A large and growing number of older adults experience progressive declines in physical function, culminating in age-related physical disability with no clear connection to a single disease. Although the etiology of age-related physical disability is complex and multi-factorial, emerging evidence implicates the mitochondria as playing a key role in the initial onset and progression of functional decline in many older adults. Additionally, our pilot data strongly suggest functional declines are associated with reductions in mitochondrial respiration, as well as decreases in oxidative mitochondrial enzyme activities and enzyme content. These changes were linked to a large decline in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1?) and specific Sirtuins (i.e., SIRT3) in skeletal muscle, both of which are regulators of mitochondria biogenesis. The natural compound resveratrol appears to oppose the reductions in mitochondrial function associated with aging by affecting the expression of key genes, such as PGC-1?;, which support oxidative phosphorylation and mitochondrial biogenesis. In another recently completed pilot study, we found resveratrol, at a dose of 1000 mg/day, significantly enhanced resting muscle oxidative metabolism (measured using near infrared spectroscopy), as well as cognitive and physical function, in older adults (age > 65 years). Despite promising findings from one recent clinical trial involving obese, middle-age men, no study to date has examined the effects of resveratrol supplementation on mitochondrial function in older adults, or whether the hypothesized changes in mitochondrial function translate to improvements in physical functioning. Thus, the proposed randomized, parallel study will determine, in older men and women (> 70 years), whether 90 days of resveratrol supplementation is associated with (i) increases in muscle mitochondrial function (State 3 & 4 respiration), (ii) increases in levels of PGC-1?, AMP-activated protein kinase (AMPK), and Sirtuins (i.e. SIRT1 and SIRT3), and (iii) improvements in functional performance, as well as metabolic risk factors. To achieve these aims, 60 moderate to low functioning participants will be randomized to receive a placebo (n=20), 1000 mg/day of resveratrol (n=20), or 1500 mg/day of resveratrol (n=20) for a 90-day period. We will collect muscle specimens from the vastus lateralis and blood at baseline and 90 days for biochemical analyses, as well as monitor blood chemistries and adverse events at monthly clinic visits. If our hypotheses are supported, this study will be the first to show that resveratrol improves mitochondrial function in muscle, and that these changes are associated with increased levels of physical function in moderate to low functioning older adults - the population who is at greatest risk of functional decline and physical disability.
Loss in physical function is a frequent complaint among many older adults, and recent findings strongly suggest that cumulative damage to mitochondria, the main energy source of cells, play a key role in contributing to this functional decline. Resveratrol, a natural compound found in the skins of grapes and red wine, may have unique promise to attenuate age-related functional decline by enhancing mitochondrial function. The critical question of whether resveratrol works in humans and by what mechanisms, however, has not been answered. The proposed study will fill this gap in the literature by examining whether resveratrol supplementation leads to beneficial changes in mitochondria and whether these changes are associated with improvements in physical function in older adults (age > 70 years).
| Buford, Thomas W; Anton, Stephen D (2014) Resveratrol as a supplement to exercise training: friend or foe? J Physiol 592:551-2 |
