Microscopic

TL;DR: Microscopic imaging of epigenetic age (miEpiAge) provides a personalized biomarker of functional age based on single-nucleus epigenetic landscapes.

Abstract: . Predictive biomarkers of functional or biological age are key for evaluating interventions aimed at increasing healthspan and, perhaps, lifespan in humans. Currently, cardiovascular performance, blood analytes, frailty indices, and DNA methylation clocks are used to provide such estimates; each technique has its own strength and limitations. We have developed a novel approach, microscopic imaging of epigenetic age (miEpiAge), which computes multiparametric signatures based on the patterns of epigenetic landscape in single nuclei. We demonstrated that such epigenetic age (EpiAge) readouts robustly distinguish young and old cells from multiple tissues and observed the emergency of epigenetic trajectories of aging using different embeddings of peripheral blood (e.g. CD3+ T cells) without linear regression or averaging. EpiAge readouts based on H3K4me1, H3K27ac, and H3K27me3 revealed distinct progression of epigenetic age in different tissues, while brain and heart were correlated (Spearman r=0.8, p=0.015), and suggested an overall slower pace of epigenetic changes in brain and kidney. Further, EpiAge readouts were consistent with expected acceleration or slowdown of biological age in chronologically identical mice treated with chemotherapy or following caloric restriction regimen, respectively. Critically, we demonstrated that miEpiAge readouts from mouse skeletal muscles correlate (Pearson r=0.92, p=5e-8) with linear combinations of circadian rhythms dependent whole organism metabolic and behavioral readouts recorded from the same mice. Because EpiAge readouts are derived from individual sample measurements without averaging or regression on chronological age, EpiAge represents a personalized biomarker. We posit that miEpiAge provides first in class approach to assess functional age in a variety of organs and tissues offering a rich collection of universal personalized biomarkers of functional age with a single cell resolution.