Identifying HIF-1 Targets that Modulate Aging

The hypoxia inducible factor (HIF) is a conserved protein that regulates the cellular response to low oxygen conditions. Under normal oxygen levels, HIF-1 is negatively regulated by the von Hippel-Lindau (VHL) tumor suppressor protein. We and others have shown that deletion of vhl-1increases life span in C. elegans throught stabilization and activation of HIF-1.  Despite HIF-1 and VHL-1 being highly-conserved, VHL-1 deficiency does not increase life span in people, but instead results in von Hippel-Lindau syndrome, a disease characterized by angiomas and increased tumor formation. In order to test whether HIF-1’s effect on longevity can be separated from its role in cancer, we are searching for HIF-1 target proteins that modulate lifespan. To accomplish this, we are inhibiting individual HIF-1 responsive genes in long-lived vhl-1 mutant worms and measuring in the abundance of age-associated autofluorescence, which is reduced in vhl-1mutants.  We have analyzed genes that influence age-associated autofluorescence for their effect on life span, and have accumulated a short list of HIF-1 targets that may have a positive effect on lifespan. We are currently testing whether any of these targets can modulate lifespan directly, and initial results are encouraging. We hope that better understanding the downstream mechanisms by which HIF-1 increases longevity in worms may lead to new approaches toward promoting health and longevity in humans.

People: Scott Leiser, Hillary Miller, Ani Begun, Marissa Fletcher, Melissa Primitivo