{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T04:46:45Z","timestamp":1791694005447,"version":"4.3.4"},"reference-count":60,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Age-linked tissue dysfunction is associated with mitochondrial degeneration manifested as organelle fragmentation and respiratory dysfunction. Efforts to mitigate downstream consequences of mitochondrial degeneration, as with ROS scavengers, have not translated to the human condition. We posit that intrinsic fusion-mediated mechanisms for mitochondrial protection modulate aspects of aging linked to mitochondrial abnormalities. In C. elegans roundworms mitochondrial fusion is mediated by the mitofusin ortholog Fuzzy Onion-1 (fzo-1). Here, the addition of a mitofusin inhibitor, MFI8, to cultures of age-synchronized C. elegans shortened worm lifespan in a concentration-dependent manner. Reciprocally, the mitofusin activators Chimera and 8015-P2 prolonged worm survival in a dose-dependent manner. The pro-survival effect of Chimera was absent in worms lacking its protein target, FZO-1, and at lower concentrations Chimera-amplified survival was further increased by absence of the mitochondrial fission protein that acts in opposition to fzo-1, DRP-1. The mitofusin activator 8015-P2, which is more potent than Chimera, exhibited greater anti-aging effects on lifespan and improved worm healthspan measured as forced swimming activity and resistance to thermal and oxidative stresses. These proof-of-concept worm studies identify aging phenotypes reciprocally related to fzo-1\/mitofusin activation status. As 8015-P2 is under development for use in human neurodegenerative diseases, it might alleviate aging phenotypes evoked by mitochondrial degeneration in higher species.<\/jats:p>","DOI":"10.3390\/cells15191789","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:19:08Z","timestamp":1790842748000},"page":"1789","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitofusin Activation Delays Aging in Caenorhabditis elegans"],"prefix":"10.3390","volume":"15","author":[{"given":"Jochen","family":"Weigele","sequence":"first","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Center for Pharmacogenomics, Washington University in St. Louis, Saint Louis, MO 63110, USA"},{"name":"Mitochondria in Motion, Inc., Saint Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Center for Pharmacogenomics, Washington University in St. Louis, Saint Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Roider","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline E.","family":"Walton","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Center for Pharmacogenomics, Washington University in St. Louis, Saint Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"II","given":"Gerald W.","family":"Dorn","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e13080","DOI":"10.1111\/acel.13080","article-title":"Measuring biological aging in humans: A quest","volume":"19","author":"Ferrucci","year":"2020","journal-title":"Aging Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1515\/mr-2025-0047","article-title":"Interplay between aging and metabolic diseases: From molecular mechanisms to therapeutic horizons","volume":"5","author":"Zhong","year":"2025","journal-title":"Med. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1175898","DOI":"10.3389\/fpubh.2023.1175898","article-title":"Editorial: Aging and chronic disease: Public health challenge and education reform","volume":"11","author":"Sun","year":"2023","journal-title":"Front. Public Health"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Hyatt, H.W., and Powers, S.K. (2021). Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity. Antioxidants, 10.","DOI":"10.3390\/antiox10040588"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1152\/physrev.1998.78.2.547","article-title":"The free radical theory of aging matures","volume":"78","author":"Beckman","year":"1998","journal-title":"Physiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100982","DOI":"10.1016\/j.arr.2019.100982","article-title":"Ageing, age-related diseases and oxidative stress: What to do next?","volume":"57","author":"Luo","year":"2020","journal-title":"Ageing Res. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"238463","DOI":"10.1155\/2014\/238463","article-title":"Mitochondrial aging and age-related dysfunction of mitochondria","volume":"2014","author":"Chistiakov","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1007\/s40279-024-02072-7","article-title":"Mitochondria as Nutritional Targets to Maintain Muscle Health and Physical Function During Ageing","volume":"54","author":"Broome","year":"2024","journal-title":"Sports Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1172\/JCI124194","article-title":"Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model","volume":"129","author":"Zhou","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"782","DOI":"10.3389\/fphys.2020.00782","article-title":"Mitofusin 2 Dysfunction and Disease in Mice and Men","volume":"11","author":"Dorn","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Dorn, G.W. (2023). Reversing Dysdynamism to Interrupt Mitochondrial Degeneration in Amyotrophic Lateral Sclerosis. Cells, 12.","DOI":"10.3390\/cells12081188"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/j.1749-6632.2010.05615.x","article-title":"Physiological functions of mitochondrial fusion","volume":"1201","author":"Chen","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e61119","DOI":"10.7554\/eLife.61119","article-title":"Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A","volume":"9","author":"Franco","year":"2020","journal-title":"eLife"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1124\/jpet.122.001332","article-title":"Mitochondrial Dysfunction and Pharmacodynamics of Mitofusin Activation in Murine Charcot-Marie-Tooth Disease Type 2A","volume":"383","author":"Franco","year":"2022","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1093\/hmg\/ddac287","article-title":"Activating