Regulation of longevity and healthspan by the hypoxic response

Model for regulation of longevity and proteotoxicity by VHL-1 and HIF-1. Reduced vhl-1 activity leads to increased life span and enhanced resistance to proteotoxicity due to reduced degradation of HIF-1 and increased activity of HIF-1 target genes, including hypoxic response genes. VHL-1 and HIF-1 act to modulate aging and protein homeostasis in a pathway that is distinct from both dietary restriction and insulin/IGF-1-like signaling but which may share a core set of similar or shared downstream target genes.

We have shown that proteasomal regulation of the hypoxic response serves as a novel determinant of longevity and resistance to proteotoxicity in the nematode Caenorhabditis elegans (see Mehta et al., Science 2009) (1).  This observation was made after the von Hipple Lindau tumor suppressor homolog, vhl-1, was identified by our lab from an RNAi screen for suppressors of polyglutamine toxicity.  VHL-1 is a negative regulator of HIF-1 that targets HIF-1 for degradation in an oxygen-dependent manner.  Loss of vhl-1 under normoxia results in stabilization of HIF-1, resistance to polyglutamine toxicity, and increased life span.  Animals lacking vhl-1 also have significantly lower levels of lipofuscin, a fluorescent age-pigment proposed as a marker of healthspan.   Reduced accumulation of lipofuscin, resistance to polyglutamine toxicity, and increased longevity of vhl-1 mutants requires hif-1, supporting the model shown in Figure 1. Epistasis analysis suggests that vhl-1 and hif-1 control longevity by a mechanism distinct from both dietary restriction and insulin/IGF-1-like signaling.

In parallel studies we have also observed that maintaining C. elegans under hypoxia (0.5% oxygen), another condition that results in stabilization of HIF-1, also increases life span.

Since publication of our initial report, studies from the Powell-Coffman (2) and Schermer (3) labs have verified our findings, both by replicating the life span extension from loss of vhl-1 and by showing that transgenic overexpression of HIF-1 is sufficient to increase life span.  Interestingly, the Powell-Coffman lab has also reported that deletion of hif-1 can also increase life span.  This observation has also been independently verified by the Kapahi lab (4) and by our own studies (see Leiser et al., Aging Cell) (5).

Several projects in the lab are aimed at defining the molecular mechanisms by which HIF-1 can act as both a pro- and anti-longevity factor in C. elegans.  We are also beginning studies aimed at determining whether these functions of HIF-1 are conserved in mammals.

Read more about specific projects: