**1. Introduction**

The telomere structure is essential for maintaining chromosomal stability. It prevents the chromosome ends from being identified as damaged DNA and, therefore, nucleolytic degra‐ dation, chromosome end‐to‐end fusion, and break‐fusion‐bridge cycle (reviewed by Kahl et al. [1]). Human telomeres are nucleoprotein structures that consist of a repeat TTAGGG se‐

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

quence, located at the end of chromosomes. Along with its complementary sequence, AATCCC, telomeres form a t‐loop structure at the terminal ends of chromosomes [2]. A single‐strand 3′ G‐rich overhang, several DNA‐binding proteins and specific telomerase‐binding proteins, named "shelterin" complex, also comprise telomeres. The shelterin complex is formed by six proteins: TRF1, TRF2, and POT1 that directly recognize TTAGGG repeats; and TIN2, TPP1, and Rap1 that interlink the first three proteins. Even though telomeres and double‐strand breaks (DSBs) are processed in the same manner, the DNA repair system clearly distinguishes the telomere region from sites of damaged DNA because of shelterin [3]. Telomere length (TL) is balanced by telomerase, a riboenzyme that synthesizes telomeric DNA *de novo* using its own RNA component as template. Even in complex organisms, telomerase‐dependent telomere elongation occurs, although it is difficult to access this *in vivo*, as this happens in leukocytes, which means moving cells [4]. Telomeres shorten in each cell division due to incomplete replication of the lagging strand, the so‐called "end replication problem". In most normal somatic cells of human adults, telomere length decreases with age, suggesting that telomere attrition contributes to the organismal senescence by reducing cell proliferation. So far, it is not yet understood how telomere length is set in an organism [5], but it is known that they are dynam‐ ic structures, especially when examined during short periods [4]. Because of their close relationship to lifespan and cellular senescence, telomeres havebeen widely studied with regard to human health and the development of diseases. One of the topics most often associated with telomere length dysfunction is, for example, how human cancers are invariably related to activation of some mechanisms to maintain telomere length [6]. Telomerase is commonly expressed in human cancer cells, mainly in 85–90% of cancers. Recent studies suggest that telomerase is implicated in tumor progression in several manners, most of them unexpected and new to science [7]. Yet, some reports have shown the reactivation of telomerase, resulting in cell immortalization, without chromosome aberrations, tumorigenic parameters or onco‐ genic activation (reviewed by Cech [6]). Although normal cells have some active telomerase, telomere dynamics is still unclear with regard to several pathologies. Further, whether telomeres shorten or elongate in different human everyday life situations, and by which mechanism this occurs, are still under investigation. What is known is that telomere length is strongly influ‐ enced by many other factors such as genetics, diseases, occupational and environmental exposures, and diet (reviewed by Kahl et al. [1]). Optimum telomere function and length are important for cell proliferation and apoptosis. Critically short telomeres initiate senescence resulting either in apoptosis or cell cycle arrest, through proteins such as BUB1,CENP‐E,CENP‐ A, Chk2, among others [8]. Therefore, it is relevant to identify yielding factors that are respon‐ sible for accelerated telomere shortening.

#### **2. Earlier telomere shortening: why?**

Due to its high content of guanine, telomeric DNA is highly susceptible to accumulation of oxidative stress through induction of a wide range of DNA lesions, including base modifica‐ tions, such as 8‐oxo‐guanine and O6 ‐methylguanine. In the first case, guanine oxidation converts it into 8‐oxo‐7,8‐dihydroguanine (8‐oxo‐G), a tautomeric form of guanine nucleotide. Thereby, 8‐oxo‐G erroneously pairs with adenine instead of cytosine, causing a mutation through transversion G‐C→T‐A [9]. This damage is not easily repaired by DNA repair mechanism and may lead to reduction of TRF1 and TRF2 linking, generating telomeric dysfunction [10, 11]. Moreover, accumulation of single‐strand breaks (SSBs), as a result of the hydroxyl radical attacks on the DNA strand throughout telomere and subtelomeric regions, leads to accelerated telomere shortening or to complete loss of telomeres [12]. Telomere integrity appears to be a critical element in chromosomal stability and telomere shortening, which is induced by an increase in oxidative stress and can also be influenced by DNA repair mechanisms and polymorphisms, epigenetic status, and lifestyle habits.

