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-1 increases 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 it’s 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 lipofuscin, a fluorescent non-degradable cellular waste product that accumulates with age, but is reduced in vhl-1 mutants.  Genes that influence lipofuscin accumulation are then analyzed for their effect on life span. Our results have suggested a number of possible HIF-1 targets that may have a positive effect on lifespan. 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, Ani Begun, Marissa Fletcher, Melissa Primitivo