SYSTEM SPECIFIC AGING SCORES: A STATE OF THE ART AGING CLOCK BUILT USING AGING SCORES FROM DIFFERENT BODILY FUNCTIONS

Abstract Aging is a highly heterogeneous process at multiple levels. Different individuals, organs, tissues, and cell types are innately diverse and age in quantitatively different manners. Epigenetic clocks have been developed to capture overall degree of aging and typically report a single biological age value. However, single measures fail to provide insight into differential aging across organ systems. Our aim was to develop novel systems-specific methylation clocks, that when assessed in blood, capture distinct aging subtypes. We utilized three large human cohort studies and employed both supervised and unsupervised machine learning models by linking DNA methylation to lower dimensional vectors composed of system specific clinical chemistry and functional assays. In doing so, we were able to develop 11 unique system-specific scores–heart, lung, kidney, liver, brain, immune, inflammatory, hematopoietic, musculoskeletal, hormone, and metabolic. We observe that in independent data, the specific systems relate to meaningful outcomes–for instance the brain score is strongly associated with cognitive functioning; musculoskeletal score is strongly associated with physical functioning; and the lung score is strongly associated with lung cancer. Additionally, system scores and the composite systems clock outperforms presently available clocks in terms of associations with a wide variety of aging phenotypes and conditions. Overall, our biological systems based epigenetic clock outperforms presently available epigenetic aging clocks and provides meaningful insights into heterogeneity in aging.