Causal effects of cardiovascular health on five epigenetic clocks

Abstract

Background: 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.

Methods and results: 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.

Conclusions: 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.

Fig. 1

Causal effects of CVH factors on GrimEAA in EUR. For the plot in the left panel, the numbers shown around the blue bars are the causal effect sizes. The number of SNPs between the two-panel plots represents the number of IVs. For the plot in the right panel, red boxes indicate significant causal effects (p-value < 0.05 & FDR q-value < 0.05). Blue boxes indicate suggestive causal effects (p-value < 0.05 & FDR q-value ≥ 0.05). Gray boxes indicate insignificant causal effects (p-value ≥ 0.05). The dark gray box indicates insufficient IVs for the MR analysis. The box numbers represent the causal effect sizes achieving significant or suggestive associations

Fig. 2

EUR Multivariable MR analysis to assess the effects of lifestyle factors on GrimEAA while adjusting for BMI Causal estimates are Beta (95% CI) in years. Blue boxes mark the original Beta (95% CI) from the IVW method, while red boxes denote the adjusted Beta (95% CI) from the IVW method. “No. of IVs” indicates the number of instruments used in the multivariable MR analysis

Fig. 3

EUR Multivariable MR analysis to assess the effects of BMI on GrimEAA while adjusting for lifestyle factors Causal estimates are Beta (95% CI) in years. Blue boxes mark the original Beta (95% CI) from the IVW method, while red boxes denote the adjusted Beta (95% CI) from the IVW method. “No. of IVs” indicates the number of instruments used in the multivariable MR analysis