Chapter 7

Telomeres and Cellular Senescence in Metabolic and

Endocrine Diseases

Ryusaku Matsumoto and Yutaka Takahashi

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/64759

Abstract
A number of observations suggest a close connection between telomere length and
mortality and age-related disease, suggesting that telomere length is a useful marker of
individual biological aging and the shortening of telomere length is causally related with
the pathogenesis in age-related diseases. To date, the significance of telomere length in
metabolic and endocrine diseases has also been clarified. It has been reported that obesity,
type 2 diabetes mellitus (T2DM), NAFLD, and hypertension were associated with
shortened telomere length. In endocrine diseases, polycystic ovary syndrome (PCOS),
Cushing’s syndrome, and acromegaly were associated with shortened telomere length.
In these conditions, an increased oxidative stress associated with the metabolic and
hormonal abnormalities appears to play a pivotal role in the shortened telomere length.
Recently, a large population-based study demonstrated that shortened telomeres at
baseline were associated with an increased risk of metabolic diseases, suggesting that the
shortened telomere itself plays a causal role for the onset or development of the metabolic
diseases. In this chapter, the pathophysiological role of shortened telomere length in
metabolic and endocrine diseases and the significance of cellular senescence are discussed.

Keywords: metabolic disease, endocrine disease, telomere, oxidative stress, cellular

senescence

1. Introduction

Telomeres consist of repetitive DNA sequences, thousands of “TTAGGG” tandem repeats,

which are located at the ends of linear chromosomes in most somatic cells [1]. Telomere ends
form a cap-like structure to protect the ends of chromosomes from degeneration and fusion.
However, telomeres shorten during each cell division, and when they reach a critically short

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144 Telomere - A Complex End of a Chromosome

length, cell cycle arrest and cellular senescence occur in the cellular level. In the body, telo‐
meres gradually shorten with aging [2]. A number of observations suggest a close connection
between telomere length, generally assessed in leukocytes, and mortality or age-related disease,
suggesting telomere length as a “mitotic clock,” a marker for individual biological aging [3]. In
this regard, to date, telomere length in various diseases has been investigated, including cancers,
immune insufficiency, and cardiovascular disease. In addition, metabolic diseases, such as
obesity and diabetes mellitus (DM), have shown a strong association with telomere shorten‐
ing. Several endocrine disorders, such as polycystic ovary syndrome (PCOS), Cushing’s
syndrome, and acromegaly, are also reportedly associated with telomere shortening (Figure
1).

Furthermore, several recent studies have focused on the pathophysiological role of telomeres
for metabolic or endocrine diseases. Telomere shortening is one of the important causes of
cellular senescence, and recently, it has emerged that cellular senescence plays a pivotal role
in the aging and pathogenesis of age-related disease [4]. Actually, several clinical studies have
shown that shortened telomeres at baseline are associated with an increased risk for develop‐
ment of age-related diseases.

Here, we review the association and pathophysiological role of telomere length in metabolic
and endocrine diseases. Furthermore, we discuss the mechanistic insight and significance of
shortened telomeres and associated cellular senescence. Finally, we discuss a possible thera‐
peutic approach for these diseases in the aspect of telomere shortening.

Figure 1. Telomere shortening and human diseases. Shortened telomere length is associated with various disorders,
including psychiatric disease, impaired immune function, and atherosclerotic disease as well as metabolic and endo‐
crine diseases.
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2. Telomeres and cellular senescence

2.1. Telomeres
Telomere is a dynamic complex at chromosome ends, which consists of repetitive DNA
sequences [1,5]. In human cells, telomeres consist of thousands of “TTAGGG” tandem repeats.
This base sequence is universal and consistent among most species. Human telomere complex
consists of chromosomal-terminal tract of telomeric repeats bound by protective shelterin
component proteins, with additional protective proteins. This complex, which binds specifi‐
cally to telomeres, forms a cap-like structure and prevents end-to-end fusion or damage of the
chromosome ends.
The general chromosomal DNA replication cannot completely copy the DNA sequence in the
ends of the linear chromosomes, which is called “end replication problem.” During the course
of cell divisions, this leads to attrition of chromosome ends. Therefore, normal telomere
maintenance requires the ribonucleoprotein enzyme named telomerase, which can add
telomeric repeat sequences to the end of the chromosomes [6]. However, in most of the human
somatic cells, the levels of telomerase are limited and telomeres shorten throughout the life
span. Other genetic or environmental factors can also contribute to telomere shortening;
defects of telomere maintenance system, DNA replication stress, increased oxidative stress,
chemical damage, and inflammatory status are involved in telomere shortening [1].

