Cellular Aging: Telomeres

There are several human syndromes that manifest as premature aging, including Hutchinson-Gilford progeria and Werner syndrome. Figure 3 Telomerase contains, at the minimum, an RNA molecule and a catalytic subunit. The catalytic subunit of the enzyme, hTERT, uses a region of the RNA moiety, hTER, as a template for the addition of telomeric DNA on the chromosome ends. In this way, net telomere gain can offset the DNA lost due to the end-replication problem. SOURCE: Reddel, Roger R. ``The Role of Senescence and Immortalization in Carcinogenesis.'' Carcinogenesis 21 (2000): 477-484. Cell lines derived from individuals with progeria are capable of attaining fewer divisions before becoming senescent than are cells from age-matched unaffected individuals. In addition, telomeres in cells derived from individuals with Hutchinson-Gilford progeria are shorter than age-matched unaffected individuals, again linking telomere length with cell division capacity and, indirectly, with aging. Interestingly, experiments have demonstrated that cells derived from individuals with Werner syndrome not only undergo senescence after fewer divisions, but also that this occurs when the telomeres in these cells are, on average, longer than those in parallel cultures not containing the Werner mutation. This observation suggested that the premature senescence in cells derived from individuals with Werner syndrome might be disconnected from telomere length, and instead result from other factors, such as accumulated DNA damage. However, David Kipling and coworkers demonstrated that forced expression of telomerase in Werner syndrome cells conferred immortality, indicating that the telomere-length-based clock is active in this genetic background.

The link between telomere shortening, replicative senescence, and aging at the organism level is supported by a series of studies carried out by the laboratories of Ronald DePinho and Carol Greider. These investigators generated a mouse that was deficient for telomerase. Mice usually have extremely long telomeres, but in the telomerase-deficient mice the telomeres became shorter with each generation, and the later generations of these mice exhibited characteristics consistent with premature aging. For example, these animals have a compromised ability to heal wounds, exhibit premature graying, and have a shortened lifespan. These studies linked short telomeres with some characteristics observed in older adults, suggesting that telomere-length-dependent effects on cellular division might also play a role in aging at the level of the organism. The strength of the contribution of telomere-length-based replicative senescence to the aging process as a whole remains to be determined, however.