REVIVE - Resveratrol to enhance vitality and vigor in elders

越来越多的老年人身体功能逐渐下降，最终导致与年龄相关的身体残疾，而这与某种疾病没有明确的联系。尽管与年龄相关的身体残疾的病因是复杂和多因素的，但新出现的证据表明，线粒体在许多老年人功能衰退的初始发作和进展中起着关键作用。此外，我们的试验数据强烈表明，功能下降与线粒体呼吸减少以及线粒体氧化酶活性和酶含量下降有关。这些变化与骨骼肌中过氧化物酶体增殖体激活受体γ辅助激活因子1- α (PGC-1α)和特异性Sirtuins（即SIRT3）的大量下降有关，这两种蛋白都是线粒体生物发生的调节剂。天然化合物白藜芦醇似乎通过影响支持氧化磷酸化和线粒体生物发生的关键基因pgc -1的表达，来对抗与衰老相关的线粒体功能下降。在最近完成的另一项初步研究中，我们发现白藜芦醇在1000毫克/天的剂量下，显着增强了老年人（50 - 65岁）的静息肌肉氧化代谢（使用近红外光谱测量），以及认知和身体功能。尽管最近一项涉及肥胖中年男性的临床试验取得了令人鼓舞的结果，但迄今为止还没有研究检验白藜芦醇补充剂对老年人线粒体功能的影响，或者线粒体功能的假设变化是否转化为身体功能的改善。因此，拟议的随机平行研究将确定，在老年男性和女性（70岁以上）中，90天的白藜芦醇补充是否与(i)肌肉线粒体功能（状态3和状态4呼吸）的增加，（ii） pgc -1， amp活化蛋白激酶（AMPK）和Sirtuins（即SIRT1和SIRT3）水平的增加，以及（iii）功能表现的改善以及代谢危险因素有关。为了实现这些目标，60名中低功能参与者将被随机分配接受安慰剂（n=20）， 1000毫克/天白藜芦醇（n=20）或1500毫克/天白藜芦醇（n=20），为期90天。我们将在基线和90天收集股外侧肌的肌肉标本和血液进行生化分析，并在每月就诊时监测血液化学和不良事件。如果我们的假设得到支持，这项研究将首次表明白藜芦醇可以改善肌肉中的线粒体功能，并且这些变化与中低功能老年人（功能下降和身体残疾风险最大的人群）身体功能水平的提高有关。

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-1α) 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-1α, 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-1α, 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.