Methylomic survival predictors, frailty, and mortality

Area of Science:

• Gerontology
• Epigenetics
• Biostatistics

Background:

• Biological age and aging-related morbidity are critical areas for health research.
• Methylomic indicators, including mortality risk score (MRscore) and age acceleration (AA), are emerging tools for assessing biological age.
• Frailty index (FI) is a well-established predictor of survival and morbidity.

Purpose of the Study:

• To assess the associations between two novel methylomic survival indicators (MRscore and AA) and the frailty index (FI).
• To compare the predictive accuracy of MRscore, AA, and FI for all-cause mortality.
• To evaluate the potential of MRscore as a surrogate endpoint in clinical research.

Main Methods:

• Utilized a large population-based cohort with a 14-year follow-up.
• Assessed associations between MRscore, AA, and FI using regression models.
• Compared predictive accuracy using prediction error curves, Harrell's C-statistics, and time-dependent AUCs.
• Validated findings in independent samples.

Main Results:

• Both MRscore and AA were independently associated with FI, with MRscore showing a stronger association.
• MRscore and FI demonstrated robust associations with all-cause mortality when analyzed together, outperforming AA.
• MRscore exhibited superior predictive accuracy for mortality compared to FI and AA, as confirmed by multiple statistical measures.
• MRscore significantly enhances survival prediction beyond established biological age markers.

Conclusions:

• The methylation-based mortality risk score (MRscore) is a powerful predictor of survival, outperforming established markers like frailty index (FI) and age acceleration (AA).
• MRscore's strong performance suggests its potential utility as a surrogate endpoint for clinical trials targeting aging and morbidity.
• These findings underscore the value of methylomic data in advancing our understanding and prediction of biological aging.