Cocoa to maximize exercise training in older adults - COMET Trial

About This Grant

Abstract Diminished mitochondrial function, excessive production of reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) damage are key contributors to age-related physical capacity and muscle strength decline. Adaptation to aerobic and strength exercise training is currently one of the most effective ways to preserve physical performance and muscle strength in older adults. Aerobic and resistance exercise training improves mitochondrial function and stabilizes production of ROS, which contribute to aerobic capacity as well as strength improvements. However, obtaining optimal effects of exercise training may be limited by heterogeneity in the responsiveness due to biological barriers in skeletal muscle energy production, regardless of the adherence. Therefore, there is an unmet need for combining non-pharmacologic therapies with exercise training to “unlock” its full energetic potential to more effectively improve physical performance and muscle strength in older adults at risk of mobility disability. (-)-Epicatechin, a flavanol and a major ingredient present in cocoa, improved survival, muscle mitochondrial function and reduced excess ROS in mice. Supplementation with (-)-epicatechin-rich cocoa improved walking performance and muscle strength in older adults. Combination of (-)-epicatechin with exercise further improved mitochondrial function and reduced muscle fatigue in mice. We hypothesize that the combination of (-)-epicatechin-rich cocoa with structured aerobic and resistance exercise training will be more effective than exercise alone in improving physical performance and muscle strength by improved mitochondrial function and reduced ROS production in moderately functioning older adults. Our proposed pilot trial will test a 6-month exercise training intervention to collect preliminary data on walking performance, muscle strength and muscle size in 36 moderately functioning (slow walking speed <1m/s) older adults (>65 years old) without major comorbidities, preceded by pre-randomization 1-month lead-in cocoa supplementation. The participants will be randomized to 6 months of daily (-)-epicatechin-rich cocoa (2 capsules/d containing 450 mg cocoa flavanols/day, including 80 mg of (-)-epicatechin) combined with aerobic (30min of moderate-intensity walking) and resistance (25 min of whole-body workout) exercise training 3 times a week (Epi-Ex, n=18) or the same exercise training regimen combined with cellulose-based placebo (PL-Ex, n=18). Our primary outcome is walking distance measured by the 6-minute walk test. The lower-limb muscle strength and size measured by the Biodex test and ultrasound will be our secondary outcomes. We will explore the potential mechanism of the hypothesized effect of Epi-Ex on walking performance and muscle strength by measuring mitochondrial function in permeabilized muscle fibers, mtDNA damage, ROS production and antioxidant enzyme activity in the vastus lateralis biopsies at baseline and 6-month follow-up. The objective of this exploratory/developmental R21 proposal is to gather preliminary data on the efficacy and explore the mechanism of the Epi-Ex intervention to support the future Phase III clinical trial testing (-)-epicatechin-rich cocoa flavanols for exercise training optimization in older adults.