2.2. Cellular senescence and senescence-associated secretary phenotype (SASP)

Cellular senescence refers to the irreversible growth arrest that occurs when cells experience
potentially oncogenic insults [7]. Telomere shortening is one of the most important causes of
cellular senescence. Telomere shortening causes DNA damage response (DDR), a signaling
pathway, in which cell cycle progression is blocked through an increased production of p53
and cyclin-dependent kinase (Cdk) inhibitor p21 protein. DDR subsequently induces cellular
senescence. Recently, accumulating evidences suggest that senescent cells are also important
for age-related pathologies, including metabolic diseases such as obesity and DM [8,9].
Elimination of senescent cells can delay age-related dysfunctions in mouse model [10],
indicating that a presence of senescent cells itself plays a causal role in the process of aging.
Aging tissues, in which senescent cells are increased, show a low-level chronic inflammation,
termed “sterile inflammation” [11]. Sterile inflammation is, at least in part, derived from
senescent cells, which secrete proinflammatory cytokines, chemokines, and proteases, which
is called “senescence-associated secretary phenotype (SASP)” [12]. Proteins that are associated
with SASP, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, matrix metalloprotei‐
nases (MMPs), and monocyte chemoattractant protein (MCP)-1, increase in multiple tissues
with chronological aging in conjunction with sterile inflammation [13]. These SASP-related
cytokines, such as TNF-α and IL-6, are reportedly associated with insulin resistance and the
development of DM [14,15]. Although whether the SASP actually causes age-related diseases
including metabolic diseases in vivo is still unclear, at least, telomere shortening and subse‐
quent cellular senescence have revealed a strong association with age-related diseases
including metabolic diseases that are discussed in the following sections.
146 Telomere - A Complex End of a Chromosome

3. Telomeres in metabolic diseases

3.1. Obesity
Obesity is a leading preventable cause of death and growing health problem worldwide with
increasing rate in both adults and children. A number of studies have reported the association
of telomere length with obesity. Although the results were inconsistent and the relationship
of telomere shortening and obesity is still inconclusive, several large population-based studies
showed telomere shortening in obesity. In cross-sectional epidemiological studies, shortened
telomeres were associated with body mass index (BMI), waist-to-hip ratio, visceral fat, and
weight gain [3,16,17]. Consistently, calorie-restricted diets and subsequent weight loss were
associated with the increased telomere length in obese men [18]. These results indicated the
relationship between obesity and shortened telomeres. As an underlying mechanism of
telomere shortening in obesity, leptin might be involved. Leptin plays an essential role in the
regulation of body fat mass, and it has some proinflammatory properties with increasing
oxidative stress [19]. Valdes et al. reported that age, smoking, and serum leptin concentration
were independently associated with telomere length, but BMI did not, suggesting that leptin
may directly contribute the telomere shortening.

3.2. Diabetes mellitus

The number of patients with type 2 DM has drastically been increasing worldwide in associ‐
ation with the changes in lifestyle and increased prevalence of obesity. DM is categorized into
several clinical types: type 1 DM (T1DM), type 2 DM (T2DM), gestational DM, and others. In
particular, T2DM accounts for the majority of DM patients and the pathophysiology of T2DM
has an age-related aspect. DM increases the risk of cardiovascular and cerebrovascular events,
and cognitive dysfunction, which are known as age-related diseases. Telomere length in
patients with DM has been examined in many studies [20]. In 1998, Jeanclos et al. [21] showed
that patients with insulin-dependent DM (IDDM) had shorter telomeres in peripheral leuko‐
cytes than non-DM individuals. Patients with T2DM also showed shortened telomeres [22,23].
Furthermore, it has been reported that telomere shortening rate increased with the duration
of T2DM [24]. As an underlying mechanism of the telomere shortening in DM, increased
production of reactive oxygen species (ROS) caused by hyperglycemia and hyperinsulinemia
is supposed. Polyol pathway activation, protein kinase C pathway activation, and increased
production of advanced glycation end products (AGEs) also play a pathological role in
increased levels of oxidative stress [25]. In fact, Sampson et al. [23] showed an inverse corre‐
lation between the level of oxidative stress marker, 8-hydroxy-deoxyguanosine, and the
telomere length. These results suggest that the increased oxidative stress in DM may accelerate
the telomere shortening.
To date, several studies have focused on the relationship between telomere length and the
mortality and progression of DM complications. In a prospective follow-up study, telomere
length in T1DM was associated with all cause of mortality [26]. However, the association of
telomere length with DM complication has been controversial. Several studies exhibited that
DM patients with shorter telomeres has tended to show severer complications of DM [27,28].
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On the other hand, Astrup et al. [26] reported that telomere length did not differ between
patients with and without nephropathy. Although further studies are needed, these results
suggest that telomere length could be used as a surrogate marker for mortality and some of
the morbidity in patients with DM.

