Frailty is a geriatric syndrome which leads to poor health outcomes in older adults, such as falls, disability, hospitalization, institutionalization, and death. Due to the dramatic growth in the U.S. aging population and the health care costs associated with frailty (estimated at more than $18 billion per year), frailty is a major health care problem. There has been little research into potential pharmacologic interventions that would delay or reduce the incidence of frailty. Thus, the major goal of this study is to test metformin as a novel intervention for the prevention of frailty. We propose that diabetes/insulin resistance and inflammation are major contributors to frailty, and that the use of metformin to modulate diabetes/insulin resistance and inflammation will prevent and/or ameliorate the progression of frailty. The rationale for testing metformin for frailty prevention is based on the following: 1) Insulin resistance has been linked to the pathogenesis of frailty and our own research shows that diabetes is a significant predictor of frailty onset or worsening in community-dwelling older adults; 2) Several studies have shown that frail older subjects (compared with non-frail) are under a state of chronic low grade ?sterile? inflammation, as evidenced by increase plasma concentration of inflammatory markers; 3) In addition to frailty, inflammation also plays a key role in the pathogenesis of insulin resistance; 4) Metformin has both insulin sensitizing and anti-inflammatory properties, and; 5) Our analyzed clinical administrative data from 2,415 adult veterans with diabetes shows that those who were taking metformin as monotherapy were at 34% reduced risk of becoming frail compared to patients taking sulfonylureas. We hypothesize that metformin will lead to reduced inflammation and insulin resistance present in older glucose-intolerant subjects and that these changes will consequently prevent the onset and/or progression of frailty in this sub-population of older adults. We propose to study glucose intolerant subjects, a population which encompasses approximately one-third of older adults, and is most likely to benefit from metformin. To our knowledge, this research will be the first to study a potential intervention targeted toward a central mechanism involved in the etiology of frailty. We will also assess potential molecular mechanisms (insulin signaling, AMPK signaling, etc.) as potential cellular defects in frailty that are alleviated by metformin. Because of the enormous costs associated with frailty (both personal and economic), a treatment that prevents or delays frailty, even in a sub-population of older adults, would have a major positive impact in our society.
Frailty is a clinical geriatric syndrome of progressive physical and physiologic decline that is known to increase risk for multiple adverse outcomes with aging. Data over the last several years has identified inflammation and insulin resistance as major risk factors for the development and acceleration of frailty. This grant application will provide the first demonstration on whether the anti-diabetic drug metformin will delay or prevent the onset of frailty in pre-diabetic older adults, who are at the highest risk of becoming frail.
