Riboflavin Depletion Promotes Longevity and Metabolic Hormesis in Caenorhabditis elegans

Riboflavin is an essential cofactor in many enzymatic processes and in the production of flavin adenine dinucleotide (FAD). Here we report that the partial depletion of riboflavin through knockdown of the C. elegans riboflavin transporter 1 ( rft-1 ) promotes metabolic health by reducing intracellular flavin concentrations. Knockdown of rft-1 significantly increases lifespan in a manner dependent on FOXO/ daf-16 , AMP-activated protein kinase (AMPK)/ aak-2 , the mitochondrial unfolded protein response, and mTOR complex 2 (mTORC2). Riboflavin depletion promotes altered energetic and redox states and increases adiposity, independent of lifespan genetic dependencies. Riboflavin depleted animals also exhibit activation of caloric restriction reporters without a reduction in TORC1 signaling. Our findings indicate that riboflavin depletion activates an integrated, hormetic response that promotes lifespan and healthspan in C. elegans. ### Competing Interest Statement The authors have declared no competing interest.