quence, located at the end of chromosomes. Along with its complementary sequence, AATCCC, telomeres form a t‐loop structure at the terminal ends of chromosomes [2]. A single‐strand 3′ G‐rich overhang, several DNA‐binding proteins and specific telomerase‐binding proteins, named "shelterin" complex, also comprise telomeres. The shelterin complex is formed by six proteins: TRF1, TRF2, and POT1 that directly recognize TTAGGG repeats; and TIN2, TPP1, and Rap1 that interlink the first three proteins. Even though telomeres and double‐strand breaks (DSBs) are processed in the same manner, the DNA repair system clearly distinguishes the telomere region from sites of damaged DNA because of shelterin [3]. Telomere length (TL) is balanced by telomerase, a riboenzyme that synthesizes telomeric DNA *de novo* using its own RNA component as template. Even in complex organisms, telomerase‐dependent telomere elongation occurs, although it is difficult to access this *in vivo*, as this happens in leukocytes, which means moving cells [4]. Telomeres shorten in each cell division due to incomplete replication of the lagging strand, the so‐called "end replication problem". In most normal somatic cells of human adults, telomere length decreases with age, suggesting that telomere attrition contributes to the organismal senescence by reducing cell proliferation. So far, it is not yet understood how telomere length is set in an organism [5], but it is known that they are dynam‐ ic structures, especially when examined during short periods [4]. Because of their close relationship to lifespan and cellular senescence, telomeres havebeen widely studied with regard to human health and the development of diseases. One of the topics most often associated with telomere length dysfunction is, for example, how human cancers are invariably related to activation of some mechanisms to maintain telomere length [6]. Telomerase is commonly expressed in human cancer cells, mainly in 85–90% of cancers. Recent studies suggest that telomerase is implicated in tumor progression in several manners, most of them unexpected and new to science [7]. Yet, some reports have shown the reactivation of telomerase, resulting in cell immortalization, without chromosome aberrations, tumorigenic parameters or onco‐ genic activation (reviewed by Cech [6]). Although normal cells have some active telomerase, telomere dynamics is still unclear with regard to several pathologies. Further, whether telomeres shorten or elongate in different human everyday life situations, and by which mechanism this occurs, are still under investigation. What is known is that telomere length is strongly influ‐ enced by many other factors such as genetics, diseases, occupational and environmental exposures, and diet (reviewed by Kahl et al. [1]). Optimum telomere function and length are important for cell proliferation and apoptosis. Critically short telomeres initiate senescence resulting either in apoptosis or cell cycle arrest, through proteins such as BUB1,CENP‐E,CENP‐ A, Chk2, among others [8]. Therefore, it is relevant to identify yielding factors that are respon‐

Due to its high content of guanine, telomeric DNA is highly susceptible to accumulation of oxidative stress through induction of a wide range of DNA lesions, including base modifica‐

converts it into 8‐oxo‐7,8‐dihydroguanine (8‐oxo‐G), a tautomeric form of guanine nucleotide. Thereby, 8‐oxo‐G erroneously pairs with adenine instead of cytosine, causing a mutation

‐methylguanine. In the first case, guanine oxidation

sible for accelerated telomere shortening.

164 Telomere - A Complex End of a Chromosome

tions, such as 8‐oxo‐guanine and O6

**2. Earlier telomere shortening: why?**

Reactive oxygen species (ROS) are generated in aerobic organisms by cellular metabolism and by exogenous sources such as ionizing radiations, UV radiation, redox cycling drugs, carci‐ nogenic compounds, and environmental toxins. DNA lesions resulting from this type of damage are mutagenic and cytotoxic and, if not repaired, can cause genetic instability, cell proliferation problems, oxidative enzyme imbalance, cell death, apoptosis, and angiogenesis. Consequences of DNA damages depend on their severity and cell type. DNA effects may lead to the development of diseases, including carcinogenesis [13].

Living organisms evolved to possess DNA repair mechanisms to repair DNA damage and thus to protect the genetic stability for survival [13, 14]. Telomeric DNA is less capable of repair, resulting in accelerated telomere attrition during the cell cycle and replicative senescence [15]. Telomeres seem to be very sensitive for both single‐strand breaks (SSBs) and double‐strand breaks (DSBs). As a mechanism to prevent end‐to‐end fusions, telomeric repeats have been shown to inhibit non‐homologous end joining (NHEJ) repair mechanism. NHEJ is a major pathway to repair DSBs and has been reported to be inhibited *in vitro* by TRF2, which could be a main contributor to a persistent DNA damage response (reviewed by Hewitt et al. [15]). Furthermore, ROS produce SSBs and in contrast to the majority of genomic DNA, telomeric DNA may be deficient in repairing this type of damage [16, 17]. Single‐strand breaks caused by hydrogen peroxide and an alkylating agent in human fibroblasts took at least 19 days to be repaired in telomeres, but it was repaired in 24 h in the bulk of genome and minisatellite regions (reviewed by Coluzzi et al. [17]). Failure to repair DNA damage may lead to detrimental biological consequences for organisms.

