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.

老年人肥胖症患病率的持续增加已成为一个主要的健康问题。老年 对于成年人来说，肥胖不仅会导致严重的医疗问题，而且还会加剧与年龄相关的衰老。 身体功能，导致虚弱，损害生活质量，并增加疗养院的入院率。因此，在本发明中， 未能帮助肥胖的老年患者控制体重增加了未来对慢性健康护理服务的需求。 我们不仅报道了由于肌肉减少性肥胖而导致的老年肥胖者的虚弱， 在这一未充分研究的人群中导致体重减轻的治疗改善了身体功能并改善了虚弱。 然而，身体功能的改善是适度的，大多数肥胖的老年人仍然虚弱。 此外，体重减轻引起的肌肉和骨量减少可能会加重年龄相关性肌肉减少症 和骨质减少。因此，许多卫生保健提供者仍然不愿意推荐生活方式疗法， 包括虚弱，肥胖的老年人的体重减轻，因为不确定其益处是否超过 尽管减肥和运动被推荐作为一般肥胖患者标准治疗的一部分， 二甲双胍是一种广泛用于治疗糖尿病的口服药物。动物研究 二甲双胍可以延长寿命和健康寿命。然而，二甲双胍是否能改善 人类的脆弱是未知的。如果二甲双胍能改善或保持身体功能， 一种常用的药物将彻底改变老年人虚弱的方法。事实上，令人鼓舞的初步 我们先前在这一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， 尽管仍然被认为是虚弱的，但在体能测试（PPT）中的基线得分较高 与非用户相比。更重要的是，在试验期间使用二甲双胍预测的 生活方式干预后PPT评分的改善。因此，这些数据与结果 从我们先前的研究中，表明生活方式治疗和二甲双胍均与改善 但两者结合的加性效应可能导致虚弱的逆转。本课题 我提出了这样一个概念，即在生活方式治疗中加入二甲双胍，通过减少细胞凋亡来逆转虚弱。 衰老和衰老相关表型（SASP），特别是在高负担的肥胖老年人中 衰老细胞和加速衰老的过程。因此，我们的目标是进行第一次头对头， 比较疗效，安慰剂对照RCT，以检验生活方式治疗+二甲双胍 在改善身体功能方面，6个月的治疗比单独的生活方式治疗或单独的二甲双胍治疗更有效 并防止肥胖（BMI ≥ 30 kg/m2）老年人体重减轻引起的肌肉和骨量减少 (age年龄≥ 65岁）的退伍军人。具体来说，我们假设与生活方式疗法相比， 单独或单独二甲双胍，生活方式治疗+二甲双胍将导致：1）身体功能的更大改善， 2)更好地保持瘦体重和肌肉质量，以及骨矿物质密度和骨质量， 和3）骨骼肌组织中细胞周期停滞和SASP标志物的减少更大，沿着更大的 端粒长度增加。我们对目标的总体假设是， 由生活方式治疗+二甲双胍组成的治疗将是逆转肌肉减少性肥胖的最有效策略， 肥胖的老年退伍军人的虚弱，通过抑制细胞衰老的叠加效应介导， 刺激肌肉和骨骼的愈合，在这个研究不足的高危人群中。 美国退伍军人肥胖的流行程度已经超过了一般人群，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。在患有肥胖症的老兵中， 虚弱易导致功能独立性的丧失和不良的健康结果。新的健康结果 从这项拟议的随机对照试验中产生的基于机制的数据将对 护理标准，为这一迅速增长的部分老龄化退伍军人人口。