表观遗传变化可能是健康的生物标志。表观遗传年龄加速（EAA），即通过表观遗传时钟测量的表观遗传年龄与实际年龄之间的差异，与发病率和死亡率相关。然而，表观遗传时钟与 microRNA (miRNA) 的交叉点以及相应的基于 miRNA 的健康影响尚未得到评估。我们分析了两项美国消防员职业研究（2015-2018 年和 2018-2020 年）中 332 名个体血液样本的 DNA 甲基化和 miRNA 谱。我们考虑了白细胞中 EAA 的 7 种测量值（PhenoAge、GrimAge、Horvath、皮肤血液和 Hannum 表观遗传时钟，以及外在和内在表观遗传年龄加速）。我们使用个体线性回归模型鉴定了与 EAA 相关的 miRNA，并根据性别、种族/民族、实际年龄和细胞类型估计进行了调整，并通过 miRNA 富集分析和基因组注释研究了相关 miRNA 的下游影响。参与者平均年龄为 38 岁，其中 88% 为男性，75% 为非西班牙裔白人。我们鉴定了 798 个 miRNA 中的 183 个与 EAA 相关（FDR q < 0.05）； PhenoAge 为 126 个，GrimAge 为 59 个，Horvath 为 1 个，皮肤血钟为 1 个。在与 Horvath 和 GrimAge 相关的 miRNA 中，有 61 个显着丰富的疾病注释，包括与年龄相关的代谢和心血管疾病以及多种癌症。富集途径包括与蛋白质和蛋白质修饰相关的途径。我们鉴定了与多个表观遗传时钟的 EAA 相关的 miRNA。 PhenoAge 与个体 miRNA 有更多关联，但 GrimAge 和 Horvath 对 miRNA 相关通路有更大的影响。了解这些表观遗传标记之间的关系可能有助于我们了解衰老和衰老相关疾病的分子基础。© 作者 2023。

Epigenetic changes may be biomarkers of health. Epigenetic age acceleration (EAA), the discrepancy between epigenetic age measured via epigenetic clocks and chronological age, is associated with morbidity and mortality. However, the intersection of epigenetic clocks with microRNAs (miRNAs) and corresponding miRNA-based health implications have not been evaluated. We analyzed DNA methylation and miRNA profiles from blood sampled among 332 individuals enrolled across 2 U.S.-based firefighter occupational studies (2015-2018 and 2018-2020). We considered 7 measures of EAA in leukocytes (PhenoAge, GrimAge, Horvath, skin-blood, and Hannum epigenetic clocks, and extrinsic and intrinsic epigenetic age acceleration). We identified miRNAs associated with EAA using individual linear regression models, adjusted for sex, race/ethnicity, chronological age, and cell type estimates, and investigated downstream effects of associated miRNAs with miRNA enrichment analyses and genomic annotations. On average, participants were 38 years old, 88% male, and 75% non-Hispanic white. We identified 183 of 798 miRNAs associated with EAA (FDR q < 0.05); 126 with PhenoAge, 59 with GrimAge, 1 with Horvath, and 1 with the skin-blood clock. Among miRNAs associated with Horvath and GrimAge, there were 61 significantly enriched disease annotations including age-related metabolic and cardiovascular conditions and several cancers. Enriched pathways included those related to proteins and protein modification. We identified miRNAs associated with EAA of multiple epigenetic clocks. PhenoAge had more associations with individual miRNAs, but GrimAge and Horvath had greater implications for miRNA-associated pathways. Understanding the relationship between these epigenetic markers could contribute to our understanding of the molecular underpinnings of aging and aging-related diseases.© The Author(s) 2023.