PDF(Pubmed)
Abstract：
Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD+ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.
摘要：
尽管胆固醇代谢失调会使衰老组织容易受到炎症和过多疾病的影响，潜在的分子机制仍然不明确。这里,我们证明了代谢和遗传毒性应激，通过肝脏X核受体发挥会聚作用，上调CD38以促进溶酶体胆固醇流出，导致巨噬细胞中烟酰胺腺嘌呤二核苷酸（NAD+）消耗。胆固醇介导的NAD+耗竭诱导巨噬细胞衰老，促进年龄相关性黄斑变性（AMD）的关键特征，包括视网膜下脂质沉积和神经变性。NAD+增强逆转细胞衰老和巨噬细胞功能障碍，防止AMD表型的发展。遗传和药理学衰老可防止AMD和神经变性的发展。视网膜下给予健康巨噬细胞促进衰老巨噬细胞的清除，逆转AMD疾病负担。因此，由过量的细胞内胆固醇诱导的NAD缺陷是巨噬细胞衰老的会聚机制和与年龄相关的神经变性的因果过程。
