CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Rapid Telomere Shortening in Children (2016)

Telomere shortening may reflect the total number of divisions experienced by a somatic cell and is associated with replicative senescence. We found that the average rate of telomere shortening in peripheral blood mononuclear cells (PBMCs) obtained longitudinally from nine different infants during the first 3 years of life (270 bp per year) is more than fourfold higher than in adults and does not correlate with telomerase activity. These results show that the rate of telomere loss changes during ontogeny, suggesting the existence of periods of accelerated cell division. Because human immunodeficiency virus (HIV) preferentially infects actively dividing cells, our observation suggesting accelerated cell division in children may provide an explanation for some of the distinctive pathogenic features of the HIV disease in infants, including higher viral loads and more rapid progression to acquired immunodeficiency syndrome (AIDS). This is a US government work. There are no restrictions on its use. B ECAUSE TELOMERES in several different cell types 1-3 shorten as a function of cell doublings in vitro and of patient age in vivo, telomere length has been proposed to be a potentially useful marker for the total number of divisions experienced by a cell and hence as a correlate of the aging process. Telomere length may serve as a mitotic clock limiting the replicative capacity of somatic cells. 4 However, most studies concerning telomere length and aging have examined telomere length in adults, particularly elderly adults. Few studies have specifically examined telomere lengths, or other correlates of aging, in the very young, even though infancy is the stage in life when the most profound developmental changes occur and when cellular replication peaks. Molecular correlates of the aging process might be expected to show their most dramatic changes during infancy, particularly for organ systems, which display the most dramatic developmental changes during infancy, such as the immune system. If rates of cell turnover vary during growth and development, the rates of telomere shortening should also change correspondingly. We therefore hypothesized that these changes should be greatest during the periods of life and in the tissues in which cellular replication is maximal. To explore this hypothesis and to obtain baseline values for the rate of telomere shortening in infants, we measured telomere length in the peripheral blood mononuclear cells (PBMCs) of infants. Because the immune system undergoes such significant changes during the first years of life and because telomere lengths and the association of age with telomere length have been extensively studied in the PBMCs of adults, we determined telomere lengths from serial samples of pediatric patients over the first years of life. We found that PBMC telomeres shorten substantially faster in infants than in adults, and that infant PBMCs contain little telomerase, suggesting that rapid cell turnover may accompany the developmental processes occurring during infancy in the cell populations sampled using PBMCs. The infant telomere shortening rates determined in this study may also serve as a baseline for comparing telomere shortening rates in patients in which PBMC turnover may be altered, for example human immunodeficiency virus (HIV) infection or congenital immunodeficiency syndromes. The implied elevation in cell turnover observed in infants may have additional ramifications for the pathogenesis of HIV disease in pediatric patients.