Sinke Lucy, Beekman Marian, Raz Yotam, Gehrmann Thies, Moustakas Ioannis, Boulinguiez Alexis, Lakenberg Nico, Suchiman Eka, Bogaards Fatih A, Bizzarri Daniele, van den Akker Erik B, Waldenberger Melanie, Butler-Browne Gillian, Trollet Capucine, de Groot C P G M, Heijmans Bastiaan T, Slagboom P Eline
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, The Netherlands.
Department of Bioscience Engineering, Research Group Environmental Ecology and Applied Microbiology, University of Antwerp, Antwerp, Belgium.
Aging Cell. 2025 Apr;24(4):e14431. doi: 10.1111/acel.14431. Epub 2024 Dec 1.
Across the lifespan, diet and physical activity profiles substantially influence immunometabolic health. DNA methylation, as a tissue-specific marker sensitive to behavioral change, may mediate these effects through modulation of transcription factor binding and subsequent gene expression. Despite this, few human studies have profiled DNA methylation and gene expression simultaneously in multiple tissues or examined how molecular levels react and interact in response to lifestyle changes. The Growing Old Together (GOTO) study is a 13-week lifestyle intervention in older adults, which imparted health benefits to participants. Here, we characterize the DNA methylation response to this intervention at over 750 thousand CpGs in muscle, adipose, and blood. Differentially methylated sites are enriched for active chromatin states, located close to relevant transcription factor binding sites, and associated with changing expression of insulin sensitivity genes and health parameters. In addition, measures of biological age are consistently reduced, with decreases in grimAge associated with observed health improvements. Taken together, our results identify responsive molecular markers and demonstrate their potential to measure progression and finetune treatment of age-related risks and diseases.
在整个生命周期中，饮食和身体活动状况对免疫代谢健康有重大影响。DNA甲基化作为一种对行为变化敏感的组织特异性标志物，可能通过调节转录因子结合及随后的基因表达来介导这些影响。尽管如此，很少有人类研究在多个组织中同时分析DNA甲基化和基因表达，或研究分子水平如何响应生活方式的改变并相互作用。“共同变老”（GOTO）研究是一项针对老年人的为期13周的生活方式干预研究，该研究给参与者带来了健康益处。在此，我们在肌肉、脂肪和血液中超过75万个CpG位点上表征了对该干预的DNA甲基化反应。差异甲基化位点富含活性染色质状态，位于相关转录因子结合位点附近，并与胰岛素敏感性基因表达变化和健康参数相关。此外，生物学年龄指标持续降低，与观察到的健康改善相关的严峻年龄（grimAge）也有所下降。综上所述，我们的研究结果确定了反应性分子标志物，并证明了它们在测量与年龄相关的风险和疾病的进展以及微调治疗方面的潜力。
