Bozack Anne K, Khodasevich Dennis, Nwanaji-Enwerem Jamaji C, Gladish Nicole, Shen Hanyang, Daredia Saher, Gamble Mary, Needham Belinda L, Rehkopf David H, Cardenas Andres
Department of Epidemiology and Population Health, Stanford University, Palo Alto, CA, United States.
Department of Epidemiology and Population Health, Stanford University, Palo Alto, CA, United States.
Am J Clin Nutr. 2025 Aug;122(2):413-423. doi: 10.1016/j.ajcnut.2025.05.029. Epub 2025 May 31.
One-carbon metabolism (OCM), a biochemical pathway dependent on micronutrients including B vitamins, plays an essential role in aging-related physiological processes. DNA methylation-based aging biomarkers may be influenced by OCM.
This study investigated associations of OCM-related biomarkers with epigenetic aging biomarkers in the cross-sectional National Health and Nutrition Examination Survey (1999-2002).
Blood DNA methylation was measured in adults aged ≥50 y. The following epigenetic aging biomarkers were included: Horvath1, Horvath2, Hannum, PhenoAge, GrimAge2, Dunedin Pace-of-Aging (DunedinPoAm), and DNA methylation telomere length (DNAmTL). We tested for associations of serum folate, red blood cell folate, vitamin B12, homocysteine (Hcy), and methylmalonic acid (MMA) concentrations with epigenetic age deviation (EAD) among 2346 participants with epigenetic and nutritional status biomarkers using adjusted survey-weighted general linear regression models.
A doubling of serum folate concentration was associated with -0.82 y (95% confidence interval: -1.40, -0.23) lower GrimAge2 EAD, -0.13 SDs (-0.22, -0.03) lower DunedinPoAm, and 0.02 kb (0.00, 0.04) greater DNAmTL EAD. Conversely, a doubling in Hcy concentration was associated with 1.05 y (0.06, 2.04) greater PhenoAge EAD, 1.93 y (1.16, 2.71) greater GrimAge2 EAD, and 0.26 SDs (0.10, 0.41) greater DunedinPoAm. Associations of serum folate with EAD were attenuated after adjusting for smoking status, alcohol intake, and estimated glomerular filtration rate. Furthermore, smoking modified the associations of Hcy with GrimAge2 EAD. Chronic kidney disease modified associations of B12 and MMA with Horvath1 and GrimAge2 EAD, respectively.
In a nationally representative sample of United States adults, higher concentration of folate, a carbon donor, was associated with lower EAD, and higher concentration of Hcys, an indicator of OCM deficiencies, was associated with greater EAD; however, some associations were influenced by smoking and renal function. Future research should focus on high-risk populations. Long-term randomized controlled trials are also needed to establish causality and investigate the clinical relevance of changes in EAD.
一碳代谢（OCM）是一种依赖包括B族维生素在内的微量营养素的生化途径，在与衰老相关的生理过程中起着至关重要的作用。基于DNA甲基化的衰老生物标志物可能受一碳代谢的影响。
本研究在横断面的美国国家健康与营养检查调查（1999 - 2002年）中调查了一碳代谢相关生物标志物与表观遗传衰老生物标志物之间的关联。
对年龄≥50岁的成年人进行血液DNA甲基化检测。纳入了以下表观遗传衰老生物标志物：霍瓦斯1（Horvath1）、霍瓦斯2（Horvath2）、汉纳姆（Hannum）、表型年龄（PhenoAge）、格里姆年龄2（GrimAge2）、达尼丁衰老速度（DunedinPoAm）以及DNA甲基化端粒长度（DNAmTL）。我们使用调整后的调查加权一般线性回归模型，在2346名具有表观遗传和营养状况生物标志物的参与者中，测试血清叶酸、红细胞叶酸、维生素B12、同型半胱氨酸（Hcy）和甲基丙二酸（MMA）浓度与表观遗传年龄偏差（EAD）之间的关联。
血清叶酸浓度翻倍与格里姆年龄2的EAD降低0.82岁（95%置信区间：-1.40，-0.23）、达尼丁衰老速度降低0.13标准差（-0.22，-0.03）以及DNAmTL的EAD增加0.02千碱基对（0.00，0.04）相关。相反，Hcy浓度翻倍与表型年龄的EAD增加1.05岁（0.06，2.04）、格里姆年龄2的EAD增加1.93岁（1.16，2.71）以及达尼丁衰老速度增加0.26标准差（0.10，0.41）相关。在调整吸烟状况、酒精摄入量和估计肾小球滤过率后，血清叶酸与EAD的关联减弱。此外，吸烟改变了Hcy与格里姆年龄2的EAD之间的关联。慢性肾脏病分别改变了维生素B12和MMA与霍瓦斯1和格里姆年龄2的EAD之间的关联。
在美国成年人具有全国代表性的样本中，较高浓度的碳供体叶酸与较低的EAD相关，而较高浓度的一碳代谢缺陷指标Hcy与较高的EAD相关；然而，一些关联受吸烟和肾功能影响。未来的研究应聚焦于高危人群。还需要长期随机对照试验来确定因果关系并研究EAD变化的临床相关性。
