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1.
Telomeres and telomerase: basic science implications for aging   总被引:2,自引:0,他引:2  
Life expectancy in the United States and other developed nations has increased remarkably over the past century, and continues to increase. However, lifespan has remained relatively unchanged over this period. As life expectancy approaches maximum human lifespan, further increase in life expectancy would only be possible if lifespan could also be increased. Although little is known about the aging process, increasing lifespan and delaying aging are the research challenges of the new century, and have caused intense debate and research activities among biogerontologists. Many theories have been proposed to explain the aging process. However, damage to deoxyribonucleic acid (DNA) is the centerpiece of most of these. Recently telomere shortening has been described to be associated with DNA damage. Located at the ends of eukaryotic chromosomes and synthesized by telomerase, telomeres maintain the length of chromosomes. The loss of telomeres can lead to DNA damage. The association between cellular senescence and telomere shortening in vitro is well established. In the laboratory, telomerase-negative differentiated somatic cells maintain a youthful state, instead of aging, when transfected with vectors encoding telomerase. Many human cancer cells demonstrate high telomerase activity. Evidence is also accumulating that telomere shortening is associated with cellular senescence in vivo. What causes changes in expression of telomerase in different cell types and premature aging syndromes? Does the key to "youthfulness" lie in our ability to control the expression of telomerase? We have reviewed the contemporary literature to find answers to these questions and explore the association between aging, telomeres, and telomerase.  相似文献   

2.
Telomeres, stem cells, and hematology   总被引:3,自引:0,他引:3       下载免费PDF全文
Lansdorp PM 《Blood》2008,111(4):1759-1766
Telomeres are highly dynamic structures that adjust the cellular response to stress and growth stimulation based on previous cell divisions. This critical function is accomplished by progressive telomere shortening and DNA damage responses activated by chromosome ends without sufficient telomere repeats. Repair of critically short telomeres by telomerase or recombination is limited in most somatic cells, and apoptosis or cellular senescence is triggered when too many uncapped telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germ line that typically express high levels of telomerase. In somatic cells, the telomere length typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal cells in which malignant progression is facilitated by genome instability resulting from uncapped telomeres. The critical role of telomeres in cell proliferation and aging is illustrated in patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Here, the role of telomeres and telomerase in human biology is reviewed from a personal historical perspective.  相似文献   

3.
Although human and rodent telomeres have been studied extensively, very little is known about telomere dynamics in other vertebrates. Moreover, our current dependence on mice as a model for human tumorigenesis and aging poses a problem because human and mouse telomere biology is very different. To explore whether chickens might provide a more useful model, we have examined telomerase activity and telomere length in chicken tissues as well as in primary cell cultures. Although chicken telomeres resemble human telomeres in that they are 8–20 kb in length, the distribution of telomerase activity in chickens resembles what is found in mice. Active enzyme is present in germline tissue as well as in a wide range of somatic tissues. Because chicken cells exhibit extremely low rates of spontaneous immortalization, this finding indicates that constitutive telomerase expression does not necessarily lead to an increased immortalization frequency. Finally, we found that telomerase activity is greatly down-regulated when primary cultures are established from chicken embryos. Although this down-regulation explains the telomere loss and replicative senescence that we observed in fibroblast cultures, it raises questions concerning how relevant studies of senescence in primary cell cultures are to aging in whole animals.  相似文献   

4.
Chromosome ends are capped by telomeres, protective DNA-protein complexes that distinguish natural ends from random DNA breaks. Telomeres erode with each successive cell division, and such divisions cease once telomeres become critically short. This proliferation limit is important as a tumor suppressive mechanism, but also contributes to the degenerative conditions associated with cellular aging. In cell types that require continuous renewal, transient expression of telomerase delays proliferation arrest by the de novo synthesis of telomere repeats. Data from our work and others' has shown that deficient telomerase activity has a negative impact on normal human physiology. In the bone marrow failure syndrome dyskeratosis congenita, telomerase enzyme deficiency leads to the premature shortening of telomeres. Premature telomere shortening most grievously affects tissues that have a rapid turnover, such as the hematopoietic and epithelial compartments. In the most severe cases, compromised renewal of hematopoietic stem cells leads to bone marrow failure and premature death. Telomerase activation/replacement shows potential as a therapy for telomere maintenance deficiency syndromes, and in tissue engineering for the degenerative conditions that are associated with normal aging. Conversely, clinical researchers are developing telomerase inhibition therapies to treat tumors, which overcome the short-telomere barrier to unrestricted proliferation by over-expressing telomerase.  相似文献   

