Telomere Length, Aging, and Somatic Cell Turnover

T elomeres are unique protein–DNA structures that comprise the termini of eukaryotic linear chromosomes (for review see references 1, 2). Telomeric DNA does not contain protein-encoding genes but rather consists of G-rich hexanu-cleotide repeats that in vertebrate cells are (TTAGGG) n sequences. Based on studies initially carried out in yeast and other single cell organisms, it appears that telomere functions include the stabilization and protection of chromo-somal ends from events such as illegitimate recombination, the determination of chromosomal localization within the nucleus, and the regulation of cellular replicative capacity. It is this last function, the role of telomeres in regulation of replicative capacity, that has received particular attention in studies of cellular senescence and organismal aging. A pivotal finding in the understanding of somatic cell biology was the observation that normal somatic cells have a finite replicative life span (3). That is, they are capable of a finite number of cell divisions, after which they undergo what has been termed replicative senescence and are incapable of further cell division. The mechanism underlying the replicative clock that monitors this process has evoked considerable attention, and it is in this context that telo-mere function has been of particularly intense interest. The most widely accepted paradigm relating telomere function to cellular aging and replicative senescence is based on the observation that in normal somatic cells telomeres shorten with each cell division (4, 5). This telomere shortening has been attributed to the primer requirement for DNA synthesis during chromosomal replication, and results in incomplete replication and a loss of terminal telomeric repeats with each cell division (6). Telomeres thus shorten progressively with successive cell divisions, and telomere length in a somatic cell may thus reflect the replicative history of that cellular lineage. In principle, this is a potentially powerful tool for the analysis of cell division under physio-logic circumstances in which it is otherwise very difficult to monitor in vivo clonal expansion. For this reason, measurement of telomere length has been widely used to analyze lineage or precursor–product relationships and rates of cell division. However, in interpreting the significance of changes in telomere length, it is critical to consider the multiple factors that may influence the net length of telomeres at any point in time. The starting point for telomere length in somatic cells is the length of telomeres in germ line cells of the individual or species, a parameter that is and must …