Effects of 12-weeks of High-intensity Resistance Aerobic Circuit Exercise Training on Epigenetic Aging and Inflammation in Older HIV-infected Veterans

12 周高强度阻力有氧循环运动训练对老年 HIV 感染退伍军人表观遗传衰老和炎症的影响

• 批准号: 10710375
• 负责人: Vincent Charles Marconi
• 金额: --
• 依托单位: SALEM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10710375
• 关键词: 11 year old; Acceleration; Acute; Address; Adult; Aerobic; Aerobic Exercise; Affect; Age; Age Years; Aging; Anaerobic Threshold; Anti-Inflammatory Agents; Attenuated; Baltimore; Benchmarking; Biological Aging; Biological Markers; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Caring; Chronic Disease; Chronology; Clinical; Cohort Studies; Control Groups; Cost Savings; DNA; DNA Methylation; Data; Disease; Educational Intervention; Elderly; Elements; Encapsulated; Epigenetic Process; Equipment; European; Event; Exercise; Exercise Test; Gases; Genes; Genetic Transcription; Goals; HIV; HIV Infections; Health Personnel; Hospitalization; IL18 gene; Individual; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Institutionalization; Interleukin-6; Knowledge; Leukocytes; Link; Measures; Mediating; Medical center; Methylation; Molecular; Muscle; Observational Study; Outcome; Pattern; Pharmaceutical Preparations; Phenotype; Physical activity; Play; Population Heterogeneity; Process; Provider; Quality of life; Randomized; Reproducibility; Research; Resistance; Resources; Risk; Role; Site; Smoking; Teleconferences; Testing; Tissues; Training; Transcriptional Regulation; United States; Veterans; Veterans Health Administration; Work; age effect; age related; anti aging; antiretroviral therapy; behavior change; cardiorespiratory fitness; comorbidity; comparison control; cost; cytokine; design; disability; disability risk; epigenetic marker; exercise intensity; exercise intervention; exercise prescription; exercise program; exercise rehabilitation; exercise training; experience; fitness; frailty; improved; indexing; innovation; lifestyle factors; methylation pattern; novel; patient population; physical inactivity; pre-clinical; precision medicine; preservation; prevent; programs; protein expression; resistance exercise; sarcopenia; sedentary; standard of care; success; systemic inflammatory response; telehealth; working group

The Veterans Health Administration (VHA) is the largest U.S. HIV health provider with 64% of these Veterans 50+ years of age. HIV infection in the setting of antiretroviral therapy represents a chronic disease with an advanced aging phenotype manifested as increased cardiovascular disease, sarcopenia, and frailty, primarily driven by systemic inflammation. We found a 42% reduction in VO2peak in older HIV+ adults that significantly improved with high-intensity aerobic (AEX) and resistance training (RT). Yet, durable strategies for high-intensity exercise in older adults remain a challenge and limited data are available in older HIV+ adults. There is an urgent need to address these knowledge gaps in order to prevent widespread disability in HIV+ Veterans. Our objective is to provide a high-intensity exercise program for older Veterans that can be widely disseminated and attenuates processes underlying aging. Epigenetic changes with increased age encapsulate the putative effects of biological aging and lifestyle factors. DNA methylation (DNAm) patterns are frequently modified in genes encoding pro-inflammatory cytokines, but can be reversed with exercise training. DNA methylation age (DNAm Age) is an epigenetic biomarker that is expressed in years and provides a concrete benchmark of advanced aging. We found that HIV+ adults have DNAm Age 11 years greater than age- matched adults without HIV. Further, in adults without HIV, increased DNAm Age is associated with physical inactivity, weakness and frailty. Our preliminary data in the Veterans Aging Cohort Study (VACS) show that DNAm Age correlates with the VACS Index, a measure of frailty in HIV+ adults. However, the impact of exercise training on DNAm Age has yet to be determined in any patient population. We propose to adapt our center-based high-intensity AEX+RT intervention in older HIV+ Veterans into a video telehealth (VTEL) delivered functional (no stationary equipment) exercise program that leverages epigenetic outcomes to demonstrate anti-aging effects of exercise. The overarching hypothesis is that VTEL high-intensity functional circuit exercise in older HIV+ Veterans will improve the advanced aging phenotype and attenuate DNAm epigenetic processes underlying aging. Our experimental approach includes a 12-week VTEL exercise intervention in 80 older HIV+ Veterans who are randomized to exercise or standard of care sedentary control groups. AIM 1 will determine the effect of VTEL exercise on VO2peak, sarcopenia, and frailty as phenotypic outcomes of advanced aging in HIV. AIM 2 will investigate the effect of VTEL exercise on DNAm Age as a biomarker of advanced aging. AIM 3 will determine the effect of VTEL exercise on DNA methylation of specific genes encoding specific pro-inflammatory cytokines in leukocytes. This approach will advance our understanding of effective and feasible exercise strategies to prevent and minimize disability in patient populations with advanced aging. Findings will provide an innovative approach to functional exercise in all older adults. DNAm Age could be used as a personalized benchmark for an individual’s benefit from exercise to promote sustainable behavior change. Findings will also provide epigenetic risk profiles that can be used to generate a personalized exercise prescription, an important next step in the next decade of precision medicine. The proposal leverages our exercise training experience in HIV and VTEL, availability of 3,000 HIV+ Veterans at Atlanta and Baltimore VAMCs, and the VHA VTEL infrastructure. The capacity to disseminate VTEL exercise with minimal cost using existing infrastructure will facilitate large-scale dissemination and national impact. Deliverables include improved clinical outcomes and substantial cost savings from reduced hospitalization and institutionalization rates.