Mutations and polymorphisms also occur in DNA repair genes adversely affecting DNA repair systems. An example of DNA damage influenced by repair polymorphisms was recently shown by Borghini et al. [18], in which authors demonstrated that individuals exposed to higher levels of arsenic combined with the hOGG1 allele were associated with significantly lower TL in leukocytes [18]. As OGG1 is a protein part of the base excision repair mechanism and catalyzes the excision of oxidized purines, mainly 8‐oxo‐dG [13], it is reasonable that it produce some effect on telomeres. Other authors showed that individuals with congenital heart disease had reduced TL when compared to controls, related to XRCC1 194Trp allele [19]. In addition to these polymorphisms, XRCC1 399Gln allele [20] and XRCC4‐null cells [21] were already associated with telomere dynamics by different repair routes.

The instable condition of telomeres can lead to activation of molecular cascades evolved in response to cellular stress, such as p53 and p16INK4a pathways, resulting in some cases in apoptosis or cellular senescence [21]. Shorter telomeres in peripheral blood lymphocytes have been shown to predict cancer risk [22, 23]. It is also relevant that p16 methylation is found in several types of cancer such as melanoma, oropharynx, and esophagus [24‐26]. In addition, increasing evidence indicates that epigenetic modifications are important regulators of mammalian telomeres [27]. Epigenetic regulators, such as histone methyltransferases and DNA methyltransferases, correlate with loss of telomere‐length control, thus telomere shortening affects the epigenetic status of telomeres and subtelomeres. It has been shown that such oxidative lesions interfere with the DNA's ability to function as a substrate for DNA methyltransferases, resulting in global hypomethylation [28]. Thus, genomic DNA, including the subtelomeric region, may become hypomethylated. Methylation in subtelomeric regions of the chromosomes is associated with telomere length and hence could be an important region for epigenetic regulation of the biology of telomere length maintenance [29]. A number of studies also indicate the posttranslational ubiquitination in TL proteins, albeit this modifica‐ tion effect on telomeres has not been directly demonstrated. The ubiquitinated telomere unbound form of TRF1 induces telomere elongation [30], while the *MKRN1* gene that encodes a portion of ubiquitin promotes the degradation of hTERT [31]. A progressive loss of DNA methylation in repetitive elements was recently shown [32], providing evidence that methyl‐ ation can decrease over time as individuals age. Therefore, the association of aging with telomere epigenetic regulation is an important factor. Links between epigenetic status and telomere‐length regulation provide important new avenues for understanding processes such as cancer development, which are characterized by telomere‐length defects.

Several studies suggest that telomere dynamics can be challenged according to lifestyle factors. Recent studies showed that smokers had shortened telomere length when compared to never smokers [33, 34]. A cohort study found shorter telomeres for active smokers in a dose‐ dependent manner [34]. Other publications reported that smokers presented shorter telomere length, and irrespective of the number of cigarettes smoked per year, the lifetime accumulating exposure to smoking was more important to this outcome [35]. The main mechanisms related to reduction of telomere length by cigarette smoking are increased oxidative stress levels and inflammation [36]. Exercise and a balanced diet can also influence telomere maintenance, in a positive manner, attempting to support a healthier life.

#### **3. Telomere length and human health**

Aging starts even before birth, that is why is necessary not only to study telomere length at birth, as a prerequisite to understand its dynamics throughout life, but also to investigate several exposures, and genetic and epigenetic factors that may contribute to accelerate this process [37]. Aging is defined as the time-dependent event that results in a progressive functional decline that affects most living organisms. This process is the subject of several scientific studies, including mutagenesis, as the accumulation of DNA damage throughout life is a common denominator of aging [38].

