Associations between five indicators of epigenetic age acceleration and all-cause and cause-specific mortality among US adults aged 50 years and older.
Level 3 - non-randomized controlled study
Prospective cohort study using linked survey and mortality registry data
PubMed 40301953 · doi:10.1186/s13148-025-01872-6
What was done
Researchers analyzed 1,966 US adults aged 50 and older from the National Health and Nutrition Examination Survey (NHANES 1999–2002) linked to the National Death Index. They assessed five DNA methylation age acceleration (EAA) metrics (HorvathAge, HannumAge, PhenoAge, GrimAge, and GrimAge2). Weighted Cox proportional hazards models adjusted for age, smoking status, chronic conditions, and other covariates were used to evaluate all-cause, cardiovascular, and non-cardiovascular mortality, with restricted cubic splines to test for non-linear relationships.
What was found
All five epigenetic clocks were significantly associated with mortality risk, with GrimAge and GrimAge2 demonstrating the strongest linear associations. Each 5-year increase in GrimAge acceleration was associated with a 44% higher risk of all-cause mortality, a 33% higher risk of cardiovascular mortality, and a 54% higher risk of non-cardiovascular mortality. Each 5-year increase in GrimAge2 acceleration was associated with a 40% higher risk of all-cause mortality, a 33% higher risk of cardiovascular mortality, and a 47% higher risk of non-cardiovascular mortality. In contrast, HorvathAge, HannumAge, and PhenoAge showed J-shaped associations with all-cause and non-cardiovascular mortality, with inflection points for all-cause mortality occurring at accelerations of 2.29, 3.07, and -7.65 years, respectively.
Why it matters
This study directly compares five prominent epigenetic clocks in a nationally representative older population, confirming that second-generation mortality-trained clocks (GrimAge and GrimAge2) exhibit superior, linear predictive performance for long-term mortality compared to earlier clocks.
Limits
The sample is restricted to US adults aged 50 and older from a 1999–2002 baseline survey. DNA methylation was measured at a single time point, precluding evaluation of longitudinal changes in epigenetic age over time. Exact confidence intervals and median follow-up duration were not reported in the abstract.
Cited by
- supports GrimAge is particularly effective at predicting cardiovascular disease mortality risk.