端粒/端粒酶在恶性血液病中的研究进展

端粒是真核细胞染色体末端特有的一段DNA序列和几种特异性蛋白质构成的复合物。端粒酶是一种核糖核酶,能以自身RNA为模板,合成端粒DNA,从而维持端粒的长度。端粒/端粒酶的表达调控对肿瘤的发生发展及细胞的衰老、永生化起着重要的作用,深入研究端粒/端粒酶的结构功能及其在恶性血液病细胞和正常造血细胞中的表达和调控,将有助于达到控制和治疗恶性血液病的目的。     

端粒体--调节端粒的多聚复合体

因端粒与衰老、肿瘤密切相关,近年来对端粒调节的研究进一步深入。最近发现端粒长度的动态平衡是由端粒、端粒酶、端粒结合蛋白组成的高分子复合体———端粒体调节的。在端粒体中,端粒、端粒酶、端粒结合蛋白相互作用,共同完成对细胞基本生命活动的调节。近年来,分子生物学技术的进展从分子水平上阐明了端粒体各组分间的关系,为端粒长度的调节开辟了新的靶点。     

SUMO修饰与端粒维持

端粒(telomere)长度维持在一定的范围内是细胞正常生理功能的一个重要的基础,端粒长度的变化可导致两个截然相反的病理生理过程-癌变和衰老,端粒过长可引起细胞永生化而癌变,端粒进行性缩短则有丝分裂能力下降导致细胞衰老[1].端粒的长度和结构依赖端粒酶的活性及端粒蛋白复合体(shelterin)的调节[2],端粒酶的激活可引起端粒DNA序列增加而延长细胞的寿命.泛素样小分子修饰(small ubiquin-like modifier,SUMO修饰)在不同的端粒维持机制中的作用途径不同,SUMO修饰可激活端粒酶的活性,促进依赖端粒酶合成端粒的途径,SUMO修饰也可促进同源重组途径合成端粒的能力[3],增加端粒的长度,在保持端粒的长度上发挥重要的调节作用.     

硒的抗氧化作用与端粒酶关系的研究

硒在生命活动中发挥着重要的作用,如延缓衰老、抗肿瘤、预防心血管疾病、降低重金属的毒性、防治克山病、大骨节病和抗氧化等。作为调节细胞氧化还原状态的重要元素,在硒与细胞端粒酶活性和端粒长度作用的研究中,已发现硒促进酵母端粒酶活性、延长或维持酵母端粒长度。硒对哺乳动物细胞端粒酶和端粒的作用的研究报导的篇数则有限。本文就端粒、端粒酶和硒的关系作一综述。     

乳腺良恶性病变组织端粒长度和端粒酶活性检测

目的　比较乳腺良恶性病变端粒长度改变及其在肿瘤发生发展中的意义 ;探讨端粒酶活性与临床病理参数的关系及其在乳腺癌诊断中的价值。方法　Southern印迹杂交检测TRF长度 ,端粒重复扩增分析 (TRAP)方法检测端粒酶活性。结果　乳腺癌组织平均TRF为 (5 2± 2 8)kb ,与正常组织比较明显缩短 (P <0 0 0 1) ,从正常乳腺组织到乳腺良性病变、乳腺原位癌及浸润性癌平均TRF呈递减趋势。 5 8例乳腺癌中 4 9例端粒酶阳性 (84 7% ) ,端粒酶活性与临床病理参数无相关性 ;癌旁组织端粒酶为阴性 ,而 7例乳腺增生症和 6例乳腺纤维腺瘤中分别有 1例端粒酶阳性 ,与乳腺癌比其差异有显著性 (P <0 0 0 1)。结论　端粒长度在肿瘤发生发展过程中渐进性缩短 ,并最终触发端粒酶的激活 ;端粒酶活性检测有望成为乳腺癌诊断的可靠标记物     

