Telomere, aging and age-related diseases - Springer Link

Aging Clin Exp Res (2013) 25:139–146 DOI 10.1007/s40520-013-0021-1

MINI REVIEW

Telomere, aging and age-related diseases Huanjiu Xi • Changyong Li • Fu Ren Hailong Zhang • Luping Zhang

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Received: 11 July 2011 / Accepted: 30 March 2012 / Published online: 3 April 2013 Ó Springer International Publishing Switzerland 2013

Abstract Aging is an inevitable biological process that affects most living organisms. The process of aging is regulated at the level of the organism, as well as at the level of tissues and cells. Despite the enormous consequences associated with the aging process, relatively little systematic effort has been expended on the scientific understanding of this important life process. Many theories have been proposed to explain the aging process, the centerpiece of which is molecular damage. Located at the ends of eukaryotic chromosomes and synthesized by telomerase, telomeres maintain the stabilization of chromosomes. Thus, the loss of telomeres may lead to DNA damage. The relationship between cellular senescence and telomere shortening is well established. Furthermore, telomere attrition occurs with age, and is proposed to be a fundamental factor in the aging process. Here, we review the contemporary literatures to explore the current views on the correlation of telomere loss and telomerase action with aging and age-related diseases. Keywords Telomere Telomerase Aging Cell senescence Age-related diseases

Introduction Aging is characterized as degenerative changes progressively occurring in most cells, organisms and species. The nature of the aging process has been the subject of considerable speculation. Over the past four decades, there has been a concerted effort, at the molecular level, to understand better the changes that take place during aging. Observations from these studies have implicated aging as a genetically programed process where the total life span of an organism is remarkably constant and species specific. Many theories have been proposed to explain the aging process. Some researchers have suggested that telomeres play an important role in cellular senescence [1–3]. Indeed, of all the various theories proposed, the telomere hypothesis has become the recent focus of debate. Telomere length shortening has been recognized as not only a marker of biological aging but also reveals an important role in multiple aging-related diseases [2, 4–7]. The aim of this review is to summarize the relationships between telomere loss and human aging and age-related diseases.

Telomere and cell senescence H. Xi (&) F. Ren H. Zhang Institute of Anthropology, Liaoning Medical University, No.40, Section 3, Songpo Road, Jinzhou, Liaoning 121001, People’s Republic of China e-mail: [email protected] C. Li Department of Physiology, School of Basic Medical Sciences, Wuhan University, Hubei 430071, People’s Republic of China L. Zhang Department of Anatomy, Second Military Medical University, Shanghai 200433, People’s Republic of China

Telomere structure and the length regulation Telomeres, located at the ends of chromosomes in eukaryotes, are composed of TTAGGG repeats that are extended 9–15 kb, which can protect the chromosomes from degradation, fusion and recombination [8]. Normal telomeres do not trigger a DNA damage response. Extensive studies in unicellular organisms have shown that telomere function requires both specific DNA sequences and specific proteins [9]. The current telomere model

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includes a telomere (T)-loop, and a displacement (D)-loop associated with telomere-binding proteins. As a protective cap, this structure can prevent the chromosome from being recognized as DNA damnification by DNA repair complexes, which would subsequently result in end-to-end fusion, recombination and degradation, and thus lead to chromosome instability and cell death [10]. The regulation of telomere length is a complex process, requiring the telomerase enzyme complex and numerous regulatory proteins. The shelterin complex consists of six proteins, TRF1, TRF2, RAP1, TIN2, TPP1 and POT1. It binds to both the duplex and ssDNA regions through specific protein–DNA interactions and shelters the telomere from a series of unwanted activities [11]. The two major telomerebinding proteins are telomeric repeat binding factor 1 (TRF1) and 2 (TRF2) [12]. They can function individually or interact with other binding proteins, such as POT1, Rap1, TIN2, hRap1, Ku86 and the Mre11/Rad50/Nbs1 DNA repair complex [13]. These binding proteins both play an important role in the regulation of telomere length. TRF1 is a negative regulator of telomere length, which depends on a feedback mechanism involving telomerase, whilst TRF2 is found in the double-strand T-loop and in the loop tail junction, and probably acts in the stabilization of the G-strand overhang at D-loop [12]. More recently, ataxia telangiectasia mutated (ATM), a PI-3 kinase essential for maintaining genomic stability, has been shown to regulate proteasome-dependent subnuclear localization of TRF1, which is important for telomere maintenance [14]. Many more proteins involved in the proper function of human telomeres are expected to be identified in the future. Telomerase is a ribonucleoprotein reverse transcriptase which stabilizes telomere length by adding TTAGGG repeats to the ends of the chromosomes. It consists of two main components, telomere RNA, which acts as template for telomere synthesis, and telomere reverse transcriptase, which catalyzes the elongation [15]. Whereas telomerase activity is low or undetectable in most normal somatic cells, it is detected at higher levels both in the germ cells and in the majority of cancer cells [2, 16], in the latter case, the activity of telomerase maintains the length of telomere and confers cancer cells high proliferation capacity. It has been shown that telomerase activity was associated with cell cycle deregulation in human cancer cells and telomerase activity was inversely associated with the level of cell differentiation [17]. Human cells must overcome two barriers to proliferate and achieve immortalization [8]. The first is mortality stage 1, which results in telomere shortening and cell proliferation arrest. Following the first stage, the telomeres continue to shorten and eventually reach the second proliferation barrier, mortality stage 2. Cells with extremely short telomeres then undergo apoptosis. Rarely, cells escape the

