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Ether lipid biosynthesis promotes lifespan extension and enables diverse pro-longevity paradigms in Caenorhabditis elegans.

Lucydalila Cedillo | Fasih M Ahsan | Sainan Li | Nicole L Stuhr | Yifei Zhou | Yuyao Zhang | Adebanjo Adedoja | Luke M Murphy | Armen Yerevanian | Sinclair Emans | Khoi Dao | Zhaozhi Li | Nicholas D Peterson | Jeramie Watrous | Mohit Jain | Sudeshna Das | Read Pukkila-Worley | Sean P Curran | Alexander A Soukas
eLife | 2023

Biguanides, including the world's most prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the incidence and morbidity associated with aging-related diseases. Despite this promise, the full spectrum of molecular effectors responsible for these health benefits remains elusive. Through unbiased screening in Caenorhabditis elegans, we uncovered a role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides prompt lifespan extension by stimulating ether lipid biogenesis. Loss of the ether lipid biosynthetic machinery also mitigates lifespan extension attributable to dietary restriction, target of rapamycin (TOR) inhibition, and mitochondrial electron transport chain inhibition. A possible mechanistic explanation for this finding is that ether lipids are required for activation of longevity-promoting, metabolic stress defenses downstream of the conserved transcription factor skn-1/Nrf. In alignment with these findings, overexpression of a single, key, ether lipid biosynthetic enzyme, fard-1/FAR1, is sufficient to promote lifespan extension. These findings illuminate the ether lipid biosynthetic machinery as a novel therapeutic target to promote healthy aging.

Pubmed ID: 37606250

Associated grants

  • Agency: NIA NIH HHS, United States
    Id: R01 AG069677
  • Agency: NIH HHS, United States
    Id: R01AI130289
  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK040561
  • Agency: NIA NIH HHS, United States
    Id: R01 AG058256
  • Agency: NIH HHS, United States
    Id: R01AG69677
  • Agency: NIA NIH HHS, United States
    Id: P30 AG068345
  • Agency: NIAID NIH HHS, United States
    Id: T32 AI132152
  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK057521
  • Agency: NIH HHS, United States
    Id: R01AG058259
  • Agency: NIH HHS, United States
    Id: P40 OD010440
  • Agency: NIH HHS, United States
    Id: R01AG058610
  • Agency: NIH HHS, United States
    Id: K12GM106996

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