Abstract
ObjectivePatients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases.MethodsWe measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts.ResultsPatients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R 2 = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence.ConclusionShortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I.
Highlights
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]
Shortened telomeres in acromegaly and cellular senescence induced by insulin-like growth factor-I (IGF-I) can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I
To investigate the factors associated with telomere length in acromegaly, we evaluated the relationship between relative telomere length (RTL) and various clinical indices (Fig 1B–1I)
Summary
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]. Telomeres shorten during each cell division and when they reach a critically short length, cell cycle arrest and senescence occur; this is known as the “Hayflick limit” in cultured human cells [3]. Telomere damage activates DNA damage response (DDR), a signaling pathway in which cell cycle progression is blocked via an increased production of p53 and cyclin-dependent kinase (Cdk) inhibitor p21 protein [4]. A number of observations suggest a close connection between telomere length and mortality and age-related disease [5]. Exposure to various stresses and age-related diseases such as diabetes, cardiovascular disease, and neurodegenerative disease are associated with shortened telomeres [7,8,9]. It has been reported that the increased oxidative stress enhances telomere DNA damage. Telomeres are rich in guanine residues and may be sensitive to reactive oxygen species (ROS) because guanine can be oxidized to 8-hydroxyguanine, which is unstable [5]
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