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crisis and telomerase is activated causing immortalization to occur [18, 19]. Currently, little information is available on how germ cells allow telomerase-mediated telomere elongation which differs from somatic cells. Lanza et al. [20] have indicated that telomeres can also be elongated during development. Research in these areas will eventually elucidate the diversities in both gene and protein expression between the germ cells and somatic cells and the importance of telomere length regulation in the latter. However, the greatest threat to telomere function seems to be the gradual loss of telomere DNA in somatic cells with each round of cell division. The gradual shortening of telomeres is assumed to limit the capability of cells to proliferate, and eventually affect the health and lifespan of an individual [21, 22]. Recently, there has been growing evidence that lifestyle factors may affect human health and lifespan by affecting telomere length [2, 11, 23, 24]. Interestingly, telomerase activity was increased with improvements in nutrition and lifestyle in peripheral blood mononuclear cells [25]. These studies provide compelling reasons to conduct intervention studies to reduce early illness and extend years of healthy living in the future. Optimal diet and healthy lifestyle behaviors have great potential to reduce the rate of telomere shortening or at least prevent excessive telomere attrition, leading to delayed onset of age-associated diseases and increased lifespan. Telomere hypothesis of cell senescence Incomplete replication of the 30 end of telomere DNA is thought to be responsible for the replication-dependent telomere shortening. In most somatic cells, telomeres shorten with successive cell divisions. Therefore, normal somatic cells undergo a finite number of cell divisions, and the maximum number of divisions is known as ‘‘Hayflick limit’’ [26]. The mechanism by which cell division ceases due to telomere shortening is not yet fully understood, although three possible hypotheses have so far been proposed. The first hypothesis suggests that telomeres are characterized by heterochromatin. After the telomere length is shorted, it will attack the nearby DNA and will thus affect the expression of genes that are responsible for the regulation of growth. It has been found that gene transferation near telomere DNA has been restrained in low-level eukaryote. The second hypothesis assumes that the total loss of telomere DNA will produce a damaging signal, which will activate P53 and thus cause an inhibition in growth. The third hypothesis proposes that it is not the damaging signal but the shortened telomere itself that activates P53 and causes permanent restraint of growth. The key mediator of the response to dysfunctional telomere is P53 [16]. Recent


evidence indicates that at the senescence stage critically short telomeres lose the capping function and this can induce DNA damage, which is partially dependent on the activity of the PI3-kinase-like kinase ATM [27]. Although the precise mechanisms causing dysfunctional telomeres to trigger a DNA damage response are unclear, the telomere erosion that occurs during normal replication induces all of the hallmarks of a DNA damage response [28]. Mutation of ATM also attenuates apoptotic responses to telomere dysfunction caused by dominant negative expression of telomere-binding protein TRF2 [29]. Thus, the disruption of the native telomere structure triggers an active DNA damage response, which is largely indistinguishable from the response to ionizing radiation [1]. Telomere and its complex are involved in biological aging and disease processes. The evidence to support the assumption that telomere shortening is related to aging was put forward by Allsopp et al. [26]. They analyzed human fibroblasts from 31 donors and found relatively weak correlations between proliferative ability and donor age. However, there was a striking correlation between replicative capacity and initial telomere length. Their findings suggested that telomere length may be used as a biomarker of somatic cell aging in humans, which is consistent with the important role of telomere loss involving in mechanisms of aging. Wright et al. [30] subsequently used widowed nucleotide acid to dispose immortal human cells in order to extend telomere length and then integrate them with fatal cells. They found that these crossbreed cells tend to have better longevity than those immortal cells that have not been disposed by widowed nucleotide acid. In this case, Wright et al. provided direct evidence to support the hypothesis that length of telomere determines the multiplying capacity of human cells. An increasing body of evidence have demonstrated that the shortening of telomeres to a critical or threshold length acts as a signal for cell senescence [3, 26]. The replicative capacity was found to be directly proportional to the mean telomere length. More importantly, the variability in mean telomere length at senescence was markedly less than that at early passage. Although initial telomere length cannot account for all of the interclonal variability in replicative capacity, these observations supported the existence of a critical telomere length in senescing cells and an important role of telomere shortening in cell senescence [31]. Importantly, when telomerase was introduced into somatic cells, it extended the proliferative lifespan and prevents replicative senescence in human lens epithelial cells [32]. Moreover, studies have also shown that the replicative life span of various human cells can be prolonged by induced expression of the telomerase reverse transcriptase (hTERT) gene. Bodnar et al. [33] transfected

