Bacalini Maria Giulia, Deelen Joris, Pirazzini Chiara, De Cecco Marco, Giuliani Cristina, Lanzarini Catia, Ravaioli Francesco, Marasco Elena, van Heemst Diana, Suchiman H Eka D, Slieker Roderick, Giampieri Enrico, Recchioni Rina, Marcheselli Fiorella, Salvioli Stefano, Vitale Giovanni, Olivieri Fabiola, Spijkerman Annemieke M W, Dollé Martijn E T, Sedivy John M, Castellani Gastone, Franceschi Claudio, Slagboom Pieternella E, Garagnani Paolo
Department of Experimental, Diagnostic and Specialty Medicine.
Interdepartmental Center "L. Galvani," University of Bologna, Bologna, Italy.
J Gerontol A Biol Sci Med Sci. 2017 Aug 1;72(8):1015-1023. doi: 10.1093/gerona/glw185.
Epigenetic remodeling is one of the major features of the aging process. We recently demonstrated that DNA methylation of ELOVL2 and FHL2 CpG islands is highly correlated with age in whole blood. Here we investigated several aspects of age-associated hypermethylation of ELOVL2 and FHL2. We showed that ELOVL2 methylation is significantly different in primary dermal fibroblast cultures from donors of different ages. Using epigenomic data from public resources, we demonstrated that most of the tissues show ELOVL2 and FHL2 hypermethylation with age. Interestingly, ELOVL2 hypermethylation was not found in tissues with very low replication rate. We demonstrated that ELOVL2 hypermethylation is associated with in vitro cell replication rather than with senescence. We confirmed intra-individual hypermethylation of ELOVL2 and FHL2 in longitudinally assessed participants from the Doetinchem Cohort Study. Finally we showed that, although the methylation of the two loci is not associated with longevity/mortality in the Leiden Longevity Study, ELOVL2 methylation is associated with cytomegalovirus status in nonagenarians, which could be informative of a higher number of replication events in a fraction of whole-blood cells. Collectively, these results indicate that ELOVL2 methylation is a marker of cell divisions occurring during human aging.
表观遗传重塑是衰老过程的主要特征之一。我们最近证明，ELOVL2和FHL2基因座的CpG岛的DNA甲基化与全血中的年龄高度相关。在这里，我们研究了ELOVL2和FHL2与年龄相关的高甲基化的几个方面。我们发现，来自不同年龄供体的原代表皮成纤维细胞培养物中，ELOVL2甲基化存在显著差异。利用来自公共资源的表观基因组数据，我们证明大多数组织随着年龄增长会出现ELOVL2和FHL2高甲基化。有趣的是，在复制率非常低的组织中未发现ELOVL2高甲基化。我们证明ELOVL2高甲基化与体外细胞复制相关，而非与衰老相关。我们在多廷赫姆队列研究中纵向评估的参与者中证实了个体内ELOVL2和FHL2的高甲基化。最后我们表明，尽管在莱顿长寿研究中这两个基因座的甲基化与长寿/死亡率无关，但ELOVL2甲基化与非agenarians中的巨细胞病毒状态相关，这可能提示全血细胞中一部分细胞有更多的复制事件。总体而言，这些结果表明ELOVL2甲基化是人类衰老过程中发生的细胞分裂的一个标志物。