Much attention has been given to the relationship of telomeres with human health in the last few decades. The natural telomere shortening can be accelerated by unhealthy lifestyle habits and a poor diet [39, 40] and also due to occupational and environmental exposures [1, 41]. Exogenous physical, biological, and chemical stressors, such as environmental pollutants, medicines, chemotherapeutics, continuously challenge DNA stability. In addition, endoge‐ nous agents such as DNA replication errors, ROS, and spontaneous hydrolytic reactions can have the same effect on DNA. Different lesions arise from this damage and may include chromosomal aberrations, translocations, point mutations, gene disruption, and telomere shortening. There are various causes of ROS overexpression and exacerbated oxidative stress increases telomere shortening [9–12, 15–17]. One example is hyperglycemia, which increases ROS from the mitochondrial electron transport chain and increased glucose auto‐oxidation, production of advanced glycation end‐products, and activation of polyol pathway and kinase K pathway [42].

been shown to predict cancer risk [22, 23]. It is also relevant that p16 methylation is found in several types of cancer such as melanoma, oropharynx, and esophagus [24‐26]. In addition, increasing evidence indicates that epigenetic modifications are important regulators of mammalian telomeres [27]. Epigenetic regulators, such as histone methyltransferases and DNA methyltransferases, correlate with loss of telomere‐length control, thus telomere shortening affects the epigenetic status of telomeres and subtelomeres. It has been shown that such oxidative lesions interfere with the DNA's ability to function as a substrate for DNA methyltransferases, resulting in global hypomethylation [28]. Thus, genomic DNA, including the subtelomeric region, may become hypomethylated. Methylation in subtelomeric regions of the chromosomes is associated with telomere length and hence could be an important region for epigenetic regulation of the biology of telomere length maintenance [29]. A number of studies also indicate the posttranslational ubiquitination in TL proteins, albeit this modifica‐ tion effect on telomeres has not been directly demonstrated. The ubiquitinated telomere unbound form of TRF1 induces telomere elongation [30], while the *MKRN1* gene that encodes a portion of ubiquitin promotes the degradation of hTERT [31]. A progressive loss of DNA methylation in repetitive elements was recently shown [32], providing evidence that methyl‐ ation can decrease over time as individuals age. Therefore, the association of aging with telomere epigenetic regulation is an important factor. Links between epigenetic status and telomere‐length regulation provide important new avenues for understanding processes such

as cancer development, which are characterized by telomere‐length defects.

positive manner, attempting to support a healthier life.

**3. Telomere length and human health**

166 Telomere - A Complex End of a Chromosome

is a common denominator of aging [38].

Several studies suggest that telomere dynamics can be challenged according to lifestyle factors. Recent studies showed that smokers had shortened telomere length when compared to never smokers [33, 34]. A cohort study found shorter telomeres for active smokers in a dose‐ dependent manner [34]. Other publications reported that smokers presented shorter telomere length, and irrespective of the number of cigarettes smoked per year, the lifetime accumulating exposure to smoking was more important to this outcome [35]. The main mechanisms related to reduction of telomere length by cigarette smoking are increased oxidative stress levels and inflammation [36]. Exercise and a balanced diet can also influence telomere maintenance, in a

Aging starts even before birth, that is why is necessary not only to study telomere length at birth, as a prerequisite to understand its dynamics throughout life, but also to investigate several exposures, and genetic and epigenetic factors that may contribute to accelerate this process [37]. Aging is defined as the time-dependent event that results in a progressive functional decline that affects most living organisms. This process is the subject of several scientific studies, including mutagenesis, as the accumulation of DNA damage throughout life

Much attention has been given to the relationship of telomeres with human health in the last few decades. The natural telomere shortening can be accelerated by unhealthy lifestyle habits Critical telomere shortening induces cellular senescence or even the definitive inability of cells to divide. Telomere attrition in stem cells results in the depletion of their tissue and self‐renewal ability. In both cases, telomere shortening can lead to different age‐related pathologies [43]. The average difference of telomere length between proliferative and minimally proliferative tissues was constant in a study performed with patients whose ages ranged from 19 to 77 years old suggesting that the first 20 years are a crucial period in establishing some differences [44]. The telomere shortening in somatic cells results in changes on telomere structure that may induce replicate senescence depending on p53 and p16/retinoblastoma proteins [45].