退伍军人健康管理局 (VHA) 是美国最大的艾滋病毒医疗服务提供者，其中 64% 50岁以上的退伍军人。抗逆转录病毒治疗中的艾滋病毒感染是一种慢性疾病 具有晚期衰老表型，表现为心血管疾病增加、肌肉减少症和虚弱， 主要由全身炎症驱动。我们发现老年 HIV 感染者的 VO2peak 降低了 42%， 高强度有氧运动（AEX）和阻力训练（RT）显着改善。然而，持久的战略 老年人的高强度运动仍然是一个挑战，并且艾滋病毒阳性老年人的可用数据有限。 迫切需要解决这些知识差距，以防止艾滋病病毒感染者普遍残疾 退伍军人。我们的目标是为老年退伍军人提供高强度锻炼计划，该计划可以广泛应用 传播并减弱衰老过程。随着年龄的增长，表观遗传发生变化 生物衰老和生活方式因素的假定影响。 DNA 甲基化 (DNAm) 模式经常出现 编码促炎细胞因子的基因被修改，但可以通过运动训练逆转。脱氧核糖核酸 甲基化年龄（DNAm Age）是一种表观遗传生物标志物，以年为单位表示，并提供了具体的 高级老龄化的基准。我们发现 HIV 阳性成年人的 DNAm 年龄比年龄大 11 岁 匹配没有艾滋病毒的成年人。此外，在没有 HIV 的成年人中，DNAm 年龄的增加与身体状况有关。 不活动、虚弱和虚弱。我们在退伍军人老龄化队列研究 (VACS) 中的初步数据表明 DNAm 年龄与 VACS 指数相关，VACS 指数是 HIV + 成年人虚弱程度的衡量标准。然而，影响 运动训练对 DNAm 年龄的影响尚未在任何患者人群中确定。我们建议调整我们的 基于中心的高强度 AEX+RT 干预老年 HIV+ 退伍军人进入视频远程医疗 (VTEL) 提供功能性（无固定设备）锻炼计划，利用表观遗传结果 证明运动的抗衰老作用。总体假设是 VTEL 高强度 老年艾滋病毒+退伍军人的功能回路锻炼将改善晚期衰老表型 减弱衰老背后的 DNAm 表观遗传过程。我们的实验方法包括为期 12 周的 对 80 名老年 HIV + 退伍军人进行 VTEL 运动干预，他们被随机分配进行运动或标准护理 久坐的对照组。 AIM 1 将确定 VTEL 运动对 VO2peak、肌肉减少症和虚弱的影响 作为艾滋病毒晚期衰老的表型结果。 AIM 2 将研究 VTEL 运动对 DNAm 的影响 年龄作为晚期衰老的生物标志物。 AIM 3 将确定 VTEL 运动对 DNA 甲基化的影响 白细胞中编码特定促炎细胞因子的特定基因。这种方法将推进我们的 了解有效且可行的运动策略，以预防和尽量减少患者的残疾 老龄化程度较高的人群。研究结果将为所有人群提供一种创新的功能锻炼方法 老年人。 DNAm 年龄可以用作个人从锻炼中获益的个性化基准 促进可持续的行为改变。研究结果还将提供表观遗传风险概况，可用于 制定个性化的运动处方，这是精准医学未来十年的重要下一步。 该提案利用了我们在 HIV 和 VTEL 方面的运动训练经验以及 3,000 名 HIV+ 退伍军人的可用性 亚特兰大和巴尔的摩 VAMC 以及 VHA VTEL 基础设施。传播 VTEL 的能力 利用现有基础设施以最低成本进行演习将有助于大规模传播和全国性 影响。可交付成果包括改善临床结果并通过减少 住院率和住院率。