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two telomerase-negative normal human cell types (retinal pigment epithelial cells and foreskin fibroblasts) with vectors encoding the human telomerase catalytic subunit. The telomerase-negative control clones exhibited telomere shortening and senescence, while the telomerase-expressing clones had elongated telomeres, divided vigorously, and showed reduced staining for beta-galactosidase, a biomarker for senescence. Notably, the telomeraseexpressing clones exhibited a normal karyotype and have already exceeded their normal life span by at least 20 doublings. Thus, this research establishes a causal relationship between telomere shortening and in vitro cellular senescence. New trends in telomerase manipulation show that hTERT can be used to immortalize a variety of differentiated human cell types including epithelial cells of renal proximal tubules [19, 34]. In humans, telomere length positively correlates with years of healthy life in health, aging, and body composition [35]. Telomere length could be considered as a biological parameter that intertwines replicative history and exposure to environmental stress [7]. In addition, there is a high variance in telomere length in humans. Telomere in female is longer than male and in African Americans than in White Americans [36]. Our own data have also demonstrated that telomeres shorten in human peripheral blood leukocytes in an age-dependent manner, and that telomere length was significantly longer in peripheral blood leukocytes from females than in those from males, specially, in two age groups (5–14 years old and 55–64 years old) [37]. Our findings suggest that estimation of human age according to telomere shortening in peripheral blood leukocytes is a novel method especially when there is no morphologic information in forensic practice [37]. In some types of premature senility syndrome, there is exceptional metabolization occurring with the normal somatic cell division. Vaziri et al. [38] have shown that Down syndrome patients showed a significantly higher rate of telomere loss with donor age compared with age-matched controls and they suggested that accelerated telomere loss is a biomarker of premature immunosenescence of Down syndrome patients and that it may play a role in this process.

Telomere and age-related diseases It is well established that telomere length and telomerase activity are important factors in the pathogenesis of human diseases [2, 6, 7, 39, 40]. Telomerase activation may prove to be useful in the treatment of chronic and degenerative diseases associated with telomere loss [41]. We summarize information on the age-related diseases below, which have been proposed to be related to telomeres.

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Cardiovascular diseases Atherosclerosis is also an aging-related systemic disease. The studies in vitro and vivo showed a tight interplay between cell senescence and atherosclerosis [42]. Telomere length is a new marker of cardiovascular risk [6, 43, 44]. In the vascular endothelium, shorter telomeres are found in those areas of the arterial wall that are more susceptible to atherosclerosis because of higher haemodynamic stress. It is believed that this stress results in a more rapid cell turnover [45]. In addition, vascular endothelial cells and smooth muscle cells in the vicinity of atherosclerotic lesions often stain positive for the activity of b-galactosidase, which is a rather nonspecific marker for cellular senescence [46, 47]. Furthermore, the induction of telomere dysfunction in endothelial cells in vitro generates a senescent phenotype with an atherogenic protein expression profile [46]. Healthy individuals with shorter telomere were likely to develop hypertension, and hypertensive individuals with shorter telomere were more susceptible to develop atherosclerosis [48]. The animal experiments showed that endothelial progenitor cells from hypertensive patients and from spontaneous hypertensive rats exhibit reduced telomerase activity and accelerated senescence [49]. Heart failure is a frequent cause of death in the aging human population. To determine whether telomere shortening leads to a cardiac phenotype, Leri et al. studied heart function in the telomerase knockout mouse. They showed that telomere attrition is a key factor in the attenuation of cardiac myocyte proliferation, myocyte hypertrophy and heart failure. Telomere shortening with age might also contribute to cardiac failure in humans, opening the possibility for new therapies [50]. Chronic heart failure is characterized by increased myocyte apoptosis and telomere erosion [51]. The degree of telomere shortening is associated with the severity of disease [52]. In humans, the formation of myocytes from telomerase-positive cardiac stem cells appears to be necessary for cardiac homeostasis [53]. Endomyocardial tissue from heart failure patients has been shown to have higher levels of both apoptotic and apparently senescent cells, and the telomeres are shorter than their control counterparts [54, 55]. These reports demonstrate that the heart diseases are characterized by shorter telomeres, increased cellular senescence and cell death. Diabetes Type 2 diabetes is caused by a combination of peripheral insulin resistance and b-cell dysfunction. Zee and Salpea et al. [56, 57] showed that short telomere were significantly associated with type 2 diabetes, which could be partially attributed to the high oxidative stress in the patients with type 2 diabetes. Moreover, short telomeres are predictors of

