Telomeres, replicative senescence and human ageing.
Ageing concerns the extracellular environment and cells that are either post-mitotic or capable of division during life. Primary human cells have a finite division capacity in culture before they enter a state of viable cell cycle arrest termed senescence. Cell division occurs during life in many tissues, either as part of normal tissue function or in response to tissue damage. The accumulation of cells at the end of their replicative lifespan in the elderly might contribute to aged tissue either because of a reduced ability to undergo proliferation or because of the known altered gene-expression patterns of senescent cells. This has been illustrated experimentally using a transgenic telomerase-negative mouse, which shows some premature ageing phenotypes. The mechanism whereby cells count divisions uses the gradual erosion of the ends of chromosomes (telomeres) with cell division caused by the repression of the telomere-maintenance enzyme telomerase in most human cells. Telomere erosion ultimately triggers replicative senescence in many cell types; this can be prevented experimentally by forcibly expressing telomerase. This extends the lifespan of normal human cells and those from progeroid syndromes such as Werner's. Telomere-driven senescence did not evolve to cause ageing, but is instead a by-product of a system devised to provide a tumour-suppression function, a concept that fits well with evolutionary arguments regarding trade-offs between somatic maintenance and reproduction. Work in the future will focus on the development of new animal models to critically address the quantitative significance of this ageing mechanism.
Kipling
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Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. kiplingd@cardiff.ac.uk
D000375:Aging / Q000235:genetics*; D000818:Animals; D004261:DNA Replication; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere
D019098:Telomerase