Caloric restriction, ageing and the liver sinusoidal endothelium: mechanisms and implications

老年是许多疾病的主要危险因素，但其机制尚不清楚。我们在肝窦内皮细胞中发现了与年龄相关的变化，这为衰老、脂代谢和血管疾病之间的联系提供了一种机制。肝窦内皮细胞影响底物在血液和肝细胞之间的转移，因此肝窦内皮细胞的变化影响肝功能。我们发现老年人肝窦内皮细胞的主要结构变化称为假性毛细血管形成，包括毛孔丢失、胶原和基底膜厚度增加和沉积。我们发现，毛孔的丧失阻止了肝脏对某些脂蛋白的摄取，这与与年龄相关的脂代谢变化和血管疾病有关。我们现在发现，卡路里限制延迟了假毛细血管形成。卡路里限制是已知的唯一可以延长最大寿命的干预措施。这种卡路里限制的效果是由一种名为SIRT1的蛋白质通过对线粒体和细胞死亡的作用来调节的。一种名为白藜芦醇的SIRT1天然激动剂已被发现可以延长酵母、蠕虫和苍蝇的寿命。我们假设，热量限制通过延缓假毛细血管形成从而维持肝脏脂蛋白代谢，特别是乳糜粒残留物，从而预防年龄相关的心血管疾病。我们认为，热量限制将通过影响SIRT1通路来防止与年龄相关的假毛细血管形成，因此白藜芦醇将延缓假毛细血管形成。这些假说的证实将产生一个独特的靶点--肝窦内皮细胞中的毛孔--用于预防老年人的血管疾病，并为白藜芦醇等新型药理药物的开发提供平台，这些药物通过维持肝窦内皮细胞的孔洞发挥作用。

Old age is the major risk factor for many diseases yet the mechanism is unknown. We discovered age-related changes in the liver sinusoidal endothelial cell that provide a mechanism for the link between old age, lipid metabolism and vascular disease. The liver sinusoidal endothelial cell influences the transfer of substrates between the blood and liver cells, therefore changes in the liver sinusoidal endothelial cell affect liver function. We discovered major structural changes in the liver sinusoidal endothelial cell in old age called pseudocapillarization, consisting of loss of pores, increased thickness and deposition of collagen and basal lamina. We showed that the loss of pores prevented the uptake by the liver of some lipoproteins, with implications for age-related changes in lipid metabolism and vascular disease. We have now found that caloric restriction delays pseudocapillarization. Caloric restriction is the only intervention known to increase maximal life span. This effect of caloric restriction is mediated by a protein called SIRT1 through actions on mitochondria and cell death. A naturally occurring agonist of SIRT1 called resveratrol has been found to increase longevity in yeast, worms and flies. We hypothesize that caloric restriction prevents age-related cardiovascular disease by delaying pseudocapillarization and hence maintaining hepatic metabolism of lipoproteins, particularly chylomicron remnants. We propose that caloric restriction will prevent age-related pseudocapillarization via its effects on the SIRT1 pathways and therefore pseudocapillarization will be delayed by resveratrol. Confirmation of these hypotheses will generate a unique target - pores in the liver sinusoidal endothelial cell - for the prevention of vascular disease in older people and provide a platform for the development of novel pharmacological agents such as resveratrol that act by maintaining the porosity of the liver sinusoidal endothelial cell.