Aging and genome maintenance

Ann N Y Acad Sci. 2005 Dec;1055:35-47. doi: 10.1196/annals.1323.007.

Abstract

Genomic instability in somatic cells has been implicated as a major stochastic mechanism of aging. Using a transgenic mouse model with chromosomally integrated lacZ mutational target genes, we found mutations to accumulate with age at an organ- and tissue-specific rate. Also the spectrum of age-accumulated mutations was found to differ greatly from organ to organ; while initially similar, mutation spectra of different tissues diverged significantly over the lifetime. To explain how genomic instability, which is inherently stochastic, can be a causal factor in aging, it is proposed that randomly induced mutations may adversely affect normal patterns of gene regulation, resulting in a mosaic of cells at various stages on a trajectory of degeneration, eventually resulting in cell death or neoplastic transformation. To directly address this question we demonstrate that it is now possible to analyze single cells, isolated from old and young tissues, for specific alterations in gene expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Aging / genetics*
  • Aging / pathology
  • Animals
  • DNA / genetics*
  • Gene Expression Regulation*
  • Genomic Instability*
  • Mice
  • Mice, Transgenic
  • Models, Genetic
  • Mutation*
  • Stochastic Processes
  • Transcription, Genetic

Substances

  • DNA