期刊
AGING CELL
卷 15, 期 2, 页码 336-348出版社
WILEY
DOI: 10.1111/acel.12439
关键词
-ketoglutarate-dependent hydroxylases; aging; Caenorhabditis elegans; EGL-9; PHD; glutaric acidemia; hypoxia-inducible factor-1; hypoxia-inducible factor isp-1; jumonji domain-containing; metabolism; Mit mutants; mitochondria
资金
- Ellison Medical Foundation [AG-NS-051908]
- NIH [AG-047561, T32 AG021890, GM-109434]
- NIH [NRSA]
- Glenn Foundation for Medical Research
Disruption of mitochondrial respiration in the nematode Caenorhabditis elegans can extend lifespan. We previously showed that long-lived respiratory mutants generate elevated amounts of -ketoacids. These compounds are structurally related to -ketoglutarate, suggesting they may be biologically relevant. Here, we show that provision of several such metabolites to wild-type worms is sufficient to extend their life. At least one mode of action is through stabilization of hypoxia-inducible factor-1 (HIF-1). We also find that an -ketoglutarate mimetic, 2,4-pyridinedicarboxylic acid (2,4-PDA), is alone sufficient to increase the lifespan of wild-type worms and this effect is blocked by removal of HIF-1. HIF-1 is constitutively active in isp-1(qm150) Mit mutants, and accordingly, 2,4-PDA does not further increase their lifespan. Incubation of mouse 3T3-L1 fibroblasts with life-prolonging -ketoacids also results in HIF-1 stabilization. We propose that metabolites that build up following mitochondrial respiratory dysfunction form a novel mode of cell signaling that acts to regulate lifespan.
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