Boston OAIC: A Translational Approach to Function Promoting Therapies

摘要 老年科学假说(即，多种与年龄相关的疾病是由有限的一组进化的 保守的分子过程)意味着齿轮驱动者和齿轮保护者之间的动态平衡 生命历程。在艾滋病毒方面，老年艾滋病毒携带者(PWH)背负着不成比例的负担 年龄相关疾病和多发性疾病，包括功能能力的显著下降，突显出 需要齿轮保护器。NAD+是一个关键的辅因子，在细胞能量代谢和调节 炎症信号。在许多物种中，NAD随着年龄的增长而下降与线粒体的缺陷有关 功能和代谢能力，以及sirtuins活性下降，sirtuins是一类依赖NAD+的酶， 控制炎症、线粒体代谢和衰老。因此，补充NAD是一种有吸引力的治疗方法。 潜在地减少与年龄相关的炎症(即发炎)和改善身体功能的方式。 我们的初步研究表明，NAD、NMN和NAD代谢体的循环浓度 可以用液相色谱串联质谱检测血液中的MIB-626 1000毫克 每日一次或每日两次的方案是安全的，并与剂量相关的血液大幅增加有关 NAD水平及其代谢体(图1)[1]。我们还表明，单核细胞的NAD水平较低(图2)和 来自我们匹配队列的慢性HIV感染者的骨骼肌(图3)。我们还表明， 骨骼肌中NAD水平与炎症呈负相关(图4)[2]。我们还观察到了损失 基于恒定工作速率跑步机疲劳性测试的比赛参与者的耐力(图5)。我们的前辈 研究表明，携带艾滋病毒的老年人表现出生物能量缺乏[3-5]，包括体能下降 基于使用可穿戴技术的自由生活活动的客观评估的活动(PA)[3，6]，以及WE 最近还观察到，与未感染的患者相比，PWH患者的认知能力下降[7]。 这项建议中检验的假设是，患有慢性艾滋病毒感染的老年人的NAD水平将是 与未感染年龄匹配的人相比更低，并将与表观遗传学变化有关 参与代谢、炎症和线粒体生物能量途径调节的基因，以及 胰岛素敏感性和整体功能结果的损害；包括基于实验室的测量 耐力和肌肉疲劳性及佩戴技术的客观测量。

ABSTRACT The geroscience hypothesis (i.e., that multiple age-related conditions result from a finite set of evolutionarily conserved molecular processes) implies a dynamic balance between gerodrivers and geroprotectors over the life course. In the context of HIV, older persons living with HIV (PWH) are disproportionately burdened with age-related conditions and multimorbidity, including significant declines in functional capacity underscoring the need for geroprotectors. NAD+ is a key cofactor, both in cellular energy metabolism and in modulation of inflammatory signaling. In multiple species, NAD decline with age has been linked to deficits in mitochondrial function and metabolic capacity, and decline in the activity of sirtuins, a class of NAD+-dependent enzymes that control inflammation, mitochondrial metabolism and aging. Thus, repletion of NAD is an attractive therapeutic modality for potentially reducing age-related inflammation (i.e., inflammaging) and improving physical function. Our preliminary studies indicate that circulating concentrations of NAD, NMN and the NAD metabolome can be measured in blood using liquid chromatography tandem mass spectrometry and that MIB-626 1000-mg once daily or twice daily regimens were safe and associated with substantial dose-related increases in blood NAD levels and its metabolome (Fig 1) [1]. We also show that NAD levels were lower in monocytes (Fig 2) and skeletal muscle (Fig 3) in persons with chronic HIV infection from our MATCH cohort [2]. We also show that NAD levels in skeletal muscle were negatively correlated with inflammation (Fig 4) [2]. We also observed loss in endurance in MATCH participants based on a constant work rate treadmill fatigability test (Fig 5). Our prior studies have shown that older persons with HIV display bioenergetic deficits [3-5], including decline in physical activity (PA) based on objective assessment of free-living activity using wearable technology [3, 6], and we also recently observed declines in cognitive performance in PWH compared to uninfected [7]. The hypothesis tested in this proposal is that NAD levels in older persons with chronic HIV infection will be lower when compared to uninfected age-matched persons and will be associated with epigenetic changes in genes involved in the regulation of metabolic, inflammatory, and mitochondrial bioenergetic pathways, and with impairment of insulin sensitivity and whole person functional outcomes; including lab based measures of endurance and muscle fatigability and objective measures of PA using wearable technology.