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1.
Signaling on telomerase: a master switch in cell aging and immortalization   总被引:3,自引:0,他引:3  
Li H  Liu JP 《Biogerontology》2002,3(1-2):107-116
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2.
Although human atherosclerosis is associated with aging, direct evidence of cellular senescence and the mechanism of senescence in vascular smooth muscle cells (VSMCs) in atherosclerotic plaques is lacking. We examined normal vessels and plaques by histochemistry, Southern blotting, and fluorescence in situ hybridization for telomere signals. VSMCs in fibrous caps expressed markers of senescence (senescence-associated beta-galactosidase [SAbetaG] and the cyclin-dependent kinase inhibitors [cdkis] p16 and p21) not seen in normal vessels. In matched samples from the same individual, plaques demonstrated markedly shorter telomeres than normal vessels. Fibrous cap VSMCs exhibited markedly shorter telomeres compared with normal medial VSMCs. Telomere shortening was closely associated with increasing severity of atherosclerosis. In vitro, plaque VSMCs demonstrated morphological features of senescence, increased SAbetaG expression, reduced proliferation, and premature senescence. VSMC senescence was mediated by changes in cyclins D/E, p16, p21, and pRB, and plaque VSMCs could reenter the cell cycle by hyperphosphorylating pRB. Both plaque and normal VSMCs expressed low levels of telomerase. However, telomerase expression alone rescued plaque VSMC senescence despite short telomeres, normalizing the cdki/pRB changes. In vivo, plaque VSMCs exhibited oxidative DNA damage, suggesting that telomere damage may be induced by oxidant stress. Furthermore, oxidants induced premature senescence in vitro, with accelerated telomere shortening and reduced telomerase activity. We conclude that human atherosclerosis is characterized by senescence of VSMCs, accelerated by oxidative stress-induced DNA damage, inhibition of telomerase and marked telomere shortening. Prevention of cellular senescence may be a novel therapeutic target in atherosclerosis.  相似文献   

3.
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   

4.
Aging is a major risk factor for hypertension and associated cardiovascular disease. In most proliferative tissues, aging is characterized by shortening of the DNA component of telomeres, the specialized genetic segments that cap the end of eukaryotic chromosomes and protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, telomere shortening is thought to contribute to organismal aging and to the development of age-related diseases. Here, we review animal and human studies that have investigated the possible links between telomere ablation and the pathogenesis of hypertension and related target organ damage. Although evidence is mounting that alterations in telomerase activity and telomere shortening may play a role in the pathogenesis of hypertension, additional studies are required to understand the molecular mechanisms by which telomere dysfunction and hypertension are functionally connected. As our knowledge on this emerging field grows, the challenge will be to ascertain whether all this information might translate into clinical applications.  相似文献   

5.
Telomeres form specialized structures at the ends of eukaryotic chromosomes, preventing them from being wrongly recognized as DNA damage. The human telomere DNA sequence is a tandem repetition of the sequence TTAGGG. In normal cells, the DNA replication machinery is unable to completely duplicate the telomeric DNA; thus, telomeres are shortened after every cell division. Having reached a critical length, telomeres may be recognized as double strand break DNA lesions, and cells eventually enter senescence. Carcinogenesis is a multistep process involving multiple mutations and chromosomal aberrations. One of the most prevalent aberrations in pre-cancerous lesions is telomere shortening and telomerase activation. We discuss the role and homeostasis of telomeres in normal cells and their implication in the early steps of carcinogenesis. We also discuss various techniques used, and their limitations, in the study of telomeres and genome instability and their role in carcinogenesis and related genomic modifications.  相似文献   

