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

Aging Cell

Gabriele De Luca¹  Ilenia Ventura¹  Valentina Sanghez⁵  Maria Teresa Russo¹  Maria Antonietta Ajmone-Cat⁵  Emanuele Cacci²  Alberto Martire³  Patrizia Popoli³  Germana Falcone⁴  Flavia Michelini⁵  Marco Crescenzi⁵  Paolo Degan⁶  Luisa Minghetti⁵  Margherita Bignami¹ 

[1] Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy;Department of Biology and Biotechnology ‘Charles Darwin’, Sapienza University, Rome, Italy;Department of Drug Safety and Evaluation, Istituto Superiore di Sanità, Rome, Italy;Institute of Cell Biology and Neurobiology, National Research Council, Monterotondo, Italy;Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy;Centro di Biotecnologie Avanzate, IST - Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy

关键词: 8‐oxoG;    aging;    oxidative stress;    senescence;    behavior;   

DOI  :  10.1111/acel.12094

来源: Wiley

【 摘 要 】

Summary

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.

【 授权许可】

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