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

Aging Cell. 2013 Aug;12(4):695-705. doi: 10.1111/acel.12094. Epub 2013 May 30.

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.

Keywords: 8-oxoG; aging; behavior; oxidative stress; senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal*
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Cellular Senescence
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism*
  • Exploratory Behavior*
  • Female
  • Gene Expression Regulation, Developmental*
  • Guanine / analogs & derivatives
  • Guanine / metabolism
  • Humans
  • Longevity*
  • Male
  • Mice
  • Mice, Transgenic
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Oxidation-Reduction
  • Oxidative Stress
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Time Factors

Substances

  • 8-hydroxyguanine
  • Guanine
  • Phosphoric Monoester Hydrolases
  • 8-oxodGTPase
  • DNA Repair Enzymes