Inflammation, Lipid Metabolism and Senescence

炎症、脂质代谢和衰老

• 批准号: 10264042
• 负责人: David A Bernlohr
• 金额: $ 38.59万
• 依托单位: UNIVERSITY OF MINNESOTA
• 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/10264042
• 关键词: 4 hydroxynonenal; Address; Adipocytes; Adipose tissue; Affect; Age; Aging; Aldehydes; Antioxidants; Attenuated; Automobile Driving; B-Lymphocytes; Binding; Biology; CCL2 gene; Catecholamines; Cell Aging; Cells; Cellular biology; Complex; DNA; Deacetylation; Diet; Diffuse; Disease; Down-Regulation; Enzymes; Fatty Acids; Fibroblasts; Galactosidase; Genetic; Genetic Transcription; Hexenal; Hormonal; Immune; Impairment; Inflammation; Inflammatory; Intervention; Laboratories; Length; Link; Lipid Peroxidation; Lipids; Lipolysis; Memory; Metabolic; Metabolic Diseases; Mitochondria; Molecular; Monounsaturated Fatty Acids; Oxidative Stress; Phenotype; Physiological; Play; Process; Production; Protein Dephosphorylation; Proteins; Publishing; Regulation; Role; SIRT1 gene; Signal Transduction; Site; Testing; Therapeutic; Time; Tissues; Triglycerides; Visceral; Work; age related; aged; antioxidant enzyme; attenuation; chemical property; healthspan; insight; interest; lipid metabolism; macrophage; mouse model; novel; programs; response; senescence; sex; unpublished works

ABSTRACT Aging is a complex process brought about by a combination of genetic, hormonal and metabolic determinants. Of the factors defined as mechanistically linked to fundamental processes of aging, often referred to as the “pillars of aging”, inflammation and cellular senescence of adipose tissue take center stage. The focus of this application is the interface between immune cells, adipocytes and cellular senescence with an emphasis on the role(s) that lipids play in orchestrating B-cell biology, adipocyte oxidative stress and senescence. Recently published work from Camell and colleagues describes the age-dependent decrease in catecholamine signaling that occurs in adipose tissue due to the expansion of resident B-cells. Aged adipose B cells (AABs) have a memory-like and inflammatory phenotype, but how they impair catecholamine signaling is unclear. Age-dependent loss of catecholamine signaling decreases adipose lipolysis and release of monounsaturated fatty acids (MUFA) from triacylglycerol droplets. Work carried out collaboratively by the Bernlohr laboratory has shown that MUFAs bind directly to SIRT1 and allosterically activate the enzyme towards some, but not all, deacetylation targets. Of the targets defined, loss of SIRT1 activation leads to attenuated dephosphorylation of PGC1a and decreased transcriptional expression of mitochondrial antioxidant enzymes leading to the production of a,b-unsaturated aldehydes such as 4-hydroxy hexenal (4HHE), 4-oxononenal (4ONE) and 4- hydroxynonenal (4HNE) that diffuse from adipocytes. Unpublished work carried out by the Robbins lab has shown that 4HNE induces senescence in fibroblasts and preadipocytes leading to expression of b- galactosidase, MCP1 and p21. This proposal represents a novel confluence of interest and expertise between the Camell, Bernlohr and Robbins laboratories’ to mechanistically define the interplay between inflammation of adipose tissue and lipid metabolism as key factors influencing senescence and aging. The central hypothesis for this application is that diet, age and sex-specific decreases in adipose lipolysis driven by resident B-cells leads to attenuated MUFA-dependent activation of SIRT1 and concomitantly increased oxidative stress. Increased oxidative stress in turn leads to secretion of reactive lipid aldehydes and activation of the senescence program by tissue resident preadipocytes. To test this hypothesis, the following specific aims are proposed: Aim 1. Define diet, age, sex and depot-specific composition of adipose B cells and their impact on adipocyte lipolysis. Aim 2. Evaluate the lipid-dependent regulation of SIRT1 and concomitant control of adipocyte oxidative stress. Aim 3. Assess aldehyde-dependent adipose senescence in murine models and in response to senolytics.

抽象的 衰老是遗传，荷尔蒙和代谢决定剂的组合带来的复杂过程。 这些因素被定义为机械与衰老的基本过程有关的因素，通常称为 脂肪组织的“衰老支柱”，炎症和细胞感应是中心阶段。重点 应用是免疫电池，脂肪细胞和细胞感染之间的界面，重点是 脂质在编排B细胞生物学，脂肪细胞氧化应激和衰老中起的作用。 Camell及其同事最近发表的工作描述了儿茶酚胺的年龄下降 由于居民B细胞的扩大，在脂肪组织中发生的信号传导。老化的脂肪B细胞（AABS） 具有记忆状和炎症表型，但是它们如何损害儿茶酚胺信号传导尚不清楚。 儿茶酚胺信号传导的年龄依赖性损失下降脂肪脂解和单不饱和的释放 来自三酰基甘油液滴的脂肪酸（MUFA）。由Bernlohr实验室共同开展的工作 已经表明，MUFA直接与SIRT1结合，并将酶激活某些但不是全部的酶 脱乙酰化靶标。在定义的目标中，SIRT1激活的损失导致减弱的去磷酸化 PGC1A并改善了线粒体抗氧化剂的转录表达，导致 产生A，B-饱和醛，例如4-羟基己纳尔（4HHE），4-氧合烯酸（4ONE）和4-- 从脂肪细胞扩散的羟基烯烯（4HNE）。罗宾斯实验室进行的未发表的工作 表明4HNE在成纤维细胞和脂肪细胞中诱导感受，导致B-表达 半乳糖苷酶，MCP1和P21。该提议代表了一种新颖的兴趣和专业知识的融合 骆驼，伯恩洛尔和罗宾斯实验室，以机械定义炎症之间的相互作用 脂肪组织和脂质代谢作为关键因素会影响感应和衰老。 此应用的中心假设是脂肪脂解中饮食，年龄和性别特异性下降 由居民驱动的B细胞导致SIRT1的MUFA依赖性激活减弱 氧化应激增加。氧化应激的增加反过来导致反应性脂质醛和 组织居民对感应程序的激活。为了检验这一假设，以下 提出了具体目标： 目的1。定义脂肪B细胞的饮食，年龄，性别和定期特异性组成及其对 脂肪细胞脂解。 目标2。评估SIRT1的脂质依赖性调节和脂肪细胞的伴随控制 氧化应激。 AIM 3。在鼠模型中评估醛依赖性脂肪的感应 Senolotics。