Investigating the Molecular Mechanisms of Conserved Aging Genes

by George Sutphin

Table 1. Genetic and environmental interventions that extend life span in evolutionarily divergent species.

The long life span of humans and other mammals makes studying mammalian aging directly impractical, particularly for the large-scale genetic approaches that have become central to modern biology. An alternative approach is to study aging in model organisms that have shorter life spans and are more amenable to maintenance and manipulation in the laboratory environment. The findings from these studies can then be used to take a more directed approach to studying mammalian aging. If environmental interventions and genetic pathways can be identified that play a conserved role in the determination of life span in evolutionarily divergent organisms, a subset are likely to play a similar role in humans and other mammals as well. Several such interventions are already known. For example, dietary restriction, reduced insulin/IGF-1-like signaling, increased sirtuin activity, and reduced target of rapamycin (TOR) signaling have all been shown to increase life span in divergent eukaryotic species (Table 1).

A recent study identified 25 homologous gene pairs for which reducing expression extends life span in both the budding yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans (Table 2; Smith et al. 2008). My research is focused on studying this set of conserved aging genes to determine whether each gene acts in one of the known aging pathways, or whether new pathway(s) are represented. Once the genes are placed in pathways I will select a subset for which to study the molecular mechanism in greater detail. The goals of this research are to add detail to our understanding of known aging pathways, potentially discover novel aging pathways, and identify genetic targets for mammalian aging studies.

Smith, E.D., Tsuchiya, M., Fox, L.A., Dang, N., Hu, D., Kerr, E.O., Johnston, E.D., Tchao, B.N., Pak, D.N., Welton, K.L., Promislow, D.E., Thomas, J.H., Kaeberlein, M., Kennedy, B.K., 2008. Quantitative evidence for conserved longevity pathways between divergent eukaryotic species. Genome Res 18, 564-70.