Quantifying the evolutionary conservation of aging genes

Many genes have been shown to modulate longevity in the soil nematode Caenorhabditis elegans, and several recent studies have used RNAi technology to screen the entire C. elegans genome for aging-related genes.  Using the data from these and other reports, we are taking a quantitative approach to determine the level of conservation of aging genes across diverse eukaryotic species. Since yeast and worms are separated by a greater evolutionary distance than worms and humans, gene-families that modulate longevity in both organisms may play a similar role in people.

In collaboration with Jim Thomas in the Department of Genome Sciences, we have identified putative yeast orthologs to the reported worm aging genes, where a worm aging gene is defined as corresponding to an RNAi clone that increases adult life span. In collaboration with Brian Kennedy in the Department of Biochemistry, we are now testing the role that each of these orthologs play in yeast aging. This is accomplished by measuring both replicative and chronological life span for the corresponding deletion mutant.

Although the studies with respect to chronological aging are still in progress, we have recently completed our analysis of the overlap between replicative aging in yeast and aging in C. elegans. The paper describing these data was published in the journal Genome Research. Two primary findings of this study are (1) quantitative evidence that genetic modifiers of longevity have been conserved between evolutionarily divergent species and (2) identification of 25 homolog pairs that similarly regulate aging in yeast and worms.

Future efforts will be devoted to characterizing the molecular mechanisms by which these conserved aging genes function to control longevity in invertebrate organisms and determining which have a similar role in mammalian aging. Through the Consortium for the Determination of Public Pathways Regulating Longevity, several mouse models corresponding to yeast/worm aging genes are being constructed and aging-related features are being characterized.