Epigenetic Age and Brain Health Events: Findings from the Health and Retirement Study
Cyprien Rivier1, Natalia Szejko2, Daniela Renedo1, Adam De Havenon1, Kevin Sheth3, Thomas Gill1, Guido Falcone4
1Yale University, 2University of Calgary, 3Yale UniversityDivision of Neuro and Critical Care, 4Yale School of Medicine
Objective:
We hypothesize that brain health events (BHE) lead to epigenetic age acceleration and that, conversely, accelerated epigenetic age leads to higher risk of BHE.
Background:
It is increasingly recognized that chronological age provides an incomplete assessment of true biological age. Epigenetic clocks use DNA methylation data to estimate biological age more accurately.
Design/Methods:
We conducted a 3-stage epigenetic study within the Health and Retirement Study (Figure). In 2016, participants provided blood samples and methylation and genomic data was generated. Epigenetic age was calculated as the average of thirteen epigenetic clocks that used different combinations of methylation data. BHE was a composite of stroke, dementia and late-life depression. Stage 1 entailed testing for association between BHE prior to 2016 (exposure) and epigenetic age (outcome). Stage 2 entailed testing for association between epigenetic age (exposure) and BHE occurring after 2016 (outcome). All models were adjusted for age, sex, race/ethnicity and cardiovascular risk factors. Stage 3 entailed testing for causal associations using Mendelian Randomization (MR).
Results:
Out of 4,018 participants with epigenomic data, 2,221 (55%) had a history of a BHE before 2016. A history of BHE was associated with an older epigenetic age (beta 0.05, SE 0.01; p<0.01). Of the 3,047 study participants with available follow-up data, 1,018 (33%) developed a BHE over a mean follow up of 4 years. Epigenetic age acceleration was associated with higher odds of BHE (OR 1.57, [1.22-2.01]). Causal associations estimated via MR analyses confirmed both results.
Conclusions:
A history of BHE was associated with epigenetic age acceleration and, conversely, epigenetic age acceleration was linked to a higher risk of brain health events. MR analyses suggest that these associations are causal. These results indicate that more nuanced strategies for ascertaining biological age are needed in neurological research and point to epigenetic clocks as a promising tool for this purpose.