Lifestyle Intervention plus Metformin to Treat Frailty in Older Veterans with Obesity

生活方式干预加二甲双胍治疗老年肥胖退伍军人的虚弱

• 批准号: 10015506
• 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: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10015506
• 关键词: Activities of Daily Living; Admission activity; Affect; Age; Aging; Anabolism; Animals; Biguanides; Blood; Body Weight decreased; Body mass index; Bone Density; Cell Aging; Cell Cycle Arrest; Cells; Chronic; Clinical; Data; Diabetes Mellitus; Diet; Drug usage; Dual-Energy X-Ray Absorptiometry; Elderly; Exercise; Failure; Finite Element Analysis; Frail Elderly; Future; Gait speed; General Population; Goals; Head; Health; Health Personnel; Healthcare Systems; Home Nursing Care; Human; Immunohistochemistry; Impairment; Intervention; Length; Life; Lifestyle Therapy; Longevity; Magnetic Resonance Imaging; Mediating; Medical; Metformin; Muscle; Muscular Atrophy; Non-Insulin-Dependent Diabetes Mellitus; Nursing Homes; Obesity; Obesity Epidemic; Observational Study; Older Population; Oral; Osteopenia; Outcome; Overweight; Performance; Peripheral; Persons; Pharmaceutical Preparations; Phenotype; Physical Function; Physical Performance; Placebos; Population; Prevalence; Process; Quality of life; Randomized Controlled Trials; Reporting; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Risk; Skeletal Muscle; Testing; Thigh structure; Uncertainty; Veterans; Veterans Health Administration; Weight Gain; Weight maintenance regimen; Western Blotting; X-Ray Computed Tomography; adult obesity; age related; base; bone; bone mass; bone quality; comparative efficacy; exercise training; frailty; functional independence; functional loss; functional outcomes; functional status; head-to-head comparison; health care service; healthspan; high risk population; human old age (65+); improved; lean body mass; lifestyle intervention; military veteran; mortality; multi-component intervention; muscle form; muscle strength; novel; obese patients; older patient; performance tests; preservation; prevent; programs; response; sarcopenia; sarcopenic obesity; secondary analysis; senescence; standard care; standard of care; telomere; treatment group

The continuing increase in prevalence of obesity in older adults has become a major health concern. In older adults, obesity not only causes serious medical problems, but it also exacerbates the age-related decline in physical function, which causes frailty, impairs quality of life, and increases nursing home admissions. Thus, failure to help obese older patients in managing weight increases future demand for chronic health care services. We reported not only that frailty is common in obese older adults due to sarcopenic obesity but also that lifestyle therapy resulting in weight loss in this understudied population improves physical function and ameliorates frailty. However, the improvement in physical function was modest and most obese older adults remained frail. Moreover, the weight loss-induced reduction of muscle and bone mass could worsen age-related sarcopenia and osteopenia. Accordingly, many health care providers remain reluctant to recommend lifestyle therapy that includes weight loss in the frail, obese elderly because of the uncertainty of whether the benefits outweigh the risks, although weight loss and exercise is recommended as part of standard care for obese patients in general. Metformin, a biguanide, is a widely available oral drug used as treatment of diabetes. Animal studies have shown that metformin improves both lifespan and health span. However, whether metformin can ameliorate frailty in humans is not known. If metformin improves or preserves physical function, this mostly safe and commonly-used drug would revolutionize the approach to frailty in the elderly. Indeed, encouraging preliminary data from our prior randomized controlled trials (RCT) in this population demonstrated that metformin users, despite being still considered frail, have higher baseline scores in the Physical Performance Test (PPT) compared to non-users. More importantly, the use of metformin during the trials predicted much larger improvements in PPT scores in response to lifestyle interventions. Hence these data, in conjunction with results from our prior studies, suggest that each of lifestyle therapy and metformin is associated with amelioration of frailty, but the additive effects of both in combination could result in reversal of the frailty. In this project, we propose the concept that the addition of metformin to lifestyle therapy reverses frailty by reducing cellular senescence and senescence-associated phenotype (SASP), especially in obese older adults with a high burden of senescent cells and accelerated aging. Accordingly, our objective is to conduct the first head-head, comparative efficacy, placebo-controlled RCT to test the novel hypothesis that lifestyle therapy + metformin for six months will be more effective than lifestyle therapy alone or metformin alone in improving physical function and preventing the weight loss-induced reduction in muscle and bone mass in obese (BMI ≥ 30 kg/m2) older (age ≥ 65 years) veterans with physical frailty. Specifically we hypothesize that compared to lifestyle therapy alone or metformin alone, lifestyle therapy + metformin will cause: 1) a greater improvement in physical function, 2) a greater preservation in lean body mass and muscle quality, and in bone mineral density and bone quality, and 3) a greater reduction in markers of cell cycle arrest and SASP in skeletal muscle tissues along with greater increase in telomere length. Our overarching hypothesis across aims is that a multicomponent intervention consisting of lifestyle therapy + metformin will be the most effective strategy for reversing sarcopenic obesity and frailty in obese older veterans, as mediated by their additive effects in suppressing cellular senescence and thus, stimulating muscle and bone anabolism in this understudied, high-risk population. The epidemic of obesity in US veterans has surpassed that of the general population and even more so, among older veterans using the Veterans Health Administration (VHA). In older veterans with obesity, frailty predisposes to loss of functional independence and adverse health outcomes. The novel health outcomes and mechanistic-based data generated from this proposed RCT will have important consequences for the standard of care for this rapidly increasing segment of the aging veteran population.

