Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA.
Virginia Commonwealth University, Mid-Atlantic Twin Registry, Richmond, VA, USA.
Geroscience. 2018 Dec;40(5-6):469-484. doi: 10.1007/s11357-018-0040-0. Epub 2018 Aug 22.
Variation in healthy aging and lifespan is ascribed more to various non-genetic factors than to inherited genetic determinants, and a major goal in aging research is to reveal the epigenetic basis of aging. One approach to this goal is to find genomic sites or regions where DNA methylation correlates with biological age. Using health data from 134 elderly twins, we calculated a frailty index as a quantitative indicator of biological age, and by applying the Infinium HumanMethylation450K BeadChip technology to their leukocyte DNA samples, we obtained quantitative DNA methylation data on genome-wide CpG sites. We analyzed the health and epigenome data by taking two independent associative approaches: the parametric regression-based approach and a non-parametric machine learning approach followed by GO ontology analysis. Our results indicate that DNA methylation at CpG sites in the promoter region of PCDHGA3 is associated with biological age. PCDHGA3 belongs to clustered protocadherin genes, which are all located in a single locus on chromosome 5 in human. Previous studies of the clustered protocadherin genes showed that (1) DNA methylation is associated with age or age-related phenotypes; (2) DNA methylation can modulate gene expression; (3) dysregulated gene expression is associated with various pathologies; and (4) DNA methylation patterns at this locus are associated with adverse lifetime experiences. All these observations suggest that DNA methylation at the clustered protocadherin genes, including PCDHGA3, is a key mediator of healthy aging.
健康衰老和寿命的变化更多归因于各种非遗传因素，而不是遗传决定因素，因此衰老研究的主要目标是揭示衰老的表观遗传基础。实现这一目标的一种方法是找到与生物年龄相关的 DNA 甲基化的基因组位点或区域。我们使用来自 134 对老年双胞胎的健康数据，计算了一个衰弱指数作为生物年龄的定量指标，并通过应用 Infinium HumanMethylation450K BeadChip 技术对他们的白细胞 DNA 样本进行分析，获得了全基因组 CpG 位点的定量 DNA 甲基化数据。我们通过两种独立的关联方法分析健康和表观基因组数据：基于参数回归的方法和非参数机器学习方法，然后进行 GO 本体分析。我们的结果表明，PCDHGA3 启动子区域的 CpG 位点的 DNA 甲基化与生物年龄相关。PCDHGA3 属于聚集性原钙黏蛋白基因，这些基因都位于人类 5 号染色体上的一个单一基因座上。以前对聚集性原钙黏蛋白基因的研究表明：（1）DNA 甲基化与年龄或与年龄相关的表型有关；（2）DNA 甲基化可以调节基因表达；（3）基因表达失调与各种病理有关；（4）该基因座上的 DNA 甲基化模式与不良的生活经历有关。所有这些观察结果表明，包括 PCDHGA3 在内的聚集性原钙黏蛋白基因的 DNA 甲基化是健康衰老的关键介质。
