Weight Loss & Exercise Effects on Telomere Length in Postmenopausal Women

减肥

• 批准号: 8028105
• 负责人: Anne M. McTiernan
• 金额: $ 24.22万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-14 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8028105
• 关键词: Aerobic Exercise; Affect; Aging; Alleles; Base Pairing; Base Sequence; Behavioral; Biological; Biological Markers; Bladder; Blood Cells; Blood specimen; Body Composition; Body Weight; Body Weight Changes; Body Weight decreased; Body fat; Body mass index; Breast; C-reactive protein; Calories; Cell Aging; Cell division; Cells; Chemoprevention; Chromosomal Instability; Chromosomes; Chronic Disease; Colon; Comet Assay; DEXA; DNA; DNA Repair; DNA Structure; Data; Development; Diet; Dietary Fats; Endometrium; Epidemiologic Studies; Estradiol; Estrogens; Estrone; Exercise; Expenditure; Fasting; Fatty acid glycerol esters; Gene Dosage; Genes; Genetic Polymorphism; Genetic Recombination; Genotype; Glucose; Goals; Gonadal Steroid Hormones; Head and neck structure; Human; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin-Like Growth-Factor Binding Protein 1; Interleukin-6; Intervention; Kidney; Lead; Length; Leptin; Leukocytes; Life Style; Link; Lung; Malignant Neoplasms; Measures; Methods; Modification; Molecular; Nucleic acid sequencing; Obesity; Observational Study; Outcome; Overweight; Parents; Pathway interactions; Peripheral; Physical activity; Postmenopause; Proteins; Randomized; Relative (related person); Research; Resources; Risk; Sampling; Serum; Serum amyloid A protein; Somatic Cell; Somatomedins; Structure; TERF1 gene; TERT gene; TNKS gene; Techniques; Telomere Shortening; Testing; Testosterone; Weight; Weight Gain; Woman; Work; adipokines; adiponectin; aged; arm; base; cancer prevention; cancer risk; cancer type; diabetes prevention program; diet and exercise; energy balance; experience; ghrelin; inflammatory marker; intervention effect; lifestyle factors; men; mimetics; novel; programs; randomized trial; response; sedentary; senescence; steroid hormone; telomere; weight loss intervention

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.

描述（由申请人提供）：超重、肥胖和久坐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体细胞水平的影响知之甚少。染色体的端粒区包括染色体的分子帽或末端。体细胞端粒随着细胞的连续分裂而逐渐缩短是细胞衰老的标志，每次细胞分裂会损失约50-100个碱基对。最近的流行病学研究表明，外周血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，但缺乏关于1)饮食减肥和运动对端粒长度的独立和联合影响以及2)可能影响端粒长度变化所必需的体重减轻量或身体成分变化的研究。我们建议在一项完整的随机试验中调查饮食减肥、运动和两者结合对白细胞端粒长度（T/S比）的独立和联合影响，与对照组相比，在基线和12个月收集的样本中，测量438名50-75岁绝经后、超重/肥胖、久坐不动的女性。女性被随机分配到“仅饮食”的低热量减肥组，平均基线体重减少9.9% (N=118)；2)“仅运动”的中等强度有氧运动（225分钟/周）干预，平均体重减轻2.6% (N=117)；3)“饮食+运动”两种干预措施平均体重减轻11.6% (N=116)；4)对照组（体重减轻0.7%）（N=87）。减肥计划是对糖尿病预防计划生活方式改变减肥计划的一种基于群体的修改，包括每天减少500-1000千卡的目标，饮食脂肪< 25%的卡路里，前6个月体重减轻10%的目标，以及行为改变技术。在两个运动组中，12个月的平均运动时间达到目标225分钟/周的83%。流失率为9%。初步分析干预对端粒缩短的影响。主要终点将是白细胞DNA相对端粒长度的变化。额外的分析将是相关的，研究端粒长度与试验中已经测量到的其他分析物之间的关系：DNA损伤修复（COMET）、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、白细胞介素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）。与端粒长度相关的基因SNP等位基因（TERT、TRF1、TNKS1、TRF2、RAP1、POT1和TERC附近的rs12696304）的效果修饰也将进行测试。拟议中的研究非常新颖，并利用了已完成试验的现有存储DNA资源。如果减肥或运动能减少端粒的缩短，这将为这些生活方式因素与患癌症和其他慢性疾病的风险之间的联系提供额外的线索，这些疾病与端粒长度有关。