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

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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.