title: A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice.
abstract: In lower organisms, such as Caenorhabditis elegans and Drosophila, many genes identified as key regulators of aging are involved in either detoxification of reactive oxygen species or the cellular response to oxidatively-damaged macromolecules. Transgenic mice have been generated to study these genes in mammalian aging, but have not in general exhibited the expected lifespan extension or beneficial behavioral effects, possibly reflecting compensatory changes during development. We administered a small-molecule synthetic enzyme superoxide dismutase (SOD) mimetic to wild-type (i.e. non-transgenic, non-senescence accelerated) mice starting at middle age. Chronic treatment not only reduced age-associated oxidative stress and mitochondrial radical production, but significantly extended lifespan. Treated mice also exhibited improved performance on the Morris water maze learning and memory task. This is to our knowledge the first demonstration that an administered antioxidant with mitochondrial activity and nervous system penetration not only increases lifespan, but rescues age-related cognitive impairment in mammals. SOD mimetics with such characteristics may provide unique complements to genetic strategies to study the contribution of oxidative processes to nervous system aging.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Quick
authors.forename: Sameh S
authors.initials: SS
authors.lastname: Ali
authors.forename: Robert
authors.initials: R
authors.lastname: Arch
authors.forename: Chengjie
authors.initials: C
authors.lastname: Xiong
authors.forename: David
authors.initials: D
authors.lastname: Wozniak
authors.forename: Laura L
authors.initials: LL
authors.lastname: Dugan
mesh_terms: D000367:Age Factors; D000375:Aging / Q000187:drug effects*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000648:ultrastructure; D003071:Cognition / Q000187:drug effects*; D004996:Ethidium / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D037741:Fullerenes / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D012737:Sex Factors; D013482:Superoxide Dismutase / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D037741:Fullerenes; C067883:dihydroethidium; D013482:Superoxide Dismutase; D004996:Ethidium; C069837:fullerene C60