Effect of randomized cocoa supplementation on inflammaging and epigenetic aging

项目总结/摘要 可可产品已成为一种广泛消费的食品，全球需求不断增长， 对它潜在的健康益处和抗衰老生物学的兴趣越来越大。然而，可可消费的作用 关于表观遗传衰老的研究基本上还未被探索。有令人信服的证据表明， 基于体外和动物模型的可可和可可衍生的黄烷醇的炎症作用。但 研究进展的关键障碍仍然是缺乏确定的大规模随机对照试验（RCT）。 包括DNA甲基化变化的加速表观遗传衰老最近已经成为一种强大的， 寿命和健康跨度、疾病易感性、发病率和死亡率风险的新预测因子。此外，本发明还 炎症是老年人发病率和死亡率的一个非常重要的危险因素，因为许多与年龄有关的疾病， 包括心血管疾病（CVD）在内的疾病都具有炎性发病机制。因此，干预 减缓或减轻表观遗传衰老和炎症对于促进健康衰老至关重要。 可可补充剂和多种维生素结局研究（COSMOS）是一项正在进行的随机、双盲、 高质量可可提取物补充剂（含600 mg/d）的盲法、安慰剂对照、2x2析因RCT 黄烷醇，包括80毫克表儿茶素），以及多种维生素补充剂，以降低心血管疾病和癌症的风险 年龄≥65岁的女性和年龄≥60岁的男性。COSMOS将21,444名参与者随机分配到试验中， 包括在基线、第1年和第2年随访时已收集生物样本的2，006名参与者。 COSMOS是唯一一个测试可可提取物对女性和男性的影响的大型RCT， 妇女因此，这项拟议的辅助研究将建立在母公司COSMOS试验的基础上，以检查 600例随机可可或多种维生素补充剂抗衰老（表观遗传性衰老和炎症） 在基线、第1年和第2年采集3份生物样本的代表性受试者， CVD危险因素，并在CVD结果的背景下检查这些发现。我们将测试我们的中央 可可补充剂降低表观遗传衰老指数的假设（例如，霍瓦特， 血清hsCRP、IL-10、TNF-α、 1β、IL-4、IL-6和TNF-α）。我们还将确定可可补充剂的效果 炎症和心血管疾病的危险因素是由表观遗传衰老介导的。 据称富含可可的产品（如黑巧克力）具有抗衰老的健康益处， 在过去十年中，可可含量丰富的产品消费量增加。此外，多元素仍然是最重要的 至少三分之一的美国老年人服用的常见膳食补充剂。它仍然是关键的公共卫生 重要的是通过大型RCT严格测试这两种补充剂的抗衰老特性， 他们的潜在功效的确切证据，并批准或反驳他们的潜在抗衰老的好处。

PROJECT SUMMARY/ABSTRACT Cocoa products have become a widely consumed food, with growing demand across the world and steadily increasing interest in its potential health benefits and anti-aging biology. However, the role of cocoa consumption on epigenetic aging remains essentially unexplored. There has been compelling evidence for the anti- inflammatory role of cocoa and cocoa-derived flavanols based upon in vitro and animal models. However, a critical barrier of research progress remains the lack of definitive large-scale randomized controlled trials (RCTs). Accelerated epigenetic aging that comprises DNA methylation changes has recently emerged as a powerful, novel predictor for lifespan and health span, disease susceptibility, morbidity, and mortality risk. Further, inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly, as many age-related diseases including cardiovascular disease (CVD) share an inflammatory pathogenesis. As such, interventions to slow or mitigate epigenetic aging and inflammaging are critical for promoting healthy aging. The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is an ongoing randomized, double- blind, placebo-controlled, 2x2 factorial RCT of a high-quality cocoa extract supplement (containing 600 mg/d flavanols, including 80 mg epicatechins), and a multivitamin supplement to reduce the risk of CVD and cancer in women aged ≥65 years and men aged ≥60 years. COSMOS has randomized 21,444 participants into the trial, including 2,006 participants with bio-samples already collected at baseline, year 1 and year 2 follow-up. COSMOS is the only large RCT testing the effects of cocoa extract in women and men, and for multivitamins in women. Thus, this proposed ancillary study will build upon the parent COSMOS trial to examine the effects of randomized cocoa or multivitamin supplementation on anti-aging (epigenetic aging and inflammaging) in 600 representative subjects with three bio-sample collections at baseline, year 1, and year 2, as well as measured CVD risk factors, and examining these findings in the context of CVD outcomes. We will test our central hypotheses that cocoa supplementation reduces epigenetic aging indices (e.g., AgeAccelHorvath, AgeAccelHannum, AgeAccelGrim, AgeAccelPheno, and DNAmTLadjAge) and inflammaging (serum hsCRP, IL- 1β, IL-4, IL-6, and TNF-α) over time. We will also determine to what extent the effects of cocoa supplementation on inflammaging and CVD risk factors are mediated by epigenetic aging. The purported anti-aging health benefits of cocoa-rich products such as dark chocolate have popularized and increased consumption of cocoa-rich products over the past decade. Moreover, multivitamins remain the most common dietary supplement taken by at least one-third of older US adults. It remains of critical public health importance to rigorously test the anti-aging properties of these two supplements via large RCTs for more definitive evidence of their potential efficacy, and to approve or refute their potential anti-aging benefits.