Investigating the role of adipose tissue in mobility and aging (SOMMA-AT)

研究脂肪组织在活动能力和衰老中的作用 (SOMMA-AT)

• 批准号: 10453682
• 负责人: ERIN E. KERSHAW
• 金额: $ 76.97万
• 依托单位: ADVENTHEALTH ORLANDO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453682
• 关键词: Address; Adipose tissue; Affect; Aging; Ancillary Study; Archives; Atrophic; Biological; Biopsy; Blood; Blood Circulation; Blood specimen; CD4 Positive T Lymphocytes; CDKN2A gene; Caliber; Cell Aging; Cells; Cessation of life; Collaborations; Contractile Proteins; Data; Denervation; Dental crowns; Elderly; Enzyme-Linked Immunosorbent Assay; Etiology; Felis catus; Funding; Future; Generations; Glycerol; Goals; Human; Hydrogen Peroxide; Immunoassay; In Vitro; Inflammation; Insulin; Insulin Resistance; Isoproterenol; Knowledge; Link; Longevity; Longitudinal Studies; Metabolic; Mission; Mitochondria; Morbidity - disease rate; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Necrosis; Outcome; Oxidative Stress; Parents; Physiological Processes; Population; Prevention strategy; Process; Production; Property; Proteins; Proteomics; Publishing; Quality of life; Reporting; Research Personnel; Resources; Respiration; Role; Skeletal Muscle; Structure; Tweens; United States National Institutes of Health; VO2max; Walking; Work; aging population; base; biobank; disability; experimental study; fitness; flexibility; functional outcomes; glycemic control; improved; in vivo; insulin sensitivity; lipid biosynthesis; man; mortality; mouse model; muscle form; novel; oxidative damage; preservation; prevent; protein expression; self-renewal; senescence; skeletal muscle wasting; stem cell proliferation; targeted treatment; translational impact; trial design; walking speed

Project Summary/Abstract Targeted therapies for aging-related mobility disability are urgently needed to preserve quality of life and pre- vent morbidity/mortality in the rapidly expanding aging population. Progressive decline in mobility with aging has been partially attributed to loss of skeletal muscle (SM) mass and function, as well as an increase in the quantity of adipose tissue (AT). The quality of AT and AT-secreted factors are also likely to influence this pro- cess, yet meager evidence exists for this notion. Cellular senescence, a phenomenon by which normal healthy cells cease to divide and therefore become programmed for cellular death, occurs in adipose tissue and is as- sociated with poorer mobility. Furthermore, secreted factors from AT, potentially from senescent or dying cells, induces insulin resistance and atrophy in human skeletal muscle cells. Collectively, these data demonstrate that AT quality (i.e., structure and function) can directly impact skeletal muscle function. This adipose-skeletal muscle crosstalk has been increasingly implicated in poor functional and metabolic outcomes in younger hu- man populations. The unique contributions of AT structure and function and AT-secreted factors to mobility de- cline and skeletal muscle function in the context of human aging have not been addressed. The proposed stud- ies will fill a critical knowledge gap by directly assessing structural and functional components of AT in aging and using their associations with mobility to identify AT-secreted proteins that negatively impact skeletal mus- cle function. The long-term goal of this ancillary study is to leverage and add to the outstanding resources of the parent SOMMA project to understand the contribution of AT quality, AT-secreted factors and AT-skeletal muscle crosstalk to mobility disability and other complications of aging in humans. Our overall objective is to identify key structural and functional components of AT quality - including necrosis, senescence, inflammation, self-renewal and metabolic flexibility - and AT-secreted proteins that influence mobility via direct effects on skeletal muscle. We hypothesize that AT structure and function influences AT-secreted proteins that contribute to aging-related mobility outcomes by directly impacting skeletal muscle function. The stated purpose of Aim 1 is to determine which structural and functional components of AT are associated with slower walking speed. We posit that increased cellular senescence, increased necrosis, increased inflammation, decreased capacity for self-renewal and metabolic inflexibility will be associated with slower walking speed. For Aim 2, we antici- pate that incubation of human muscle cells with known and novel secreted proteins - identified through stand- ard immunoassay panels and unbiased proteomics and shown to be associated with aberrations in AT struc- ture and/or function - will worsen mitochondrial respiration, increase oxidative stress, decrease contractility and muscle cell diameter. This work will have a positive translational impact by improving strategies for prevention and/or treatment of aging-related mobility disability and by promoting knowledge and facilitating future studies to understanding AT-skeletal muscle crosstalk across the lifespan.

项目概要/摘要 迫切需要针对与衰老相关的行动障碍进行靶向治疗，以保持生活质量和预防老年痴呆症。 缓解迅速扩大的老龄化人口中的发病率/死亡率。随着年龄的增长，活动能力逐渐下降 部分归因于骨骼肌 (SM) 质量和功能的丧失，以及 脂肪组织（AT）的数量。 AT 和 AT 分泌因子的质量也可能影响这种亲 过程，但这一概念的证据很少。细胞衰老，正常健康细胞的一种现象 细胞停止分裂，因此被编程为细胞死亡，发生在脂肪组织中，并且是- 与流动性较差有关。此外，AT 分泌的因子，可能来自衰老或垂死的细胞， 诱导人体骨骼肌细胞的胰岛素抵抗和萎缩。总的来说，这些数据表明 AT 质量（即结构和功能）可以直接影响骨骼肌功能。这种脂肪骨骼 肌肉串扰越来越多地与年轻人类的功能和代谢结果不良有关 男性人口。 AT 结构和功能以及 AT 分泌因子对流动性的独特贡献 人类衰老背景下的肌肉和骨骼肌功能尚未得到解决。拟议的研究- IES 将通过直接评估衰老过程中 AT 的结构和功能成分来填补关键的知识空白 并利用它们与活动性的关联来识别对骨骼肌产生负面影响的 AT 分泌蛋白 cle 函数。这项辅助研究的长期目标是利用和补充优秀资源 父 SOMMA 项目了解 AT 质量、AT 分泌因子和 AT 骨骼的贡献 肌肉串扰导致人类行动障碍和其他衰老并发症。我们的总体目标是 识别 AT 质量的关键结构和功能成分 - 包括坏死、衰老、炎症、 自我更新和代谢灵活性 - 以及 AT 分泌的蛋白质通过直接影响影响流动性 骨骼肌。我们假设 AT 结构和功能影响 AT 分泌蛋白，这些蛋白有助于 通过直接影响骨骼肌功能来达到与衰老相关的活动结果。目标 1 的既定目的 是为了确定 AT 的哪些结构和功能组件与较慢的步行速度相关。 我们认为细胞衰老增加、坏死增加、炎症增加、能力下降 自我更新和新陈代谢的不灵活性将与较慢的步行速度相关。对于目标 2，我们预计 帕特将人类肌肉细胞与已知和新颖的分泌蛋白一起孵育——通过标准鉴定 ard 免疫分析面板和无偏蛋白质组学，并显示与 AT 结构畸变相关 性质和/或功能 - 会恶化线粒体呼吸，增加氧化应激，降低收缩力和 肌细胞直径。这项工作将通过改进预防策略产生积极的转化影响 和/或治疗与衰老相关的行动障碍，并通过促进知识和促进未来的研究 了解 AT 骨骼肌在整个生命周期中的串扰。