Ether lipid biosynthesis promotes lifespan extension and enables diverse prolongevity paradigms in Caenorhabditis elegans

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 C. 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.