Inflammation, Lipid Metabolism and Senescence

摘要 衰老是一个复杂的过程，由遗传、激素和代谢决定因素共同作用而成。 被定义为与衰老的基本过程有机械联系的因素，通常被称为 “衰老之柱”、炎症和脂肪组织的细胞衰老占据了中心舞台。这件事的重点是 应用是免疫细胞、脂肪细胞和细胞衰老之间的接口，重点是 脂质在调节B细胞生物学、脂肪细胞氧化应激和衰老中所起的作用(S)。 Camell和他的同事最近发表的研究报告描述了儿茶酚胺的年龄相关性下降 由于常驻B细胞的扩张而出现在脂肪组织中的信号。老年脂肪B细胞(AABS) 具有记忆性和炎症性表型，但它们如何损害儿茶酚胺信号尚不清楚。 儿茶酚胺信号的年龄依赖性丢失减少脂肪脂解和单不饱和脂肪酸的释放 三酰甘油液滴中的脂肪酸(MUFA)。伯恩洛尔实验室合作开展的工作 已证明MUFA直接与SIRT1结合，并变构激活某些但不是全部的酶， 去乙酰化靶标。在所定义的靶点中，SIRT1活性的丧失会导致减弱的去磷酸化 PGC1a和线粒体抗氧化酶转录表达下降导致 A，b-不饱和醛的生产，如4-羟基己烯醛(4HHE)、4-羟基己烯醛(4-One)和4-羟基己烯醛(4-One) 从脂肪细胞扩散而来的羟基壬烯醛(4HNE)。罗宾斯实验室进行的未发表的工作 研究表明，4HNE可诱导成纤维细胞和前脂肪细胞衰老，导致b-受体的表达 半乳糖苷酶、MCP1和p21。这项建议代表了兴趣和专业知识的新颖融合 Camell，Bernlohr和Robbins实验室从机械上定义炎症之间的相互作用 脂肪组织和脂肪代谢是影响衰老和衰老的关键因素。 这一应用的中心假设是饮食、年龄和性别相关的脂肪分解作用减少 由常驻B细胞驱动导致MUFA依赖的SIRT1激活减弱，并伴随而来 氧化应激增加。氧化应激增加进而导致活性脂醛的分泌和 组织驻留的前脂肪细胞激活衰老程序。要检验这一假设，请看以下内容 提出了具体目标： 目的1.确定饮食、年龄、性别和特定仓库的脂肪B细胞组成及其对 脂肪细胞脂肪分解。 目的2.评价SIRT1对脂肪细胞的脂依赖调节及伴随调控 氧化应激。 目的3.在小鼠模型中评估醛依赖性脂肪衰老，并对 感光剂。

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 Unpublished work carried out by the Robbins lab has shown that 4HNE induces senescence in fibroblasts and preadipocytes leading to expression of b- galactosidase, MCP1 and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.