Genes, telomeres and mammalian ageing.

Although there appear to be several influences, which contribute to the ageing of mammals, the role of DNA appears to be pivotal. There is increasing evidence that oxidative damage is an important factor in producing mutations in genes, shortening telomeres and damaging mitochondrial DNA. Accumulation of mutations in genomic DNA could result in the gradual decline in cellular function, which is exhibited in a variety of tissues. The random nature of these mutations, could also offer an explanation for differences in the degree and time of onset of age-related changes, exhibited by different individuals. Shortening of telomeres, caused by oxidative damage or the end-replication problem, could result in the accumulation of post-mitotic cells in-vivo during ageing. This might impair certain aspects of physiology, such as wound healing. Mutation of mitochondrial DNA may also be important in causing loss of cells in post-mitotic tissues such as muscle or brain. In addition changes in the redox state during the life of an animal may alter transcription factor activities, leading to consistent changes in the gene expression profiles of mammalian tissues. The latter could explain consistent age-related changes that have been observed in cell structure and physiology. Although all of these mechanisms may make a contribution to ageing, it is likely that it is the interplay between them that produces the most prominent effects.