3.3. Hypertension

Hypertension can develop with various genetic and environmental factors, which is consid‐
ered to be an essential risk factor for cardiovascular or cerebrovascular diseases. However,
most of the pathogenesis remains unclear. Recent evidence suggests that telomere length may
be, at least in part, involved in the pathogenesis of hypertension [29]. Jeanclos et al. [30]
reported the results of a twin study, in which 49 twin pairs were assessed their relation of blood
pressure parameters with telomere length in leukocytes. They showed that telomere length
were highly familial and negatively correlated with pulse pressure, implying that telomere
shortening might be genetically regulated and associated with vascular aging. The Framing‐
ham Heart Study also demonstrated that hypertensive individuals exhibited shorter telomere
length in leukocytes compared with normotensive individuals [31]. Furthermore, telomere
shortening is associated with an increased atherosclerosis and cardiovascular risk [32–34].
These results suggest a close connection of telomeres and hypertension and its complications.

The underlying mechanism of telomere shortening in hypertension is still unclear. Mice

lacking telomerase activity showed hypertension as a result of increased plasma endothelin-1
levels [35]. Telomerase activity was decreased in endothelial progenitor cells from both
hypertensive rats and patients with essential hypertension [36]. These data suggest that
endothelial cells play a key role in the association of telomere length and premature vascular
aging.

3.4. Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

The role of telomeres in chronic liver diseases, such as viral hepatitis, nonalcoholic fatty liver
disease (NAFLD)/nonalcoholic steatohepatitis (NASH), and liver cirrhosis, has been investi‐
gated [37]. It is well known that in these conditions, fibrosis generally determines the severity
and prognosis of the disease. Older age and duration of chronic liver disease are the major risk
factors for fibrosis [38].

Kitada et al. [39] first reported that telomere shortening was accelerated in hepatocyte of
chronic liver disease, including chronic viral hepatitis or liver cirrhosis. Aikata et al. [40] also
confirmed that telomere length was significantly shorter in the liver with chronic viral hepatitis
or cirrhosis. Telomere length was significantly shorter in cirrhotic liver induced by broad
etiologies compared with noncirrhotic liver [41]. Furthermore, telomerase-deficient mice
showed impaired hepatic regenerative potential and developed liver cirrhosis. The regenera‐
tive potential of organ depends on the amount of the cells with sufficient telomere length,
which reserves the potential for cell proliferation. Telomere shortening restricts the replicative
capacity of these cells. Interestingly, adenoviral telomerase gene delivery inhibited the
progression of liver cirrhosis [42]. These data indicate that telomere shortening in hepatocytes
148 Telomere - A Complex End of a Chromosome

might impair the regenerative capacity in response to liver injury, which might result in liver
fibrosis.

4. Telomeres in endocrine diseases

4.1. Polycystic ovary syndrome (PCOS)

To the best of our knowledge, the first endocrine disease, in which telomere length was
investigated, was polycystic ovary syndrome (PCOS) [43]. PCOS is characterized by polycystic
ovaries, irregular menstrual cycles, androgen excess, and insulin resistance [44]. PCOS is a
complex and multigenetic disorder, in which single nucleotide polymorphisms (SNPs) in
several genes have been found to be associated. Phenotypes of the disease vary according to
the ethnic origin, race, genetic factors, and other environmental factors [45,46]. In addition, no
single etiologic factor was able to fully account for the pathogenesis of this disorder. Interest‐
ingly, patients with PCOS exhibited a significantly shorter telomere length than the controls
after adjusting for age [43]. In addition, significant negative correlation between telomere
length and dehydroepiandrosterone sulfate (DHEA-S) was observed. There are several lines
of evidences, which suggest that oxidative stress plays a role in the pathogenesis of PCOS [47,
48]. Telomere shortening can cause dysregulation of the insulin sensitivity, mitochondrial
function, and Ca2+ metabolism [49,50], suggesting a causal role of shortened telomere length
in the development of PCOS. Conversely, an elevated oxidative stress associated with the
androgen excess, abdominal adiposity, insulin resistance, and obesity might play a role in
telomere shortening.

