Telomere Dynamics in Mice and Humans
Section snippets
Telomeres, Aging, and Longevity
As telomeres erode with cell division, serving as a “mitotic clock” for the proliferative history of a cell or tissue and resulting in cell senescence and apoptosis, telomere biology has been postulated as the molecular mechanism for physiologic and pathologic aging.10
In mice, specific serum proteins (CRAMP, stathmin, EF-1α, and chitinase) are elevated in late generation telomerase “knockout” mice.11 However, these changes only occur in aging mice, which are telomerase-deficient for several
Telomeres and Disease
In humans, defects in telomerase function result in progressive telomere shortening, which clinically manifests as severe diseases that are often fatal. X-linked dyskeratosis congenita is the prototypical human telomere disease; it is characterized by mucocutaneous dystrophy in boys associated with aplastic anemia, the most common cause of death, usually in the first decade of life.35 Patients with dyskeratosis congenita commonly have other organs affected, mainly the lungs (pulmonary fibrosis),
Telomeres and Cancer
Almost 100 years ago, Boveri postulated chromosomal instability as the initiating pathogenic event in oncogenesis.60 Consistent with this hypothesis, most cancers have an aneuploid genome, as well as qualitative chromosome changes, as deletions or translocations. Telomere attrition has been proposed as a mechanism for the loss or gain of chromosomes. In the absence or decrease of telomerase activity, mutation rates increase as a result of terminal chromosome deletions and repeated cycles of
Conclusions
In mammals, telomere length inversely correlates with life span, whereas telomerase expression inversely correlates with body mass; short-lived species with small body mass, such as mice, evolved to have much longer telomeres and express telomerase at the expense of abandoning a role of telomeres in replicative aging, as observed in humans. Thus, murine telomerase knockout models have been useful in identifying and characterizing the major basic biology of telomeres and telomerase, but in depth
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Conflicts of interest: none.
Supported in part by FAPESP (R.T.C.) and the NIH Intramural Research Program (B.D.).