Leukocyte TelomerE Dynamics, Gender, Menopause, Insulin Resistance and Survival

白细胞端粒E动态、性别、更年期、胰岛素抵抗和生存

• 批准号: 8417671
• 负责人: ABRAHAM AVIV
• 金额: $ 27.7万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417671
• 关键词: Adult; Age; Aging; Atherosclerosis; Biological Markers; Biology; Birth; CD28 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Cells; Cigarette Smoker; Complex Genetic Trait; Cross-Sectional Studies; Cytomegalovirus; Dementia; Development; Disease; Elderly; Elements; Endowment; Environmental Risk Factor; Epidemiology; Epstein-Barr Virus Infections; Fatty acid glycerol esters; Gap Junctions; Gender; Gender Role; Genetic; Human; Human Herpesvirus 4; IGFBP3 gene; Individual; Inflammation; Insulin Resistance; Insulin-Like Growth Factor I; Length; Leukocytes; Life; Life Expectancy; Link; Longevity; Longitudinal Studies; Measurement; Men' s Role; Menopausal Status; Menopause; Metabolic; Metabolism; Modeling; Newborn Infant; Non obese; Obesity; Overweight; Oxidative Stress; Persons; Phenotype; Postmenopause; Premenopause; Records; Research; Resort; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Signal Transduction; Smoker; Socioeconomic Status; Southern Blotting; Telomere Shortening; Testing; Time; Twin Multiple Birth; Variant; Woman; age related; aged; base; boys; cohort; design; girls; indexing; insight; low socioeconomic status; men; mortality; non-smoker; peer; sedentary; sex; telomere; trait

Project Summary Leukocyte telomere length (LTL) is a complex genetic trait. LTL undergoes attrition with age and is associated with a host of aging related diseases and environmental conditions that diminish the human lifespan. Moreover, LTL forecasts mortality in the elderly. Cross-sectional studies have established that LTL is shorter in adult men than women and in individuals with cardiovascular diseases than in their healthy peers. LTL is also relatively short in individuals who are smokers, sedentary, overweight or of low socio-economic status. Collectively, such observations suggest that LTL is a biomarker of human aging. The two elements that contribute to leukocyte telomere dynamics are LTL and its age-dependent attrition rate. Whereas considerable information is available about LTL, little is known about the links between LTL attrition rate and aging related diseases. This project will resort to a longitudinal model in same-sex twin pairs to test the following central hypotheses: (i) Age-dependent leukocyte telomere attrition is faster in men than in women and in post-menopausal than pre- menopausal women; (ii) Leukocyte telomere attrition rate is faster under conditions of increased oxidative stress/inflammation, which are often associated with increased insulin resistance and diminished circulating IGF-1; (iii) In the elderly, LTL but not age-dependent telomere attrition rate is a predictor of mortality. This feature explains in part the longer lifespan of women than men; (iv) Age-dependent leukocyte telomere attrition is heritable. These hypotheses will be tested in two cohorts of Danish twins: the Geminakar Study and the Longitudinal Study of Aging Danish Twins (LSADT). The following are the project's specific aims: 1) Examine leukocyte telomere dynamics by Southern blots and real time-PCR measurements of telomeres, based on two occasions that span 10 years in adult twins (aged 18-63 at the baseline examination) and explore the roles of gender and menopause in telomere attrition and their links with obesity, insulin resistance, IGF-1 and indices of oxidative stress/inflammation; 2) Examine the links between leukocyte telomere dynamics and mortality/survival, based on leukocyte telomere measurements on two occasions, spanning 10 years, in elderly twins (at least 73 years old at the baseline examination). We will also explore the role of CMV and EBV infections in LTL dynamics. In a subset of the elderly, we will evaluate by flow FISH telomere signal intensities in CD8+ and CD4+ cells. Findings will refine our understanding of human telomere biology and its connections with aging and lifespan.

