MultiAge: A New Multidimensional Biomarker of Biological Age Derived from Comprehensive Phenotypic and Molecular Profiling

Background: It is an everyday observation that people of the same chronological age differ with respect to their physical and mental capacity. However, assessing these differences in biological age remains challenging. Methods: Here, we aggregate 89 age-associated variables from the Berlin Aging Study II (BASE-II, n=1,631) to generate MultiAge, a new marker of biological age that summarizes information from ten domains reflecting organ health and global biological age. We then used methylation data obtained from an Illumina MethylationEPIC array and supervised machine learning to translate MultiAge into a DNA methylation signature, MultiAgeEpi (309 CpGs), which was subsequently validated in four independent external validation cohorts (KORA FF4, KORA Age, SHIP-TREND, BiDirect, total n=4,339). MultiAgeEpi results were compared with previously published epigenetic clocks (GrimAge, DunedinPACE, SystemsAge). Results: We report that MultiAgeEpi showed similar, and in several cases, stronger associations with age-associated outcomes such as diabetes, metabolic syndrome, multimorbidity, frailty and mortality (q < 0.05) compared to the other clocks. Conclusions: MultiAge and MultiAgeEpi thus provide a comprehensive assessment of biological age through aggregation of numerous age-associated variables and the use of the high-resolution methylomics data makes transfer of this marker to other cohorts possible.