University of California, San Francisco (UCSF)

Mechanistic Investigation of Aging and Age-Related Neurodegeneration in C. Elegans

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My study has been focused on understanding how the insulin/IGF endocrine system (IIS) controls life expectancy by regulating many downstream target genes in C. elegans.

One major outstanding question is how DAF-16/FOXO, a master longevity controlling transcription factor, regulates the expression of a diversity of genes to promote longevity in daf-2 mutant animals with decreased insulin/IGF signaling activity. Answering this question would help us understand the molecular and genetic mechanisms by which the IIS controls lifespan in animals.

My major finding is that limited activation of DAF-16/FOXO in one tissue is sufficient to induce the expression of a downstream target gene in a different tissue that lacks daf-16. In this case of cell non-autonomous gene regulation, daf-16(+) tissues must be able to produce yet unidentified signals to control gene expression in daf-16(-) responding tissues. I have performed RNAi genetic screen to look for genes that mediate this type of regulation. I have isolated several candidate RNAi clones, including one that affects a nuclear hormone receptor, suggesting that novel lipophilic hormonal signaling may be involved in the cell non-autonomous gene regulation and lifespan control.

Surprisingly, I have also found that DAF-16/FOXO indeed controls the expression of many of its downstream target genes in a cell autonomous fashion. Moreover, other transcription factors/co-factors (e.g., GATA factors) are involved to assume the appropriate regulation, suggesting that a complex network involving the actions of multiple transcription factors is required in gene regulation and lifespan control in long-lived daf-2 mutant animals.