Intermittent hypoxia therapy engages multiple longevity pathways to double lifespan in C.elegans

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. One-Sentence Summary Intermittent hypoxia therapy is frequency dependent, HIF independent, and requires FOXO, PLCβ, Go/iα, IPMK, and IPPK. ### Competing Interest Statement The authors have declared no competing interest.