Impact of Creatine Supplementation on Vascular Endothelial Function, Blood Flow and Functional Capacity in Older Adults

INTRODUCTION: Cardiovascular disease (CVD) remains the leading cause of mortality in United States (US) [1], and the inevitable process of aging, or one's age, remains the primary unmodifiable risk factor and independent predictor of CVD events across the lifespan [2]. With aging comes a progressive deterioration in vascular health, characterized by arterial stiffening and endothelial dysfunction (ED) [3-5]. Furthermore, oxidative stress, marked by an accumulation of reactive oxygen species (ROS), increases with age and is a prominent feature of vascular disease [6]. These vascular changes, in addition to other age-related declines in strength and cognition, all contribute to reduced functionality in many older adults. While popular dietary interventions have been applauded for their benefits upon cardiovascular health [7, 8], there is emerging evidence that suggests creatine supplementation may also serve as a therapeutic supplement [9]. Although well known for its metabolic properties, recent research has exposed a much broader application for creatine in clinical populations, acting as an antioxidant, energy shuttle and neuroprotective compound [10-12]. Despite these benefits however, there is scarce information on the application of creatine for vascular health and functional capacity in older adults. PURPOSE: Thus, the purpose of this study was to determine the effects of 4 weeks of creatine monohydrate supplementation, as compared to placebo, on vascular endothelial function, blood flow, oxidative stress, and functional capacity in older adults. Methods: Twelve, healthy older adults (M = 6, W = 6, age: 58 ± 3 years, BMI: 26 ± 6) participated in this randomized, double-blind, placebo-controlled crossover study. Eligible participants completed 4 official study visits: Pre-Testing 1, Post-Test 1, Pre-Testing 2, Post-Test 2. At every study visit participants were fasted and completed anthropometric assessments (height, weight, BMI), body composition [dual-energy x-ray absorptiometry (DXA)], and venous blood draw. Participants then completed assessments of vascular function [flow mediated dilation (FMD%), brachial-ankle pulse wave velocity (baPWV), pulse wave analysis (PWA), near-infrared microvascular reperfusion (NIRS MOXY)], cognitive function [forward digit span test (FDS), backward digit span test (BDS), trail making test part A (TMT-A) and B (TMT-B)], and physical function [6-minute walking test (6MWT), BioDex assessment of isometric muscle strength and endurance]. Once all Pre-Testing assessments were complete, participants were randomized to receive one of two blinded supplements: placebo (maltodextrin) or creatine monohydrate. Participants were asked to consume supplements for the following 4 weeks (4 x 5 g/day for 5 days, followed by 1 x 5g for 23 days). Following supplementation, participants returned for Post-Testing. During this visit, all procedures from the Pre-Testing Visit were repeated. Participants were then asked to return to their normal daily lifestyles for a 4-week "wash-out" period. After the washout, participants returned for their second Pre-Testing visit. Following this, participants were given their remaining supplement. Following the final supplementation, participants returned to the lab to complete their final Post-Test visit. Results: After creatine supplementation there was a significant improvement in FMD% (Pre: 7.68 ± 2.25 %, Post: 8.9 ± 1.99 %; p < .005), absolute change in diameter (Pre: 0.33 ± 0.12 mm, Post: 0.38 ± 0.12 mm; p < .05), normalized FMD% (Pre: 2.57E-04 ± 1.03E-04 %/SSAUC, Post: 3.42E-04 ± 1.69E-04 %/SSAUC; p < .05), and microvascular reperfusion (Pre: 2.29 ± 1.42 %/sec, Post: 3.71 ± 1.44 %/sec; p < .05); however, there were no significant changes in baPWV or PWA compared to placebo. There were no significant interactions found for any of the blood biomarkers; however, there was a significant effect of time for oxLDL (p < .05), and a trending toward significant effect of treatment for MDA (p = 0.055). There were significant improvements seen in both FDS (Pre: 7.08 ± 0.99, Post: 7.83 ± 1.27; p < .05) and BDS (Pre: 4.83 ± 1.64, Post: 5.83 ± 1.27; p < .05) following creatine, but no significant changes in TMT-A or TMT-B following either creatine or placebo. There were also no significant changes in 6MWT distance covered or isometric muscle strength; however, isometric muscle endurance, as indicated by total torque produced per set, improved for Set 1 (Pre: 2046.03 ± 823.78 Nm, Post: 2341.92 ± 896.02 Nm, p < .001), Set 2 (Pre: 1753.3 ± 484.26 Nm, Post: 1892.78 ± 583.18 Nm, p < .05), and Set 3 (Pre: 1642.35 ± 463.76 Nm, Post: 1745.7 ± 522.5 Nm, p < .05) following creatine, but not placebo. Conclusion: Our findings indicate that 4 weeks of creatine supplementation, but not placebo, improves endothelial function and microvascular reactivity in older adults; however, there was no benefit for arterial stiffness. Creatine supplementation, in comparison to placebo, can also improve markers of short-term memory and isokinetic muscle endurance, but neither creatine or placebo improved visuospatial awareness or isokinetic muscle strength. However, findings indicate that these improvements were not mediated by any creatine-dependent antioxidant effects. Further research is warranted to determine the mechanism in which creatine elicits these reported vascular benefits in older adults.