Novel Epigenetic Clock Biomarkers of Age-Related Macular Degeneration.
Novel Epigenetic Clock Biomarkers of Age-Related Macular Degeneration.
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DOI：
10.3389/fmed.2022.856853
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发表时间：
2022
影响因子：
3.9
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中科院分区：
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年龄相关性黄斑变性(AMD)是一种双眼疾病，由于位于视网膜中央的黄斑区域光感受器的进行性丧失而导致不可逆转的视力损害。光感受器的渐进性丧失是干性AMD的一个重要特征，但并非总是湿性AMD，尽管这两种形式的AMD都会导致视力丧失。基于回归的生物年龄时钟是最有前途的衰老生物标志物之一，但尚未在AMD中使用。在这里，我们进行了分析，以确定基于回归的视网膜生物年龄时钟，并使用转录数据探索它们在AMD中的应用，这些数据包括总共453个视网膜样本，包括105个明尼苏达分级系统(MGS)1级样本、175个MGS 2级样本、112个MGS 3级样本和61个MGS 4级样本，以及167个成纤维细胞样本。无论时钟是在视网膜组织、真皮成纤维细胞还是在组合数据集中训练，时钟在AMD样本中产生了良好的分离，严重程度评分增加，即MGS1-4。时钟应用于培养的成纤维细胞、胚胎干细胞和诱导的多能干细胞(IPSCs)与IPSCs中的AGE重新编程是一致的。此外，时钟在体外神经元分化中的应用表明了更广泛的应用。有趣的是，许多已确定的年龄时钟基因包括与AMD和衰老机械相关的已知靶点，如GDF11、C16ORF72和FBN2。这项研究为视网膜年龄时钟提供了新的观察结果，并为监测体外神经元分化提供了新的应用。这些时钟可以为AMD监测和可能的干预提供有用的标记，以及体外筛查的潜在靶点。
Age-Related Macular Degeneration (AMD) is a bilateral ocular condition resulting in irreversible vision impairment caused by the progressive loss of photoreceptors in the macula, a region at the center of the retina. The progressive loss of photoreceptor is a key feature of dry AMD but not always wet AMD, though both forms of AMD can lead to loss of vision. Regression-based biological age clocks are one of the most promising biomarkers of aging but have not yet been used in AMD. Here we conducted analyses to identify regression-based biological age clocks for the retina and explored their use in AMD using transcriptomic data consisting of a total of 453 retina samples including 105 Minnesota Grading System (MGS) level 1 samples, 175 MGS level 2, 112 MGS level 3 and 61 MGS level 4 samples, as well as 167 fibroblast samples. The clocks yielded good separation among AMD samples with increasing severity score viz., MGS1-4, regardless of whether clocks were trained in retina tissue, dermal fibroblasts, or in combined datasets. Clock application to cultured fibroblasts, embryonic stem cells, and induced Pluripotent Stem Cells (iPSCs) were consistent with age reprograming in iPSCs. Moreover, clock application to in vitro neuronal differentiation suggests broader applications. Interesting, many of the age clock genes identified include known targets mechanistically linked to AMD and aging, such as GDF11, C16ORF72, and FBN2. This study provides new observations for retina age clocks and suggests new applications for monitoring in vitro neuronal differentiation. These clocks could provide useful markers for AMD monitoring and possible intervention, as well as potential targets for in vitro screens.