biostudies-literatureUnknownChang SMNIGMS NIH HHSNIH HHSMitochondrial sirtuins regulate metabolism and are emerging drug targets for metabolic and age-related diseases such as cancer, diabetes, and neurodegeneration. Yet, the extent of their functions remain unclear. Here, we uncover a physiological role for the C. elegans mitochondrial sirtuins, sir-2.2 and sir-2.3, in lifespan regulation. Using genetic alleles with deletions that destroy catalytic activity, we demonstrate that sir-2.2 and sir-2.3 mutants live an average of 25% longer than controls when fed the normal lab diet of live E. coli OP50. While decreased consumption of food is a known mechanism for lifespan extension, we did not find evidence of reduced pharyngeal pumping. Interestingly, lifespan extension effected by loss of sir-2.2 or sir-2.3 is sensitive to the diet. The lifespan Geneticsiyaf185https://www.ebi.ac.uk/biostudies/studies/S-EPMC12428508biostudies-literatureMitochondrial sirtuins sir-2.2 and sir-2.3 regulate lifespan in C. elegans.PMC12428508R01 GM086786P40 OD010440Sattar SLaGanke NGHanna-Rose WFranklin LPMoro CADeGennaro MVChang SMfalseMitochondrial sirtuins sir-2.2 and sir-2.3 regulate lifespan in C. elegans.Mitochondrial sirtuins regulate metabolism and are emerging drug targets for metabolic and age-related diseases such as cancer, diabetes, and neurodegeneration. Yet, the extent of their functions remain unclear. Here, we uncover a physiological role for the C. elegans mitochondrial sirtuins, sir-2.2 and sir-2.3, in lifespan regulation. Using genetic alleles with deletions that destroy catalytic activity, we demonstrate that sir-2.2 and sir-2.3 mutants live an average of 25% longer than controls when fed the normal lab diet of live E. coli OP50. While decreased consumption of food is a known mechanism for lifespan extension, we did not find evidence of reduced pharyngeal pumping. Interestingly, lifespan extension effected by loss of sir-2.2 or sir-2.3 is sensitive to the diet. The lifespan 2025-01-01T00:00:00Z2025 Sep2026-06-02T10:06:39.963Z2026-05-26T03:06:10.173ZS-EPMC124285084090878310.1093/genetics/iyaf185