Exploring the role of β2-microglobulin in the relationship between physical activity and DNAm-predicted PhenoAge: Evidence from a population-based and mice single-cell RNA-sequencing study

作者：Yanwei You, Jinwei Li, Yang Zhang, Qiyu Liu, Alimjan Ablitip, Yongjie Lao, Jingtong Wang, Kailin Xu, Zhengbang Yao, Yuquan Chen, Xindong Ma · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.11.047 · 被引用次数：14 · 研究领域：Genetics, Aging, and Longevity in Model Organisms、Telomeres, Telomerase, and Senescence、Single-cell and spatial transcriptomics

INTRODUCTION: Physical activity (PA) is recognized as a cornerstone of healthy aging, yet the molecular mechanisms linking PA to biological aging remain poorly understood. β2-microglobulin (β2M), an inflammatory and aging biomarker, has emerged as a potential mediator of these effects. DNA methylation (DNAm)-based biological aging indicators, such as PhenoAge, provide a means to assess the relationship between PA, β2M, and aging at the molecular level. OBJECTIVES: This study aimed to investigate whether β2M mediates the association between PA and DNAm-predicted PhenoAge. Additionally, this study sought to explore the underlying molecular mechanisms using single-cell RNA sequencing (scRNA-seq) in mice. METHODS: This study analyzed data from 936 participants in the U.S. population, assessing associations between PA, β2M levels, and PhenoAge using weighted multivariable regression and mediation models. β2M levels and PhenoAge were measured in blood samples and calculated using validated DNA methylation algorithms. To investigate molecular mechanisms, scRNA-seq was performed on peripheral blood samples from exercise and control mice. RESULTS: In fully adjusted models, higher PA levels were significantly associated with lower PhenoAge (β = -0.014, p = 0.034) and β2M levels (β = -0.006, p = 0.032). Mediation analysis revealed that β2M mediated 37.67 % of the association between PA and PhenoAge (p = 0.042). Stratified analyses showed stronger effects in males and individuals with hi...