LIFE SPAN EXTENSION FROM LOSS OF HIF-1


In 2009, we reported that activation of HIF-1 can increase life span in C. elegans by a mechanism that is genetically distinct from both dietary restriction and insulin-like signaling (Mehta et al., Science).  Soon after that, work from 3 different labs confirmed our results, but also made the surprising observation that deletion of HIF-1 could also extend life span (Figure 1).  Recently, we have resolved this apparent discrepancy by finding that life span extension in hif-1 null mutants is temperature-dependent (Figure 2); whereas, life span extension in vhl-1 null mutants (in which HIF-1 is stabilized) is temperature-independent (see Leiser et al., Aging Cell 2011).  

Consistent with data from the Powell-Coffman lab, we find that  life span extension from loss of HIF-1 requires the FOXO-family transcription factor DAF-16.  DAF-16 is required for life span extension resulting from reduced insulin-like signaling in C. elegans. We also find that loss of HIF-1 causes DAF-16 to relocalize to the nucleus, consistent with the idea that DAF-16 is activated under these conditions.  The goal of our ongoing studies is to understand how loss of HIF-1 causes DAF-16 to become activated and determining whether a similar relationship exists between FOXO and HIF proteins in mammalian cells. 

People: Scott Leiser, Ani Begun