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Lee SW; Wei JY
Gerontology Division, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Clin Geriatr Med, 1997 Feb, 13:1, 69-77
The increased incidence of cancer as a function of age has long been interpreted to suggest that multiple genetic changes are required for tumorigenesis. Cancer cells differ from normal cells in many characteristics, including loss of differentiation, increased invasiveness, and decreased drug sensitivity. Although recent molecular advances have helped to clarify the possible relationships between carcinogenesis and aging, it remains unclear whether genetic markers may be common to all cancer types or which markers may be associated with increased age of cancer patients. Fundamental aspects of cancer development for older people are not well understood. Further insight into the genetic factors that may be responsible for the initiation and progression of cancer and their connections to the aging process may be gained in part by studying in vitro cellular or replicative senescence.
Berkeley National Laboratory, University of California 94720, USA.
J Am Geriatr Soc, 1997 Apr, 45:4, 482-8
Normal cells do not divide indefinitely. This trait, termed the finite replicative life span of cells, limits the capacity for cell division by a process termed cellular or replicative senescence. Replicative senescence is thought to be a tumor suppression mechanism and also a contributor to organismic aging. This article reviews what is known about the genetics and molecular biology of cell senescence. It discusses the evidence that replicative senescence suppresses tumorigenesis, at least in young organisms, and that it also contributes to the aging of mitotic tissues. Finally, it puts forth the somewhat unorthodox view that, in older organisms, senescent cells may actually contribute to carcinogenesis.
Pan C; Xue BH; Ellis TM; Peace DJ; Díaz MO
Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University at Chicago, Maywood, Illinois 60153, USA.
Exp Cell Res, 1997 Mar 15, 231:2, 346-53
It has been proposed that telomeres shorten with every cell cycle because the normal mechanism of DNA replication cannot replicate the end sequences of the lagging DNA strand. Telomerase, a ribonucleoprotein enzyme that synthesizes telomeric DNA repeats at the DNA 3' ends of eukaryotic chromosomes, can compensate for such shortening, by extending the template of the lagging strand. Telomerase activity has been identified in human germline cells and in neoplastic immortal somatic cells, but not in most normal somatic cells, which senesce after a certain number of cell divisions. We and others have found that telomerase activity is present in normal human lymphocytes and is upregulated when the cells are activated. But, unlike the immortal cell lines, presence of telomerase activity is not sufficient to make T cells immortal and telomeres from these cells shorten continuously during in vitro culture. After senescence, telomerase activity, as detected by the TRAP technique, was downregulated. A cytotoxic T lymphocyte (CTL) cell line that was established in the laboratory has very short terminal restriction fragments (TRFs). Telomerase activity in this cell line is induced during activation and this activity is tightly correlated with cell proliferation. The level of telomerase activity in activated peripheral blood T cells, the CTL cell line, and two leukemia cell lines does not correlate with the average TRF length, suggesting that other factors besides telomerase activity are involved in the regulation of telomere length.
Faragher RG; Hardy SP; Davis T; Dropcova S; Allen MC
Department of Pharmacy, University of Brighton, Brighton, BN2 4GJ, United Kingdom.
Exp Cell Res, 1997 Feb 25, 231:1, 119-22
Werner's Syndrome (WS) fibroblasts undergo premature senescence. Two hypotheses have been proposed to explain this phenomenon: (i) the phenotype is due to the overexpression of senescence-specific proteins in every cell in the population. Such proteins are known to suppress calcium-dependent potassium currents. (ii) The WS mutation greatly increases the proportion of cells that stop cycling at each generation and become senescent. If hypothesis (i) is correct, such currents should be suppressed in all WS fibroblasts; whereas hypothesis (ii) predicts that they will be retained in the cycling fraction of the population. To distinguish between these hypotheses whole-cell patch-clamp currents were recorded from cycling cells. Slowly activating outward calcium-dependent potassium currents were detected in both cycling WS and control fibroblasts. These findings support hypothesis (ii): the premature senescence of WS fibroblasts is due to an increased rate of transition from cycling to senescence in the total cell population.
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