老年人肥胖患病率的持续增加已成为一个主要的健康问题。 对于成年人来说，肥胖不仅会导致严重的健康问题，还会加剧与年龄相关的智力下降。 身体功能，导致虚弱，损害生活质量，并增加疗养院的入院人数。 未能帮助肥胖老年患者控制体重会增加未来对慢性医疗保健服务的需求。 我们不仅报道了由于肌肉减少性肥胖而导致肥胖老年人普遍虚弱，而且还报道了生活方式 在这一未被充分研究的人群中，导致体重减轻的治疗可改善身体机能并改善虚弱。 然而，身体机能的改善有限，大多数肥胖老年人仍然虚弱。 此外，减肥引起的肌肉和骨质减少可能会加重与年龄相关的肌肉减少症 许多医疗保健提供者仍然不愿意推荐生活方式疗法。 包括体弱、肥胖老年人的减肥，因为不确定其益处是否大于副作用 尽管建议将减肥和锻炼作为一般肥胖患者标准护理的一部分，但存在风险。 二甲双胍是一种双胍类药物，是一种广泛使用的口服药物，用于治疗糖尿病。动物研究表明。 表明二甲双胍可以延长寿命和健康寿命，但是二甲双胍是否可以改善。 二甲双胍是否能改善或保持身体机能，这在很大程度上是安全且安全的。 事实上，常用药物将彻底改变老年人虚弱的治疗方法，这令人鼓舞。 我们之前针对该人群的随机对照试验 (RCT) 的数据表明，二甲双胍使用者， 尽管仍然被认为虚弱，但在体能测试 (PPT) 中具有较高的基线分数 更重要的是，试验期间使用二甲双胍的预测要大得多。 因此，将这些数据与结果结合起来，可以提高 PPT 分数对生活方式干预的反应。 根据我们之前的研究，生活方式疗法和二甲双胍均与改善 脆弱，但两者结合起来可能会导致脆弱的逆转。 提出了这样的概念：在生活方式疗法中添加二甲双胍可以通过减少细胞数量来逆转虚弱。 衰老和衰老相关表型（SASP），尤其是负担重的肥胖老年人 因此，我们的目标是进行第一次研究， 比较疗效，安慰剂对照随机对照试验，测试生活方式疗法+二甲双胍治疗的新假设 六个月在改善身体功能方面比单独的生活方式疗法或单独的二甲双胍更有效 预防肥胖（BMI ≥ 30 kg/m2）老年人因减肥引起的肌肉和骨量减少 （年龄≥65岁）身体虚弱的退伍军人，与生活方式疗法相比，我们特别追求这一点。 单独使用或单独使用二甲双胍，生活方式疗法+二甲双胍会导致：1）身体机能的更大改善， 2) 更好地保持去脂体重和肌肉质量以及骨矿物质密度和骨质量， 3) 骨骼肌组织中细胞周期停滞和 SASP 标记物的更大程度减少以及更大的 我们的总体假设是多成分干预。 生活方式疗法+二甲双胍将是逆转肌肉减少性肥胖的最有效策略 肥胖老年退伍军人的虚弱是由其抑制细胞衰老的累加效应介导的，因此， 刺激这个尚未充分研究的高危人群的肌肉和骨骼合成代谢。 美国退伍军人的肥胖流行率已超过普通人群，甚至更多 因此，在使用退伍军人健康管理局 (VHA) 的老年退伍军人中，在患有肥胖症的老年退伍军人中， 虚弱容易导致功能独立性的丧失和不良的健康结果。 从这项拟议的 RCT 中生成的基于机制的数据将对 为这一迅速增长的老龄化退伍军人群体提供护理标准。