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Premature aging in mice deficient in DNA repair and transcription

Jan de Boer1, Jaan Olle Andressoo, Jan de Wit

  • 1Medical Genetics Center, Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus University, 3000 DR Rotterdam, Netherlands.

Science (New York, N.Y.)
|April 16, 2002
PubMed

Insights

DNA damage accumulation may drive aging. Studies show mice with XPD gene mutations, linked to trichothiodystrophy, exhibit premature aging symptoms and reduced lifespan, supporting this DNA damage hypothesis.

Area of Science:

  • Genetics
  • Molecular Biology
  • Aging Research

Background:

  • Accumulation of DNA damage is a proposed driver of the aging process.
  • The XPD gene encodes a DNA helicase involved in DNA repair and transcription.
  • Mutations in XPD cause the human disorder trichothiodystrophy (TTD).

Purpose of the Study:

  • To investigate the role of DNA damage in aging using a mouse model.
  • To examine the effects of XPD gene mutations on aging phenotypes.
  • To explore the link between DNA repair defects and accelerated aging.

Main Methods:

  • Studied mice with mutations in the XPD gene.
  • Assessed aging phenotypes in TTD mice, including bone density, lifespan, and fertility.
  • Introduced an additional mutation in XPA to enhance DNA repair defects.
  • Correlated cellular sensitivity to oxidative DNA damage with aging acceleration.

Main Results:

  • TTD mice displayed numerous signs of premature aging, such as osteoporosis, kyphosis, osteosclerosis, early greying, cachexia, infertility, and shortened lifespan.
  • Mice with combined XPD and XPA mutations showed a significantly accelerated aging phenotype.
  • Accelerated aging correlated with increased cellular sensitivity to oxidative DNA damage.

Conclusions:

  • Unrepaired DNA damage in TTD mice likely causes aging by impairing gene transcription.
  • Compromised transcription leads to the functional inactivation of critical genes and increased apoptosis.
  • This study provides strong support for the DNA damage theory of aging.

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