Unfolding the role of the hypoxic response in aging

The TOR (“target of rapamycin”) protein is a master regulator of cell growth, governing connect nutrient sensing, protein synthesis, and proliferation. It has become increasingly clear that the TOR pathway plays an essential role in longevity determination — specifically, higher TOR activity is associated with more rapid aging and shorter lifespan.

In mammals, TOR interferes with stem cell functions, and TOR activity is downregulated by exercise. It has been proposed that TOR inhibitors might even be used as anti-aging drugs (and in fact we’re going to investigate some recent relevant tests of that idea, sometime next week). The relationship between TOR and lifespan holds true across great evolutionary distances: loss of TOR function (in conjunction with other mutations) can dramatically increase the chronological lifespan of yeast.

How does TOR control the rate of aging? In order to answer this question, we must look downstream, to proteins that are controlled by TOR. A recent study from the Kapahi lab (our neighbors at the Buck Institute for Age Research) investigated the role of one such TOR target: HIF-1 (“hypoxia inducible factor”; it is also involved in metabolism). The authors find that loss-of-function mutations in HIF-1 result in longer-lived C. elegans. Chen et al.:

HIF-1 Modulates Dietary Restriction-Mediated Lifespan Extension via IRE-1 in Caenorhabditis elegans

Dietary restriction (DR) extends lifespan in various species and also slows the onset of age-related diseases. Previous studies from flies and yeast have demonstrated that the target of rapamycin (TOR) pathway is essential for longevity phenotypes resulting from DR. TOR is a conserved protein kinase that regulates growth and metabolism in response to nutrients and growth factors. While some of the downstream targets of TOR have been implicated in regulating lifespan, it is still unclear whether additional targets of this pathway also modulate lifespan. It has been shown that the hypoxia inducible factor-1 (HIF-1) is one of the targets of the TOR pathway in mammalian cells. HIF-1 is a transcription factor complex that plays key roles in oxygen homeostasis, tumor formation, glucose metabolism, cell survival, and inflammatory response. Here, we describe a novel role for HIF-1 in modulating lifespan extension by DR in Caenorhabditis elegans. We find that HIF-1 deficiency results in extended lifespan, which overlaps with that by inhibition of the RSKS-1/S6 kinase, a key component of the TOR pathway. Using a modified DR method based on variation of bacterial food concentrations on solid agar plates, we find that HIF-1 modulates longevity in a nutrient-dependent manner. The hif-1 loss-of-function mutant extends lifespan under rich nutrient conditions but fails to show lifespan extension under DR. Conversely, a mutation in egl-9, which increases HIF-1 activity, diminishes the lifespan extension under DR. This deficiency is rescued by tissue-specific expression of egl-9 in specific neurons and muscles. Increased lifespan by hif-1 or DR is dependent on the endoplasmic reticulum (ER) stress regulator inositol-requiring protein-1 (IRE-1) and is associated with lower levels of ER stress. Therefore, our results demonstrate a tissue-specific role for HIF-1 in the lifespan extension by DR involving the IRE-1 ER stress pathway.

The mutants’ life extension was observed when the worms could eat ad libitum but not when they were dietarily restricted (DR), implying that the mechanism of the HIF-1 mutation is similar to that of DR. Conversely, activation of HIF-1 expression (by mutating EGL-9, which ubiquitinates HIF-1) decreases the lifespan extension due to DR. Taken together, the findings imply that downregulation of HIF-1 expression is both necessary and sufficient for DR-mediated longevity enhancement.

One more step down the rabbit hole, then: What are HIF-1 and DR doing? The authors find that lifespan extension requires the IRE1-gene, a principle mediator of the unfolded protein response (UPR). The UPR is activated when the endoplasmic reticulum (ER) is stressed — when protein folding is inefficient, or the secretory machinery is overloaded; the pathway returns the cell to homeostasis by inducing expression of genes that fold, sort, and process proteins in the ER (or degrade the proteins that can’t be saved). Perhaps lifespan extension requires increased ER capacity, or more efficient degradation of misfolded proteins?

On a closing note: Attentive readers will have recalled that not very long ago, we reported on a paper that appears to have reached the opposite conclusion — specifically, that high expression of HIF-1 (induced the same way as here, by mutation in the ubiquitin E3 ligase EGL-9) results in extended lifespan and decreased proteotoxicity. I don’t want to get in the middle of this controversy, except to point out that the systems were different in a number of ways, and that it is a formal possibility that a gene’s activity could be “tuned” such that either an increase or a decrease in expression could increase lifespan (implying that the wildtype expression levels are at a “sweet spot” of lower lifespan but presumably higher fitness, due to some sort of tradeoff between longevity and reproductive success). I am sure that the authors of both studies are working to reconcile the apparent contradiction. We’ll look forward to learning more as the story develops.

ResearchBlogging.orgChen, D., Thomas, E., & Kapahi, P. (2009). HIF-1 Modulates Dietary Restriction-Mediated Lifespan Extension via IRE-1 in Caenorhabditis elegans PLoS Genetics, 5 (5) DOI: 10.1371/journal.pgen.1000486


One comment

  1. Another recent paper of interest is…

    Dioum, E.M. et al. (2009) “Regulation of HIF-2-alpha signaling by the stress-responsive deacetylase sirtuin 1”. Science 324, p1289-1293 (also a nice editorial by Len Guarente in the same issue).

    So, Hif1 regulates CR (which requires SIRTs), and SIRTs regulate Hif2. Sounds like a feed-back loop to me!

    This also brings up some interesting epidemiological thoughts… Do the effects of CR change at high altitude? Do hypoxic responses diminish with age (like everything else)?

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