Syndecan-4 as a molecular link between adipose tissue and aging

摘要。越来越多的证据表明，脂肪组织是机制的中心， 参与长寿的途径，年龄相关疾病的发生，炎症和代谢功能障碍。 参与脂肪组织功能障碍及其全身效应的一个过程是细胞衰老。是 众所周知，衰老细胞在肥胖和衰老时积累在脂肪组织中。但 在脂肪组织中引起细胞衰老的机制仍然是难以捉摸的， 需要开发有效的衰老清除疗法细胞外基质（ECM）的重塑是至关重要的 健康脂肪组织的形成和可塑性。ECM提供结构和锚固支撑， 细胞，但它也调节细胞的动态行为的许多方面，通过结合细胞表面整合素， 多配体由于其关键功能，需要将"健康细胞"附着到ECM上以进行正确的细胞分化。 细胞增殖和存活以及缺乏细胞-ECM接触可导致细胞死亡。然而，其他战略， 例如自噬激活，被细胞用来在没有ECM接触的情况下存活。我们报道 Syndecan（Sdc）基因突变会降低果蝇的能量代谢和寿命， 黑腹菌我们还发现，脂肪体中Sdc表达减少的果蝇磷酸化水平较低， Akt的水平，自噬的调节剂，但也增加了脂肪水平，更耐饥饿比 对照此外，脂肪体特异性Sdc敲除果蝇显示出血管紧张素 转化酶相关基因哺乳动物脂肪细胞表达肾素-血管紧张素 RAS系统（RAS）和局部RAS的长期激活增加了氧化应激，并触发细胞 几种组织/器官细胞的衰老。因此，根据这些观察和我们在苍蝇中的发现， 假设脂肪组织中Sdc活性缺乏促进自噬以维持细胞和组织 在不存在细胞-ECM接触的情况下的稳态。然而，这种年轻个体的生存策略最终 通过激活RAS诱导的细胞衰老导致脂肪组织功能障碍和加速衰老。 为了验证我们的假设，并开始描绘Sdc调节自噬的机制， 细胞衰老，我们提出使用脂肪细胞特异性Sdc 4敲除（KO）小鼠。我们的初步研究 显示了整体和脂肪细胞特异性Sdc4 KO雌性小鼠比对照组具有更多的总脂肪量， 年轻的年龄，支持该模式的可行性。该项目的研究结果可能具有重大意义 翻译价值，因为我们在人类中的遗传研究表明，SDC4基因的变异与 与儿童肥胖症和甘油三酯水平增加， 百岁老人在健康老年人的队列中。同样的遗传变异也被发现与 体重指数、高血压和冠状动脉疾病患病率增加的队列研究 这证实了SDC4在年龄相关表型中起关键作用的观点。

ABSTRACT. A growing body of evidence suggests that adipose tissue is at the center of mechanisms and pathways involved in longevity, the genesis of age-related diseases, inflammation, and metabolic dysfunction. One process that is involved in adipose tissue dysfunction and its systemic effects is cellular senescence. It is well-recognized that senescent cells accumulate in adipose tissue in obesity and with aging. However, the mechanisms eliciting cellular senescence in adipose tissue remain elusive and more research in this area is needed to develop effective senolytic therapies. The remodeling of the extracellular matrix (ECM) is essential for healthy adipose tissue formation and plasticity. The ECM provides structural and anchoring support to the cells, but it also regulates many aspects of the cell’s dynamic behavior by binding to cell-surface integrins and syndecans. Because of its pivotal function, the attachment of “healthy cells” to the ECM is needed for correct cell proliferation and survival, and lack of cell-ECM contact can lead to cell death. However, other strategies, such as autophagy activation, are employed by the cell to survive in the absence of ECM contact. We reported that mutations in the Syndecan (Sdc) gene reduce energy metabolism and life span in the fruit fly Drosophila melanogaster. We also found that flies with reduced Sdc expression in the fat body had lower phosphorylation levels of Akt, a regulator of autophagy, but also increased fat levels and were more resistant to starvation than controls. Moreover, fat body-specific Sdc knockdown flies displayed higher expression of the Angiotensin converting enzyme-related gene. Mammalian adipocytes express components of the renin-angiotensin systems (RAS) and prolonged activation of local RAS increases oxidative stress and triggers cellular senescence in several tissue/organ cells. Thus, based on these observations and our findings in flies our hypothesis is that deficiency of Sdc activity in the fat tissue promotes autophagy to maintain cellular and tissue homeostasis in the absence of cell-ECM contact. However, this survival strategy in young individuals ultimately leads to fat tissue dysfunction and accelerated aging through activation of RAS-induced cellular senescence. To test our hypothesis and start delineating the mechanism (s) through which Sdc regulates autophagy and cellular senescence, we propose to use adipocyte-specific Sdc4 knockout (KO) mice. Our preliminary studies show that global and adipocyte-specific Sdc4 KO female mice have more total fat mass than controls at a young age, supporting the feasibility of the model. Findings from this project will likely have significant translational value since our genetic studies in humans showed that a variant in the SDC4 gene is associated with adiposity in children and with increased triglyceride levels and decreased likelihood to become centenarian in a cohort of healthy elderly individuals. The same genetic variant was also found associated to body mass index, hypertension, and increased prevalence of coronary artery disease in a cohort of middle- aged individuals, corroborating the idea that SDC4 plays a critical role in age-related phenotypes.