Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; Neuroscience Graduate Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA.
Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA.
EBioMedicine. 2018 Jun;32:9-20. doi: 10.1016/j.ebiom.2018.05.035. Epub 2018 Jun 11.
Macrophage aging is pathogenic in numerous diseases, including age-related macular degeneration (AMD), a leading cause of blindness in older adults. Although prior studies have explored the functional consequences of macrophage aging, less is known about its cellular basis or what defines the transition from physiologic aging to disease. Here, we show that despite their frequent self-renewal, macrophages from old mice exhibited numerous signs of aging, such as impaired oxidative respiration. Transcriptomic profiling of aged murine macrophages revealed dysregulation of diverse cellular pathways, especially in cholesterol homeostasis, that manifested in altered oxysterol signatures. Although the levels of numerous oxysterols in human peripheral blood mononuclear cells and plasma exhibited age-associated changes, plasma 24-hydroxycholesterol levels were specifically associated with AMD. These novel findings demonstrate that oxysterol levels can discriminate disease from physiologic aging. Furthermore, modulation of cholesterol homeostasis may be a novel strategy for treating age-associated diseases in which macrophage aging is pathogenic.
巨噬细胞衰老在许多疾病中具有致病性，包括年龄相关性黄斑变性（AMD），这是老年人失明的主要原因。尽管先前的研究已经探讨了巨噬细胞衰老的功能后果，但对于其细胞基础或定义生理衰老向疾病转变的因素知之甚少。在这里，我们表明，尽管衰老的小鼠巨噬细胞经常自我更新，但它们表现出许多衰老迹象，例如氧化呼吸受损。对衰老的鼠巨噬细胞的转录组分析显示，多种细胞途径失调，特别是胆固醇稳态，表现在改变的氧化固醇特征。虽然人外周血单核细胞和血浆中的许多氧化固醇水平与年龄相关变化，但血浆 24-羟胆固醇水平与 AMD 特别相关。这些新发现表明，氧化固醇水平可以区分疾病与生理衰老。此外，胆固醇稳态的调节可能是治疗巨噬细胞衰老具有致病性的与年龄相关疾病的一种新策略。