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progression of diabetic nephropathy [58] and of all-cause mortality in the patients with type 1 diabetes [59]. In a prospective follow-up study, Astrup et al. [59] found no differences in telomere length between patients with or without diabetic nephropathy. Young adult mice that are deficient in telomerase exhibit impaired glucose tolerance, which suggests short telomere can impair replicative capacity of pancreatic b-cell [60]. Telomeres also were shorter in pre-diabetes patients with impaired glucose tolerance than in healthy controls and in diabetic patients with atherosclerotic plaques than patients without atherosclerosis [61]. Information from the Framingham Heart Study suggests that subclinical presence of insulin resistance was associated with reduced telomere length [62]. The subjects with type 2 diabetes and with atherosclerotic plaques had shorter telomere than those without plaques [61]. Cancer The classical telomere hypothesis suggests that the telomere shortening provides a tumor suppressor mechanism to cease the growth of transformed cells. In normal somatic cells, the absence of telomerase can lead to telomere shortening and cell senescence. However, the majority of cancer cells exhibit a high telomerase activity [16]. The reappearance of telomerase activity is triggered by as yet unclear molecular mechanisms and enables cancer cells to maintain telomere length. Studies have revealed a dual role of telomere shortening in carcinogenesis. On the one hand, shortened telomeres induce chromosomal instability, which is the most important cause of cancer initiation during aging [27]. On the other hand, telomere stabilization is required for tumor progression [27, 63]. The initiation of chromosomal aberrations by telomere shortening might contribute to the increased cancer rate of cancer onset during aging. The necessity of telomere stabilization for tumor progression in most human cancers is achieved by the reactivation of telomerase [63]. However, reports of cancer formation in telomerase transgenic mice suggest that telomerase also exhibits tumor-promoting activity. Several observations on the presence of telomerase in non-transformed human cells [63] and the extra-telomeric function of telomerase [64] might provide some explanations for the tumor initiating activity of telomerase. Further understanding of the genetic alterations that cooperate with telomere dysfunction might help us to find new tumor marker genes and therapeutic targets to prevent and treat cancer in old people. Clinical data showed that telomere length of lymphocytes is shorter in patients with some cancers in the head, neck, breast, bladder, prostate, lung and kidney [65].


Telomere length undergoes shortening in early stage gastric carcinoma and lengthening in advanced gastric carcinoma. Additionally, telomere shortening may initiate the tumorigenesis of gastric carcinoma [66]. The ongoing basic research in this field helps to constantly define new targets and to increase the specificity, safety and efficacy of existing therapeutic approaches directed against telomeres and telomerase. Hahn et al. [67] have demonstrated that inhibition of telomerase limits the growth of human cancer cells. Therefore, therapies targeting telomerase with telomerase inhibitors revealed the potential for cancer therapy [68–70]. Recent research developments for each of the anti-telomerase approaches including antisense-oligonucleotides, hammerhead ribozymes, dominant negative hTERT, reverse-transcriptase inhibitors, immunotherapy, G-quadruplex stabilisers, gene therapy, small molecule inhibitors and RNA interference have been provided [71]. However, there are several limitations of anti-telomerase cancer therapy. For example, there is a lag phase between telomerase inhibition and the occurrence of senescence as a reversal of the immortal phenotype, and so their use will be probably restricted to enhance the efficiency of other anticancer agents or to prevent cancer relapse following standard therapies. Moreover, the role played by the telomerase-independent mechanism, which was reported to maintain telomere length in cell lines as well as in particular subset of tumors is still unclear. Uncoupling tumor suppression from aging represents undoubtedly one of the most daunting challenges for telomere and cellular senescence research [72]. Despite these problems, it is still exciting to discover that a promising therapeutic vaccine and a telomerase antagonist are now being employed in clinical and preclinical studies. Immune system diseases The immune system is a prime example of a highly dynamic cellular system, for which telomere maintenance is pivotal. Immune competence is strictly dependent on rapid expansions of clonal T- and B-cell populations, and telomere loss may contribute to defective immune responses in the elderly. Equally interestingly, accelerated T-cell aging combined with telomeric shortening may prompt an autoimmune response and thereby explain the increased susceptibility for chronic inflammatory diseases in the elderly [73]. Recent reports have suggested that telomere shortening is involved in the dramatic age-related alterations of the immune system, and this is considered one of the major factors affecting morbidity and mortality [74]. More recent data indicate that telomerase activity and telomere length are modified in various systemic immunemediated diseases and appear to be connected with premature immunosenescence [75].

