Intermittent Hypoxia Doubles Nematode Life Span
A number of interventions can produce a doubling or greater extension of life span in the nematode C. elegans. Nematode worms demonstrate the plasticity of longevity in short-lived animals, far greater than is the case in long-lived mammals such as our own species. Interventions that alter metabolism in ways that upregulate cellular stress responses, and in doing so produce greatly extended nematode longevity, might be expected to only improve long-term health and add a few years of life in humans. We only have to look at the practice of calorie restriction to see a direct comparison and illustration of this point. Thus while it is interesting to see in this preprint paper that the hypoxia response can be guided to produce a large effect on life span in nematodes, we should not expect that to imply that hypoxia mechanisms are of great worth as a basis for interventions to slow aging in humans.
Genetic activation of the hypoxia response robustly extends lifespan in C. elegans, while environmental hypoxia shows more limited benefit. Here we describe an intermittent hypoxia therapy (IHT) able to double the lifespan of wildtype worms. The lifespan extension observed in IHT does not require HIF-1 but is partially blocked by loss of DAF-16/FOXO. RNAseq analysis shows that IHT triggers a transcriptional state distinct from continuous hypoxia and affects down-stream genes of multiple longevity pathways.
We performed a temperature sensitive forward genetic screen to isolate mutants with delayed nuclear localization of DAF-16 in response to IHT and suppression of IHT longevity. One of these mutations mapped to the enzyme Inositol Polyphosphate MultiKinase (IPMK-1). ipmk-1 mutants, like daf-16 mutants, partially suppress the benefits of IHT, while other effectors of phosphatidyl inositol signaling pathways (PLCβ4, IPPK, Go/iα) more robustly suppress IHT longevity.