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: 10382206
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382206
• 关键词: 11 year old; Acute; Address; Adult; Aerobic; 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; Individual; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Institutionalization; Interleukin-18; Interleukin-6; Knowledge; Leukocytes; Life; 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; Testing; Tissues; Training; Transcriptional Regulation; United States; Veterans; Veterans Health Administration; Work; age effect; age related; anti aging; antiretroviral therapy; base; behavior change; cardiorespiratory fitness; comorbidity; 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; sarcopenia; sedentary; standard of care; strength training; success; systemic inflammatory response; telehealth; working group; 11 year old; Acute; Address; Adult; Aerobic; 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; Individual; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Institutionalization; Interleukin-18; Interleukin-6; Knowledge; Leukocytes; Life; 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; Testing; Tissues; Training; Transcriptional Regulation; United States; Veterans; Veterans Health Administration; Work; age effect; age related; anti aging; antiretroviral therapy; base; behavior change; cardiorespiratory fitness; comorbidity; 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; sarcopenia; sedentary; standard of care; strength training; 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.

退伍军人卫生管理局（VHA）是美国最大的艾滋病毒卫生提供商，其中64％ 退伍军人50岁以上。抗逆转录病毒疗法的HIV感染代表了一种慢性疾病 高级衰老表型表现为增加的心血管疾病，肌肉减少症和脆弱， 首先是由全身性炎症驱动的。我们发现年龄较大的艾滋病毒+成年人的VO2PEAK降低了42％ 高强度有氧（AEX）和耐药训练（RT）可显着改善。但是，持久的策略 老年人的高强度运动仍然是一个挑战，在老年艾滋病毒+成年人中，数据有限。 迫切需要解决这些知识差距，以防止艾滋病毒+的宽度残疾 退伍军人。我们的目标是为年长的退伍军人提供高强度的练习计划 传播并削弱了衰老基础的过程。表观遗传变化随着年龄的增加而增加 DNA甲基化（DNAN）模式经常是 在编码促炎性细胞因子的基因中进行了修饰，但可以通过运动训练来逆转。脱氧核糖核酸 甲基化年龄（DNAM年龄）是一种表观遗传生物标志物，以年份表示并提供混凝土 高级衰老的基准。我们发现，艾滋病毒+成年人的年龄大于年龄超过年龄 - 匹配没有艾滋病毒的成年人。此外，在没有艾滋病毒的成年人中，dnam年龄增加与身体有关 不活动，无力和脆弱。我们在退伍军人衰老队列研究（VAC）中的初步数据表明 DNAM年龄与VACS指数相关，VACS指数是艾滋病毒+成年人中脆弱的量度。但是， 在任何患者人群中，尚未确定对DNAM年龄的运动训练。我们建议适应我们的 较老的艾滋病毒+退伍军人中心的高强度AEX+ RT干预到视频远程医疗（VTEL） 提供的功能性（无固定设备）锻炼计划，该计划利用表观遗传学结果 展示运动的抗衰老作用。总体假设是VTEL高强度 老年艾滋病毒+退伍军人的功能电路运动将改善高级衰老表型和 衰老的DNAM表观遗传过程。我们的实验方法包括12周 VTEL运动干预在80位年龄较大的艾滋病毒+退伍军人中，他们被随机进行运动或护理标准 久坐的对照组。 AIM 1将确定VTEL运动对Vo2peak，Sarcopenia和脆弱的影响 作为艾滋病毒晚期衰老的表型结果。 AIM 2将研究VTEL练习对DNAM的影响 年龄是高级衰老的生物标志物。 AIM 3将确定VTEL运动对DNA甲基化的影响 在白细胞中编码特定促炎细胞因子的特定基因。这种方法将推动我们的 了解有效且可行的运动策略，以预防和最大程度地减少患者的残疾 人群高龄衰老。调查结果将为所有人提供创新的功能锻炼方法 老年人。 Dnam Age可以用作个性化的基准，以使个人受益于锻炼 促进可持续行为改变。调查结果还将提供可以用来用于的表观遗传风险概况 生成个性化的锻炼处方，这是下一十年的精密药物的重要下一步。 该提案利用了我们在艾滋病毒和VTEL中的运动培训经验，可获得3,000名艾滋病毒+退伍军人 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 使用现有基础设施以最低的成本进行锻炼将有助于大规模传播和国家 影响。可交付成果包括改善的临床结果和减少的大量成本节省 住院和制度化率。