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In C. elegans, an insulin-like signaling pathway controls adult longevity through the action of a
single transcription factor, DAF-16. We have focused on attempting to identify transcriptional
outputs of DAF-16, and how they may mediate the effects of insulin signaling on longevity.
Previously, we have used microarrays and genomic analysis to characterize DAF-16 dependent
transcriptional changes that occur in long-lived C. elegans strains. Expanding on this data,
we are currently conducting microarray studies of insulin signaling and longevity using C.elegans,
D. melanogaster, and M. musculus. In these three diverse species, reducing insulin-like signaling
has been shown to result in increased lifespan, which implies that there may be an evolutionarily
conserved mechanism controlling longevity. Using microarry analysis, we hope to identify a
conserved “regulon” of transcriptional changes shared by all three species. We have recently
finished microarray analyses for C.elegans (20 arrays), D. melanogaster (22 arrays), and initial
experiments in M. musculus (16 arrays), and are currently analyzing the data.
We are also performing experiments to characterize where DAF-16 functions to control aging in C.
elegans, and if it does so in a cell-autonomous or non-autonomous way. We have created several
fusion constructs that express DAF-16 under tissue-specific promoters, and have created transgenic
lines in a daf-16 null background. These lines will be assessed for effects on longevity, as well
as other phenotypes controlled by DAF-16.
Finally, experiments to examine oxidative defense genes in C. elegans have begun. We have created
transgenic strains which over-express manganese superoxide dismutases (SOD’s), which are a key
component of the mitochondrial oxidative defense machinery. Oxidative defense genes, and SOD’s
in particular, have been implicated in increased longevity, and are thought to be direct targets
of DAF-16. We are examining the effects of over-expression of these genes on longevity, their
tissue distribution, and their transcriptional response to DAF-16 activity.
Publications resulting from support:
1. Gems D, McElwee JJ. Ageing: Microarraying mortality. Nature. 2003 Jul 17; 424(6946): 259-61.
2. McElwee J, Bubb K, Thomas JH. Transcriptional outputs of the Caenorhabditis elegans forkhead
protein DAF-16. Aging Cell. 2003 Apr; 2(2): 111-21.
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