5.
Accelerated telomere shortening in response to life stress   总被引:4,自引:0,他引:4       下载免费PDF全文
Numerous studies demonstrate links between chronic stress and indices of poor health, including risk factors for cardiovascular disease and poorer immune function. Nevertheless, the exact mechanisms of how stress gets "under the skin" remain elusive. We investigated the hypothesis that stress impacts health by modulating the rate of cellular aging. Here we provide evidence that psychological stress--both perceived stress and chronicity of stress--is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, which are known determinants of cell senescence and longevity, in peripheral blood mononuclear cells from healthy premenopausal women. Women with the highest levels of perceived stress have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women. These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age-related diseases.  相似文献   

6.
Telomere shortening and telomerase activation in human somatic cells have been implicated in cell immortalization and cellular senescence. To further study the role of telomerase in immortalization, we assayed telomere length and telomerase activity in primary mouse fibroblasts, in spontaneously immortalized cell clones, and in mouse tissues. In the primary cell cultures, telomere length decreased with increased cell doublings and telomerase activity was not detected. In contrast, in spontaneously immortalized clones, telomeres were maintained at a stable length and telomerase activity was present. To determine if telomere shortening occurs in vivo, we assayed for telomerase and telomere length in tissues from mice of different ages. Telomere length was similar among different tissues within a newborn mouse, whereas telomere length differed between tissues in an adult mouse. These findings suggest that there is tissue-specific regulation of mouse telomerase during development and aging in vivo. In contrast to human tissues, most mouse tissues had active telomerase. The presence of telomerase in these tissues may reflect the ease of immortalization of primary mouse cells relative to human cells in culture.  相似文献   

7.
Division-dependent telomere shortening correlating with age triggers senescence on a cellular level and telomere dysfunction can facilitate oncogenesis. Therefore, the study of telomere biology is critical to the understanding of aging and cancer. The domestic chicken, a classic model for the study of developmental biology, possesses a telomere genome with highly conserved aspects and distinctive features which make it uniquely suited for the study of telomere maintenance mechanisms, their function and dysfunction. The purpose of this review is to highlight the chicken as a model for aging research, specifically as a model for telomere and telomerase research, and to increase its utility as such by describing developments in the study of chicken telomeres and telomerase in the context of related research in human and mouse.  相似文献   

8.
9.
Telomerase activity in human ovarian carcinoma.   总被引:19,自引:0,他引:19       下载免费PDF全文
Telomeres fulfill the dual function of protecting eukaryotic chromosomes from illegitimate recombination and degradation and may aid in chromosome attachment to the nuclear membrane. We have previously shown that telomerase, the enzyme which synthesizes telomeric DNA, is not detected in normal somatic cells and that telomeres shorten with replicative age. In cells immortalized in vitro, activation of telomerase apparently stabilizes telomere length, preventing a critical destabilization of chromosomes, and cell proliferation continues even when telomeres are short. In vivo, telomeres of most tumors are shorter than telomeres of control tissues, suggesting an analogous role for the enzyme. To assess the relevance of telomerase and telomere stability in the development and progression of tumors, we have measured enzyme activity and telomere length in metastatic cells of epithelial ovarian carcinoma. We report that extremely short telomeres are maintained in these cells and that tumor cells, but not isogenic nonmalignant cells, express telomerase. Our findings suggest that progression of malignancy is ultimately dependent upon activation of telomerase and that telomerase inhibitors may be effective antitumor drugs.  相似文献   

10.
Eukaryotic chromosomes terminate with long stretches of short, guanine-rich repeats. These repeats are added de novo by a specialized enzyme, telomerase. In humans telomeres shorten during differentiation, presumably due to the absence of telomerase activity in somatic cells. This phenomenon forms the basis for several models of telomere role in cellular senescence. Barley (Hordeum vulgare L.) telomeres consist of thousands of TTTAGGG repeats, closely resembling other higher eukaryotes. In vivo differentiation and aging resulted in reduction of terminal restriction fragment length paralleled by a decrease of telomere repeat number. Dedifferentiation in callus culture resulted in an increase of the terminal restriction fragment length and in the number of telomere repeats. Long-term callus cultures had very long telomeres. Absolute telomere lengths were genotype dependent, but the relative changes due to differentiation, dedifferentiation, and long-term callus culture were consistent among genotypes. A model is presented to describe the potential role of the telomere length in regulation of a cell's mitotic activity and senescence.  相似文献   

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