1型糖尿病、2型糖尿病及2型糖尿病伴动脉硬化患者外周血白细胞端粒长度的研究

目的:检测1型糖尿病(T1DM)、2型糖尿病(T2DM)、2型糖尿病伴动脉硬化(DAS)患者外周血白细胞端粒长度,分析糖尿病患者端粒长度变化的因素。方法:选择T1DM患者30例、T2DM患者60例、DAS患者40例和健康对照(NC组)40例,分别提取外周血白细胞,然后提取基因组DNA进行real-time PCR检测端粒长度。利用多元线性回归分析影响端粒长度变化的因素。结果:T1DM组、T2DM组和DAS组的端粒长度均小于NC组(P0.05);T1DM组端粒长度短于T2DM组和DAS组;DAS组较T2DM组更短。多元线性回归分析显示,T1DM组中,年龄与端粒长度呈负相关(P0.05);T2DM组中,年龄、体重指数(BMI)与端粒长度呈负相关(P0.05);DAS组中,患病时间、BMI与端粒长度呈负相关(P0.05)。结论:糖尿病患者的外周血白细胞端粒长度明显短于正常人,并且T1DM患者端粒长度短于T2DM;在2型糖尿病的对比中,DAS患者的端粒长度明显短于T2DM。患者的年龄、患病时间、BMI与端粒长度的缩短有密切的关系。     

端粒(酶)同癌症与衰老关系的研究进展

端粒是真核生物染色体的天然末端,具有稳定染色体结构,避免遗传信息在复制过程中丢失的作用.端粒酶是端粒复制所必须的一种特殊的DNA聚合酶,在大多数的正常人体细胞中没有活性.在近年来的研究中,人们发现“衰老者的端粒缩短”,而且在约85％的肿瘤细胞中检测到了端粒酶活性.这些事实提示人们:端粒、端粒酶同癌症与衰老之间存在相关性.     

端粒、端粒酶、衰老与癌变

端粒和端粒酶与细胞增殖密切相关，在衰老和癌变过程中发挥重要作用。端粒的结构和长度变化、端粒酶的表达水平在众多相关蛋白所组成的复杂调控网络的作用下保持平衡。端粒酶也通过非端粒依赖性机制发挥细胞保护作用，可以促进干细胞激活和增殖。     

人端粒相关蛋白

端粒是染色体末端的特殊结构,由端粒DNA与端粒蛋白构成,维持染色体的稳定。端粒相关蛋白直接影响端粒的功能,调节端粒DNA的长度,与细胞的衰老和癌变密切相关。端粒蛋白包括端粒双链DNA结合蛋白、端粒单链DNA结合蛋白、其它端粒相关蛋白。端粒结合蛋白直接保护端粒DNA,端粒相关蛋白通过与端粒结合蛋白的相互作用间接影响端粒的功能。本文对这些端粒相关蛋白的细胞生物学功能的研究进展进行概述。     

端粒、端粒酶与抗衰老的研究进展

端粒是染色体末端的DNA重复序列,是染色体末端的"保护帽",它能维持染色体的稳定,防止染色体相互融合.端粒酶可以合成端粒,在端粒受损时能把端粒修复延长,可以让端粒不会因细胞分裂而有所损耗,使得细胞分裂的次数增加.本文就端粒、端粒酶与衰老的关系及其在抗衰老中的应用作一综述.     

端粒、端粒酶与肿瘤

瑞粒、端粒酶与肿瘤之间的密切关系提示攻克肿瘤的可能性,因此越来越引起人们的重视。本文就端粒、端粒酶与肿瘤的关系研究进展予以阐述。l端粒（Telomere）瑞拉是真核生物线形染色体3’末端一段重复DNA序列与结合蛋白的复合体l’］。在人类细胞中,这段重复DNA序列以（TTAGGG）n的形式存在,而在其他真核生物细胞,重复的端粒DNA单位的长度多为5到8个碱基对,亦富含鸟瞟吟（G）I’］。瑞拉结合蛋白是与端粒重复DNA序列结合的特异性蛋白。它能使端粒DNA避免被化学修饰和降解,还能参与瑞粒长度和瑞粒酶活性的调节［’］。瑞拉结…     

Telomeres and aging

Telomeres play a central role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on the basis of previous cell divisions and DNA damage. At least a few hundred nucleotides of telomere repeats must "cap" each chromosome end to avoid activation of DNA repair pathways. Repair of critically short or "uncapped" 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 germline which typically express high levels of telomerase. In somatic cells, telomere length is very heterogeneous but 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 and malignant cells, a process facilitated by the genome instability and aneuploidy triggered by dysfunctional telomeres. The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer. Here the role of telomeres and telomerase in human aging and aging-associated diseases is reviewed.     

