Epigenetic Clock Explains White Matter Hyperintensity Burden Irrespective of Chronological Age

SIMPLE SUMMARY: Biological age (B-age), or the degree of aging of an individual, can differ from chronological age. B-age is affected by epigenetics, and we calculate it based on the degree of methylation of multiple specific regions of human DNA. For previous research, we know that patients with ischemic stroke are biologically older than healthy individuals without stroke. On the other hand, white matter hyperintensities (WMH) observed in brain magnetic resonance images are an unspecific sign that has been associated with brain aging and also with the increased risk of stroke or dementia. It is unknown whether epigenetic biological age is associated with this sign of brain aging. In this manuscript, we interrogated the association between B-age and WMH volume and found that patients with high WMH burden are biologically older. Moreover, we found that 42.7% of the effects of chronological age on WMH can be explained by B-age, suggesting a role of epigenetics in WMH pathophysiology. Our study also generates a potential number of questions that might be addressed in further articles, such as whether this relationship depends on WMH location. ABSTRACT: In this manuscript we studied the relationship between WMH and biological age (B-age) in patients with acute stroke. We included in this study 247 patients with acute stroke recruited at Hospital del Mar having both epigenetic (DNA methylation) and magnetic resonance imaging data. WMH were measured using a semi-automated method. B-age was calculated using two widely used methods: the Hannum and Horvath formulas. We used multiple linear regression models to interrogate the role of B-age on WMH volume after adjusting for chronological age (C-age) and other covariables. Average C-age of the sample was 68.4 (±11.8) and we observed a relatively high median WMH volume (median = 8.8 cm(3), Q1–Q3 = 4.05–18.8). After adjusting for potential confounders, we observed a significant effect of B-age(Hannum) on WMH volume (β(Hannum) = 0.023, p-value = 0.029) independently of C-age, which remained significant (β(C-age) = 0.021, p-value = 0.036). Finally, we performed a mediation analysis, which allowed us to discover that 42.7% of the effect of C-age on WMH is mediated by B-age(Hannum). On the other hand, B-age(Hoarvath) showed no significant associations with WMH after being adjusted for C-age. In conclusion, we show for the first time that biological age, measured through DNA methylation, contributes substantially to explain WMH volumetric burden irrespective of chronological age.