Epigenetic Clock Explains White Matter Hyperintensity Burden Irrespective of Chronological Age

Jiménez-Baladó, Joan; Giralt‐Steinhauer, Eva; Fernández-Pérez, Isabel; Rey, Lucía; Cuadrado-Godia, Elisa; Ois, Ángel; Rodríguez-Campello, Ana; Soriano-Tárraga, Carolina; Lazcano, Uxue; Macias-Gómez, Adrià; Suárez-Pérez, Antoni; Revert, Anna; Estragués, Isabel; Beltrán-Mármol, Brigitte; Medrano-Martorell, Santiago; Capellades, Jaume; Roquer-González, Jaume; Jiménez‐Conde, Jordi

doi:10.3390/biology12010033

Cited by 6 publications

(5 citation statements)

References 39 publications

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“…Epigenetic age acceleration signi cantly contributes to explaining the volumetric burden of white matter hyperintensities, which has been found to be associated with brain aging, an increased risk of stroke, and dementia. 32,33 Several cross-sectional studies have shown a positive correlation between PhenoAge and C-reactive protein level, triglyceride levels, and waistto-hip ratio and a negative correlation with high-density lipoprotein cholesterol level. These factors have strong associations with stroke.…”

Section: Discussionmentioning

confidence: 99%

Causal Associations of Epigenetic Age Acceleration with Stroke and Its Functional outcome: A Two-Sample, Two-Step Mendelian Randomization Study

Qiu,

Wen,

et al. 2024

Preprint

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Background Emerging evidence from observational studies suggested that epigenetic age acceleration may result in an increased incidence of stroke and poorer functional outcomes after a stroke. However, the causality of these associations remains controversial and may be confounded by bias. We aimed to investigate the causal effects of epigenetic age on stroke and its functional outcomes. Methods We conducted a two-sample Mendelian randomization (MR) analysis to explore the causal relationships between epigenetic age and stroke and its outcomes. Additionally, a two-step MR analysis was performed to investigate whether lifestyle factors affect stroke via epigenetic age. Datasets of epigenetic age were obtained from a recent meta-analysis (n = 34710), while those of stroke and its outcomes were sourced from the MEGASTROKE (n = 520000) consortium and Genetics of Ischaemic Stroke Functional Outcome network (n = 6165). Results Two-sample MR analysis revealed a causal relationship between PhenoAge and small vessel stroke (OR = 1.07; 95% CI, 1.03–1.12; p = 2.01 × 10− 3). Mediation analysis through two-step MR indicated that the increased risk of small vessel stroke due to smoking initiation was partially mediated by PhenoAge, with a mediation proportion of 9.5% (95% CI, 1.6–20.6%). No causal relationships were identified between epigenetic age and stroke outcomes. Conclusions Our study confirms a causal relationship between epigenetic age acceleration and stroke, indicating that epigenetic age acceleration may mediate the increased stroke risk due to smoking. Interventions specifically aimed at decelerating epigenetic aging, such as specific lifestyle changes, offer effective strategies for reducing stroke risk.

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Section: Discussionmentioning

confidence: 99%

Causal Associations of Epigenetic Age Acceleration with Stroke and Its Functional outcome: A Two-Sample, Two-Step Mendelian Randomization Study

Qiu,

Wen,

et al. 2024

Preprint

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“…A 2021 study revealed that internalized, but not externalized, anger mediated the association between racial discrimination and JAMA Network Open | Psychiatry accelerated epigenetic aging in Black women, suggesting that this may be a viable explanation for our findings. 93 Relatedly, accelerated epigenetic aging has been associated with compromised white matter throughout the brain in different populations, 94,95 and epigenetic age acceleration has been linked to stress-related disorders and neurodegenerative disorders. [45][46][47][48]96 As such, our findings extend earlier research on accelerated aging in racially marginalized populations, showing links with brain mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Racial Discrimination, Neural Connectivity, and Epigenetic Aging Among Black Women

