Testosterone Replacement to Augment Lifestyle Therapy in Obese Older Veterans

睾酮替代疗法可增强肥胖老年退伍军人的生活方式治疗

• 批准号: 8794262
• 负责人: DENNIS T. VILLAREAL
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8794262
• 关键词: Admission activity; Adult; Affect; Age; Aging; American; Anabolism; Biological Preservation; Body Weight decreased; Bone Density; Bone Resorption; Chronic; Chronic Care; Clinical; Data; Databases; Diet; Double-Blind Method; Dual-Energy X-Ray Absorptiometry; Elderly; Equilibrium; Exercise; Failure; Fatty acid glycerol esters; Frail Elderly; Future; Gene Expression; General Population; Geometry; Goals; Growth Factor; Guidelines; Health; Health Services; Healthcare; Healthcare Systems; Hip region structure; Hormones; Hyperphagia; Inflammation; Insulin-Like Growth Factor I; Interleukin-6; Intervention; Intramuscular; Life Style; Lifestyle Therapy; Magnetic Resonance Imaging; Mediating; Medical; Methods; Morbidity - disease rate; Muscle; Nursing Homes; Obesity; Osteogenesis; Osteopenia; Outcome; Overweight; Patients; Performance; Physical Function; Placebo Control; Placebos; Population; Prevalence; Protein Isoforms; Public Health; Quality of life; Randomized; Reverse Transcriptase Polymerase Chain Reaction; Serum; Skeletal Muscle; TNF gene; Testing; Testosterone; Thigh structure; Tissue Sample; Training; Veterans; Weight; Western Blotting; X-Ray Computed Tomography; age related; base; bone; bone mass; bone quality; comparative efficacy; cytokine; efficacy trial; frailty; functional outcomes; functional status; hormone deficiency; improved; lean body mass; lifestyle intervention; male; mortality; multi-component intervention; muscle form; muscle strength; neglect; novel; obesity treatment; older men; older patient; performance tests; prevent; programs; protein expression; restoration; sarcopenia; sedentary lifestyle; standard care; standard of care; success; testosterone replacement therapy

DESCRIPTION (provided by applicant): Obesity is not only highly prevalent among Americans, but even more so among veterans using VA medical facilities. Failure to assist veterans in managing weight and sedentary lifestyle affects current treatment and increases future demand for VA health care services. Decreased muscle mass with aging and the need to carry extra mass due to obesity make it particularly difficult for obese older veterans to function independently and results in frailty leading to increased nursing home admissions and increased morbidity and mortality. Data from preliminary studies showed that lifestyle therapy resulting in weight loss in this understudied population improves physical function and ameliorates frailty. However, this improvement in physical function is modest at best and most obese older adults remain physically frail. More importantly, there are concerns that lifestyle therapy may exacerbate underlying sarcopenia and osteopenia from weight loss- induced loss of lean body mass and bone mineral density (BMD). As a result, most geriatricians are reluctant to recommend lifestyle therapy that includes weight loss in obese frail elderly patients although the combination of weight loss and exercise is recommended as part of standard care for obese patients in general. Thus, it is not surprising that among veterans, the MOVE (Managing Overweight/Obese Veterans) program does not have any guidelines for eligible veterans if they are 70 or older. In addition to overeating and lack of exercise, age-related decline in anabolic hormone (i.e. testosterone) may contribute to sarcopenia and osteopenia, which in turn is exacerbated by obesity. Indeed, our preliminary studies discovered that obese older men had markedly low levels of serum testosterone at baseline which remained low throughout the duration of lifestyle therapy. Because testosterone replacement therapy has been shown to increase muscle mass and BMD, it is therefore likely that concomitant testosterone replacement during lifestyle therapy in obese older adults would preserve lean body mass and BMD, and reverse frailty. Accordingly, the optimal management to the problem of sarcopenic obesity and frailty might require a comprehensive approach of a combination of lifestyle intervention and the correction of anabolic hormone deficiency. Therefore, the primary goal of this proposal is to conduct a randomized, comparative efficacy, double-blind, placebo-controlled (for testosterone) trial of the effects of 1) lifestyle therapy (1% diet-induced weight loss and exercise training) + testosterone replacement therapy versus 2) lifestyle therapy without testosterone replacement (testosterone placebo) in obese (BMI e 30 kg/m2) older (age e 65 yrs) male veterans. We hypothesize that 1) lifestyle therapy + testosterone replacement will cause a greater improvement in physical function than lifestyle therapy without concomitant testosterone replacement; 2) lifestyle therapy + testosterone replacement will cause a greater preservation of fat-free mass and thigh muscle volume than lifestyle therapy without testosterone replacement, 3) lifestyle therapy + testosterone replacement will cause a greater preservation in BMD and bone quality than lifestyle therapy without testosterone replacement, and 4) lifestyle therapy + testosterone replacement will cause a greater reduction in intramuscular proinflammatory cytokines than lifestyle therapy without testosterone replacement. Our overarching hypothesis across aims is that a multifactorial intervention by means of lifestyle therapy plus testosterone replacement will be the most effective approach for reversing sarcopenic obesity and frailty in obese older male adults, as mediated by their additive effects in suppressing chronic inflammation, and stimulating muscle and bone anabolism. Obesity in older adults, including many aging veterans, is a major public health problem. In fact, the public health success that has occurred in recent years could be in danger if lifestyles of older adults are neglected. The novel health outcomes and mechanistic-based data generated from this proposed RCT will have important ramifications for the standard of care for this rapidly increasing segment of the aging veteran population.

