Stanford University

Transcriptional Circuit for Aging in C. Elegans

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To define the C. elegans aging process at the molecular level, we used DNA microarray experiments to identify a set of 1294 age-regulated genes, and found that their upstream regions were enriched for GATA consensus DNA binding sites. 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 including ugt-9, col-144 and sod-3. elt-5(RNAi) and elt-6(RNAi) worms have extended longevity, and elt-3 null mutants live shorter (in a genetic background that is longlived), 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. This is a clear example of antagonistic pleiotropy as hypothesized by many pre-molecular theorists and provides an integrative view bringing the molecular and evolutionary views of aging to a mutual understanding.