Elbasheir,

Katrinli,

Kearney

et al. 2024

JAMA Netw Open

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ImportanceRacial discrimination increases the risk of adverse brain health outcomes, potentially via neuroplastic changes in emotion processing networks. The involvement of deep brain regions (brainstem and midbrain) in these responses is unknown. Potential associations of racial discrimination with alterations in deep brain functional connectivity and accelerated epigenetic aging, a process that substantially increases vulnerability to health problems, are also unknown.ObjectiveTo examine associations of racial discrimination with brainstem and midbrain resting-state functional connectivity (RSFC) and DNA methylation age acceleration (DMAA) among Black women in the US.Design, Setting, and ParticipantsThis cohort study was conducted between January 1, 2012, and February 28, 2015, and included a community-based sample of Black women (aged ≥18 years) recruited as part of the Grady Trauma Project. Self-reported racial discrimination was examined in association with seed-to-voxel brain connectivity, including the locus coeruleus (LC), periaqueductal gray (PAG), and superior colliculus (SC); an index of DMAA (Horvath clock) was also evaluated. Posttraumatic stress disorder (PTSD), trauma exposure, and age were used as covariates in statistical models to isolate racial discrimination–related variance. Data analysis was conducted between January 10 and October 30, 2023.ExposureVarying levels of racial discrimination exposure, other trauma exposure, and posttraumatic stress disorder (PTSD).Main Outcomes and MeasuresRacial discrimination frequency was assessed with the Experiences of Discrimination Scale, other trauma exposure was evaluated with the Traumatic Events Inventory, and current PTSD was evaluated with the PTSD Symptom Scale. Seed-to-voxel functional connectivity analyses were conducted with LC, PAG, and SC seeds. To assess DMAA, the Methylation EPIC BeadChip assay (Illumina) was conducted with whole-blood samples from a subset of 49 participants.ResultsThis study included 90 Black women, with a mean (SD) age of 38.5 (11.3) years. Greater racial discrimination was associated with greater left LC RSFC to the bilateral precuneus (a region within the default mode network implicated in rumination and reliving of past events; cluster size k = 228; t85 = 4.78; P &lt; .001, false discovery rate-corrected). Significant indirect effects were observed for the left LC-precuneus RSFC on the association between racial discrimination and DMAA (β [SE] = 0.45 [0.16]; 95% CI, 0.12-0.77).Conclusions and RelevanceIn this study, more frequent racial discrimination was associated with proportionately greater RSFC of the LC to the precuneus, and these connectivity alterations were associated with DMAA. These findings suggest that racial discrimination contributes to accelerated biological aging via altered connectivity between the LC and default mode network, increasing vulnerability for brain health problems.

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“…This approach captures relevant differential DNAm signatures associated with a phenotype of interest. For instance, regarding cerebrovascular diseases, previous studies have demonstrated the role of DNAm in the pathogenesis of ischemic stroke, intracerebral hemorrhage, and subclinical cerebrovascular disease [ 16 , 17 , 18 ]. However, the contribution of DNAm in IA and aSAH has been less studied so far.…”

Section: Overview Of Epigenetics and Its Mechanismsmentioning

confidence: 99%

The Role of Epigenetics in Brain Aneurysm and Subarachnoid Hemorrhage: A Comprehensive Review

Fernández-Pérez,

Macias-Gómez,

Suárez-Pérez

et al. 2024

IJMS

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This comprehensive review explores the emerging field of epigenetics in intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (aSAH). Despite recent advancements, the high mortality of aSAH needs an understanding of its underlying pathophysiology, where epigenetics plays a crucial role. This review synthesizes the current knowledge, focusing on three primary epigenetic mechanisms: DNA methylation, non-coding RNA (ncRNA), and histone modification in IA and aSAH. While DNA methylation studies are relatively limited, they suggest a significant role in the pathogenesis and prognosis of IA and aSAH, highlighting differentially methylated positions in genes presumably involved in these pathologies. However, methodological limitations, including small sample sizes and a lack of diverse population studies, temper these results. The role of ncRNAs, particularly miRNAs, has been more extensively studied, but there are still few studies focused on histone modifications. Despite methodological challenges and inconsistent findings, these studies underscore the involvement of miRNAs in key pathophysiological processes, including vascular smooth muscle regulation and the inflammatory response. This review emphasizes methodological challenges in epigenetic research, advocating for large-scale epigenome-wide association studies integrating genetic and environmental factors, along with longitudinal studies. Such research could unravel the complex mechanisms behind IA and aSAH, guiding the development of targeted therapeutic approaches.

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Epigenetic Clock Explains White Matter Hyperintensity Burden Irrespective of Chronological Age

Cited by 6 publications

References 39 publications

Causal Associations of Epigenetic Age Acceleration with Stroke and Its Functional outcome: A Two-Sample, Two-Step Mendelian Randomization Study

Causal Associations of Epigenetic Age Acceleration with Stroke and Its Functional outcome: A Two-Sample, Two-Step Mendelian Randomization Study

Racial Discrimination, Neural Connectivity, and Epigenetic Aging Among Black Women

The Role of Epigenetics in Brain Aneurysm and Subarachnoid Hemorrhage: A Comprehensive Review

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