Testosterone Replacement to Augment Lifestyle Therapy in Obese Older Veterans

描述(由申请人提供)： 肥胖不仅在美国人中非常普遍，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不动的生活方式影响了当前的治疗，并增加了未来对退伍军人保健服务的需求。随着年龄的增长，肌肉质量下降，肥胖导致需要携带额外的肌肉，这使得肥胖的老年退伍军人特别难以独立运作，导致虚弱，导致疗养院入院人数增加，发病率和死亡率增加。来自初步研究的数据显示，在这一未被研究的人群中，生活方式疗法导致体重减轻，改善了身体功能，改善了虚弱。然而，身体机能的这种改善充其量是适度的，大多数肥胖的老年人身体仍然虚弱。更重要的是，人们担心生活方式治疗可能会加剧因减肥导致的瘦体重和骨密度(BMD)下降而导致的潜在的骨量减少和骨量减少。因此，大多数老年医生不愿建议对肥胖虚弱的老年患者进行包括减肥在内的生活方式治疗，尽管建议将减肥和运动相结合作为一般肥胖患者标准护理的一部分。因此，在退伍军人中，MOVE(管理超重/肥胖退伍军人)计划没有任何针对70岁或以上符合条件的退伍军人的指导方针。除了暴饮暴食和缺乏锻炼外，与年龄相关的合成激素(即睾酮)的下降可能会导致骨质疏松症和骨质疏松症，而肥胖又会加剧这种情况。事实上，我们的初步研究发现，肥胖的老年男性的血清睾酮水平在基线水平明显较低，在整个生活方式治疗期间保持在较低水平。由于睾酮替代疗法已被证明可以增加肌肉质量和骨密度，因此在肥胖老年人的生活方式治疗中伴随的睾酮替代可能会保持瘦体重和骨密度，并扭转虚弱。因此，对骨质疏松性肥胖和虚弱问题的最佳管理可能需要一种综合的方法，即生活方式干预和纠正合成激素缺乏。因此，这项建议的主要目标是进行一项随机、疗效比较、双盲、安慰剂对照(针对睾酮)的试验，比较1)生活方式疗法(1%饮食诱导的减肥和运动训练)+睾酮替代疗法与2)不使用睾酮替代疗法(睾酮安慰剂)在肥胖(BMI e 30 kg/m2)老年(e 65岁)男性退伍军人中的效果。我们假设：1)生活方式治疗+睾酮替代疗法对身体功能的改善比没有睾酮替代的生活方式疗法更大；2)生活方式疗法+睾酮替代疗法比没有睾酮替代的生活方式疗法对脱脂质量和大腿肌肉体积的保护更大；3)生活方式疗法+睾酮替代疗法比没有睾酮替代的生活方式疗法更能保存骨密度和骨质量；4)生活方式疗法+睾酮替代疗法比没有睾酮替代的生活方式疗法将导致肌肉内促炎细胞因子的更大减少。我们横跨AIMS的总体假设是，通过生活方式治疗和睾酮替代的多因素干预将是扭转肥胖老年男性肌肉源性肥胖和虚弱的最有效方法，因为它们在抑制慢性炎症和刺激肌肉和骨骼合成代谢方面具有相加作用。老年人的肥胖，包括许多年迈的退伍军人，是一个主要的公共卫生问题。事实上，如果忽视老年人的生活方式，近年来取得的公共卫生成功可能会受到威胁。这项拟议的随机对照试验产生的新的健康结果和基于机制的数据将对这一快速增长的老年退伍军人人口的护理标准产生重要影响。

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.