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。我们发现了肝窦内皮细胞的年龄相关变化，为老年、脂质代谢和血管疾病之间的联系提供了机制。肝窦内皮细胞影响血液和肝细胞之间的底物转移，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毛细血管化，包括孔隙的损失，厚度增加和胶原蛋白和基底层的沉积。我们发现，毛孔的损失阻止了肝脏对某些脂蛋白的摄取，这与脂质代谢和血管疾病中与年龄相关的变化有关。我们现在发现，限制热量可以延缓假毛细血管化。热量限制是已知的唯一可以延长最长寿命的干预措施。这种热量限制的效果是由一种称为SIRT 1的蛋白质通过对线粒体和细胞死亡的作用介导的。一种叫做白藜芦醇的SIRT 1天然激动剂被发现可以延长酵母、蠕虫和苍蝇的寿命。我们推测，热量限制通过延迟假毛细血管化，从而维持脂蛋白，特别是乳糜微粒残留的肝脏代谢，预防与年龄相关的心血管疾病。我们建议，热量限制将防止年龄相关的pseudocapillarization通过其对SIRT 1途径的影响，因此pseudocapillarization将被白藜芦醇延迟。这些假设的证实将产生一个独特的目标-肝窦内皮细胞中的孔-用于预防老年人的血管疾病，并为开发新的药理学药物（如白藜芦醇）提供平台，这些药物通过维持肝窦内皮细胞的孔隙率发挥作用。

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.