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. 2023 Dec;131(12):127016.
doi: 10.1289/EHP11981. Epub 2023 Dec 22.

Arsenic Exposure and Epigenetic Aging: The Association with Cardiovascular Disease and All-Cause Mortality in the Strong Heart Study

Enoch X Jiang  1 , Arce Domingo-Relloso  1   2   3 , Ahlam Abuawad  1 , Karin Haack  4 , Maria Tellez-Plaza  2 , M Danielle Fallin  5   6 , Jason G Umans  7   8 , Lyle G Best  9 , Ying Zhang  10 , Allison Kupsco  1 , Daniel W Belsky  11   12 , Shelley A Cole  4 , Ana Navas-Acien  1
Affiliations

Arsenic Exposure and Epigenetic Aging: The Association with Cardiovascular Disease and All-Cause Mortality in the Strong Heart Study

Enoch X Jiang et al. Environ Health Perspect. 2023 Dec.

Abstract

Background: Inorganic arsenic (As) may increase the risk of cardiovascular disease (CVD) and all-cause mortality through accelerated aging, which can be estimated using epigenetic-based measures.

Objectives: We evaluated three DNA methylation-based aging measures (PhenoAge, GrimAge, DunedinPACE) (epigenetic aging measures) as potential mediators of the previously reported association of As exposure with CVD incidence, CVD mortality, and all-cause mortality in the Strong Heart Study (SHS), an epidemiological cohort of American Indian adults.

Methods: Blood DNA methylation and urinary As levels were measured in 2,323 SHS participants (41.5% men, mean age of 55 years old). PhenoAge and GrimAge values were calculated using a residual-based method. We tested the association of urinary As with epigenetic aging measures using linear regression, the association of epigenetic aging measures with the three health outcomes using additive hazards models, and the mediation of As-related CVD incidence, CVD mortality, and all-cause mortality by epigenetic aging measures using the product of coefficients method.

Results: SHS participants with higher vs. lower urinary As levels had similar PhenoAge age, older GrimAge age, and faster DunedinPACE. An interquartile range increase in urinary As was associated with higher of PhenoAge age acceleration [mean difference (95% confidence interval)=0.48 (0.17, 0.80) years], GrimAge age acceleration [0.80 (0.60, 1.00) years], and DunedinPACE [0.011 (0.005, 0.018)], after adjusting for age, sex, center location, genetic components, smoking status, and body mass index. Of the 347 incident CVD events per 100,000 person-years associated with a doubling in As exposure, 21.3% (9.1, 57.1) and 22.6% (9.5, 56.9), were attributable to differences in GrimAge and DunedinPACE, respectively.

Discussion: Arsenic exposure was associated with older GrimAge and faster DunedinPACE measures of biological age. Furthermore, accelerated biological aging measured from DNA methylation accounted for a relevant fraction of As-associated risk for CVD, CVD mortality, and all-cause mortality in the SHS, supporting the role of As in accelerated aging. Research of the biological underpinnings can contribute to a better understanding of the role of aging in arsenic-related disease. https://doi.org/10.1289/EHP11981.

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Figures

Figure 1 is a correlation matrix. On the left are scatter plots, plotting associations between each epigenetic clock (y-axis) and chronological age (x-axis). Each plot has a different y-axis scale to capture the range of values for each clock: for Hannum and Horvath, 30 to 90 in increments of 10; for PhenoAge, 20 to 80 in increments of 20; for GrimAge, 30 to 60 in increments of 10; for DunedinPACE, 0.8 to 1.6 in increments of 0.2. In the diagonal are histograms depicting the range of values for each epigenetic clock or chronological age. On the right are boxes containing simple correlation coefficients and p-values to illustrate the magnitude and significance of correlation between each epigenetic clock as well as chronological age. For example, one of these boxes contains the correlation between PhenoAge and GrimAge (coefficient of 0.73, p<0.01).
Figure 1.
(Left) Scatter plots of participants’ epigenetic age against their chronological age. (Middle) Distribution of participants’ chronological and epigenetic ages. (Right) Simple correlations (Spearman’s ρ) between the chronological/epigenetic ages for each participant (n=2,323) in the Strong Heart Study. Corresponding data is in Excel Table S1.
Figures 2A and 2B are box and whiskers plots, plotting epigenetic age acceleration (years), ranging from negative 20 to 20 in increments of 5, and pace of aging, ranging from 0.7 to 1.7 in increments of 0.1 (y-axis) across arsenic quartile (micrograms per gram creatinine), ranging as less than 5.24, 5.24 to 8.56, 8.56 to 14.42, and greater than 14.42 (x-axis), for PhenoAge and GrimAge.
Figure 2.
Distribution of participants’ (A) PhenoAge and GrimAge age acceleration values and (B) DunedinPACE pace of aging values by quartile of urinary arsenic levels (μg/g creatinine). Epigenetic age acceleration is reported in years based on the residual method, and pace of aging is reported in years of biological aging per chronological year. n=2,323 in the Strong Heart Study. Corresponding data is in Excel Table S2. Note: In panel A, four participants with PhenoAge age acceleration values out of the graph’s range are not displayed (their data is still included in all analyses). Each box represents the interquartile range (IQR) of the epigenetic age acceleration or pace of aging value, and each whisker represents values up to 1.5 IQRs away from the first or third quartile; outlier values are beyond that.
Figure 3 is a set of three clustered bar graphs titled cardiovascular disease incidence, cardiovascular disease mortality, and total mortality, plotting effect sizes, ranging from 0 to 800 in increments of 200 (y-axis) across PhenoAge Acceleration, GrimAge Acceleration, and DunedinPACE (x-axis) for total effect and indirect effect, respectively.
Figure 3.
Contribution of PhenoAge age acceleration, GrimAge age acceleration, and DunedinPACE to total effect of urinary arsenic exposure on incident CVD (A), fatal CVD (B), and all-cause mortality (C) in fully adjusted mediation models. Effect size is reported as cases per 100,000 person-years attributable to a doubling in urinary arsenic levels (TE) or percent attributable to the mediating effect of the epigenetic aging measure (IE). n=2,323, Missing=0. Corresponding data is in Table 5. Note: CVD, cardiovascular disease; IE, indirect effect; TE, total effect.
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