Telomere biology in healthy aging and disease

Aging is a biological process that affects most cells, organisms and species. Telomeres have been postulated as a universal biological clock that shortens in parallel with aging in cells. Telomeres are located at the end of the chromosomes and consist of an evolutionary conserved repetitive nucleotide sequence ranging in length from a few hundred base pairs in yeast till several kilo base pairs in vertebrates. Telomeres associate with shelterin proteins and form a complex protecting the chromosomal deoxyribonucleic acid (DNA) from recognition by the DNA damage-repair system. Due to the “end-replication problem” telomeres shorten with each mitotic cycle resulting in cumulative telomere attrition during aging. When telomeres reach a critical length the cell will not further undergo cell divisions and become senescent or otherwise dysfunctional. Telomere shortening has not only been linked to aging but also to several age associated diseases, including tumorigenesis, coronary artery disease, and heart failure. In the current review, we will discuss the role of telomere biology in relation to aging and aging associated diseases.     

Role of telomere dysfunction in aging and its detection by biomarkers

Aging is a complex process that has been shown to be linked to accumulation of DNA damage. Telomere shortening represents a cell-intrinsic mechanism leading to DNA damage accumulation and activation of DNA damage checkpoints in aging cells. Activation of DNA damage checkpoints in response to telomere dysfunction results in induction of cellular senescence—a permanent cell cycle arrest. Senescence represents a tumor suppressor mechanism protecting cells from evolution of genomic instability and transformation. As a drawback, telomere shortening may also limit tissue renewal and regenerative capacity of tissues in response to aging and chronic disease. In aged organs, telomere shortening may also increase the cancer risk by initiation of chromosomal instability, loss of proliferative competition of aging stem cells, and selection of aberrant growing clones. Consequently, aged individuals are more susceptible and vulnerable to various diseases and show an increased cancer risk. Recently, proteins were discovered, which are induced by telomere dysfunction and DNA damage. It was shown that these proteins represent new biomarkers of human aging and disease. Here, we review the scientific background and experimental data on these newly discovered biomarkers.     

From cellular senescence to Alzheimer’s disease: The role of telomere shortening

The old age population is increasing worldwide as well as age related diseases, including neurodegenerative disorders, such as Alzheimer’s disease (AD), which negatively impacts on the health care systems. Aging represents per se a risk factor for AD. Thus, the study and identification of pathways within the biology of aging represent an important end point for the development of novel and effective disease-modifying drugs to treat, delay, or prevent AD. Cellular senescence and telomere shortening represent suitable and promising targets. Several studies show that cellular senescence is tightly interconnected to aging and AD, while the role of telomere dynamic and stability in AD pathogenesis is still unclear. This review will focus on the linking mechanisms between cellular senescence, telomere shortening, and AD.     

An evolutionary review of human telomere biology: The thrifty telomere hypothesis and notes on potential adaptive paternal effects

Telomeres, repetitive DNA sequences found at the ends of linear chromosomes, play a role in regulating cellular proliferation, and shorten with increasing age in proliferating human tissues. The rate of age‐related shortening of telomeres is highest early in life and decreases with age. Shortened telomeres are thought to limit the proliferation of cells and are associated with increased morbidity and mortality. Although natural selection is widely assumed to operate against long telomeres because they entail increased cancer risk, the evidence for this is mixed. Instead, here it is proposed that telomere length is primarily limited by energetic constraints. Cell proliferation is energetically expensive, so shorter telomeres should lead to a thrifty phenotype. Shorter telomeres are proposed to restrain adaptive immunity as an energy saving mechanism. Such a limited immune system, however, might also result in chronic infections, inflammatory stress, premature aging, and death—a more “disposable soma.” With an increased reproductive lifespan, the fitness costs of premature aging are higher and longer telomeres will be favored by selection. Telomeres exhibit a paternal effect whereby the offspring of older fathers have longer telomeres due to increased telomere lengths of sperm with age. This paternal effect is proposed to be an adaptive signal of the expected age of male reproduction in the environment offspring are born into. The offspring of lineages of older fathers will tend to have longer, and thereby less thrifty, telomeres, better preparing them for an environment with higher expected ages at reproduction. Am. J. Hum. Biol., 2011. © 2010 Wiley‐Liss, Inc.     

