Nutrition Interventions as Geroprotectors: Design and Interpretation of Early-Stage Clinical Trial of Strawberries

In this issue, Hartmann and colleagues present the design of a 10-week, 5-group dose-escalating randomized clinical trial testing whether polyphenol-rich nutritional intervention lowers low-density lipoprotein cholesterol (LDL-C) or inflammation as measured by c-reactive protein (CRP) in healthy middle-aged and older adults 1 .Demonstrating that any dietary or nutritional intervention can deflect biomarkers of cardiometabolic risk would be a major milestone, but this study is framed within the context of geroscience, which hypothesizes that human health can be improved by targeting the biology of aging 2 .Studies of model organisms show that targeting these biological pathways with a variety of therapeutic approaches-including the administration of drugs, biologics, dietary restrictions, and nutraceuticals-can increase health and lifespan.These studies are now being translated to clinical trials in humans, and the breadth of potential geroprotective (preventative) and gerotherapeutic (reparative) approaches is ever-expanding.The testing of geroprotectors and gerotherapeutics in clinical trials is relatively new, and there is uncertainty regarding how to optimally design studies-including early-stage "proof-of-concept" (PoC) trials and those testing nutritional interventions relevant to aging.Early-stage PoC trials are typically short, relatively inexpensive studies to help design and justify larger clinical trials 3 .Unlike efficacy trials, PoC trials evaluate the feasibility of therapeutic approaches and dosing, present initial estimates of safety, and provide supportive data on clinical outcomes or biomarkers needed for trial planning.These PoC trials may or may not include an untreated control group, commonly feature dose-finding study designs, and may use criteria for success ("go/no-go" decision criteria) that differ from next-stage efficacy trials.There are also subtle differences between disease-centric and geroscienceoriented PoC trials.For example, a key difference between most traditional diseasetargeting studies (which target pathophysiologic mechanisms identified within the disease pathway) and PoC studies testing geroprotectors or gerotherapeutics is that the biological target in geroscience-related studies should be identified from the field of aging and should not directly act on risk factors specific to a disease process (e.g., cholesterol in atherosclerosis studies or HbA1c in diabetes prevention).In this issue, Hartmann and colleagues report results from an early-stage PoC trial of a nutritional intervention that was AgingBio, 2, e20240027, June 26, 2024