Epigenetic age acceleration is associated with blood lipid levels in a multi-ancestry sample of older U.S. adults

Abstract

Background: Dyslipidemia, which is characterized by an unfavorable lipid profile, is a key risk factor for cardiovascular disease (CVD). Understanding the relationships between epigenetic aging and lipid levels may help guide early prevention and treatment efforts for dyslipidemia.

Methods: We used weighted linear regression to cross-sectionally investigate the associations between five measures of epigenetic age acceleration estimated from whole blood DNA methylation (HorvathAge Acceleration, HannumAge Acceleration, PhenoAge Acceleration, GrimAge Acceleration, and DunedinPACE) and four blood lipid measures (total cholesterol (TC), LDL-C, HDL-C, and triglycerides (TG)) in 3,813 participants (mean age = 70 years) from the Health and Retirement Study (HRS). As a sensitivity analysis, we examined the same associations in participants who fasted prior to the blood draw (n = 2,531) and in participants who did not take lipid-lowering medication (n = 1,869). Using interaction models, we also examined whether demographic factors including age, sex, and educational attainment modified the relationships between epigenetic age acceleration and blood lipids.

Results: After adjusting for age, race/ethnicity, sex, fasting status, and lipid-lowering medication use, greater epigenetic age acceleration was associated with lower TC, HDL-C, and LDL-C, and higher TG (p < 0.05), although the effect sizes were relatively small (e.g., < 7 mg/dL of TC per standard deviation in epigenetic age acceleration). GrimAge acceleration and DunedinPACE associations with all lipids remained significant after further adjustment for body mass index, smoking status, and educational attainment. These associations were stronger in participants who fasted and who did not use lipid-lowering medication, particularly for LDL-C. We observed the largest number of interactions between DunedinPACE and demographic factors, where the associations with lipids were stronger in younger participants, females, and those with higher educational attainment.

Conclusion: Multiple measures of epigenetic age acceleration are associated with blood lipid levels in older adults. A greater understanding of how these associations differ across demographic groups can help shed light on the relationships between aging and downstream cardiovascular diseases. The inverse associations between epigenetic age and TC and LDL-C could be due to sample limitations or non-linear relationships between age and these lipids, as both TC and LDL-C decrease faster at older ages.

Keywords: Aging; Cholesterol; DNA methylation; Epigenetic age acceleration; HDL cholesterol; LDL cholesterol; Lipids; Triglycerides.

Fig. 1

Plots of predicted blood lipid levels by DunedinPACE at the 25th (62 years) and 75th percentile (77 years) of age (top panels), sex (middle panels) and college degree (bottom panels). TC, total cholesterol; HDL-C, high-density lipoprotein; TG, triglycerides Interaction model: blood lipid level ~ epigenetic age acceleration + age at methylation measurement + sex + race/ethnicity + fasting status + lipid-lowering medication use + body mass index + smoking status + high school degree or equivalent + college degree and above + DunedinPACE × demographic factor Only interactions with DunedinPACE and demographic factors with P_interaction < 0.05 in the interaction model are shown. Age was centered for the interaction analysis. The line and corresponding confidence intervals represent the predicted blood lipid level at the corresponding value of DunedinPACE