Riboflavin depletion promotes longevity and metabolic hormesis in Caenorhabditis elegans

• Published in: Aging cell 2022-11, Vol.21 (11), p.e13718-n/a
• Main Authors: Yerevanian, Armen, Murphy, Luke M., Emans, Sinclair, Zhou, Yifei, Ahsan, Fasih M., Baker, Daniel, Li, Sainan, Adedoja, Adebanjo, Cedillo, Lucydalila, Stuhr, Nicole L., Gnanatheepam, Einstein, Dao, Khoi, Jain, Mohit, Curran, Sean P., Georgakoudi, Irene, Soukas, Alexander A.
• Format: Article
• Language: English
• Subjects: Adipose tissue; Adults; AMPK; Animals; C. elegans; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Chromatography; dietary restriction; Dietary restrictions; Enzymes; Flavin; Flavin-adenine dinucleotide; Forkhead protein; Forkhead Transcription Factors - metabolism; FOXO; Genotype & phenotype; Hormesis; Kinases; Life span; longevity; Longevity - genetics; Mass spectrometry; Metabolism; Mitochondria; Physiology; Protein folding; Protein kinase; Proteins; rft‐1 riboflavin transporter; Riboflavin; Riboflavin - metabolism; Scientific imaging; UPRmt; Vitamin B
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13718

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 upon AMP‐activated protein kinase (AMPK)/aak‐2, the mitochondrial unfolded protein response, and FOXO/daf‐16. Riboflavin depletion promotes altered energetic and redox states and increases adiposity, independent of lifespan genetic dependencies. Riboflavin‐depleted animals also exhibit the activation of caloric restriction reporters without any reduction in caloric intake. Our findings indicate that riboflavin depletion activates an integrated hormetic response that promotes lifespan and healthspan in C. elegans. Riboflavin depletion via knockdown of the C. elegans riboflavin transporter rft‐1 promotes longevity and metabolic hormesis. Riboflavin depletion mimics features of dietary restriction, and lifespan extension occurs through the activation of AMPK, FOXO, and the mitochondrial unfolded protein response.