Causal effects of cardiovascular health on five epigenetic clocks

This work delves into the relationship between cardiovascular health (CVH) and aging. Previous studies have shown an association of ideal CVH with a slower aging rate, measured by epigenetic age acceleration (EAA). However, the causal relationship between CVH and EAA has remained unexplored.

We performed genome-wide association studies (GWAS) on the (12-point) CVH score and its components using the Taiwan Biobank data, in which weighted genetic risk scores were treated as instrumental variables. Subsequently, we conducted a one-sample Mendelian Randomization (MR) analysis with the two-stage least-squares method on 2383 participants to examine the causal relationship between the (12-point) CVH score and EAA. As a result, we observed a significant causal effect of the CVH score on GrimAge acceleration (GrimEAA) (β [SE]: - 0.993 [0.363] year; p = 0.0063) and DNA methylation-based plasminogen activator inhibitor-1 (DNAmPAI-1) (β [SE]: - 0.294 [0.099] standard deviation (sd) of DNAmPAI-1; p = 0.0030). Digging individual CVH components in depth, the ideal total cholesterol score (0 [poor], 1 [intermediate], or 2 [ideal]) was causally associated with DNAmPAI-1 (β [SE]: - 0.452 [0.150] sd of DNAmPAI-1; false discovery rate [FDR] q = 0.0102). The ideal body mass index (BMI) score was causally associated with GrimEAA (β [SE]: - 2.382 [0.952] years; FDR q = 0.0498) and DunedinPACE (β [SE]: - 0.097 [0.030]; FDR q = 0.0044). We also performed a two-sample MR analysis using the summary statistics from European GWAS. We observed that the (12-point) CVH score exhibits a significant causal effect on Horvath's intrinsic epigenetic age acceleration (β [SE]: - 0.389 [0.186] years; p = 0.036) and GrimEAA (β [SE]: - 0.526 [0.244] years; p = 0.031). Furthermore, we detected causal effects of BMI (β [SE]: 0.599 [0.081] years; q = 2.91E-12), never smoking (β [SE]: - 2.981 [0.524] years; q = 1.63E-7), walking (β [SE]: - 4.313 [1.236] years; q = 0.004), and dried fruit intake (β [SE]: - 1.523 [0.504] years; q = 0.013) on GrimEAA in the European population.

Our research confirms the causal link between maintaining an ideal CVH and epigenetic age. It provides a tangible pathway for individuals to improve their health and potentially slow aging.