Resveratrol and exercise combined to treat functional limitations in late life: A pilot randomized controlled trial

Abstract

Purpose: To evaluate the safety and feasibility of combining exercise (EX) and resveratrol to treat older adults with physical function limitations.

Methods: Three-arm, two-site pilot randomized, controlled trial (RCT) for community-dwelling adults (N = 60), 71.8 ± 6.3 years of age with functional limitations. Participants were randomized to receive either 12 weeks of (1) EX + placebo [EX0], (2) EX + 500 mg/day resveratrol [EX500], or (3) EX + 1000 mg/day resveratrol [EX1000]. EX consisted of two sessions a week for 12 weeks of center-based walking and whole-body resistance training. Safety was assessed through adverse events and feasibility through exercise session and supplement (placebo, or resveratrol) protocol adherence. Outcome measures included a battery of indices of physical function as well as skeletal muscle mitchondrial function. Data were adjusted for age and gender using the Intent-To-Treat approach.

Results: Adverse event frequency and type were similar between groups (n = 8 EX0, n = 12 EX500, and n = 7 EX1000). Overall, 85% of participants met the supplement adherence via pill counts while 82% met the exercise session adherence. Adjusted within group mean differences (95% confidence interval) from week 0 to 12 for gait speed ranged from -0.04 (EX0: -0.1, 0.03) m/s to 0.04 (EX1000: -0.02, 0.11) and the six-minute walk test mean differences were 9.45 (EX0: -9.02, 27.7), 22.9 (EX500: 4.18, 41.6), and 33.1 (EX1000: 13.8, 52.4) meters. Unadjusted mean differences for citrate synthase were -0.80 (EX0: -15.45, 13.84), -1.38 (EX500: -12.16, 9.39), and 7.75 (EX1000: -4.68, 20.18) mU/mg. COX activity mean within group changes ranged from -0.05 (EX0) to 0.06 (EX500) k/s/mg. Additional outcomes are detailed in the text.

Conclusion: The pilot RCT indicated that combined EX + resveratrol was safe and feasible for older adults with functional limitations and may improve skeletal muscle mitochondrial function and mobility-related indices of physical function. A larger trial appears warranted and is needed to formally test these hypotheses.

Keywords: Aging; Clinical trial; Exercise; Functional status; Mitochondria.

Figure A.1. Consolidated standards of reporting trials (CONSORT)

The overview of study trial includes the intent-to-treat and efficacy analyses. The efficacy analysis included participants who had ≥ 75% adherence for both the exercise session and pill counts.

Figure A.2. Walking distance per session

Data are reported as the unadjusted participant average session walking distance (m) over 24 sessions, based on 12 weekly visits, twice a week represented as a red, orange, or blue dot. The treatment group (EX0, EX500, or EX1000) overall average walking distance for each group is representative by the colored line.

Figure A.3. Indices of physical function

Data are presented as the intent-to-treat adjusted relative changes in (A) 4 meter usual gait speed, (B) walking endurance, (C) the Short Physical Performance Battery (SPPB), (D) quadriceps strength (Nm) across three angular velocities of movement (60, 90, 120°/s) is presented as the mean composite strength, (E) late life function and disability instrument limitation total, F) late life function and disability instrument frequency total in which a higher score indicates less limitation among older adults following 12-weeks of either EX0, EX500, or EX1000. Data indicate estimated marginal mean ± 95% confidence intervals.

Figure A.4. Skeletal muscle mitochondrial damage and biogenesis

Presented as the unadjusted within group changes, 12-week changes for citrate synthase (A), cytochrome c oxidase (COX) activity (B), lesion frequency (C), and MtDNA (D). Data indicate unadjusted mean ± SE. Abbreviations: EX0 = exercise + placebo, EX500 = exercise + 500 mg/d resveratrol, EX1000 = exercise + 1,000 mg/d resveratrol.

Figure A.5. Skeletal muscle mitochondrial protein abundance

Presented as the unadjusted within group changes, 12-week changes. Data are reported as mean ± SE. Abbreviations: TFAM: Transcription factor A (A); NRF1: Nuclear respiratory factor 1 (B); MFN2: Mitofusin-2 (C); OPA1 mitochondrial dynamin like GTPase Opa1 (D); FIS1: Mitochondrial fission 1 (E); SIRT1: Sirtuin 1 (F); RIP140: Nuclear receptor-interacting protein 1 (G); PGC-1a: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (H); P38a mitogen-activated protein kinase (I). Abbreviations: EX0 = exercise + placebo, EX500 = exercise + 500 mg/d resveratrol, EX1000 = exercise + 1,000 mg/d resveratrol.

Figure A.6. Systematic inflammation and oxidative stress measures

Circulating markers of vascular inflammation and oxidative stress including vascular cellular adhesion molecule 1 (VCAM-1, A), E-selectin (B), interleukin-6 (IL-6, C), myeloperoxidase (MPO, D), and oxidized low density lipoprotein (OxLDL, E). High Performance Liquid Chromatography (HPLC) with the ENO-30 NOx Analyzer (Eicom, Corp., Kyoto, Japan) was used to assess nitrite and nitrate values the Griess reaction measuring indirect colorimetric of nitric oxide in plasma for nitrite (NO₂-, F), and nitrate (NO₃-, G). Data are presented as week 12 relative to week 0, reported as mean ± SE. Abbreviations: EX0 = exercise + placebo, EX500 = exercise + 500 mg/d resveratrol, EX1000 = exercise + 1,000 mg/d resveratrol, No_2- = nitrite, No_3- = nitrate.