HIF and Nematode Longevity

It's fascinating to see a system that evolution has apparently fine-tuned to minimize longevity - either increase its operation or disable it and longevity increases: "During normal development or during disease, animal cells experience hypoxic (low oxygen) conditions, and the hypoxia-inducible factor (HIF) transcription factors implement most of the critical changes in gene expression that enable animals to adapt to this stress. ... We examined the effects of HIF-1 over-expression and of hif-1 loss-of-function mutations on longevity in C. elegans ... We constructed transgenic lines that expressed varying levels of HIF-1 protein and discovered a positive correlation between HIF-1 expression levels and lifespan. The data further showed that HIF-1 acted in parallel to the SKN-1/NRF and DAF-16/FOXO transcription factors to promote longevity. HIF-1 over-expression also conferred increased resistance to heat and oxidative stress. We isolated and characterized additional hif-1 mutations, and we found that each of 3 loss-of-function mutations conferred increased longevity in normal lab culture conditions, but, unlike HIF-1 over-expression, a hif-1 deletion mutation did not extend the lifespan of daf-16 or skn-1 mutants. We conclude that HIF-1 over-expression and hif-1 loss-of-function mutations promote longevity by different pathways." The more longevity mutations that work in conjunction with one another the better.

Link: http://www.pubmedcentral.nih.gov/articlerender.fcgi?pubmedid=19633713

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