Senior Scholar Award in Aging
Judith Campisi, Ph.D.
Lawrence Berkeley National Laboratory

Telomeres, Cell Phenotype and Aging

Telomeres are structures composed of a specific DNA sequence and specialized proteins that cap the ends of chromosomes. Telomeres stabilize the chromosome, and thus ensure that the genome is maintained in a normal, stable state. Normal human cells lose a small amount of telomeric DNA each time they divide. When the telomeres reach a critically short length, the cells irreversibly lose their ability to divide. Thus, the gradual shortening of telomeres that occurs at each cell division ensures that normal cells divide only a finite number of times. It is now clear that this loss of cell division potential, also known as replicative or cellular senescence, is extremely important for preventing the development of cancer. There is, however, a down-side to replicative senescence. Senescent cells also develop an altered pattern of gene expression, which causes the cell to function aberrantly, and senescent cells slowly accumulate with age in human tissues. The accumulation of dysfunctional senescent cells is thought to contribute to a number of disorders that are hallmarks of aging, such as atherosclerosis, susceptibility to infection, macular degeneration, osteoporosis, and others. Why do cells that lose telomeric DNA become dysfunctional? The answer to this question is not known. Our hypothesis is that telomere shortening releases telomere-associated proteins, which are capable of changing the pattern of gene expression within a cell. To test this idea, we must first identify the proteins that associate with human telomeres, about which very little is known. We must then determine the effects of these proteins on cell function (also known as cell phenotype) when they are released from the telomere. Thus far, we have cloned one gene encoding a new human telomere protein, bringing the total number of novel human telomere-associated proteins to four. This protein, which we termed TIN2, appears to be important for controlling the length of human telomeres and, very likely, for maintaining a normal telomere structure. Our preliminary experiments suggest that when we upset the balance between the amounts of TIN2 protein and telomeric DNA in human mammary epithelial cells, the cells' ability to form a normal tissue structure (a breast alveolus) is disrupted. Thus, the idea that telomere-associated proteins can derange normal cellular functions may be valid. We have, of course, a long way to go before we understand how telomere proteins influence cell phenotype. However, once we have a better understanding of the mechanism, it may be possible to prevent the loss of cell function, while preserving the loss of cell division potential. This strategy would ensure that we continue to reap the benefits of replicative senescence (evading cancer), while preventing the development of age-associated disorders that result from the accumulation of dysfunctional senescent cells.

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