Stress, Mood, Omega-3 Fatty Acids, & Telomeric Aging: Randomized Controlled Trial

描述(申请人提供)：端粒对染色体的稳定性和复制很重要，端粒酶对端粒的形成、维持和恢复很重要。端粒酶活性和端粒长度是衡量细胞老化的指标，它们对健康具有临床意义：越来越多的文献将端粒酶活性降低和端粒缩短与健康行为、年龄相关疾病和死亡率联系在一起。炎症和氧化应激加速端粒缩短；氧化应激在细胞复制过程中促进端粒侵蚀，炎症提高白细胞周转率。Omega-3(n-3)多不饱和脂肪酸(PUFAs)可以减轻炎症和减少氧化应激。因此，通过将细胞老化研究添加到正在进行的NIA资助的双盲安慰剂对照随机对照试验(RCT)中，该试验解决了补充n-3多不饱和脂肪酸对炎症和情绪的影响(R01 AG029562)，这项研究将评估与饮食相关的炎症和氧化应激减少对端粒酶活性和白细胞端粒长度的影响。加州大学旧金山分校和俄亥俄州立大学合作实验室的关键初步数据支持成功的相关性和可能性。加州大学旧金山分校最近对稳定的冠心病患者进行的大型前瞻性研究表明，基线n-3多不饱和脂肪酸水平较高与5年后端粒磨损减慢有关，而另一项加州大学旧金山分校的研究显示，干预3个月后端粒酶活性增加，提供了合理的机制。与这一发现一致的是，来自OSU n-3 RCT的OSU/UCSF初步合作数据显示，在为期四个月的试验结束时，接受n-3补充剂的个体端粒较长，与安慰剂受试者中观察到的适度端粒缩短形成了显著的时间相互作用。因此，这项拟议的研究将评估简单的饮食干预对细胞衰老过程的影响。此外，它还将测试特定的机制，如n-3多不饱和脂肪酸是否通过改变促炎细胞因子和/或氧化应激来减少细胞衰老。简而言之，将细胞老化评估添加到OSU RCT将利用我们特征良好的样本来同时解决重要的创新基础科学和临床健康问题。我们的主要目的是：(1)评估补充n-3PUFA对端粒酶活性的影响，其次是端粒长度的变化，以及这些变化与n-3PUFA剂量的关系。次要目标：(2)确定促炎细胞因子和氧化应激的变化是否介导了n-3补充对细胞衰老的影响；(3)复制和扩展先前关于端粒酶活性和端粒长度与促炎细胞因子和抑郁症状之间的横截面关系的报道；以及(4)复制最近的证据，表明实验室应激源增加端粒酶的反应性，并探索n-3补充可能如何改变端粒酶对急性应激的反应性。 公共卫生相关性：端粒酶活性和端粒长度、细胞老化措施，对健康有临床意义。较低水平的端粒酶活性和较短的端粒与衰老、年龄相关疾病和死亡率有关。初步数据表明，血液中较高水平的omega-3脂肪酸可能有助于减缓与年龄相关的端粒磨损。通过将细胞老化评估添加到正在进行的补充omega-3的随机对照试验中，我们可以评估补充omega-3如何影响端粒酶活性和端粒长度，以及可能的机制。

DESCRIPTION (provided by applicant): Telomeres are important for chromosomal stability and replication, and the enzyme telomerase is important for telomere formation, maintenance, and restoration. Telomerase activity and telomere length, cell aging measures, have clinical significance for health: a growing literature has linked lower levels of telomerase activity and shorter telomeres with health behaviors, age-related diseases, and mortality. Inflammation and oxidative stress accelerate telomere shortening; oxidative stress promotes telomere erosion during cellular replication, and inflammation enhances the leukocyte turnover rate. The omega-3 (n-3) polyunsaturated fatty acids (PUFAs) can reduce inflammation and decrease oxidative stress. Accordingly, by adding cell aging studies to an ongoing NIA-funded double-blind, placebo-controlled randomized controlled trial (RCT) that addresses the impact of n-3 PUFA supplementation on inflammation and mood (R01 AG029562), this study will assess the impact of diet-related reductions in inflammation and oxidative stress on telomerase activity and leukocyte telomere length. Key preliminary data from the collaborating UCSF and OSU laboratories support both the relevance and likelihood of success. UCSF's recent large prospective study with stable coronary heart disease patients demonstrated that higher baseline n-3 PUFA levels were associated with slower telomere attrition 5 years later, and another UCSF study showed increased telomerase activity following a 3-month intervention, providing a reasonable mechanism. In accord with this finding, preliminary collaborative OSU/UCSF data from the OSU n-3 RCT show that individuals receiving n-3 supplementation had longer telomeres at the end of the four-month trial, in contrast to modest telomere shortening observed among placebo subjects, producing a significant group by time interaction. Thus, the proposed study will assess the impact of a simple dietary intervention on the cell aging process. Further, it will test specific mechanisms such as whether the n-3 PUFAs reduce cell aging through alterations in proinflammatory cytokines and/or oxidative stress. In short, the addition of cell aging assessments to the OSU RCT will leverage our well-characterized sample to simultaneously address important and innovative basic science and clinical health questions. Our primary aim is: (1) To assess the impact of n-3 PUFA supplementation on changes in telomerase activity, and secondarily, in telomere length, as well as the relationship of these changes to n-3 dose. Secondary Aims: (2) To determine if changes in proinflammatory cytokines and oxidative stress mediate the effect of n-3 supplementation on cell aging; (3) to replicate and extend prior reports of cross-sectional relationships between telomerase activity and telomere length with proinflammatory cytokines and depressive symptoms; and (4) To replicate recent evidence showing that a laboratory stressor increases telomerase responsivity, and to explore how telomerase responsivity to acute stress may be altered by n-3 supplementation. PUBLIC HEALTH RELEVANCE: Telomerase activity and telomere length, cell aging measures, have clinical significance for health. Lower levels of telomerase activity and shorter telomeres are associated with aging, age-related diseases, and mortality. Preliminary data suggest that higher blood levels of omega-3 fatty acids may serve to slow age- related telomere attrition. By adding cell aging assessments to an ongoing randomized controlled trial of omega-3 supplementation, we can assess how omega-3 supplementation affects both telomerase activity and telomere length, as well as possible mechanisms.