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）是一个复杂的遗传性状。LTL随着年龄的增长而消耗，并与许多与衰老相关的疾病和减少人类寿命的环境条件有关。此外，LTL还能预测老年人的死亡率。横断面研究已经证实，成年男性的LTL短于女性，心血管疾病患者的LTL短于健康同龄人。在吸烟者、久坐不动、超重或社会经济地位低下的人群中，LTL也相对较短。总的来说，这些观察结果表明LTL是人类衰老的生物标志物。促成白细胞端粒动力学的两个因素是LTL及其年龄依赖的损耗率。尽管关于LTL的信息相当多，但对于LTL损耗率与衰老相关疾病之间的联系知之甚少。本项目将采用同性双胞胎的纵向模型来检验以下中心假设：(i)年龄依赖性白细胞端粒损耗在男性中比在女性中快，在绝经后比在绝经前的妇女中快；（ii）在氧化应激/炎症增加的情况下，白细胞端粒磨损速度更快，这往往与胰岛素抵抗增加和循环IGF-1减少有关；（iii）在老年人中，LTL是死亡率的预测因子，而不是与年龄相关的端粒磨损率。这一特征在一定程度上解释了为什么女性比男性寿命更长；（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 blots和端粒实时pcr测量检测白细胞端粒动力学，基于两个跨越10年的成年双胞胎（基线检查年龄为18-63岁），探索性别和更年期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10年间两次对老年双胞胎（基线检查时至少73岁）的白细胞端粒测量，研究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动力学中的作用。在老年人的一个子集中，我们将通过流式FISH评估CD8+和CD4+细胞的端粒信号强度。这些发现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，我们将研究白细胞端粒缩短率是否记录了成人胰岛素抵抗发展的风险，并预测了老年人的死亡率。我们还将研究端粒磨损率男性是否比女性快，绝经后的女性是否比绝经前的女性快。我们的发现将为人类寿命的性别差异（女性比男性寿命更长）和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.