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The gradual decline with age in the capacity of the immune system to recognize and eliminate antigens is an important causal factor for many diseases in the elderly [40]. Although both the innate and adaptive immune responses are weakened in old people, it is the decline in T-cell action that proves to have the most injurious effect on the elderly [76]. T cells become clonally exhausted, which leads to a decline in the adaptability of the response of the immune system [77]. The senescence of T cells in vivo is well documented: as the number of population doublings in culture increases then there is a progressive decrease in the proportion of T cells that express CD28. This results in an inability of the T cells to proliferate [78] and a reduction in telomerase induction by CD28, as well as a resistance to apoptosis [79, 80]. In addition, research on bone marrow transplantation has provided important clues for the in vivo interactions of immunosenescence and telomere length and consequences [81]. The main body of clinical evidence that provides a role for telomere erosion in the decline of immunity comes from studies on premature aging syndromes such as ataxia telangiectasia and dyskeratosis congenital where dysfunctional telomeres are associated with a higher susceptibility to infection. In addition, it has been shown that individuals with short telomeres are eight times more likely to die of infectious diseases than those with long telomeres [82]. Dyskeratosis congenital Defective telomere function or mutations in the DNA repair system can induce some human disorders associated with shorter telomere length, such as dyskeratosis congenital (DC) [83]. Most direct evidence for telomere shortening during human aging comes from research on DC, which is a premature aging disease characterized by telomerase and telomere dysfunction [84, 85]. Autosomal dominant dyskeratosis congenita is associated with mutations in the RNA component of telomerase, while X-linked dyskeratosis congenita is due to mutations in the gene encoding dyskerin, a protein implicated in both telomerase function and ribosomal RNA processing [86]. Thus, it might be one of the first diseases where a telomerase activating gene therapy can be implemented. This approach might help to prolong the lifespan of DC patients and might also shed some light on the therapeutic potentials and risks involved in telomerase activation therapy.

A concluding remark Although an increased knowledge about the biomarker value of telomere length in human aging might significantly

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improve our insight into the pathophysiology of human aging and aging-associated diseases, and yield a valuable risk factor, the true nature of the association remains unclear. Fewer studies have assessed the relationship between telomere length and age-sensitive measures of function that decline with normal aging in human population studies [87]. In addition, it is difficult to explain rationally some of the research results. For example, the ‘‘forced’’ expression of telomerase in cells with normallength telomeres has shown that telomerase promotes growth and survival in a manner that is uncoupled from telomere lengthening. This finding suggests that telomerase might play a fundamental role in tumor growth and survival, even at stages when telomeres are sufficiently long [88]. In addition, telomerase activity is low or undetectable in the endothelial and epithelial cells from the human cornea. These human corneal endothelial cells have long telomeres throughout life and their limited replicative ability does not appear to result from critically short telomere lengths [89]. As we know, the regulation of the process of aging is highly complex, involving a combination of telomere alterations, DNA damage, DNA methylation and cellular oxidation. Many theories have been proposed to explain the aging process. Telomeres have been proposed to play an important role in cellular senescence, and the telomere hypothesis, which is the focus of much debate and some controversy, will manifest an important theoretical and practical significance in anti-aging research. Indeed, the current findings have already inspired a number of potential therapeutic strategies that are based on telomerase and telomeres. Although the impact of these findings remains speculative, it is a hopeful thought that telomere elongation could possibly originate from an increased telomerase activity. Acknowledgments This work was supported by grants from the National Natural and Science Foundation of China (30830062, 30971529, 30840047). Conflict of interest

The authors disclose no conflicts.

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