6.
Telomeres lie at the ends of human chromosomes and contain long tandem repeats of a simple nucleotide sequence. Because DNA replication cannot proceed to the very end of chromosomes, copies of these repeats are lost at each cell division. If the telomeres shorten below a critical length, the cells will eventually die as a result of genomic instability. Aging cells usually avoid death by entering senescence before the critical telomere length is reached. Malignantly transformed, immortal cells overcome senescence but they must still avoid the final, critical shortening of telomeres to survive. In the vast majority of cases, tumor cells achieve this by activating the telomerase enzyme, a ribonucleoprotein complex which repairs the end of chromosomes and prevents telomere shortening. Normal mortal cells do not normally express telomerase, although some stem cell populations which must regenerate thought the life span of the organism, retain enzyme activity. Cellular senescence can be overcome by inducing telomerase expression in mortal cells, firmly establishing the role of telomere length in the senescence signaling pathway. In tumor cells, the evidence of a role for telomerase in immortality is still largely correlative, with 80–90% of tumors expressing telomerase activity. To establish whether telomerase activity is important in maintaining the malignant phenotype, attempts have been made to inactivate it in tumor cells, using a variety of approaches, where there is evidence that disrupting telomerase function can result in the induction of apoptosis. The background and implications of these observations is discussed.  相似文献   

7.
Telomerase is an enzyme capable of elongating telomeres, the caps at the ends of chromosomes associated with aging, lifespan and survival. We investigated tissue-level variation in telomerase across different ages in four bird species that vary widely in their life history. Telomerase activity in bone marrow may be associated with the rate of erythrocyte telomere shortening; birds with lower rates of telomere shortening and longer lifespans have higher bone marrow telomerase activity throughout life. Telomerase activity in all of the species appears to be tightly correlated with the proliferative potential of specific organs, and it is also highest in the hatchling age-class, when the proliferative demands of most organs are the highest. This study offers an alternative view to the commonly held hypothesis that telomerase activity is down-regulated in all post-mitotic somatic tissues in long-lived organisms as a tumor-protective mechanism. This highlights the need for more comparative analyses of telomerase, lifespan and the incidence of tumor formation.  相似文献   

8.
Accumulation of cellular damage with advancing age leads to atherothrombosis and associated cardiovascular disease. Ageing is also characterized by shortening of the DNA component of telomeres, the specialized genetic segments located at the end of eukaryotic chromosomes that protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, shortening of the telomeric DNA is thought to contribute to organismal ageing. In this Review, we discuss experimental and human studies that have linked telomeres and associated proteins to several factors which influence cardiovascular risk (eg, estrogens, oxidative stress, hypertension, diabetes, and psychological stress), as well as to neovascularization and the pathogenesis of atherosclerosis and heart disease. Two chief questions that remain unanswered are whether telomere shortening is cause or consequence of cardiovascular disease, and whether therapies targeting the telomere may find application in treating these disorders (eg, cell "telomerization" to engineer blood vessels of clinical value for bypass surgery, and to facilitate cell-based myocardial regeneration strategies). Given that most research to date has focused on the role of telomerase, it is also of up most importance to investigate whether alterations in additional telomere-associated proteins may contribute to the pathogenesis of cardiovascular disease.  相似文献   

9.
In the absence of telomerase or other mechanisms to maintain their length, telomeres in human cells shorten at each round of cell division. This has been suggested to ultimately cause cell cycle exit when a critical telomere length is reached, leading to replicative senescence of the cell. At present, it is not clear whether the division potential of human cells is limited by the overall shortening of telomeres at all chromosomes or the shortening of specific telomeres on certain particular chromosomes. By computer simulations, my previous work has suggested that if the telomere theory is correct, the shortening of only a few, most likely two, telomeres might be preferentially involved in restricting the division of human cells. In this work, the length dynamics of individual telomeres in simulated cell clones were examined over their life span. It is shown that if the shortening of only two telomeres is responsible for restricting the proliferation of a cell, these two specific telomeres will shorten at different rates and have different length distributions from those of the rest telomeres. The unique pattern of length dynamics associated with the proliferation-restricting telomeres (PRT) provides a possibility of experimentally identifying these particular telomeres in human cells.  相似文献   

10.
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   

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