**5. Telomere shortening as a risk for onset of metabolic diseases**

Telomere length is closely associated with morbidity and mortality [66,67]. Therefore, telomere length has been thought as a marker for individual cellular aging [68,69]. However, several recent studies have focused on the possibility of causal role of shortened telomeres as a risk for the development of several age-related diseases, including metabolic diseases [70–72].

#### **5.1. Diabetes mellitus**

Telomere length is already reduced in pre-diabetic stage; impaired glucose tolerance and this is recognized as a risk factor for the onset of T2DM [73]. To date, several prospective studies have focused on the telomere shortening as a risk factor for the onset of T2DM [74–76]. Although these results have been inconsistent, some studies showed positive results. You et al. [76] conducted a large-scale prospective study of healthy postmenopausal women with 6 year follow-up. However, there was no relationship between telomere shortening and the onset of DM. Recently, Zhao et al. [75] also reported the results of a large-scale cohort study of American Indians. Among 2328 participants who were free of DM at baseline, 292 subjects developed DM during an average 5.5 years of follow-up. Subjects in the lowest quartile of telomere length showed approximately twofold-increased risk of DM incidence compared with the highest quartile. Willeit et al. [74] also reported the similar results of prospective cohort study of healthy subjects. Over 15 years of follow-up, 44 of 606 participants developed DM. The adjusted hazard ratio for DM comparing the lowest and highest quartile of baseline telomere length was 2.0. These results may indicate that telomere shortening is not only a mere marker of biological aging but also plays a causal role in the development of DM.

#### **5.2. Metabolic syndrome**

As shown above, many studies have demonstrated that the components of metabolic syn‐ drome individually exhibited a significant association with shortened telomeres [21,30,33]. Very recently, Revesz et al. [70] reported the result of a large population-based study with 6 years of follow-up, which included 2981 adult individuals (age: 18–65 years); the subject consists of 1701 persons with a diagnosis of depression and/or anxiety disorder, 907 persons with subthreshold depressive or anxiety symptoms, and 373 healthy controls. They assessed that whether shorter telomere length at baseline was associated with a worse metabolic profile. This study demonstrated that shorter telomere length at baseline was not only cross-sectionally associated with metabolic syndrome components (decreased HDL and increased waist circumference, triglycerides, and fasting glucose) but also associated with an increased risk of having an abnormal metabolic profile, which continues to be unfavorable even after a followup period of 6 years. Based on the results, they advocated that cellular aging assessed by telomere length might play a role in the metabolic alterations.

#### **5.3. Liver cirrhosis**

with the increased serum levels of IGF-I may lead to the telomere shortening in patients with

Telomere length is closely associated with morbidity and mortality [66,67]. Therefore, telomere length has been thought as a marker for individual cellular aging [68,69]. However, several recent studies have focused on the possibility of causal role of shortened telomeres as a risk for the development of several age-related diseases, including metabolic diseases [70–72].

Telomere length is already reduced in pre-diabetic stage; impaired glucose tolerance and this is recognized as a risk factor for the onset of T2DM [73]. To date, several prospective studies have focused on the telomere shortening as a risk factor for the onset of T2DM [74–76]. Although these results have been inconsistent, some studies showed positive results. You et al. [76] conducted a large-scale prospective study of healthy postmenopausal women with 6 year follow-up. However, there was no relationship between telomere shortening and the onset of DM. Recently, Zhao et al. [75] also reported the results of a large-scale cohort study of American Indians. Among 2328 participants who were free of DM at baseline, 292 subjects developed DM during an average 5.5 years of follow-up. Subjects in the lowest quartile of telomere length showed approximately twofold-increased risk of DM incidence compared with the highest quartile. Willeit et al. [74] also reported the similar results of prospective cohort study of healthy subjects. Over 15 years of follow-up, 44 of 606 participants developed DM. The adjusted hazard ratio for DM comparing the lowest and highest quartile of baseline telomere length was 2.0. These results may indicate that telomere shortening is not only a mere

marker of biological aging but also plays a causal role in the development of DM.

telomere length might play a role in the metabolic alterations.

As shown above, many studies have demonstrated that the components of metabolic syn‐ drome individually exhibited a significant association with shortened telomeres [21,30,33]. Very recently, Revesz et al. [70] reported the result of a large population-based study with 6 years of follow-up, which included 2981 adult individuals (age: 18–65 years); the subject consists of 1701 persons with a diagnosis of depression and/or anxiety disorder, 907 persons with subthreshold depressive or anxiety symptoms, and 373 healthy controls. They assessed that whether shorter telomere length at baseline was associated with a worse metabolic profile. This study demonstrated that shorter telomere length at baseline was not only cross-sectionally associated with metabolic syndrome components (decreased HDL and increased waist circumference, triglycerides, and fasting glucose) but also associated with an increased risk of having an abnormal metabolic profile, which continues to be unfavorable even after a followup period of 6 years. Based on the results, they advocated that cellular aging assessed by

**5. Telomere shortening as a risk for onset of metabolic diseases**

acromegaly.

