2011 Jul;39) reveals telomeric Desilencing, and an enrichment for the binding site of ribosomal protein transcription factor Fhl1. Acknowledgements Financial support for these studies was provided by the National Institute of Health grant R01 AG024287 to BKK, Ellison Medical Foundation Senior Scholar in Aging award to BKK, and NIH T32 AG000266 to MM. Length-corrected p-value for enrichment of significant fold-change vs <10kb from telomeres Predicted Fhl1 transcription factor binding site, tgtayggrtg (Nature. 2004 Sep 2;431(7004):99-104). Additional characterization of this pathway (not shown here) has been done in collaboration with Amanda Mason, Lorraine Pillus, and Al LaSpada at UCSD.