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引起。 在被定义为与衰老的基本过程有机械联系的因素中，通常被称为 “衰老的支柱”，脂肪组织的炎症和细胞衰老占据中心舞台。的重点 应用是免疫细胞，脂肪细胞和细胞衰老之间的界面，重点是 脂质在协调B细胞生物学、脂肪细胞氧化应激和衰老中的作用。 Camell及其同事最近发表的工作描述了儿茶酚胺的年龄依赖性减少， 由于驻留B细胞的扩增而在脂肪组织中发生的信号传导。老化脂肪B细胞（AAB） 具有记忆样和炎性表型，但它们如何损害儿茶酚胺信号传导尚不清楚。 肾上腺素依赖性的儿茶酚胺信号传导的损失减少脂肪脂解和单不饱和脂肪酸的释放。 脂肪酸（MUFA）从三酰甘油液滴。Bernlohr实验室合作开展的工作 已经表明MUFA直接与SIRT 1结合，并变构激活该酶对一些，但不是全部， 脱乙酰化目标。在所定义的靶点中，SIRT 1活化的丧失导致SIRT 1的去磷酸化减弱。 PGC 1a和线粒体抗氧化酶的转录表达降低，导致 a，b-不饱和醛如4-羟基己烯醛（4 HHE）、4-氧代壬烯醛（4 ONE）和4- 从脂肪细胞扩散羟基壬烯醛（4 HNE）。罗宾斯实验室进行的未发表的工作 显示4 HNE诱导成纤维细胞和前脂肪细胞衰老，导致B- 半乳糖苷酶、MCP 1和p21。这一建议代表了一种新的利益和专业知识之间的融合， Camell，Bernlohr和Robbins实验室机械地定义了炎症与炎症之间的相互作用， 脂肪组织和脂质代谢是影响衰老和老化的关键因素。 该应用的中心假设是，饮食、年龄和性别特异性脂肪分解减少 由常驻B细胞驱动导致SIRT 1的MUFA依赖性激活减弱， 增加氧化应激。氧化应激的增加反过来导致活性脂质醛的分泌， 通过组织驻留前脂肪细胞激活衰老程序。为了验证这一假设， 提出了具体目标： 目标1。定义饮食、年龄、性别和脂肪B细胞的特定库组成及其对 脂肪细胞脂解 目标2.评估SIRT 1的脂质依赖性调节和脂肪细胞的伴随控制 氧化应激 目标3.在小鼠模型中评估脂肪依赖性脂肪衰老， senolytics。

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 Unpublished work carried out by the Robbins lab has shown that 4HNE induces senescence in fibroblasts and preadipocytes leading to expression of b- galactosidase, MCP1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