Telomeres, cell senescence and human ageing

Abstract

Telomeres in most human cell types shorten during DNA replication in vitro because of various factors including the inability of DNA polymerases to fully copy the lagging strand, DNA end processing and random damage, often caused by oxidative stress. Short, uncapped telomeres activate replicative senescence, an irreversible cell cycle arrest and are thus a major cause of cell ageing in vitro. We will review how uncapped telomeres initiate a signalling cascade toward senescence, and why oxidative stress is a major cause of telomere shortening. Telomeres in most human cells shorten during ageing in vivo as well, suggesting two distinct possibilities. (1) Telomere shortening could be among the causes for ageing in vivo: Short telomeres might lead to senescence of (stem) cells in a tissue-specific fashion, and this might contribute to age-related functional attenuation in this tissue and even to systemic effects. Evidence for this is mostly indirect. (2) Telomere length could be a biomarker of ageing and age-related morbidity: Short telomeres might indicate a history of high stress and damage in the individual and could thus act as risk markers for age-related disease residing in a completely different tissue. There is evidence to support this possibility, although it is mostly correlative and is often derived from underpowered studies.