Hypoxia-inducible factor regulatory networks and their roles in aging in Caenorhabditis elegans

Molecular oxygen, as the final electron accepter of aerobic respiration, is essential for the survival of most metazoans. Oxygen deprivation (hypoxia) is often involved in development, homeostasis and many diseases. In order to adapt to hypoxia, multi-cellular organisms have evolved complex networks that regulate metabolic changes in both systemic and cellular levels to mediate changes in angiogenesis/vascular remodeling, glycolytic metabolism and cell proliferation. Many of these metabolic changes are also involved in aging, suggesting that hypoxia response signaling may be intertwined with the pathways modulating aging. The hypoxia-inducible factor (HIF) transcription factor is a master regulator that mediates most of the transcriptional changes during hypoxia adaptation. Recent studies have suggested that HIF can influence replicative senescence in mammals, but the roles of HIF in aging are not fully understood.;The C.elegans hif-1 gene is orthologous to mammalian HIF-1 alpha genes. C. elegans has proven to be a premier model for studying aging and also a powerful system for deciphering the regulation and function of HIF. In this dissertation research, I studied the roles of HIF-1 and hypoxia response in organismal aging in C.elegans. My results established HIF-1 as an important modulator of aging in C.elegans. I discovered that both HIF-1 over-expression and hif-1 loss-of-function mutations extend life span. I further demonstrated that hypoxia treatment promotes longevity in C.elegans. My studies also provided evidence for HIF-1-independent pathways for hypoxia response to modulate aging. Finally, using forward genetic approaches, I identified a novel protein that regulates the activity of C. elegans HIF-1 in mechanisms distinct from the VHL-1-dependent proteosomal degradation pathway.