A wide range of studies have shown that dysfunctional telomere length in biological human samples is usually related to increased risk of degenerative diseases of aging, diabetes, cardiovascular diseases (CVD), dementia, cognitive impairments, and cancer [46–51]. Ulti‐ mately, cancer and aging can be considered two different expressions of the same process: the accumulation of DNA damage. Specific location of shelterin complex is what lastly enables chromosome end protection. It is also known that within shelterin, certain components are responsible for preventing specific aspects of DNA damage repair mechanism [5]. The great challenge is to understand what signal triggers checkpoint activation at dysfunctional telomeres [5, 52].

Telomere length in pancreatic β‐cells is reduced in individuals with type 2 diabetes mellitus (DM) [49] as a pathophysiology of diabetes shows an age‐related aspect. The authors propose that shorter telomeres in type 2 DM could lead to an impaired ability for proliferation and insulin secretion, accelerating cell death. Obesity, which is also associated with shortened telomere length [53], is frequently associated with type 2 DM. In both cases, it is considered that excessive oxidative stress induces telomere damage, together with hyperglycemia in DM patients. In cancer biology, telomere dysfunction has been linked to tissue decrease on mitochondrial DNA copy number, while mitochondrial oxidative stress appears to be required to maintain cellular senescence [54]. A recent review suggests the hypothesis that heteroge‐ neity of mitochondria uncoupling proteins may affect oxidative stress that imbalance telomere and cell cycle regulation, further diabetes risk and metabolic disease progression [55]. In diabetes mellitus, oxidative stress is higher in leukocytes, but also in pancreatic β‐cells, which could result in shortening of β‐cell telomeres, subsequently causing dysfunction of insulin secretion [49]. Results show that obesity can be associated with shortened telomeres [53], as the excessive accumulation of adipose tissue and the associated metabolic imbalance increases oxidative stress and may deregulate inflammatory cytokines. Chronic heart failure and coronary disease are strongly associated with inflammatory processes, and as expected, have also been linked to telomere shortening [41].

Cardiovascular diseases (CVD) are the main reason for heart failure, the leading cause of mortality worldwide. Two different studies have shown that telomere biology plays a role in CVD [56, 57]. The first study found an association of risk factors for CVD and telomere length, mainly with interleukin‐6, an inflammatory factor. Burnett‐Hartman et al. [56] observed that two single nucleotide polymorphisms in *OBCF1* and *TERC* genes (both related to leukocyte telomere length) were similarly associated with CVD mortality in women. CVD is strongly linked to the inflammation process, which may lead to increased oxidative stress. In both cases, telomere attrition may be attributed to increased oxidative stress and inflammation [56, 57].

Telomeres are related to several other humans diseases in which some mutations of TERC are reported, such as dyskeratosis congenita, several hereditary, several hereditary syndromes of bone marrow failure, and idiopathic pulmonary fibrosis (reviewed by Armanios [58]). Although the presentation of these diseases is different, shortened telomeres are present in all patients with dyskeratosis congenita, in some with bone marrow failure syndromes, and in an unknown proportion of idiopathic pulmonary fibrosis patients [59]. Shortened telomeres were also observed in patients with aplastic anemia. Some studies suggest that baseline TL is associated with late events of hematologic relapse in aplastic anemia patients treated with immunosuppressant therapy [60]. Valdes et al. [61] showed that clinical osteoporosis is related to shorter telomeres in over 2000 women, in whom leukocyte telomere length was significantly correlated with bone mineral density. This result was corroborated by Tang et al. [62], who analyzed women and men regarding telomere length and bone marrow density, and a positive correlation was found for females. These studies even suggest that TL could be a new bone aging biomarker, but these conclusions should be carefully observed as other reports did not find the same correlations [63, 64]. Both short and long telomeres have been associated with neurodegenerative and cardiovascular diseases, cancer risk [46, 59], and some human poly‐ morphisms [65]. Indeed, several loci were identified by linkage analysis of modulators supposedly linked to telomeres and through genome global association studies. *DDX11* [66], *SIRT1*, and *XRCC6* [67] genes, as chromosome 14 and loci 10q26.13 and 3p26.1 [68], seem to be involved in telomeric dynamics. Mostly, loci near the RNA component of telomerase (TERC) are more evident in studies that correlate genetic heritage and telomere length [59]. Some polymorphisms of *OBCF1* [56] and *MEN1* [65] genes, as the ‐1327C/T hTERT polymorphism [69], were associated with critically shorter and longer telomeres. However, two studies showed a greater influence of environmental effect than the genetic one on telomere length (reviewed by Andrew et al. [68]).

