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

退伍军人健康管理局(VHA)是美国最大的艾滋病毒健康提供者，拥有这些服务的 退伍军人年龄在50岁以上。在抗逆转录病毒治疗的背景下艾滋病毒感染是一种慢性病 随着年龄的增长，表现为心血管疾病增加，骨质疏松症和虚弱， 主要由全身性炎症驱动。我们发现，在HIV+以上的老年人中，VO2峰值降低了42% 高强度有氧训练(AEX)和耐力训练(RT)显著改善。然而，持久的战略 老年人的高强度运动仍然是一个挑战，在艾滋病毒+的老年人中可以获得的数据有限。 迫切需要解决这些知识差距，以防止艾滋病毒+中普遍存在残疾。 退伍军人。我们的目标是为年长的退伍军人提供一个高强度的运动计划，可以广泛地 分散和减弱潜在的衰老过程。随着年龄的增长，表观遗传学的变化被包裹 生物老化和生活方式因素的推定效应。DNA甲基化(DNaM)模式经常是 在编码促炎细胞因子的基因上进行了修饰，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记物，以年为单位表达，并提供具体的 高级老龄化的基准。我们发现HIV+成人的dNaM年龄比年龄大11岁- 与没有感染艾滋病毒的成年人相匹配。此外，在没有感染艾滋病毒的成年人中，dNaM年龄的增加与身体状况有关 无所作为、虚弱和脆弱。我们在退伍军人老龄化队列研究(VAS)中的初步数据显示 DNaM年龄与Vacs指数相关，Vacs指数是衡量HIV+成年人虚弱程度的指标。然而， 关于dNaM年龄的运动训练尚未在任何患者群体中确定。我们建议调整我们的 基于中心的高强度AEX+RT干预将老年HIV+退伍军人转变为视频远程保健(VTEL) 提供功能性(无固定设备)锻炼计划，利用表观遗传结果 展示运动的抗衰老效果。最重要的假设是VTEL的高强度 老年HIV+退伍军人的功能回路锻炼将改善晚期衰老表型和 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 VTEL运动干预对80名随机接受运动或标准护理的老年HIV+退伍军人的影响 久坐对照组。目标1将确定VTEL运动对VO2峰值、骨质疏松症和虚弱的影响 作为艾滋病毒晚期衰老的表型结果。目的2研究VTEL运动对dNaM的影响 年龄作为晚期衰老的生物标志物。目标3将确定VTEL运动对DNA甲基化的影响 在白细胞中编码特定的促炎细胞因子的特定基因。这种方法将推进我们的 了解有效和可行的运动策略以预防和减少患者的残疾 老龄化程度较高的人口。研究结果将为所有人提供一种创新的功能锻炼方法 上了年纪的人。DNaM年龄可以作为个人从运动中受益的个性化基准 以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 生成个性化的运动处方，这是下一个十年精准医学的重要下一步。 该建议利用了我们在艾滋病毒和VTEL方面的运动培训经验，以及3,000名艾滋病毒+退伍军人的可用性 在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促进大规模传播和国家 冲击力。可交付成果包括改善临床结果和通过降低成本节省大量成本 住院率和住院率。

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.