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. © 2013 John Wiley & Sons Ltd and the Anatomical Society.

Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1 / Gabriele De, Luca; Ilenia, Ventura; Valentina, Sanghez; Maria Teresa, Russo; Maria Antonietta Ajmone, Cat; Cacci, Emanuele; Alberto, Martire; Patrizia, Popoli; Germana, Falcone; Flavia, Michelini; Marco, Crescenzi; Paolo, Degan; Luisa, Minghetti; Margherita, Bignami; Gemma, Calamandrei. - In: AGING CELL. - ISSN 1474-9718. - STAMPA. - 12:4(2013), pp. 695-705. [10.1111/acel.12094]

Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1

CACCI, Emanuele;
2013

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. © 2013 John Wiley & Sons Ltd and the Anatomical Society.
2013
8-oxog; aging; senescence; behavior; oxidative damage; oxidative stress
01 Pubblicazione su rivista::01a Articolo in rivista
Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1 / Gabriele De, Luca; Ilenia, Ventura; Valentina, Sanghez; Maria Teresa, Russo; Maria Antonietta Ajmone, Cat; Cacci, Emanuele; Alberto, Martire; Patrizia, Popoli; Germana, Falcone; Flavia, Michelini; Marco, Crescenzi; Paolo, Degan; Luisa, Minghetti; Margherita, Bignami; Gemma, Calamandrei. - In: AGING CELL. - ISSN 1474-9718. - STAMPA. - 12:4(2013), pp. 695-705. [10.1111/acel.12094]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/516608
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