Weight Loss & Exercise Effects on Telomere Length in Postmenopausal Women

描述(由申请人提供)：超重、肥胖和久坐不动的生活方式会增加患几种癌症的风险。目前，人们对生活方式改变对人类细胞水平的影响知之甚少。染色体的端粒区域由染色体的分子帽或末端组成。随着细胞的连续分裂，体细胞的端粒逐渐缩短是细胞衰老的一个标志，每个细胞分裂失去大约50-100个碱基对。最近的流行病学研究表明，外周血细胞端粒缩短与几种癌症风险增加之间存在关联。观察数据表明，超重和肥胖与端粒缩短有关，但缺乏以下方面的研究：1)饮食减肥和运动对端粒长度的独立和综合影响；2)体重减少量，即可能影响端粒长度变化所必需的身体成分变化。我们建议在一项完整的随机试验中调查饮食减肥、运动以及两者结合对438名50-75岁的绝经后、超重/肥胖、久坐不动的妇女在基线和12个月时测量的样本中白细胞端粒长度(T/S比率)的独立和联合影响。女性被随机分为四组：1)中等强度有氧运动(225分钟/周)干预，平均体重下降2.6%(N=117)；3)两种干预措施(饮食+锻炼)，平均体重下降11.6%(N=116)；4)对照组(N=87)，平均体重下降0.7%。减肥计划是对糖尿病预防计划生活方式改变减肥计划的小组修改，包括每天减少500-1000卡路里的目标，饮食脂肪和热量的25%，前6个月体重减轻10%的目标，以及行为改变技术。两个运动组12个月的平均运动量是目标225分钟/周的83%。流失率为9%。主要分析意向治疗对端粒缩短的干预作用。主要终点将是白细胞DNA相对端粒长度的变化。其他分析将是相互关联的，调查端粒长度与试验中已经测量的其他分析指标之间的关系：DNA损伤修复(彗星)、性激素、胰岛素和葡萄糖、炎症(C-反应蛋白、血清淀粉样蛋白A、白介素6)、胰岛素样生长因子1和结合蛋白3以及脂肪因子(脂联素、瘦素)。与端粒长度相关的SNP等位基因(TERT、TRF1、TNKS1、TRF2、RAP1、POT1和位于TERC附近的rs12696304)的效果修饰也将进行测试。这项拟议的研究具有很高的新颖性，并利用了已完成试验中存储的现有DNA资源。如果减肥或锻炼减少了端粒缩短，这将为这些生活方式因素与癌症和其他与端粒长度有关的慢性病风险之间的联系提供更多线索。 与公共健康相关：该项目将调查体育活动、低卡路里减肥以及这两种干预措施的组合对端粒长度的影响，端粒是DNA的一部分。端粒越短，患癌症的风险越高。该项目包括438名绝经后、超重/肥胖、久坐不动的女性，她们已经完成了将使用血液样本的试验。

DESCRIPTION (provided by applicant): Overweight, obesity, and a sedentary lifestyle increase risk for several types of cancer. Currently, little is known about the effects of lifestyle change at the cellular level in humans. The telomeric regions of chromosomes comprise the molecular caps or ends of the chromosomes. Progressive telomere shortening of somatic cells with successive cell division is a hallmark of cellular aging, with loss of ~ 50-100 base pairs per cell division. Recent epidemiologic studies have suggested an association between telomere shortening in peripheral blood cells and increased risk of several cancers. Observational data suggests that overweight and obesity are associated with telomere shortening, but there is a lack of research on 1) the independent and combined effects of dietary weight loss and exercise on telomere length and 2) the amount of weight loss, or change in body composition that may be necessary to effect changes in telomere length. We propose to investigate within a completed randomized trial the independent and combined effects of dietary weight loss, exercise, and the two combined, compared with controls, on leukocyte telomere length (T/S ratio) measured in samples collected at baseline and 12 months in 438 postmenopausal, overweight/obese, sedentary women aged 50-75 years. Women were randomized to reduced calorie weight loss "diet-only" that achieved a mean 9.9% loss of baseline weight (N=118); 2) moderate intensity aerobic exercise (225 min/wk) intervention "exercise-only" that produced a mean 2.6% weight loss (N=117); 3) both interventions "diet+exercise" with mean 11.6% weight loss (N=116); and 4) control (0.7% weight loss) (N=87). The weight loss program was a group-based modification of the Diabetes Prevention Program lifestyle change weight loss program, and included goals of 500-1000 kcal/day reduction, dietary fat < 25% of calories, goal 10% weight loss in first 6 months, and behavioral change techniques. Mean exercise over 12 months was 83% of goal 225 minutes/week in the 2 exercise groups. Attrition was 9%. Primary analyses will be intent-to-treat of intervention effect on telomere shortening. The primary endpoint will be changes in relative telomere length of leukocyte DNA. Additional analyses will be correlational, investigating associations between telomere length and other analytes already measured in the trial: DNA damage repair (COMET), sex hormones, insulin & glucose, inflammation (C-reactive protein, serum amyloid A, interleukin-6), insulin like growth factor 1 and binding protein 3, and adipokines (adiponectin, leptin). Effect modification by gene SNP alleles related to telomere length (TERT, TRF1, TNKS1, TRF2, RAP1, POT1, and rs12696304 near TERC) will also be tested. The proposed research is highly novel, and takes advantage of an existing resource of stored DNA from a completed trial. If weight loss or exercise reduces telomere shortening, it will provide additional clues to the links between these lifestyle factors and risks for cancer and other chronic diseases that have been associated with telomere length. PUBLIC HEALTH RELEVANCE: This project will investigate the effects of physical activity, reduced-calorie weight loss and the combination of these two interventions, on the length of telomeres, which is a part of DNA. Shorter telomeres have been linked to cancer risk. The project includes 438 postmenopausal, overweight/obese, sedentary women who have already completed the trial from which blood samples will be used.