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

描述（由申请人提供）：白细胞端粒长度（LTL）是一种复杂的遗传性状。LTL随着年龄的增长而磨损，并与许多与衰老相关的疾病和环境条件有关，这些疾病和环境条件减少了人类的寿命。此外，LTL预测老年人的死亡率。横断面研究表明，成年男性的LTL比女性短，心血管疾病患者的LTL比健康同龄人短。吸烟者、久坐者、超重者或社会经济地位低者的LTL也相对较短。总的来说，这些观察表明LTL是人类衰老的生物标志物。影响白细胞端粒动力学的两个因素是LTL及其年龄依赖性损耗率。虽然有相当多的信息是关于LTL，很少有人知道LTL损耗率和老龄化相关疾病之间的联系。该项目将采用同性双胞胎对中的纵向模型来检验以下中心假设：（i）男性中的依赖性白细胞端粒消耗比女性中的快，并且绝经后的女性比绝经前的女性中的依赖性白细胞端粒消耗快;（ii）在增加的氧化应激/炎症的条件下，白细胞端粒消耗速率更快，这通常与增加的胰岛素抵抗和减少的循环IGF-1相关;（iii）在老年人中，LTL而不是年龄依赖性端粒磨损率是死亡率的预测因子。这一特征部分解释了女性比男性寿命长的原因;（iv）依赖性白细胞端粒磨损是可遗传的。这些假设将在丹麦双胞胎的两个队列中进行测试：Geminakar研究和丹麦双胞胎老龄化纵向研究（LSADT）。以下是该项目的具体目标：1）通过Southern印迹和端粒的真实的时间PCR测量来检查白细胞端粒动力学，基于两个跨越10年的成年双胞胎（基线检查时年龄为18-63岁），并探讨性别和绝经在端粒磨损中的作用及其与肥胖、胰岛素抵抗、IGF-1和氧化应激/炎症指数的联系; 2）基于跨越10年的两次白细胞端粒测量，在老年双胞胎（基线检查时至少73岁）中检查白细胞端粒动力学与死亡率/存活率之间的联系。我们还将探讨CMV和EBV感染在LTL动态中的作用。在老年人的一个亚组中，我们将通过流式细胞术评估CD 8+和CD 4+细胞中的FISH端粒信号强度。研究结果将完善我们对人类端粒生物学及其与衰老和寿命的联系的理解。公共卫生相关性：在这项研究中，我们将检查白细胞端粒缩短率是否记录了成年人胰岛素抵抗的发展风险，并预测老年人的死亡率。我们还将研究男性端粒的磨损速度是否比女性快，以及绝经后女性是否比绝经前女性快。我们的研究结果将为人类寿命的性别差距（女性比男性寿命长）以及胰岛素抵抗在人类寿命中的作用提供新的见解。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: In this study we will examine whether the rate of telomere shortening in leukocytes records the risk for the development of insulin resistance in adults and forecasts mortality in the elderly. We will also examine whether the rate of telomere attrition is faster in men than in women and in post-menopausal than pre-menopausal women. Our findings will provide a new insight into the gender gap in human longevity (women live longer than men) and the role of insulin resistance in the human lifespan.