These authors equally contributed to this work.
Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1
Version of Record online: 30 MAY 2013
© 2013 John Wiley & Sons Ltd and the Anatomical Society
Volume 12, Issue 4, pages 695–705, August 2013
How to Cite
De Luca, G., Ventura, I., Sanghez, V., Russo, M. T., Ajmone-Cat, M. A., Cacci, E., Martire, A., Popoli, P., Falcone, G., Michelini, F., Crescenzi, M., Degan, P., Minghetti, L., Bignami, M. and Calamandrei, G. (2013), Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1. Aging Cell, 12: 695–705. doi: 10.1111/acel.12094
The authors declare no conflict of interest.
- Issue online: 16 JUL 2013
- Version of Record online: 30 MAY 2013
- Accepted manuscript online: 4 MAY 2013 11:41AM EST
- Manuscript Accepted: 21 APR 2013
- Telethon. Grant Number: GGP06100
- oxidative stress;
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.