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, Emanuele Cacci, Alberto Martire, Patrizia Popoli, Germana Falcone, Flavia Michelini, Marco Crescenzi, Paolo Degan, Luisa Minghetti, Margherita Bignami, Gemma Calamandrei

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)695-705
Number of pages11
JournalAging Cell
Volume12
Issue number4
DOIs
Publication statusPublished - Aug 2013

Keywords

  • 8-oxoG
  • Aging
  • Behavior
  • Oxidative stress
  • Senescence

ASJC Scopus subject areas

  • Cell Biology
  • Ageing

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