Telomere biology in human aging and aging syndromes

Telomeres, the extreme ends of the chromosomes play a key role in the process of cellular aging. Due to the 'end-replication-problem', successive shortening of the telomeres with each cell division results in a mitotic clock and it was shown in vitro that this clock limits the replicative capacity of cell proliferation. Telomerase counteracts telomere erosion and provides some somatic cells an unlimited proliferative potential in vitro. The present views of telomeres and telomerase functions in cellular aging in vitro are presented. Possibilities and limitations in the evaluation of the in vivo impact of telomere erosion on human aging, aging syndromes and age related diseases are reviewed. Unresolved questions, future experimental approaches and emerging therapeutic applications are discussed.     

Telomere biology and the molecular basis of aging

Process of aging is regulated on the level of organism, clones and cellular level. Genes regulating aging on the individual (organism) level are detected in unicellular fungi. Mutations of such genes may lead to life lengthening by 60%. A similar gene is found in mice. Aging at the clonal level takes place by means of telomere shortening--that of DNA regions close to chromosome endings. Telomere shortening results in the chromosomes instability, their breaks and mutations, this apparently being a mechanism responsible for the increase of cancer incidence at advanced age. Telomerase is an enzyme responsible for the stability of the telomere length, supporting proliferation and by this that of life. This explains the increase of telomerase activity practically in all cases of malignant tumors. Aging is regulated by molecular components of cell cycle on cellular level.     

Epigenetic clock: A promising biomarker and practical tool in aging

As a complicated process, aging is characterized by various changes at the cellular, subcellular and nuclear levels, one of which is epigenetic aging. With increasing awareness of the critical role that epigenetic alternations play in aging, DNA methylation patterns have been employed as a measure of biological age, currently referred to as the epigenetic clock. This review provides a comprehensive overview of the epigenetic clock as a biomarker of aging and a useful tool to manage healthy aging. In this burgeoning scientific field, various kinds of epigenetic clocks continue to emerge, including Horvath’s clock, Hannum’s clock, DNA PhenoAge, and DNA GrimAge. We hereby present the most classic epigenetic clocks, as well as their differences. Correlations of epigenetic age with morbidity, mortality and other factors suggest the potential of epigenetic clocks for risk prediction and identification in the context of aging. In particular, we summarize studies on promising age-reversing interventions, with epigenetic clocks employed as a practical tool in the efficacy evaluation. We also discuss how the lack of higher-quality information poses a major challenge, and offer some suggestions to address existing obstacles. Hopefully, our review will help provide an appropriate understanding of the epigenetic clocks, thereby enabling novel insights into the aging process and how it can be manipulated to promote healthy aging.     

Telomere length – A cellular aging marker for depression and Post-traumatic Stress Disorder

Telomeres play a central role in cell fate and aging by adjusting the cellular response to both biological and psychological stress. Human telomeres are regions of tandem TTAGGG repeats at chromosomal ends that protect chromosomes from degradation, fusion, and recombination. They are made up of approximately 1000–2500 copies of the repeated DNA sequence. Over time, at each cell division, the telomere ends become shorter. Thus, telomere length (TL) has been considered a cellular marker for age-related diseases. In addition to biochemical stressors such as oxidation and inflammation, psychosocial traumatic stress has also been linked to shorter telomeres. TL is significantly inversely correlated with long-term depression, even after controlling for age. Average TL in depressed subjects, who were above the median of lifetime depression, was 281 base pairs shorter than that in controls, corresponding to approximately 7 years of accelerated cell aging. Several recent studies have also demonstrated an inverse relationship between leukocyte telomere length (LTL) and the risk of PTSD. TL was inversely correlated with the duration of caregiving and PTSD. Here, we focus on the discussion of findings in studies of the relationships between stress-related disorders (e.g., depression and PTSD) and telomeres. We also present direct evidence that TL is associated with traumatic stress, depression, and PTSD, and hypothesize that traumatic stress affects not only mental disorders but also cellular aging. The nature of this relationship between stress and TL warrants further evaluation in psychiatry.