Another study analyzed telomere length in white blood cells and buccal cells in patients with Alzheimer's disease (AD). The researchers observed reduced telomere length in both cell types for individuals with AD. More than that, telomeres with less than 115 kb per diploid genome in white blood cells showed an odds ratio of 10.8 for a diagnosis of AD, while telomeres shorter than 40 kb per diploid genome had an odds ratio of 4.6 for AD diagnosis [48]. In concordance with this study, Hochstrasser et al. [70] also suggests that AD may contribute to telomere shortening. They found shorter telomeres on monocytes of AD patients compared to healthy subjects. In fact, a recent work found out that telomere length is significantly shorter in AD patients with alipoprotein E (ApoE) homozygote than in those with ApoE heterozygote and noncarriers. ApoE is a strong genetic risk factor for developing Alzheimer's, and seems to be associated with shorter TL when in homozygosis [71].

the excessive accumulation of adipose tissue and the associated metabolic imbalance increases oxidative stress and may deregulate inflammatory cytokines. Chronic heart failure and coronary disease are strongly associated with inflammatory processes, and as expected, have

Cardiovascular diseases (CVD) are the main reason for heart failure, the leading cause of mortality worldwide. Two different studies have shown that telomere biology plays a role in CVD [56, 57]. The first study found an association of risk factors for CVD and telomere length, mainly with interleukin‐6, an inflammatory factor. Burnett‐Hartman et al. [56] observed that two single nucleotide polymorphisms in *OBCF1* and *TERC* genes (both related to leukocyte telomere length) were similarly associated with CVD mortality in women. CVD is strongly linked to the inflammation process, which may lead to increased oxidative stress. In both cases, telomere attrition may be attributed to increased oxidative stress and inflammation [56, 57].

Telomeres are related to several other humans diseases in which some mutations of TERC are reported, such as dyskeratosis congenita, several hereditary, several hereditary syndromes of bone marrow failure, and idiopathic pulmonary fibrosis (reviewed by Armanios [58]). Although the presentation of these diseases is different, shortened telomeres are present in all patients with dyskeratosis congenita, in some with bone marrow failure syndromes, and in an unknown proportion of idiopathic pulmonary fibrosis patients [59]. Shortened telomeres were also observed in patients with aplastic anemia. Some studies suggest that baseline TL is associated with late events of hematologic relapse in aplastic anemia patients treated with immunosuppressant therapy [60]. Valdes et al. [61] showed that clinical osteoporosis is related to shorter telomeres in over 2000 women, in whom leukocyte telomere length was significantly correlated with bone mineral density. This result was corroborated by Tang et al. [62], who analyzed women and men regarding telomere length and bone marrow density, and a positive correlation was found for females. These studies even suggest that TL could be a new bone aging biomarker, but these conclusions should be carefully observed as other reports did not find the same correlations [63, 64]. Both short and long telomeres have been associated with neurodegenerative and cardiovascular diseases, cancer risk [46, 59], and some human poly‐ morphisms [65]. Indeed, several loci were identified by linkage analysis of modulators supposedly linked to telomeres and through genome global association studies. *DDX11* [66], *SIRT1*, and *XRCC6* [67] genes, as chromosome 14 and loci 10q26.13 and 3p26.1 [68], seem to be involved in telomeric dynamics. Mostly, loci near the RNA component of telomerase (TERC) are more evident in studies that correlate genetic heritage and telomere length [59]. Some polymorphisms of *OBCF1* [56] and *MEN1* [65] genes, as the ‐1327C/T hTERT polymorphism [69], were associated with critically shorter and longer telomeres. However, two studies showed a greater influence of environmental effect than the genetic one on telomere length (reviewed

Another study analyzed telomere length in white blood cells and buccal cells in patients with Alzheimer's disease (AD). The researchers observed reduced telomere length in both cell types for individuals with AD. More than that, telomeres with less than 115 kb per diploid genome in white blood cells showed an odds ratio of 10.8 for a diagnosis of AD, while telomeres shorter than 40 kb per diploid genome had an odds ratio of 4.6 for AD diagnosis [48]. In concordance

also been linked to telomere shortening [41].

168 Telomere - A Complex End of a Chromosome

by Andrew et al. [68]).

