Testing the Geroscience Hypothesis: Early Days

Abstract

In this issue, Espinoza and colleagues present the design of a 2-year randomized, double-blind, controlled, clinical trial testing whether 2,000 mg/day of metformin retards the advancement of frailty in prediabetic older adults. Demonstrating that any drug can deflect the progression of frailty would be a major milestone in geriatrics, but this study is also important within the larger frame of geroscience which hypothesizes that human health can be improved by directly targeting the biology of aging (1). Support for this hypothesis is found in studies of model organisms, which show that targeting these pathways in a variety of ways—including the administration of metformin—can increase health span and lifespan (2). The study by Espinoza is one of the few rigorously designed trials to test a drug in a context that has direct implications for evaluating the geroscience hypothesis. The geroscience hypothesis is relatively new, and there is uncertainty regarding how to optimally design studies to test it. A key uncertainty is end-point selection. Espinoza and colleagues selected the Fried Cardiovascular Health Study (CHS) frailty phenotype as the primary end-point (3). This measure has good face validity with geriatricians and its use is supported by a great deal of observational data underscoring its robust prediction of health outcomes in older adults. However, the frailty phenotype domains were originally operationalized using data from the CHS study, an on-going observationa…