title: Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1.
abstract: The contribution that oxidative damage to DNA and/or RNA makes to the aging process remains undefined. In this study, we used the hMTH1-Tg mouse model to investigate how oxidative damage to nucleic acids affects aging. hMTH1-Tg mice express high levels of the hMTH1 hydrolase that degrades 8-oxodGTP and 8-oxoGTP and excludes 8-oxoguanine from both DNA and RNA. Compared to wild-type animals, hMTH1-overexpressing mice have significantly lower steady-state levels of 8-oxoguanine in both nuclear and mitochondrial DNA of several organs, including the brain. hMTH1 overexpression prevents the age-dependent accumulation of DNA 8-oxoguanine that occurs in wild-type mice. These lower levels of oxidized guanines are associated with increased longevity and hMTH1-Tg animals live significantly longer than their wild-type littermates. Neither lipid oxidation nor overall antioxidant status is significantly affected by hMTH1 overexpression. At the cellular level, neurospheres derived from adult hMTH1-Tg neural progenitor cells display increased proliferative capacity and primary fibroblasts from hMTH1-Tg embryos do not undergo overt senescence in vitro. The significantly lower levels of oxidized DNA/RNA in transgenic animals are associated with behavioral changes. These mice show reduced anxiety and enhanced investigation of environmental and social cues. Longevity conferred by overexpression of a single nucleotide hydrolase in hMTH1-Tg animals is an example of lifespan extension associated with healthy aging. It provides a link between aging and oxidative damage to nucleic acids.
authors: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors: Gabriele
authors: G
authors: De Luca
authors: Ilenia
authors: I
authors: Ventura
authors: Valentina
authors: V
authors: Sanghez
authors: Maria Teresa
authors: MT
authors: Russo
authors: Maria Antonietta
authors: MA
authors: Ajmone-Cat
authors: Emanuele
authors: E
authors: Cacci
authors: Alberto
authors: A
authors: Martire
authors: Patrizia
authors: P
authors: Popoli
authors: Germana
authors: G
authors: Falcone
authors: Flavia
authors: F
authors: Michelini
authors: Marco
authors: M
authors: Crescenzi
authors: Paolo
authors: P
authors: Degan
authors: Luisa
authors: L
authors: Minghetti
authors: Margherita
authors: M
authors: Bignami
authors: Gemma
authors: G
authors: Calamandrei
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D005106:Exploratory Behavior; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D008136:Longevity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: C024829:8-hydroxyguanine; D006147:Guanine; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes
keywords: 8-oxoG; aging; behavior; oxidative stress; senescence