项目概要 白细胞端粒长度（LTL）是一个复杂的遗传特征。 LTL 会随着年龄的增长而减少 并与许多与衰老相关的疾病和环境条件有关 缩短人类的寿命。此外，LTL 还可以预测老年人的死亡率。横截面 研究表明，成年男性和患有以下疾病的个体的 LTL 比女性短 心血管疾病的发病率高于健康同龄人。零担对于个人来说也相对较短 吸烟者、久坐、超重或社会经济地位低下的人。总的来说，这样的 观察表明，LTL 是人类衰老的生物标志物。这两个要素 影响白细胞端粒动态的是 LTL 及其年龄依赖性损耗率。 尽管有大量有关 LTL 的信息，但人们对这些链接知之甚少 零担损耗率与衰老相关疾病之间的关系。该项目将采用纵向 在同性双胞胎中建立模型来测试以下中心假设：（i）年龄依赖性 男性白细胞端粒磨损比女性快，绝经后比绝经前快。 更年期妇女； (ii) 在以下条件下白细胞端粒磨损率更快 氧化应激/炎症增加，这通常与胰岛素增加有关 抵抗力和循环 IGF-1 减少； (iii) 对于老年人，LTL 但与年龄无关 端粒损耗率是死亡率的预测指标。此功能部分解释了更长的 女性的寿命比男性长； (iv) 年龄依赖性白细胞端粒磨损是可遗传的。 这些假设将在两组丹麦双胞胎中进行检验：Geminakar 研究和 丹麦老年双胞胎的纵向研究 (LSADT)。以下是该项目的具体情况 目标：1) 通过 Southern 印迹和实时 PCR 检查白细胞端粒动态 端粒测量，基于成年双胞胎（年龄 18-63 在基线检查）并探讨性别和更年期的作用 端粒磨损及其与肥胖、胰岛素抵抗、IGF-1 和指数的关系 氧化应激/炎症； 2) 检查白细胞端粒动力学之间的联系 和死亡率/生存率，基于两次白细胞端粒测量， 跨越 10 年，老年双胞胎（基线检查时至少 73 岁）。我们 还将探讨 CMV 和 EBV 感染在 LTL 动态中的作用。在一个子集中 对于老年人，我们将通过流式 FISH 评估 CD8+ 和 CD4+ 细胞中的端粒信号强度。 研究结果将加深我们对人类端粒生物学及其与人类的联系的理解 衰老和寿命。

项目成果

Estimating telomere length from whole genome sequence data.

从全基因组序列数据估计端粒长度。

• 发表时间: 2014-05
• 影响因子: 14.9
• 作者: Ding, Zhihao;Mangino, Massimo;Aviv, Abraham;Spector, Tim;Durbin, Richard;UK10K Consortium
• 通讯作者: UK10K Consortium

A model of canine leukocyte telomere dynamics.

犬白细胞端粒动力学模型。

• 发表时间: 2011-12
• 影响因子: 7.8
• 作者: Benetos, Athanase;Kimura, Masayuki;Labat, Carlos;Buchoff, Gerald M;Huber, Shell;Labat, Laura;Lu, Xiaobin;Aviv, Abraham
• 通讯作者: Aviv, Abraham

Sex difference in leukocyte telomere length is ablated in opposite-sex co-twins.

异性双胞胎中白细胞端粒长度的性别差异消失。

• 发表时间: 2014-12
• 影响因子: 7.7
• 作者: Benetos, Athanase;Dalgård, Christine;Labat, Carlos;Kark, Jeremy D;Verhulst, Simon;Christensen, Kaare;Kimura, Masayuki;Horvath, Kent;Kyvik, Kirsten Ohm;Aviv, Abraham
• 通讯作者: Aviv, Abraham

The heritability of leucocyte telomere length dynamics.

白细胞端粒长度动态的遗传力。

• 发表时间: 2015-05
• 影响因子: 4
• 作者: Hjelmborg, Jacob B;Dalgård, Christine;Möller, Soren;Steenstrup, Troels;Kimura, Masayuki;Christensen, Kaare;Kyvik, Kirsten O;Aviv, Abraham
• 通讯作者: Aviv, Abraham

Leukocyte telomere length dynamics in women and men: menopause vs age effects.

女性和男性白细胞端粒长度动态：更年期与年龄的影响。

• 发表时间: 2015-10
• 影响因子: 7.7
• 作者: Dalgård, Christine;Benetos, Athanase;Verhulst, Simon;Labat, Carlos;Kark, Jeremy D;Christensen, Kaare;Kimura, Masayuki;Kyvik, Kirsten Ohm;Aviv, Abraham
• 通讯作者: Aviv, Abraham