150 Telomere - A Complex End of a Chromosome

**5.1. Diabetes mellitus**

**5.2. Metabolic syndrome**

Liver cirrhosis is the end-stage complication of chronic liver disease, which leads to impair‐ ment of liver function and increased risk of hepatocellular carcinoma. In particular, viral hepatitis, fatty liver disease, and alcohol consumption have been reportedly associated with an increased risk of cirrhosis, and the majority of the patients have these risks. However, even in the same condition, a part of the patients progress to cirrhosis, whereas others do not. The reason that determines the progression remains still unclear. Several SNPs have been report‐ edly associated with the development of cirrhosis. Interestingly, it has been recently reported that telomere shortening might be a risk factor for the liver cirrhosis [77]. In the liver tissue with chronic liver injury, because a high cellular turnover was required for the regeneration and repair process, telomere shortening was accelerated. Telomerase-deficient mice were prone to develop cirrhosis in response to chronic liver injury, and restoration of telomerase activity was able to improve fibrosis and liver function [42]. Furthermore, patients with telomere diseases, in which telomerase complex gene mutation was identified, such as dyskeratosis congenita showed a shortened telomeres and increased prevalence of liver disease including fibrosis and cirrhosis [61]. These data suggest that shortened telomeres are causally involved in the development of liver cirrhosis.

### **6. Telomere as therapeutic targets**

The analysis of mouse genetic models demonstrated the causal role of shortened telomeres in aging. Mice deficient for *TERC* show accelerated telomere shortening, chromosome instability, premature aging phenotype, and premature death [78,79]. Another mouse model, *TERT*deficient mice also showed a shorter telomere length and genome instability [80,81]. In contrast, mice with increased transgenic telomerase expression were able to maintain longer telomeres through their lifespan and showed decreased appearance of age-related disorders and increased longevity. These results indicate that the maintenance of telomere length, at least in mice, plays an essential role in the regulation of aging and longevity [82]. In this regard, to prevent the onset of age-related diseases, telomere and telomerase as a potential therapeutic target have been emerged [83].

#### **6.1. Telomerase activator**

Small molecule named TA-65 derived from an extract of a plant used in traditional Chinese medicine, *Astragalus membranaceus*, upregulates telomerase activity *in vivo* [84]. TA-65 has been shown a mild increase in telomere length in mice [85] and humans [84]. However, there was no increase in longevity in mice [85]. Recently, the result of a randomized control study conducted on 117 healthy subjects using TA-65 has been reported [86]. Low dose oral admin‐ istration of TA-65 significantly increased telomere length over the 12-month period, whereas subjects in the placebo group significantly lost telomere length. The high dose administration of TA-65 showed a trend of improvement in telomere length; however, it did not reach statistical significance. Although it remains elusive that telomerase activator can increase life span and delay the onset of age-related diseases, these findings suggest a possibility of telomere/telomerase as a therapeutic target for preventing aging.

#### **6.2. Danazol**

Androgen has been used to treat bone mallow failure and aplastic anemia with the anabolic effect on bone marrow [87], although precise mechanisms have not been fully understood. It has been reported that telomere diseases with mutations in genes responsible for telomere maintenance and repair lead to bone mallow failure [88]. Interestingly, considerable evidence suggests that androgen directly regulates telomerase activity [89]. Recently, it has been reported that the treatment with androgen leads to telomere elongation in a mouse model of telomerase dysfunction [90]. In addition, serum dihydrotestosterone and estradiol levels and aromatase gene polymorphisms were associated with telomere length [91]. Very recently, Townsley et al. reported that danazol, the synthetic sex hormone, which has androgen activity, was efficacious to elongate the telomere length in bone marrow cells [92]. Patients with mutations in the genes related to the telomere maintenance or repairment, such as *TERT*, *TERC*, and *DKC1*, were enrolled and orally administered danazol at a dose of 800 mg/day for a total of 24 months. Surprisingly, almost all the patients (11 of 12) had a substantial gain in telomere length at 24 months when compared with baseline. Hematologic responses were also observed in 10 of 12 patients at 24 months. As an underlying mechanism, *in vitro* study showed a direct effect of androgen on telomerase activity by upregulation of *TERT* expression [93]. Although whether androgen is also effective to subjects without gene mutations in telomererelated genes is still unclear, there is a possibility that pharmacological intervention for telomere elongation may be applicable for the treatment of age-related disease.

#### **7. Conclusion**

In summary, telomere length assessed in peripheral leukocytes is associated with various metabolic and endocrine diseases **Figure 2A**. In addition, recent studies suggest that shortened telomeres may have a causal role in the pathophysiology of age-related diseases, such as T2DM, metabolic syndrome, and cardiovascular disease **Figure 2B** [70,94]. However, it has not yet been elucidated that how shortened telomeres cause these age-related diseases. One possible explanation is SASP. Shortened telomeres activate DDR pathway, which results in apoptosis and/or cell cycle arrest, and cellular senescence. Recently, it has emerged that cellular senescence and the related SASP play important roles in the development of age-related diseases [8,9,95,96]. In conclusion, although there is a strong association between telomere shortening and metabolic and endocrine diseases, further studies are needed to understand the mechanisms underlying these associations. Also, it is suggested that interventions that restore telomere length may be a potential therapeutic target for age-related disease **Figure 2C**.

**Figure 2.** Schematic summary. A) Various factors such as oxidative stress, mitotic stress, and hormonal dysfunction can shorten telomere length. B) Shortened telomeres are not a mere marker for individual aging but a pathological con‐ tributor to the development of age-related disease, including metabolic and endocrine diseases. As the underlying mechanism, cellular senescence and/or SASP might be involved. C) These pathways might be potential therapeutic tar‐ gets for prevention of these age-related disorders.