mitofusins interrupts mitochondrial degeneration and delays disease progression in SOD1 mutant amyotrophic lateral sclerosis","volume":"32","author":"Dang","year":"2023","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1124\/jpet.124.002258","article-title":"Sensory-Motor Neuropathy in Mfn2 T105M Knock-in Mice and Its Reversal by a Novel Piperine-Derived Mitofusin Activator","volume":"391","author":"Weigele","year":"2024","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.cell.2007.06.026","article-title":"Mitochondrial fusion protects against neurodegeneration in the cerebellum","volume":"130","author":"Chen","year":"2007","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4827","DOI":"10.1093\/hmg\/dds352","article-title":"Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons","volume":"21","author":"Lee","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cmet.2014.12.011","article-title":"Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts","volume":"21","author":"Song","year":"2015","journal-title":"Cell Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.cmet.2017.09.023","article-title":"Abrogating Mitochondrial Dynamics in Mouse Hearts Accelerates Mitochondrial Senescence","volume":"26","author":"Song","year":"2017","journal-title":"Cell Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.cell.2010.02.026","article-title":"Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations","volume":"141","author":"Chen","year":"2010","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e84235","DOI":"10.7554\/eLife.84235","article-title":"A human mitofusin 2 mutation can cause mitophagic cardiomyopathy","volume":"12","author":"Franco","year":"2023","journal-title":"eLife"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1080\/07924259.2014.940470","article-title":"Using C. elegans for aging research","volume":"59","author":"Tissenbaum","year":"2015","journal-title":"Invertebr. Reprod. Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1093\/genetics\/77.1.71","article-title":"The genetics of Caenorhabditis elegans","volume":"77","author":"Brenner","year":"1974","journal-title":"Genetics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1126\/science.aao1785","article-title":"MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A","volume":"360","author":"Rocha","year":"2018","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3775","DOI":"10.1038\/s41467-022-31324-1","article-title":"Modulating mitofusins to control mitochondrial function and signaling","volume":"13","author":"Zacharioudakis","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/nature20156","article-title":"Correcting mitochondrial fusion by manipulating mitofusin conformations","volume":"540","author":"Franco","year":"2016","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"100586","DOI":"10.1016\/j.xpro.2021.100586","article-title":"C. elegans survival assays to discern global and transcription-coupled nucleotide excision repair","volume":"2","author":"Lans","year":"2021","journal-title":"STAR Protoc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6069354","DOI":"10.1155\/2020\/6069354","article-title":"A Dihydroflavonoid Naringin Extends the Lifespan of C. elegans and Delays the Progression of Aging-Related Diseases in PD\/AD Models via DAF-16","volume":"2020","author":"Zhu","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"380","DOI":"10.6061\/clinics\/2015(05)13","article-title":"Lifespan extension and increased resistance to environmental stressors by N-acetyl-L-cysteine in Caenorhabditis elegans","volume":"70","author":"Oh","year":"2015","journal-title":"Clinics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1534\/genetics.117.202747","article-title":"Heat-Induced Calcium Leakage Causes Mitochondrial Damage in Caenorhabditis elegans Body-Wall Muscles","volume":"206","author":"Momma","year":"2017","journal-title":"Genetics"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Peixoto, H., Roxo, M., Rohrig, T., Richling, E., Wang, X., and Wink, M. (2017). Anti-Aging and Antioxidant Potential of Paullinia cupana var. sorbilis: Findings in Caenorhabditis elegans Indicate a New Utilization for Roasted Seeds of Guarana. Medicines, 4.","DOI":"10.3390\/medicines4030061"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"491","DOI":"10.6061\/clinics\/2017(08)07","article-title":"Selenocysteine modulates resistance to environmental stress and confers anti-aging effects in C. elegans","volume":"72","author":"Kim","year":"2017","journal-title":"Clinics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1080\/19768354.2025.2549756","article-title":"Xanthoxyline prevents aging and neuronal damage by activating autophagy and DAF-16 expression in Caenorhabditis elegans","volume":"29","author":"Kim","year":"2025","journal-title":"Anim. Cells Syst."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1006\/jmbi.2000.4042","article-title":"T-Coffee: A novel method for fast and accurate multiple sequence alignment","volume":"302","author":"Notredame","year":"2000","journal-title":"J. Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1093\/jb\/mvm245","article-title":"An RNAi screen for mitochondrial proteins required to maintain the morphology of the organelle in Caenorhabditis elegans","volume":"143","author":"Ichishita","year":"2008","journal-title":"J. Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1007\/s00018-019-03024-5","article-title":"Disruption of mitochondrial dynamics affects behaviour and lifespan in Caenorhabditis elegans","volume":"76","author":"Byrne","year":"2019","journal-title":"Cell Mol. Life Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1016\/j.devcel.2021.04.021","article-title":"Neuronal mitochondrial dynamics coordinate systemic mitochondrial morphology and stress response to confer pathogen resistance in C. elegans","volume":"56","author":"Chen","year":"2021","journal-title":"Dev. Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s12915-022-01241-2","article-title":"Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness","volume":"20","author":"Meshnik","year":"2022","journal-title":"BMC Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.semcdb.2023.10.006","article-title":"The mechanisms and roles of mitochondrial dynamics in C. elegans","volume":"156","author":"Campbell","year":"2024","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.tips.2022.11.004","article-title":"Mitochondrial dynamics proteins as emerging drug targets","volume":"44","author":"Zacharioudakis","year":"2023","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"12506","DOI":"10.1021\/acs.jmedchem.1c00163","article-title":"Pharmacophore-Based Design of Phenyl-[hydroxycyclohexyl] Cycloalkyl-Carboxamide Mitofusin Activators with Improved Neuronal Ac-tivity","volume":"64","author":"Dang","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Dang, X., Walton, E.K., Zablocka, B., Baloh, R.H., Shy, M.E., and Dorn, G.W. (2022). Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation. Cells, 11.","DOI":"10.3390\/cells11061053"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7033","DOI":"10.1021\/acs.jmedchem.0c00366","article-title":"Discovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases","volume":"63","author":"Dang","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"655","DOI":"10.3390\/chemistry4030047","article-title":"Piperine Derivatives Enhance Fusion and Axonal Transport of Mitochondria by Activating Mitofusins","volume":"4","author":"Zhang","year":"2022","journal-title":"Chemistry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.arr.2011.11.005","article-title":"Of mice and men: The benefits of caloric restriction, exercise, and mimetics","volume":"11","author":"Mercken","year":"2012","journal-title":"Ageing Res. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/s41467-017-00274-4","article-title":"Increased mitochondrial fusion allows the survival of older animals in diverse C. elegans longevity pathways","volume":"8","author":"Chaudhari","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3777","DOI":"10.1073\/pnas.84.11.3777","article-title":"Aging can be genetically dissected into component processes using long-lived lines of Caenorhabditis elegans","volume":"84","author":"Johnson","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"23829","DOI":"10.1073\/pnas.1909210116","article-title":"Swim exercise in Caenorhabditis elegans extends neuromuscular and gut healthspan, enhances learning ability, and protects against neurodegeneration","volume":"116","author":"Laranjeiro","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e982437","DOI":"10.4161\/21624054.2014.982437","article-title":"Robust tracking and quantification of C. elegans body shape and locomotion through coiling, entanglement, and omega bends","volume":"3","author":"Roussel","year":"2014","journal-title":"Worm"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"777","DOI":"10.18632\/aging.100939","article-title":"Aging causes decreased resistance to multiple stresses and a failure to activate specific stress response pathways","volume":"8","author":"Dues","year":"2016","journal-title":"Aging"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e2774","DOI":"10.21769\/BioProtoc.2774","article-title":"Measurement of Intracellular ROS in Caenorhabditis elegans Using 2\u2032,7\u2032-Dichlorodihydrofluorescein Diacetate","volume":"8","author":"Yoon","year":"2018","journal-title":"Bio-Protocol"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"12592","DOI":"10.1038\/s41598-017-12719-3","article-title":"Triclosan Disrupts SKN-1\/Nrf2-Mediated Oxidative Stress Response in C. elegans and Human Mesenchymal Stem Cells","volume":"7","author":"Yoon","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/s41392-022-01251-0","article-title":"Aging and aging-related diseases: From molecular mechanisms to interventions and treatments","volume":"7","author":"Guo","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e76","DOI":"10.1371\/journal.pmed.0040076","article-title":"Calorie restriction increases muscle mitochondrial biogenesis in healthy humans","volume":"4","author":"Civitarese","year":"2007","journal-title":"PLoS Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"628157","DOI":"10.3389\/fcell.2021.628157","article-title":"Beneficial and Detrimental Effects of Reactive Oxygen Species on Lifespan: A Comprehensive Review of Comparative and Experimental Studies","volume":"9","author":"Shields","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/ng1056","article-title":"A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity","volume":"33","author":"Lee","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Srivastava, S. (2017). The Mitochondrial Basis of Aging and Age-Related Disorders. Genes, 8.","DOI":"10.3390\/genes8120398"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1152\/japplphysiol.00819.2013","article-title":"Acute exercise remodels mitochondrial membrane interactions in mouse skeletal muscle","volume":"115","author":"Picard","year":"2013","journal-title":"J. Appl. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"146532","DOI":"10.1016\/j.brainres.2019.146532","article-title":"Overlapping spectrums: The clinicogenetic commonalities between Charcot-Marie-Tooth and other neurodegenerative diseases","volume":"1727","author":"Martin","year":"2020","journal-title":"Brain Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/19\/1789\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T04:12:59Z","timestamp":1791691979000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/19\/1789"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":60,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cells15191789"],"URL":"https:\/\/doi.org\/10.3390\/cells15191789","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]}}}