Telomere end-replication problem and cell aging

Levy, Michael Z.; Allsopp, Richard; Futcher, A. B.; Greider, Carol W.; Harley, Calvin B.

doi:10.1016/0022-2836(92)90096-3

Cited by 950 publications

(624 citation statements)

References 25 publications

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“…We now know that this limit is due in large measure to the loss of telomeric DNA that occurs when cells that do not express telomerase undergo DNA replication (Levy et al, 1992;Wright and Shay, 2001). Telomeres, the DNA sequence and proteins that cap the ends of linear chromosomes, are essential chromosomal elements, loss of which causes genomic instability, an enormous risk factor for malignant transformation (Artandi and DePinho, 2000;Shay and Wright, 2001;Kim et al, 2002;Blasco, 2003).…”

Section: Causes Of Senescencementioning

confidence: 99%

Aging, tumor suppression and cancer: high wire-act!

Campisi

2005

Mechanisms of Ageing and Development

151

119

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Evolutionary theory holds that aging is a consequence of the declining force of natural selection with age. We discuss here the evidence that among the causes of aging in complex multicellular organisms, such as mammals, is the antagonistically pleiotropic effects of the cellular responses that protect the organism from cancer. Cancer is relatively rare in young mammals, owing in large measure to the activity of tumor suppressor mechanisms. These mechanisms either protect the genome from damage and/or mutations, or they elicit cellular responsesapoptosis or senescence-that eliminate or prevent the proliferation of somatic cells at risk for neoplastic transformation. We focus here on the senescence response, reviewing its causes, regulation and effects. In addition, we describe recent data that support the idea that both senescence and apoptosis may indeed be the double-edged swords predicted by the evolutionary hypothesis of antagonistic pleiotropyprotecting organisms from cancer early in life, but promoting aging phenotypes, including late life cancer, in older organisms. # 2004 Published by Elsevier Ireland Ltd.

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Section: Causes Of Senescencementioning

confidence: 99%

Aging, tumor suppression and cancer: high wire-act!

Campisi

2005

Mechanisms of Ageing and Development

151

119

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“…The telomeres, regions of DNA located at the ends of eukaryotic chromosomes, are considered to protect chromosomes against degeneration, reconstruction, fusion and loss 3 and also to ensure the complete replication of DNA molecules. 4 Telomeric DNA has a very simple structure, with hundreds to thousands of-I-I-AGGG repeats, in humans and other vertebrates. ~ Although it has been known for many years that these repeats are shortened by about 50-150 base pairs (bp) at each cell division in human fibroblasts 6 and lymphocytes in vitro, 7 telomere shortening with aging in many other human cell types in vivo has not been studied.…”

Section: Introductionmentioning

confidence: 99%

Telomere shortening with aging in human esophageal mucosa

Takubo

Nakamura

Izumiyama

et al. 1999

AGE

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Progressive telomere shortening with aging was studied using normal esophageal mucosal specimens from 177 human subjects aged between 0 and 102 years (yrs). We observed age-related shortening of the telomere, at a rate of 60 base pairS (bp) per year (yr). The mean telomere length of 12 neonates was 15.2 kilobase pairs (kbp) and that of 2 centenarians was 9.3 kbp. Mean (+ SD) telomere lengths were 14.9+1.3, 14.0-~_1.8, 10.1+3.7, 10.4+3.3 and 9.5+3.1 kbp for the age groups less than 2 yrs, 2-20 yrs, 21-60 yrs, 61-80 yrs and 81-102 yrs, respectively. The variation in telomere length among individuals in the same age group was greater for the 3 older groups than for the 2 younger groups, as shown by the SDs. Furthermore, older individuals had greater telomere length variation than younger individuals, based on the lengths of DNA digested smears. Although the telomere length decreased significantly with aging at the rate of 60 bp per yr, differences in the mean telomere lengths between the 3 older age groups were not significant. Rapid shortening occurred in the young generations and there was no further substantial decrease in the esophageal mucosa after 60 yrs of age. Compared to the very rapid renewal rate of the esophageal epithelial cells, the annual reduction rate in telomere length was very low. These findings support the hypothesis that germ cells in the esophageal epithelium have a mechanism to lengthen telomeres.

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“…In the absence of telomerase, the length of the reiterated telomere sequences, (TTAGGG)n in human, should processively shorten because of the end replication problem (Watson, 1972). Using cultured cells and cell lines, evidence for a close correlation between telomere length and the capacity of proliferative potentials has been documented (Allshire et al, 1988(Allshire et al, , 1989Moyzis et al, 1988;Harley et al, 1990;Harley, 1991Harley, , 1995Hastie et al, 1990;Wilkie et al, 1990;Yu et al, 1990;Allsopp et al, 1992;Levy et al, 1992;Counter et al, 1992Counter et al, , 1994aKruk et al, 1995). On the other hand, it has been demonstrated that activated telomerase is evidently associated with more than 85% of cancer cells and the majority of established cell lines but is undetectable in normal cellular counterparts (Kim et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Telomerase activity in a specific cell subset co-expressing integrinβ1/EGFR but not p75NGFR/bcl2/integrin β4 in normal human epithelial cells

Kikuchi

Ahmed

et al. 1998

Oncogene

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Telomerase activity is correlated with the immortality of various cultured cells and cancer cells. The activity, however, is also demonstrated in various normal regenerating cells which normally have a ®nite life span in vivo and in vitro, though its biological implication remains unclear. Using cultured normal human epithelial cells, we show that telomerase activity is associated with epithelial cell subsets which actively proliferate in vitro. Unlike in most cancer cell lines, telomerase activity was evidently up-regulated when the cells entered into S phase in primary human epithelial cells. To characterize the cells which have telomerase activity, the primary human epithelial cell population of uterine cervix was dissociated into several distinctive cellular subsets by means of immunocytochemical cell fractionation. Telomerase activity was found to be closely associated with the subset which expressed predominantly integrin b1 and epidermal growth factor receptor. We further identi®ed the telomerase-negative subpopulation which contained a small subset that strongly coexpresses p75 NGFR low a nity nerve growth factor receptor, integrin b4 and bcl-2 protein. The location of the p75 NGFR -expressing cells contrasts to that of the Ki-67 positive cells in vivo and is distinctive of telomerase positive cycling cells, indicating that these cells remain at the G0 phase. The present study supports the notion that telomerase activity is linked to cell cycle regulation, implying that telomerase is activated upon cell proliferation in regenerating normal human epithelial cells.

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Telomere end-replication problem and cell aging

Cited by 950 publications

References 25 publications

Aging, tumor suppression and cancer: high wire-act!

Aging, tumor suppression and cancer: high wire-act!

Telomere shortening with aging in human esophageal mucosa

Telomerase activity in a specific cell subset co-expressing integrinβ1/EGFR but not p75NGFR/bcl2/integrin β4 in normal human epithelial cells

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