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

项目摘要 白细胞端粒长度（LTL）是一个复杂的遗传性状。LTL随年龄增长而减少 并与许多与衰老有关的疾病和环境条件有关， 减少人类的寿命。此外，LTL预测老年人的死亡率。横截面 研究表明，成年男性的LTL比女性短， 心血管疾病的发病率比健康的同龄人高。LTL在个体上也相对较短 吸烟者、久坐者、超重者或社会经济地位低下者。等集体方式 观察表明LTL是人类衰老的生物标志物。的两个要素 导致白细胞端粒动力学的主要因素是LTL及其年龄依赖性损耗率。 虽然关于零担运费的信息相当多，但人们对这种联系知之甚少 LTL损耗率与衰老相关疾病之间的关系。该项目将采取纵向 模型在同性双胞胎对测试以下中心假设：（一）依赖性 男性白细胞端粒磨损快于女性，绝经后白细胞端粒磨损快于绝经前。 绝经期妇女;（ii）白细胞端粒磨损率在绝经期妇女的条件下更快， 氧化应激/炎症增加，通常与胰岛素增加有关 抵抗和减少循环IGF-1;（iii）在老年人中，LTL 但不依赖于年龄 端粒磨损率 是死亡率的预测指标这一特点在一定程度上解释了 女性的寿命比男性;（iv）依赖性白细胞端粒磨损是遗传的。 这些假设将在两组丹麦双胞胎中进行测试：Geminakar研究和 老年丹麦双胞胎纵向研究（LSADT）。以下是该项目的具体 目的：1）应用Southern印迹和真实的time-PCR技术检测白细胞端粒的动态变化 端粒的测量，基于两次跨越10年的成年双胞胎（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和胰岛素抵抗指数的关系 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/存活率，基于两次白细胞端粒测量， 年龄跨度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。的子集中 在老年人中，我们将通过流式FISH来评估CD 8+和CD 4+细胞中的端粒信号强度。 研究结果将完善我们对人类端粒生物学的理解， 老化和寿命。

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.