描述（由申请人提供）： 肥胖不仅在美国人中非常普遍，而且在使用退伍军人管理局医疗设施的退伍军人中更是如此。未能帮助退伍军人控制体重和久坐的生活方式会影响当前的治疗并增加未来对退伍军人管理局医疗保健服务的需求。随着年龄的增长，肌肉质量下降，并且由于肥胖而需要携带额外的体重，这使得肥胖的老年退伍军人独立运作变得特别困难，并导致身体虚弱，导致疗养院入院人数增加，发病率和死亡率增加。初步研究的数据表明，生活方式疗法可以减轻这一被研究人群的体重，从而改善身体机能并改善虚弱状况。然而，这种身体机能的改善充其量是有限的，大多数肥胖老年人仍然身体虚弱。更重要的是，人们担心生活方式疗法可能会加剧因减肥引起的去脂体重和骨矿物质密度（BMD）损失而引起的潜在肌肉减少症和骨质减少症。因此，大多数老年病学家不愿意推荐包括减肥在内的生活方式疗法，对肥胖体弱的老年患者进行减肥，尽管减肥和运动相结合被推荐作为一般肥胖患者标准护理的一部分。因此，毫不奇怪，在退伍军人中，MOVE（管理超重/肥胖退伍军人）计划没有针对 70 岁或以上符合条件的退伍军人提供任何指导方针。 除了暴饮暴食和缺乏运动之外，与年龄相关的合成代谢激素（即睾酮）下降可能会导致肌肉减少症和骨质减少症，而肥胖又会加剧这种情况。事实上，我们的初步研究发现，肥胖老年男性的基线血清睾酮水平明显较低，并且在整个生活方式治疗期间一直保持较低水平。由于睾酮替代疗法已被证明可以增加肌肉质量和 BMD，因此肥胖老年人在生活方式治疗期间伴随睾酮替代可能会保持去脂体重和 BMD，并逆转虚弱。因此，对肌肉减少性肥胖和虚弱问题的最佳管理可能需要采取生活方式干预和纠正合成代谢激素缺乏相结合的综合方法。因此，本提案的主要目标是进行一项随机、疗效比较、双盲、安慰剂对照（睾酮）试验，比较 1) 生活方式疗法（1% 饮食诱导减肥和运动训练）+ 睾酮替代疗法与 2) 无睾酮替代的生活方式疗法（睾酮安慰剂）对肥胖（BMI e 30 kg/m2）老年人（年龄 e 65）的效果 年）男性退伍军人。我们假设 1) 生活方式疗法 + 睾酮替代疗法将比不同时进行睾酮替代疗法的生活方式疗法带来更大的身体功能改善； 2) 生活方式疗法 + 睾酮替代将比没有睾酮替代的生活方式疗法更好地保留无脂肪质量和大腿肌肉体积，3) 生活方式疗法 + 睾酮替代将比没有睾酮替代的生活方式疗法更好地保留 BMD 和骨质量，4) 生活方式疗法 + 睾酮替代将导致肌内促炎性物质更大程度地减少 细胞因子比没有睾酮替代的生活方式疗法更有效。我们的总体假设是，通过生活方式疗法加睾酮替代进行多因素干预将是逆转肥胖老年男性肌肉减少性肥胖和虚弱的最有效方法，其介导的作用是抑制慢性炎症、刺激肌肉和骨骼合成代谢的附加效应。 老年人（包括许多老年退伍军人）的肥胖是一个重大的公共卫生问题。事实上，如果忽视老年人的生活方式，近年来在公共卫生领域取得的成功可能会面临危险。这项拟议的随机对照试验产生的新颖的健康结果和基于机制的数据将对这一快速增长的老龄化退伍军人群体的护理标准产生重要影响。