THE BIOLOGY OF REPLICATIVE SENESCENCE

Most cells cannot divide indefinitely due to a process termed cellular or replicative senescence. Replicative senescence appears to be a fun damental feature of somatic cells, with the exception of most tumour c ells and possibly certain stem cells. How do cells sense the number of divisions they have completed? Although it has not yet been criticall y tested, the telomere shortening hypothesis is currently perhaps the best explanation for a cell division 'counting' mechanism. Why do cell s irreversibly cease proliferation after completing a finite number of divisions? It is now known that replicative senescence alters the exp ression of a few crucial growth-regulatory genes. It is not known how these changes in growth-regulatory gene expression are related to telo mere shortening in higher eukaryotes. However, lower eukaryotes have p rovided several plausible mechanisms. Finally, what are the physiologi cal consequences of replicative senescence? Several lines of evidence suggest that, at least in human cells, replicative senescence is a pow erful tumour suppressive mechanism. There is also indirect evidence th at replicative senescence contributes to ageing. Taken together curren t findings suggest that, at least in mammals, replicative senescence m ay have evolved to curtail tumorigenesis, but may also have the unsele cted effect of contributing to age-related pathologies, including canc er. (C) 1997 Elsevier Science Ltd.