Can epigenetic clocks be associated with atrial fibrillation?

December 30, 2022

As we age naturally, we tend to be at increased risk for various chronic illnesses. People most often think of aging as the increase in years, also known as chronological aging. However, there is a second type of aging sometimes referred to as biological or epigenetic aging. In recent years, scientists are conducting more research linking disease and our epigenetic clocks

In this paper published in Circulation, authors found an association between epigenetic aging and irregular heart, specifically atrial fibrillation (AF). This relationship was independent of chronological age. 

As referred to above, we measure chronological age in the amount of years since birthdate. On the other hand, biological age is the age that cells, tissues, and organ systems appear to be. This appearance is based on biochemistry. Original biological clocks were based on the length of telomeres, structures on the end of chromosomes that assist in cell division. 

Epigenetic clocks are a novel way of looking at biological aging based on epigenetic modifications to the human genome. Specifically, these alterations are DNA methylation. That is, scientists evaluate the pattern of how methyl groups attach to cysteine groups on DNA over time, a known regulator of genetic expression. Heritable genetic factors, as well as lifestyle and environmental factors, impact these patterns. Unlike heredity, individuals can modify the latter two to either accelerate or decelerate biological age. 
Several commercial testing companies have started offering epigenetic tests for individuals, including Elysium Health, ToolBox Genomics, Muhdo, and TruDiagnostic.

DNA molecules
DNA molecule. Photo by Warren Umoh on Unsplash

Making connections with AF

Scientists know that AF risk increases with age. However, the authors of the Circulation study wanted to evaluate whether biological age had an independent relationship with the condition. If this is true, one could imagine that it could help as a diagnostic tool to identify younger people at higher risk earlier and allow doctors to prescribe preventative measures sooner.

The researchers used three population-based cohort studies that assessed people with incident AF over time. Overall, the studies covered 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%) with 905 instances of AF. The breakdown of AF incidence was:

  • Framingham Heart Study (FHS): 2362 individuals without prevalent AF. 278 individuals were diagnosed with incident AF during a median follow-up period of 11.8 years.
  • Atherosclerosis Risk in Communities (ARIC): 2519 Black participants without prevalent AF. 351 individuals were diagnosed with incident AF during a median follow-up period of 21.8 years.
  • Cardiovascular Health Study (CHS): 719 individuals without prevalent AF. 276 individuals were diagnosed with incident AF during a median follow-up period of 10.2 years.

They performed methylation analysis on each participant using publicly available data, measuring a total of four epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1). These five “clocks” are measures of accelerated biological aging, or the condition in which an individual’s biological age is higher than their chronological age.

Finding association, not causation

Overall, chronological aging was still the most prevalent indicator of AF development. However, out of the five measures of accelerated biological aging, four (Hannum, DNAm PhenoAge, DNAm GrimAge, and DNAm PAI-1) showed an association with incidental AF after adjustment for chronological age, sex, race, and smoking variables. Out of these four, the two newest and most robust clocks (DNAm PhenoAge and DNAm GrimAge) showed association after adjustment for seven additional clinical factors.

hands going over a heart beat chart
Heart beat. Photo by Towfiqu barbhuiya on Unsplash

As the authors note, epigenetic aging is a complex process with many confounding variables. Although their data did not find a causal relationship with epigenetic clocks and AF, they believe that the associations can partially account for AF and are strong enough to warrant further research. Specifically, future investigation may reveal more genetic contributions to epigenetic accelerated aging and enable more powerful genetic instruments. Then, scientists can investigate the link between epigenetic aging and AF further.

Clinically, they do not believe their results will have much impact on improving AF risk prediction beyond current models. However, it is conceivable that epigenetic aging may one day guide prevention and treatment strategies. Unlike chronological aging, biological aging can be altered and improved through environmental exposures, such as diet and exercise and potentially through emerging therapies.

Citation: Roberts JD, Vittinghoff E, Lu AT, Alonso A, Wang B, Sitlani CM, Mohammadi-Shemirani P, Fornage M, Kornej J, Brody JA, Arking DE, Lin H, Heckbert SR, Prokic I, Ghanbari M, Skanes AC, Bartz TM, Perez MV, Taylor KD, Lubitz SA, Ellinor PT, Lunetta KL, Pankow JS, Paré G, Sotoodehnia N, Benjamin EJ, Horvath S, Marcus GM. Epigenetic Age and the Risk of Incident Atrial Fibrillation. Circulation. 2021 Dec 14;144(24):1899-1911. doi: 10.1161/CIRCULATIONAHA.121.056456. Epub 2021 Sep 30. PMID: 34587750; PMCID: PMC8671333.

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