A multi-omics approach unveils an association between subclinical atherosclerosis and epigenetic age acceleration mediated by systemic inflammation

Authors: SANCHEZ-CABO, FATIMA - National Center For Cardiovascular Research(CNIC); FUSTER, VALENTIN - National Center For Cardiovascular Research(CNIC); SILLA, JUAN CARLOS - National Center For Cardiovascular Research(CNIC); GONZALEZ, GEMA - National Center For Cardiovascular Research(CNIC); LORENZO-VIVAS, ERIKA - National Center For Cardiovascular Research(CNIC); ALVAREZ, REBECCA - National Center For Cardiovascular Research(CNIC); CALLEJAS, SERGIO - National Center For Cardiovascular Research(CNIC); BENGURIA, ALBERTO - National Center For Cardiovascular Research(CNIC); GIL, EDUARDO - National Center For Cardiovascular Research(CNIC); NUNEZ, ESTEFANIA - National Center For Cardiovascular Research(CNIC); OLIVA, BELEN - National Center For Cardiovascular Research(CNIC); MENDIGUREN, JOSE - National Center For Cardiovascular Research(CNIC); CORTES-CANTELI, MARTA - National Center For Cardiovascular Research(CNIC); BUENO, HECTOR - National Center For Cardiovascular Research(CNIC); ANDRES, VINCENTE - National Center For Cardiovascular Research(CNIC); ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; FERNANDEZ-FREIRA, LETICIA - National Center For Cardiovascular Research(CNIC); QUESADA, ANTONIO - National Center For Cardiovascular Research(CNIC); GARCIA, JOSE - National Center For Cardiovascular Research(CNIC); ROSSELLO, XAVIER - National Center For Cardiovascular Research(CNIC); VASQUEZ, JESUS - National Center For Cardiovascular Research(CNIC); DOPAZO, ANA - National Center For Cardiovascular Research(CNIC); FERNANDEZ-ORTIZ, ANTONIO - National Center For Cardiovascular Research(CNIC); IBANEZ, BORJA - National Center For Cardiovascular Research(CNIC); FUSTER, JOSE - National Center For Cardiovascular Research(CNIC); LARA-PEZZI, ENRIQUE - National Center For Cardiovascular Research(CNIC)

Submitted to: European Heart Journal
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/22/2023
Publication Date: 8/1/2023
Citation: Sanchez-Cabo, F., Fuster, V., Silla, J., Gonzalez, G., Lorenzo-Vivas, E., Alvarez, R., Callejas, S., Benguria, A., Gil, E., Nunez, E., Oliva, B., Mendiguren, J.M., Cortes-Canteli, M., Bueno, H., Andres, V., Ordovas, J.M., Fernandez-Freira, L., Quesada, A.J., Garcia, J.M., Rossello, X., Vasquez, J., Dopazo, A., Fernandez-Ortiz, A., Ibanez, B., Fuster, J.J., Lara-Pezzi, E. 2023. A multi-omics approach unveils an association between subclinical atherosclerosis and epigenetic age acceleration mediated by systemic inflammation. European Heart Journal. https://doi.org/10.1093/eurheartj/ehad361.
DOI: https://doi.org/10.1093/eurheartj/ehad361

Interpretive Summary: This study investigated the link between early, hidden stages of heart disease and "epigenetic age," a measure of biological age that can be different from chronological age. The research was conducted on a group of 391 participants who were part of Progression of Early Subclinical Atherosclerosis (PESA) study, a study on the progression of early heart disease. The main finding was that individuals showing signs of early heart disease had an 'older' epigenetic age. This was true even after considering traditional risk factors for heart disease. In other words, the presence of early-stage heart disease appeared to speed up a person's biological clock. This biological age was also tied to higher levels of inflammation in the body, an important factor contributing to heart disease. In practical terms, these results highlight the potential importance of interventions aimed at reducing inflammation for preventing heart disease. The findings are particularly relevant for scientists and clinicians, as they suggest that monitoring epigenetic age and inflammation could provide early warning signs of developing heart disease. This, in turn, could lead to earlier interventions and improved health outcomes for the public.

Technical Abstract: Background and Aims: Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical atherosclerosis with accelerated epigenetic age and to investigate the underlying mechanisms mediating this association. Methods: Whole blood methylomics, transcriptomics and plasma proteomics were obtained for 391 participants of the Progression of Early Subclinical Atherosclerosis (PESA) study. Epigenetic age was calculated from methylomics data for each participant. Its divergence from chronological age is termed epigenetic age acceleration. Subclinical atherosclerosis burden was estimated by multi-territory 2D/3D vascular ultrasound and by coronary artery calcification. Results: In healthy individuals, the presence, extension and progression of subclinical atherosclerosis was associated with a significant acceleration of the Grim epigenetic age, a predictor of health and lifespan, regardless of traditional CV risk factors. Individuals with an accelerated Grim epigenetic age were characterized by an increased systemic inflammation and associated with a score of low-grade, chronic inflammation. Mediation analysis using transcriptomics and proteomics data revealed key pro-inflammatory pathways (IL6, Inflammasome, IL10) and genes (IL1B, OSM, TLR5 and CD14) mediating the association between subclinical atherosclerosis and epigenetic age acceleration. Conclusions: The presence, extension and progression of subclinical atherosclerosis in middle-aged asymptomatic individuals is associated with an acceleration in the Grim epigenetic age. Mediation analysis using transcriptomics and proteomics data suggests a key role of systemic inflammation in this association, reinforcing the relevance of interventions on inflammation to prevent CVD.