A Randomized Study of the Physiologic and Molecular Effects of Resveratrol

骨质疏松症，在衰老过程中失去无脂肪的肌肉质量，导致力量、灵活性和独立性的丧失，是导致虚弱综合征的主要因素。研究表明，老化过程中肌纤维的数量损失占力量损失的不到一半，表明老化肌肉存在质的缺陷。最近对衰老小鼠和高脂饮食小鼠的临床前研究表明，肌肉功能障碍的一个重要组成部分是肌原纤维线粒体的质量和数量缺陷。这包括线粒体数量的减少和涉及电子传输链(ETC)、三羧酸循环(TCA循环)和脂肪酸(FA)β氧化的氧化代谢缺陷。这些异常似乎与一系列转录调节因子的活性降低有关，这些转录调节因子包括PGC-1α、NRF-1、PPAR亚型和TFAM，它们控制着参与线粒体生物发生和中间代谢的基因的表达。虽然衰老和肥胖会降低这些因子的活性，但最近在小鼠模型和人类中的研究表明，可以通过特定的干预措施上调这些因子的活性，包括限制热量(CR)、运动，至少在小鼠中，可以通过口服白藜芦醇来上调。拟议的随机试验旨在确定口服白藜芦醇，每天2克，连续12周，是否可以诱导特定的生理和/或分子变化，改善肌肉功能，与在小鼠模型中观察到的相似。提出了一系列研究，使我们能够确定白藜芦醇在人体内的药效学活性。 该议定书正在提交给IRB进行审查。我们已经得到阿尔伯特·爱因斯坦医学院医学博士梅雷迪思·霍金斯的许可，可以交叉提交她的白藜芦醇IND。白藜芦醇将由RevGenetics以成本价与对照胶囊一起提供，他们已同意允许FDA检查主文件。我们将在不久的将来向FDA提交申请。

Sarcopenia, the loss of fat-free muscle mass during aging, leads to the loss of strength, mobility, and independence, and is a major contributor to the frailty syndrome. Studies indicate that the quantitative loss of myofibers during aging accounts for less than half of the loss of strength, indicating a qualitative defect in aging muscle. Recent pre-clinical studies in aging mice and mice fed high fat diets indicate that an important component of muscle dysfunction is due qualitative and quantitative defects in myofibril mitochondria. This includes decrease in the number of mitochondria and defects in oxidative metabolism involving the electron transport chain (ETC), tricarboxylic acid cycle (TCA cycle), and fatty acid (FA) beta-oxidation. These abnormalities appear to be linked to decreased activity of a set of transcriptional regulators including PGC-1 alpha, Nrf-1, PPAR isoforms, and TFAM that govern the expression of genes involved in mitochondrial biogenesis and intermediary metabolism. While aging and obesity diminish the activity of these factors, recent studies in murine models and man suggest that they can be upregulated by specific interventions, including calorie restriction (CR), exercise, and at least in mice, by the oral intake of resveratrol. The proposed randomized trial is designed to determine if oral resveratrol, when administered to elderly individuals at a dose of 2 grams per day for 12 weeks, can induce specific physiologic and/or molecular alterations that improve muscle function similar to those observed in the murine models. A series of studies is proposed that should allow us to identify pharmacodynamic activities of resveratrol in human subjects. The protocol is being submitted to the IRB for review. We have received permission from Meredith Hawkins, MD, at the Albert Einstein College of Medicine, to cross-file on her IND for resveratrol. The resveratrol will be supplied by RevGenetics, along with control capsules, at cost, and they have agreed to allow the FDA to examine the Master File. We shall submit the application to the FDA in the near future.