Ether Lipid Biosynthesis Promotes Lifespan Extension and Enables Diverse Prolongevity Paradigms

Biguanides, including the world’s most commonly 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, such as cancer. In spite of these promising observations, the full spectrum of the molecular effectors responsible for these health benefits remains elusive. Through unbiased genetic screening in C. elegans, we uncovered a novel role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides govern lifespan extension via a complex effect on the ether lipid landscape requires enzymes responsible for both ether lipid biogenesis and polyunsaturated fatty acid synthesis. Remarkably, 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. Furthermore, 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. Significance Statement Metformin is the most widely used drug to treat patients with type 2 diabetes and extends lifespan in multiple species, yet the molecular targets responsible for these prolongevity benefits remain incompletely understood. To this end, we demonstrate that a subset of lipids, known as ether lipids, are necessary for biguanides’ anti-aging effects and various other paradigms of lifespan extension. Strikingly, modulation of the machinery responsible for ether lipid biosynthesis is sufficient to stimulate lifespan extension, illuminating the possibility of using these lipids as therapeutic targets to promote healthy aging.