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: 10289701
• 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/10289701
• 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; Placebo Control; 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.

老年人肥胖率的持续上升已经成为一个主要的健康问题。在更老的版本中 对于成年人来说，肥胖不仅会造成严重的医疗问题，还会加剧与年龄相关的 身体机能导致身体虚弱，损害生活质量，并增加疗养院的入院率。因此， 未能帮助肥胖的老年患者控制体重增加了未来对慢性医疗保健服务的需求。 我们不仅报告了由于骨质疏松性肥胖而导致的老年人的虚弱，而且还报道了生活方式 在这一研究不足的人群中，通过减肥的治疗可以改善身体功能，改善虚弱状况。 然而，身体功能的改善并不明显，大多数肥胖的老年人仍然很虚弱。 此外，减肥导致的肌肉和骨量的减少可能会加重与年龄相关的骨量减少。 骨质疏松症。因此，许多保健提供者仍然不愿推荐这样的生活方式疗法 包括在虚弱、肥胖的老年人中减肥，因为不确定这样做的好处是否超过 风险，尽管减肥和锻炼被推荐为一般肥胖患者的标准护理的一部分。 二甲双胍是一种双胍类药物，是一种广泛用于治疗糖尿病的口服药物。动物研究表明 研究表明，二甲双胍既能延长寿命，又能延长健康时间。然而，二甲双胍是否能改善 人类的脆弱还不得而知。如果二甲双胍改善或保留了身体功能，这基本上是安全和 通常使用的药物将彻底改变老年人的虚弱状况。的确，令人鼓舞的是，初步 我们先前在该人群中进行的随机对照试验(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)中有较高的基线分数 与非用户相比。更重要的是，试验期间二甲双胍的使用量要大得多。 生活方式干预后PPT分数的改善。因此，这些数据与结果相结合 我们之前的研究表明，生活方式疗法和二甲双胍每一种都与改善 脆弱性，但两者的相加效应可能导致脆弱性的逆转。在这个项目中，我们 提出在生活方式治疗中加入二甲双胍通过减少细胞数量来逆转脆弱的概念 衰老和衰老相关表型(SASP)，特别是在高负担的肥胖老年人中 衰老的细胞和加速衰老。因此，我们的目标是进行第一个头部， 比较疗效，安慰剂对照随机对照试验，以检验生活方式治疗+二甲双胍治疗的新假设 在改善身体功能方面，六个月将比单独的生活方式治疗或单独的二甲双胍更有效 防止肥胖(体重指数≥30 kg/m2)老年人因体重减轻而导致的肌肉和骨量减少 (AGE≥65岁)身体虚弱的退伍军人。具体来说，我们假设与生活方式疗法相比 单独或单独使用二甲双胍，生活方式疗法+二甲双胍将导致：1)身体功能有更大的改善， 2)更好地保存瘦体重和肌肉质量，以及骨密度和骨质量， 3)骨骼肌组织中细胞周期停滞和SASP标志物的减少幅度更大， 端粒长度增加。我们横跨AIMS的首要假设是，多成分干预 由生活方式疗法+二甲双胍组成的治疗将是逆转骨质源性肥胖和 在肥胖的老年退伍军人中，由于他们在抑制细胞衰老方面的相加作用而产生的脆弱，因此， 在这个研究不足的高危人群中刺激肌肉和骨骼的合成代谢。 美国退伍军人中肥胖症的流行已经超过了普通人群，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， 虚弱易导致功能独立性丧失和不良的健康后果。新的健康结果 由这项拟议的RCT产生的基于机械的数据将对 对这一快速增长的老年退伍军人群体的护理标准。