Marrow Adipose Tissue as a Novel Regulator of Systemic Metabolism and Inflammation During Aging.

摘要 衰老是一系列疾病的最大风险因素，包括糖尿病、心脏病、神经变性、 癌症和中风。衰老的一个主要特征是肥胖率增加。脂肪组织是内分泌器官， 并假设衰老引起的脂肪功能障碍通过以下途径影响疾病病因 一种分子的分泌，作用于各种不同的组织，以协调组织的动态平衡。脂肪 位于全身不同的仓库中，而且很可能是特定的仓库对 疾病的脆弱性。骨髓脂肪组织(MAT)库在衰老相关疾病病因学中的作用 没有得到很好的确立，而且关于质量表型和 老化过程中垫子的分泌情况。本研究的长期目标是定义角色和 MAT影响人一生中健康和疾病的机制。R21的目标是 建议确定老化对MAT表型的影响，并确定MAT的潜在贡献 在衰老过程中脂肪衍生分子的系统特征。我们的中心假设是衰老会导致 MAT中的转录反应，改变其分泌特征，从而影响全身新陈代谢和 通过直接影响循环肽、脂类和代谢物成分实现炎症动态平衡；我们进一步 假设衰老对垫子表型和分泌体的影响是性二态的。我们的理由是 这个项目是，一旦知道衰老如何影响MAT的表型和对循环脂肪的贡献- 衍生因子，我们很有可能从药理上针对MAT重新编程它的分泌组，产生新的 以及创新的方法，以最大限度地延长健康寿命，减少与年龄有关的疾病的脆弱性。指导原则 强劲的初步数据，我们的中心假设将通过追求两个具体目标来检验：1)定义性别- MAT对衰老的特异性转录反应并确定转录反应的程度 与功能结果(即蛋白质组、代谢组、脂组)有关，以及2)确定转移的程度 在衰老过程中，从垫子到循环肽、脂肪和代谢物的变化。在这个项目完成后，我们 希望已经确定1)MAT表型对衰老和衰老的时间影响敏感 MAT表型因性别而异，2)与其他脂肪相比，MAT对衰老的分子反应是独一无二的 3)MAT是脂肪来源的信号分子循环池的中心贡献者 衰老。这些结果将从根本上推动脂肪组织生物学领域的发展，并将提供积极的 通过将MAT和MAT内的特定信号通路确定为主要治疗目标来产生翻译影响 用于预防和治疗衰老相关疾病。

ABSTRACT Aging is the strongest risk factor for a range of diseases including diabetes, heart disease, neurodegeneration, cancer, and stroke. A central characteristic of aging is increased adiposity. Adipose tissues are endocrine organs, and it is hypothesized that aging-induced adipose dysfunction causally influences disease etiology through the secretion of molecules that act across a diverse range of tissues to coordinate organismal homeostasis. Adipose is located in distinct depots throughout the body, and it is likely that specific depots differentially contribute to disease vulnerability. The role of the bone marrow adipose tissue (MAT) depot in aging-related disease etiology is not well established, and there is a fundamental knowledge gap regarding the qualitative phenotype and secretory profile of MAT during aging. The long-term objective of this research is to define the roles and mechanisms by which MAT influences health and disease throughout the lifespan. The objective of this R21 proposal is to determine the impact of aging on MAT phenotype and establish the potential contribution of MAT to the systemic profile of adipose-derived molecules during aging. Our central hypothesis is that aging induces a transcriptional response in MAT that alters its secretory profile, which influences systemic metabolic and inflammatory homeostasis by directly impacting circulating peptide, lipid, and metabolite composition; we further hypothesize the impact of aging on the MAT phenotype and secretome is sexually dimorphic. Our rationale for this project is that once it is known how aging influences MAT’s phenotype and contribution to circulating adipose- derived factors, it is likely we can pharmacologically target MAT to reprogram its secretome, producing novel and innovative approaches to maximize healthspan and reduce age-related disease vulnerability. Guided by strong preliminary data, our central hypothesis will be tested by pursuing two specific aims: 1) define the sex- specific transcriptional response of MAT to aging and determine the extent to which the transcriptional response relates to functional outcomes (i.e., proteome, metabolome, lipidome) and 2) establish the extent of transference from MAT to circulating peptide, lipid, and metabolite profiles during aging. At the completion of this project, we expect to have established that 1) MAT phenotype is sensitive to aging and the temporal impact of aging on MAT phenotype is sex-specific, 2) the molecular response to aging is unique in MAT compared to other adipose depots, and 3) MAT is a central contributor to the circulating pool of adipose-derived signaling molecules during aging. Such results will fundamentally advance the field of adipose tissue biology and will provide a positive translational impact by identifying MAT, and specific signaling pathways within MAT, as a prime therapeutic target for the prevention and treatment of aging-related diseases.