
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.08.21.24312373
preprint
2
Article
Epigenetic age acceleration and mortality risk prediction in U.S. adults
Mendy Angelico http://orcid.org/0000-0002-8227-6830

Mersha Tesfaye B. http://orcid.org/0000-0002-9189-8447

29 8 2024
2024.08.21.24312373https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
http://medrxiv.org/lookup/doi/10.1101/2024.08.21.24312373
nihpp-2024.08.21.24312373.pdf
Abstract

Background

Epigenetic clocks have emerged as novel measures of biological age and potential predictors of mortality. We aimed to test whether epigenetic age acceleration (EAA) estimated using different epigenetic clocks predict long-term overall, cardiovascular or cancer mortality.

Methods

We analyzed data from 2,105 participants to the 1999-2002 National Health and Nutrition Examination Survey aged ≥50 years old who were followed for mortality through 2019. EAAs was calculated from the residuals of Horvath, Hannum, SkinBlood, Pheno, Zhang, Lin, Weidner, Vidal-Bralo and Grim epigenetic clocks regressed on chronological age. Using cox proportional hazards regression, we estimated the hazard ratio (HR) and 95% confidence interval (CI) for the association of EAA (per 5-year) and the DunedinPoAm pace of aging (per 10% increase) with overall, cardiovascular and cancer mortality, adjusting for covariates and white blood cell composition.

Results

During a median follow-up of 17.5 years, 998 deaths occurred, including 272 from cardiovascular disease and 209 from cancer. Overall mortality was most significantly predicted by Grim EAA ( P < 0.0001; HR: 1.50, 95% CI: 1.32-1.71) followed by Hannum ( P = 0.001; HR: 1.16, 95% CI: 1.07-1.27), Pheno ( P = 0.001; HR: 1.13, 95% CI: 1.05-1.21), Horvath ( P = 0.007; HR: 1.13, 95% CI: 1.04-1.22) and Vidal-Bralo ( P = 0.008; HR: 1.13, 95% CI: 1.03-1.23) EAAs. Grim EAA predicted cardiovascular mortality ( P < 0.0001; HR: 1.55, 95% CI: 1.29-1.86), whereas Hannum ( P = 0.006; HR: 1.24, 95% CI: 1.07-1.44), Horvath ( P = 0.02; HR: 1.18, 95% CI: 1.02-1.35) and Grim ( P = 0.049; HR: 1.37, 95% CI: 1.00-1.87) EAAs predicted cancer mortality. DunedinPoAm pace of aging was associated with overall ( P = 0.003; HR: 1.23, 95% CI: 1.08-1.38) and cardiovascular ( P = 0.04; HR: 1.25, 95% CI: 1.01-1.55) mortality.

Conclusions

In a U.S. representative sample, Horvath, Hannum, Pheno, Vidal-Bralo and Grim EAA all predicted overall mortality but only Grim EAA predicted cardiovascular mortality and Horvath, Hannum or Grim EAA predicted cancer mortality. Pace of aging predicted overall and cardiovascular mortality.
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