The HIF-1 Hypoxia-Inducible Factor Modulates Lifespan in C. elegans

Abstract

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. Here, we examine the roles of HIF-1 in post-mitotic aging. We examined the effects of HIF-1 over-expression and of hif-1 loss-of-function mutations on longevity in C. elegans, a powerful genetic system in which adult somatic cells are post-mitotic. 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. These data establish HIF-1 as one of the key stress-responsive transcription factors that modulate longevity in C. elegans and advance our understanding of the regulatory networks that link oxygen homeostasis and aging.

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

“…C. elegans HIF‐1 also plays key roles in various physiologic processes, including stress and pathogen responses, axon guidance, iron and protein homeostasis, and reproduction (Pocock & Hobert, 2008; Bellier et al ., 2009; Mehta et al ., 2009; Zhang et al ., 2009; Powell‐Coffman, 2010; Romney et al ., 2011; Ackerman & Gems, 2012; Fawcett et al ., 2015). Recent studies demonstrate that HIF‐1 activation promotes longevity in C. elegans (Mehta et al ., 2009; Muller et al ., 2009; Zhang et al ., 2009; Lee et al ., 2010; Leiser et al ., 2011; Hwang et al ., 2014).…”

“…Recent studies demonstrate that HIF‐1 activation promotes longevity in C. elegans (Mehta et al ., 2009; Muller et al ., 2009; Zhang et al ., 2009; Lee et al ., 2010; Leiser et al ., 2011; Hwang et al ., 2014). However, the components that mediate longevity in response to HIF‐1 activation remain unclear.…”

Mitochondrial metabolites extend lifespan

“…Construction of ZG580 has been described previously (Zhang et al ., 2009). SLR0047 was constructed by crossing ZG580 with CB1141.…”

New insights into cell non-autonomous mechanisms of theC. eleganshypoxic response

“…18 Soon after our initial publication, two other labs reported similar findings by showing that either knockdown of vhl-1 or constitutive stabilization of HIF-1 could increase lifespan in C. elegans. 19,20 These studies and others that have followed have established HIF-1 and the hypoxic response as a pro-longevity pathway that is genetically distinct from the other major longevity pathways such as insulin-like signaling and dietary restriction. 21,22 Intriguingly, although constitutive activation of HIF-1 is sufficient to increase lifespan, loss of function mutations in hif-1 can also increase lifespan under certain conditions.…”

“…21,22 Intriguingly, although constitutive activation of HIF-1 is sufficient to increase lifespan, loss of function mutations in hif-1 can also increase lifespan under certain conditions. 19,23 The effect of hif-1 deletion on lifespan appears to be largely dependent on temperature; hif-1(ia4) animals are long-lived at 25C but not at 15C. 24 The effect of hif-1 deletion on lifespan at 20C appears somewhat variable and may depend on additional experimental conditions that have yet to be defined.…”