Figure 2. Mortality Prediction by DNAm PhenoAge. (A) Using five samples from large epidemiological cohorts—two samples from the Women’s health Initiative, the Framingham Heart Study, the Normative Aging Study, and the Jackson Heart Study—we tested whether DNAm PhenoAge was predictive of all-cause mortality. The Fig. displays a forest plot for fixed-effect meta-analysis, based on Cox proportional hazard models, and adjusting for chronological age. Results suggest that DNAm PhenoAge is predictive of mortality in all samples, and that overall, a one-year increase in DNAm PhenoAge is associated with a 4.5% increase in the risk of death (p=9.9E-47). This is contrasted against the first generation of epigenetic biomarkers of aging by Hannum and Horvath, which exhibit less significant associations with lifespan (p=1.7E-21 and p=4.5E-5, respectively). (B and C) Using the WHI sample 1, we plotted Kaplan-Meier survival estimates using actual data from the fastest versus the slowest agers (panel B). We also applied the equation from the proportional hazard model to predict remaining life expectancy and plotted predicted survival assuming a chronological age of 50 and a DNAm PhenoAge of either 40 (slow ager), 50 (average ager), or 60 (fast ager) (panel C). Median life expectancy at age 50 was predicted to be approximately 81 years for the fastest agers, 83.5 years for average agers, and 86 years for the slowest agers.