{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T17:56:07Z","timestamp":1793642167479,"version":"4.5.1"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging"],"abstract":"<jats:p>\n                    A mild impairment of mitochondrial function activates the hypoxia inducible factor (HIF-1)-mediated hypoxia stress response pathway leading to a HIF-1-dependent increase in lifespan. Lifespan extension resulting from HIF-1 stabilization is dependent on activation of flavin-containing monooxygenase-2 (FMO-2). In this work, we explored the role of\n                    <jats:italic>fmo-2<\/jats:italic>\n                    in the long lifespan of genetic mitochondrial mutants in\n                    <jats:italic>C. elegans.<\/jats:italic>\n                    We found that\n                    <jats:italic>fmo-2,<\/jats:italic>\n                    but not other\n                    <jats:italic>fmo<\/jats:italic>\n                    genes, are specifically upregulated in the long-lived mitochondrial mutants\n                    <jats:italic>clk-1, isp-1<\/jats:italic>\n                    and\n                    <jats:italic>nuo-6.<\/jats:italic>\n                    Disruption of\n                    <jats:italic>fmo-2<\/jats:italic>\n                    through RNA interference or genetic mutation shortens the lifespan of these mitochondrial mutants indicating that\n                    <jats:italic>fmo-2<\/jats:italic>\n                    is required for lifespan extension in these worms. Moreover, signaling molecules that have been shown to be involved in upregulation of\n                    <jats:italic>fmo-2<\/jats:italic>\n                    are also required for the long life of\n                    <jats:italic>clk-1, isp-1<\/jats:italic>\n                    and\n                    <jats:italic>nuo-6<\/jats:italic>\n                    mutants including HLH-30, NHR-49 and MDT-15. Finally, we examined the effect of multiple lifespan-promoting pathways in\n                    <jats:italic>clk-1<\/jats:italic>\n                    mutants on the expression of\n                    <jats:italic>fmo-2.<\/jats:italic>\n                    We found that in all cases, genes required for\n                    <jats:italic>clk-1<\/jats:italic>\n                    longevity are also required for the upregulation of\n                    <jats:italic>fmo-2<\/jats:italic>\n                    in\n                    <jats:italic>clk-1<\/jats:italic>\n                    worms. These genes included DAF-16, PMK-1, SKN-1, CEH-23, AAK-2, HIF-1 and ELT-2. Combined, this work advances our understanding of the molecular mechanisms contributing to longevity in the long-lived mitochondrial mutants and identifies FMO-2 as a common downstream effector of multiple pathways that modulate longevity.\n                  <\/jats:p>","DOI":"10.3389\/fragi.2026.1808540","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T08:49:46Z","timestamp":1774428586000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Mild mitochondrial impairment activates overlapping longevity pathways converging on the flavin-containing monooxygenase FMO-2"],"prefix":"10.3389","volume":"7","author":[{"given":"Jeremy M.","family":"Van Raamsdonk","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurosurgery, McGill University","place":["Montreal, QC, Canada"]},{"name":"Metabolic Disorders and Complications Program, Research Institute of the McGill University Health Centre","place":["Montreal, QC, Canada"]},{"name":"Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre","place":["Montreal, QC, Canada"]},{"name":"Division of Experimental Medicine, Department of Medicine, McGill University","place":["Montreal, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1038\/45544","article-title":"Regulation of lifespan by sensory perception in Caenorhabditis elegans","volume":"402","author":"Apfeld","year":"1999","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3004","DOI":"10.1101\/gad.1255404","article-title":"The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans","volume":"18","author":"Apfeld","year":"2004","journal-title":"Genes Dev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e1006695","DOI":"10.1371\/journal.pgen.1006695","article-title":"Transaldolase inhibition impairs mitochondrial respiration and induces a starvation-like longevity response in Caenorhabditis elegans","volume":"13","author":"Bennett","year":"2017","journal-title":"PLoS Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e52964","DOI":"10.15252\/embr.202152964","article-title":"Mild mitochondrial impairment enhances innate immunity and longevity through ATFS-1 and p38 signaling","volume":"22","author":"Campos","year":"2021","journal-title":"EMBO Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1111\/acel.12218","article-title":"A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans","volume":"13","author":"Chamoli","year":"2014","journal-title":"Aging Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1111\/j.1474-9726.2006.00205.x","article-title":"Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways","volume":"5","author":"Curtis","year":"2006","journal-title":"Aging Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/s1534-5807(01)00071-5","article-title":"Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans","volume":"1","author":"Feng","year":"2001","journal-title":"Dev. 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