Telomere dynamic has been also correlated with psychological and psychosocial effects. Some authors observed telomere shortening associated with severe and/or chronic diseases in childhood, besides adverse events, such as anxiety disorders and mistreatment in childhood [39, 72]. Children aged 4‐14 from over 80 neighborhoods in Louisiana, USA, were evaluated with regard to the influence of social stress on telomere length. Children living in highly disturbed neighborhoods showed shorter salivary telomere length when compared with less disturbed environments [73]. These data may indicate that childhood adversities have an impact on wellbeing throughout life. High levels of stress related to psychosocial facts and high levels of depressive symptoms were observed in caregivers of individuals with Alzheim‐ er's, and shortened telomeres were associated with those stress factors (reviewed by Lin et al. [39]). A recent review of telomerase activity and its associations with psychological and mental factors observed a mixture of results, but some consistent findings reported decreased telomerase activity in individuals under chronic stress and increased telomerase activity in individuals with depressive disorders [74]. Oxidative stress has been suggested to play a role in the etiology of anxiety disorders and psychological distress, supporting the involvement of oxidative stress in the regulation of telomere length in psychological and psychosocial adverse effects.

Telomere shortening is a risk factor for several types of cancer [46]. A recent review investi‐ gated telomere length in several types of cancer in surrogate tissues and observed only longer telomeres in melanoma skin and hepatocellular carcinoma. No effect on telomere length was seen for colorectal, prostate, and endometrial cancers and squamous‐cell carcinoma. For breast cancer, although longer and shorter telomeres were found in nine different studies, no effect on telomere length was prevalent among the findings. Two kinds of cancer were linked to both longer and shorter telomeres: lung and kidney [46]. Up to now, reduced telomere length has been prevalently found in patients with these cancers. As regards lung cancer, a study included 122 Chinese with clinical symptoms [22]. In general, telomere length was not associated with lung cancer. Nevertheless, three SNPs in telomere length maintenance genes were linked to risk of lung cancer. The *G* variant at *POT1* rs10244817 and the *A* variant of *TERT* rs2075786 were associated with decreased risk of developing lung cancer; while the *G* variant of *TERT* rs251796 was associated with increased risk. The *POT1* SNP interacted significantly with telomere length and lung cancer risk, showing the close relation between shelterin proteins and cancer [22]. In the review, for most types of cancers evaluated, only shorter telomeres were found: bladder, head/neck, ovarian, gastric, skin (basal cell carcinoma), osteosarcoma, and esophagus [46]. It is interesting to observe that for different types of skin cancer, the cancer etiology has a different telomere dynamic, which only shows that telomere dynamic is heterogeneous according to tissues and even with their differentiation process.

In another meta‐analysis with regard to telomere length and cancer risk population studies, authors reviewed more than 50 publications [50]. Their results revealed heterogeneous association between different cancer types. In opposition to other reviews, they did not observe a significant association of short telomeres with the overall risk of cancer. Still, shorter telomeres were found associated with increased risk of gastrointestinal and head and neck cancers, similar to prior review [46]. Both are mainly cases of epithelial malignancies, which mostly appear to develop from morphologically defined precursor lesions termed intraepi‐ thelial neoplasia. The meta‐analyses also revealed a significant dose‐response association of gastrointestinal tumor and head and neck cancer with telomere length. The authors also highlight that telomere length is critically shortened in more than 90% of intraepithelial neoplasias. It is accepted that telomeres have different roles in different types of cancer, but again, this review indicates that short telomeres may be risk factors for tumors, especially of the digestive system [50]. A shorter TL in individuals with cancer when compared to healthy controls is biologically plausible. The accumulated mutations from critically shortened telomeres, genetic lesions, and inactivated tumor suppressor checkpoints may ultimately result in cancer [6, 7, 47, 52].

For many years, oncogenesis has been linked to telomerase activity in somatic cells [6, 7]. In fact, overexpression of telomerase is enough to neutralize the natural telomere shortening and to indefinitely extend the replicative lifespan of cultured cells when genomic instability is lacking, turning them into cancerous cells. The active telomerase complex may be more necessary to cancerous cells than to normal somatic cells due to its chromosomal aneuploidy and rapid cell division cycle [47, 75]. Thus, it seems conflicting that shortened telomeres are linked to several types of cancer. However, the mechanism of the shortened telomere rela‐ tionship with cancer is through genomic instability. In the oncogenesis process, the inactivation of senescence pathways by some viral oncogenes, mutations on key‐genes or chemical substances allows cells to bypass replicative checkpoints. This enables the propagation of cells with damaged telomere leading to end‐to‐end fusions and genome instability, and then to age‐ associated diseases, like cancer [43].
