Senior Scholar Award in Aging
Stanford University Medical Center
Genomic approaches to studying aging in C. elegans
Aging is among the most universal of biological processes and perhaps also among the most mysterious. Numerous age-related changes are apparent at the organismic level, but we are only now starting to understand age-related changes at the molecular level. Oxidative damage, replicative senescence, accumulated stress and metabolic rate have each been proposed to specify life span. My lab is beginning a new area of research, which is to use functional genomics approaches to uncover the underlying genetic networks that determine longevity.
We are using the nematode C. elegans because it is an excellent model organism to study aging. The normal life span for worms is 2 weeks but under poor growth conditions, worms enter the dauer state and have life spans that can be 10 times longer. Powerful genetic screens have been used to identify mutants with increased life span. In particular, loss-of-function mutations in genes in the C. elegans insulin signaling pathway (such as daf-2 insulin receptor and age-1 PI3 kinase) extend life span. These results indicate that insulin signaling plays an important role in specifying life span, probably by regulating rates of cellular metabolism. Although previous genetic experiments have identified upstream regulatory pathways that influence the rate of aging, metabolic processes and genetic pathways that lie downstream of the insulin signaling pathway and that directly influence cellular senescence and organismic longevity are poorly understood.
To identify terminal effector genes that may directly influence life span, we are using DNA microarrays containing nearly every gene in C. elegans to profile gene _expression changes during normal life span, during the dauer stage and in mutants with increased longevity. By analyzing these gene _expression patterns, we wish to identify common genetic mechanisms involved in specifying life span.
A surprising result from our preliminary studies is that we found only 164 aging-regulated genes from an extensive microarray analysis of gene _expression changes during the normal life span. This result indicates that gene _expression in old worms is relatively stable. The 164 aging-regulated genes include two insulin-like genes and a sir-2 homolog that increase at the end of life. Previous studies have shown that insulin signaling and sir-2 regulation act to specify life span in C. elegans. Heat shock genes decrease in old age, possibly resulting in increased levels of protein denaturation, decreased cell function and organismal senescence.