Ancient metabolic switches underpinning organismal longevity

Abstract

Biguanides, including metformin, the world’s most prescribed drug for the treatment of type 2 diabetes mellitus, robustly extend lifespan and health-span across multiple invertebrate and vertebrate species. Given the safety, efficacy, and well-tolerated nature of metformin, there is an urgent need to identify how biguanides exert their favorable pro-longevity effects, to illuminate novel geroprotective targets and heretofore underappreciated molecular and cellular mechanisms that modulate aging. In this dissertation, we integrated functional genetic strategies with molecular metabolic assessment across metazoans to identify a series of genetic elements required for biguanide-mediated lifespan extension and the enabling of diverse pro-longevity paradigms. First, through curated genetic screening in the nematode roundworm Caenorhabditis elegans, we highlight ether lipid biosynthesis as a critical effector of the biological action of biguanides and further demonstrate that key ether lipid-producing enzymes are required to enable the pro-longevity effects of multiple conserved geroprotective interventions. Second, we leveraged translatomics, metabolomics, and unbiased functional genetics to highlight post-transcriptional protection of de novo fatty acid biosynthesis as an ancient, conserved compensatory metabolic response that buffers against the onset of reductive stress, an underappreciated toxicity associated with chronic biguanide administration. We further demonstrate that inactivation of de novo fatty acid biosynthesis during biguanide treatment drives NADPH toxicity, resulting in aggravated electron spillover across NADH/GSH redox pools and subsequent acceleration of death. Moreover, we find that multiple NADPH-producing metabolic insults require de novo fatty acid biosynthesis to prevent accelerated death outcomes, suggesting that its compensatory protection is broadly mobilized across intervention and species. We thus propose that mRNA translation of de novo fatty acid biosynthesis functions as a tunable rheostat to minimize biguanide-induced reductive stress whilst reciprocally maximizing its geroprotective effects. Finally, we demonstrate through unbiased classic genetic screening in C. elegans that activation of a cytoprotective nucleolar stress response through a conserved rRNA surveillance pathway may uncouple reductive-stress toxicity from the geroprotective action of biguanides. Combined, these studies illuminate a series of ancient metabolic pathways that may be leveraged to maximize the geroprotective action of biguanides and other related pro-longevity interventions across metazoans.