4.2. Cushing’s syndrome

Cushing’s syndrome is characterized by excessive secretion of cortisol, which leads to

increased mortality and severe morbidity, including cardiovascular risk, obesity, fatigability,
osteopenia, and impaired quality of life [51]. These comorbidities are not completely reversible
after the biochemical control [52]. Hyperstimulation of hypothalamus-pituitary-adrenal
(HPA) axis and subsequent hypercortisolemia may also occur in several kinds of psychiatric
disorders or life stressors [53]. Interestingly, these situations are reportedly associated with
shortened telomeres, in which chronic stress and enhanced HPA axis are observed. For
example, patients with depression exhibited shorter telomere length than healthy controls [54].
Telomere length of newborn baby was shorter in proportion to the stress levels experienced
by the mother during her pregnancy [55]. The exposure to violence or neglect in childhood
was associated with shorter telomere length either in children or retrospectively in adults [56].
In vitro analysis has revealed that high levels of glucocorticoid reduce a 50% of telomerase
activity in lymphocytes [57]. In this aspect, to elucidate the reason why comorbidities of
Cushing’s syndrome are not completely recover after a biochemical control, Aulinas et al. [58]
hypothesized that shortening of telomere might occur in Cushing’s syndrome and evaluated
the telomere length in patients with Cushing’s syndrome. They evaluated 77 patients with
Cushing’s syndrome (59 pituitary adenoma, 17 adrenal adenoma, and 1 ectopic; 21 with active
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disease). Although mean telomere length in patients with Cushing’s syndrome and age-, sex-,
and smoking-matched controls were comparable, in the longitudinal evaluation, telomere
length was shorter in active disease than controlled disease after adjustment for age. They also
showed that dyslipidemic patients with Cushing’s syndrome had shorter telomere length than
non-dyslipidemic patients with Cushing’s syndrome and total cholesterol and triglycerides
negatively correlated with telomere length. In addition, inflammatory markers and serum
levels of CRP and IL-6 were also negatively correlated with telomere length in patients with
Cushing’s syndrome [59]. These observations suggested that hypercortisolism might nega‐
tively regulate telomere maintenance through the production of inflammatory cytokines or
lipids.

4.3. Acromegaly

Patients with acromegaly exhibit reduced life expectancy and increased comorbidities, such
as DM, hypertension, cardiovascular and cerebrovascular diseases, and malignant diseases,
which are also known as age-related diseases. Underlying mechanisms of these increased age-
related diseases are mainly explained by over secretion of GH and IGF-I; however, precise
mechanisms have not been fully elucidated. Therefore, we investigated the telomere length of
peripheral leukocytes in patients with acromegaly [60]. Intriguingly, patients with acromegaly
exhibited shorter telomere length compared with patients with nonfunctioning pituitary
adenoma or healthy control subjects. In addition, telomere length in acromegaly was nega‐
tively correlated with the disease duration, suggesting that exposure to increased serum GH
or IGF-I levels may reduce telomere length. In vitro analysis revealed that not GH but IGF-I
increased the telomere shortening rate per one cell division in human skin fibroblasts.
Furthermore, IGF-I–treated cells showed cellular senescence and increased expression of
SASP-related cytokines (e.g., IL-6). It has been reported that the development of age-related
diseases, such as DM and vascular diseases, is associated with cellular senescence and SASP
[8]. Together with our data, it is suggested that cellular senescence induced by telomere
shortening may be involved in the increased morbidity and mortality in acromegalic patients.

The underlying mechanisms of how excess IGF-I induces telomere shortening and subsequent
cellular senescence remain unclarified. It has been reported that various factors, including
ROS, defects in the telomere repair system, inflammatory reactions, and increased cellular turn
over, cause telomere shortening [61]. Intriguingly, oxidative stress was enhanced both in GH-
transgenic rats and patients with acromegaly [62]. In addition, it has been reported that IGF-I
enhances ROS-p53 pathway and subsequent cellular senescence in cultured cells with a
confluent status [63]. Bayram et al. [64] also reported that patients with acromegaly exhibited
increased oxidative stress and DNA damage. Furthermore, the causal role of increased
oxidative stress in telomere shortening has been reported. Human fibroblasts cultured under
40% oxygen, in which oxidative stress is increased, exhibited an accelerated rate of telomere
shortening [33] and inhibition of the glutathione-dependent antioxidant system results in
telomere shortening and senescence in human endothelial cells [65]. Taken together, although
further investigations are needed, we speculate that the increased oxidative stress associated
150 Telomere - A Complex End of a Chromosome

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

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 follow-
up 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.
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5.3. Liver cirrhosis

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
152 Telomere - A Complex End of a Chromosome

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 telomere-
related 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.
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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.

Author details

Ryusaku Matsumoto and Yutaka Takahashi*

*Address all correspondence to: [email protected]

Division of Diabetes Endocrinology, Kobe University Graduate School of Medicine, Kobe,

Japan

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