C. elegans aging

Aging is a complex process driven by diverse molecular pathways and biochemical events. We are using the nematode C. elegans as a model system for aging, because it has a rapid lifespan, a small size, a powerful genetic toolkit and many mutants are already known to lengthen lifespan. Our approach is to first identify genes that are differentially expressed in old versus young animals, and then to dissect apart how changes in these genes lead to functional decline and senescence in old age.



A gene expression clock

We used DNA microarrays to perform a genome-wide screen for genes that change expression in old worms, in the dauer state (an alternative stage with an extremely long lifespan), and in four mutants with altered lifespans.

developmental drift

Regulators of skin aging

We found that the GATA transcription factors ELT-3, ELT-5 and ELT-6 are responsible for age-regulation of a large fraction of these genes.  Expression of elt-5 and elt-6 increases during normal aging and both of these GATA factors repress expression of elt-3, which shows a corresponding decrease in expression in old worms. elt-3 regulates a large number of downstream genes that change expression in old age.  elt-5(RNAi) and elt-6(RNAi) worms have extended longevity indicating that elt-3, elt-5 and elt-6 play an important functional role in the aging process. These results identify a novel transcriptional circuit that guides the rapid aging process in C. elegans, and indicates that this circuit is driven by drift of developmental pathways rather than accumulation of damage.



A proteome clock

The goal of this project is to provide a global, quantitative view of the aging proteome, by measuring changes in protein expression, changes in the rate of production and degradation for individual proteins, and the molecular age of protein populations in young and old animals. These data will provide insight into the biological processes that are most susceptible to dysregulation during aging, as well as hypotheses about interventions that may reverse these age-related changes and rejuvenate the proteome.

Wang, J. and Kim, S. K. Global Analysis of Gene Expression in the Dauer Larvae of Caenorhabditis elegans. Development 130: 1621-1634, 2003

Lund et al., Global Profile of Aging in Caenorhabditis elegans. Current Biology, 12, 1566, 2002.

An elt-3/elt-5/elt-6 GATA transcription circuit guides aging in C. elegans Cell 134, 291-303.