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.

老年人肥胖症患病率的持续增加已成为主要的健康问题。在较旧的地方 成人，肥胖不仅引起严重的医疗问题，而且还加剧了与年龄有关的下降 身体功能会导致脆弱，损害生活质量，并增加护士家庭入院。那， 不帮助肥胖老年患者管理体重会增加对慢性保健服务的未来需求。 我们报告不仅报道了由于肌肉减少肥胖，肥胖的老年人很常见，而且生活方式也很常见 治疗导致这种理解的人群体重减轻可改善身体机能并改善脆弱性。 但是，身体机能的改善是适度的，大多数肥胖的老年人仍然很虚弱。 此外，减肥引起的肌肉和骨骼质量的减少可能与年龄有关的肌肉减少症较差 和骨质减少。根据所有医疗保健提供者的说法，仍然不愿意推荐生活方式疗法 包括体重减轻 风险，尽管建议减肥和运动作为对肥胖患者的标准护理的一部分。 二甲甲酰胺是一种广泛可用的口服药物，用作治疗糖尿病的治疗。动物研究有 表明二甲双胍可改善寿命和健康跨度。但是，二甲双胍是否可以改善 人类中的脆弱是不知道的。如果二甲双胍改善或保留身体功能，那么这主要是安全的 常用的药物将彻底改变人们的脆弱方法。确实，鼓励初步 我们先前的随机对照试验（RCT）的数据表明，二甲双胍用户， 尽管仍然被认为脆弱，但在身体绩效测试（PPT）中的基线得分更高 与非用户相比。更重要的是，试验期间的二甲双胍的使用预测更大 对生活方式干预措施的响应，PPT分数的改善。因此，这些数据与结果结合 从我们先前的研究中，提出每种生活方式疗法和二甲双胍都与改善有关 脆弱的，但两者结合的额外影响可能会导致脆弱的逆转。在这个项目中，我们 提出一个概念，即在生活方式疗法中添加二甲双胍可以减少细胞来逆转脆弱 衰老和与衰老相关的表型（SASP），特别是在肥胖的老年人中 感觉细胞和加速衰老。据认为，我们的目标是进行第一个头头， 比较效率，安慰剂对照的RCT，以检验新的假设，即生活方式疗法 +二甲双胍 六个月将比单独的生活方式疗法或仅二甲双胍更有效 并防止肥胖（BMI≥30kg/m2）的肌肉和骨骼质量减少降低 （年龄≥65岁）有身体虚弱的退伍军人。具体而言，我们假设与生活方式疗法相比 生活方式疗法 +二甲双胍单独或单独或二甲双胍会导致：1）身体机能的改善， 2）瘦体重和肌肉质量以及骨矿物质密度和骨质质量的更大保存， 3）骨骼肌时机中细胞周期停滞和SASP的标记较大的标记以及更大的降低 端粒长度的增加。我们各个目标的总体假设是多组分干预 由生活方式疗法 +二甲双胍组成将是逆转肌肉减少肥胖和的最有效策略 肥胖老年退伍军人的脆弱，是由它们的成瘾性抑制细胞感应的作用所介导的，因此 在这种可理解的高风险人群中刺激肌肉和骨变性。 美国退伍军人的肥胖症流行已经幸免于难 因此，在使用退伍军人卫生管理局（VHA）的老年退伍军人中。在肥胖的老年退伍军人中 脆弱的功能独立性和不利健康结果的损失。新颖的健康结果 从该提出的RCT产生的基于机械的数据将对 这一迅速增长的老年退伍军人人口的护理标准。