Laboratory of Retinal Cell Biology, Keio University School of Medicine, Tokyo, Japan.
Ophthalmic Res. 2010;44(3):199-203. doi: 10.1159/000316484. Epub 2010 Sep 9.
The process of aging involves the accumulating changes in the microenvironment that lead to cell senescence or apoptosis, and subsequent tissue or organ dysfunction. Multiple extrinsic and intrinsic events that cause DNA instability are associated with aging. Cells containing unstable DNA are biologically vulnerable, and if the DNA damage is too great for the cell to repair, it becomes senescent or dies by apoptosis. Thus, the cell's capacity to repair its DNA determines the progress of aging, at least in part. Here, we focus on the sirtuins, the mammalian homologs of the yeast life-span-extending molecule, Sir2. Among the sirtuin family proteins in mammals, the one most similar to yeast Sir2 is SIRT1, which is involved in multiple pathways, including the repair of DNA double-strand breaks. Although the role of SIRT1 in mammalian longevity is not clear, it is expressed throughout the retina, where it may suppress aging. In fact, a mutant mouse model of retinal degeneration shows an abnormal subcellular localization of SIRT1 protein and accelerated retinal cell apoptosis. Further analyses are required to elucidate the mechanism of DNA damage and repair, including the contributions of the sirtuins, in the aged or diseased retinas, which will help us understand the mechanisms of retinal aging.
衰老过程涉及导致细胞衰老或凋亡的微环境累积变化，以及随后的组织或器官功能障碍。与衰老相关的是导致 DNA 不稳定的多种外在和内在事件。含有不稳定 DNA 的细胞在生物学上是脆弱的，如果 DNA 损伤太大，细胞无法修复，它就会衰老或通过细胞凋亡死亡。因此，细胞修复其 DNA 的能力至少在一定程度上决定了衰老的进程。在这里，我们专注于沉默信息调节因子 2 (Sir2) 酵母寿命延长分子的哺乳动物同源物——沉默信息调节因子 2 家族蛋白。在哺乳动物的沉默信息调节因子家族蛋白中，与酵母 Sir2 最相似的是 SIRT1，它参与多种途径，包括 DNA 双链断裂的修复。尽管 SIRT1 在哺乳动物长寿中的作用尚不清楚，但它在整个视网膜中表达，在那里它可能抑制衰老。事实上，视网膜变性的突变小鼠模型显示 SIRT1 蛋白的亚细胞定位异常和视网膜细胞凋亡加速。需要进一步分析来阐明 DNA 损伤和修复的机制，包括沉默信息调节因子 2 家族蛋白的贡献，在衰老或患病的视网膜中，这将有助于我们理解视网膜衰老的机制。
