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.

项目摘要/摘要 迫切需要针对与衰老相关的衰老相关流动性残疾的有针对性疗法，以保持生活质量和预先 迅速扩大的老龄化人口的发泄发病/死亡率。随着衰老的流动性逐渐下降 部分归因于骨骼肌（SM）质量和功能的丧失，以及增加 脂肪组织的量（AT）。 AT和分泌因素的质量也可能会影响这一目标 塞斯（Cess），但有微不足道的证据。细胞衰老，这种现象正常健康 细胞不再分裂，因此在细胞死亡中编程，发生在脂肪组织中，是 - 社交活动较差。此外，分泌的因素来自AT，可能来自衰老或垂死的细胞， 在人骨骼肌细胞中诱导胰岛素抵抗和萎缩。这些数据共同证明了 在质量（即结构和功能）上可以直接影响骨骼肌肉功能。这种脂肪 - 骨骼 肌肉串扰越来越多地与年轻的Hu-的功能和代谢结局相关。 人口。 AT结构和功能的独特贡献以及分泌因素对迁移率的贡献 在人衰老的背景下，骨骼和骨骼肌功能尚未得到解决。提议的螺柱 IES将通过直接评估AT的结构和功能组件来填补关键的知识差距 并利用他们与迁移率的关联来确定对骨骼肌肉产生负面影响的分泌蛋白 CLE功能。这项辅助研究的长期目标是利用并增加 父母索玛（Somma）的项目旨在了解AT质量，分泌因素和骨骼的贡献 肌肉串扰与流动性残疾和人类衰老的其他并发症。我们的总体目标是 确定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 - 通过直接影响影响移动性的定位蛋白 骨骼肌。我们假设在结构和功能上会影响贡献的分泌蛋白 通过直接影响骨骼肌肉功能，与衰老相关的迁移率结果。 AIM 1的既定目的1 是确定AT的结构和功能组件与步行速度较慢有关。 我们认为，增加细胞衰老，坏死增加，炎症增加，容量降低 为了自我更新和代谢的不灵活性，步行速度将与步行速度较慢有关。对于AIM 2，我们反对 PATE将人类肌肉细胞与已知和新颖的分泌蛋白一起孵育 - 通过独立鉴定 ARD免疫测定面板和无偏蛋白质组学，并显示与构造的畸变有关 TURE和/或功能 - 将恶化线粒体呼吸，增加氧化应激，降低收缩力和 肌肉细胞直径。这项工作将通过改善预防策略而产生积极的翻译影响 和/或与衰老相关的流动性残疾的治疗，并通过促进知识和促进未来的研究 了解整个生命周期的骨骼肌肉串扰。