Imaging of Chromatin Structure as a Basis for an Aging Clock

Researchers here report a novel approach to building an aging clock, a system that can usefully measure biological age, the growing burden of damage and dysfunction. Epigenetic data, usually the status of DNA methylation at various sites on the genome, has been used to construct aging clocks in the past. Epigenetic changes of all sorts alter gene expression by altering the structure of chromatin, folded DNA in the cell nucleus, determining which regions and genes are exposed to transcriptional machinery. Thus why not directly assess changes in the structure of chromatin via microscopy imaging approaches? Researchers have now tried that, and it seems to work.

Biomarkers of biological age that predict the risk of disease and expected lifespan better than chronological age are key to efficient and cost-effective healthcare. Several years ago, we pioneered microscopic imaging of epigenetic landscapes rooted in the analysis of chromatin topography in single cells. We employed immunolabeling with antibodies specific for histone modifications (e.g. acetylation and methylation marks) and automated microscopy to capture cell-specific patterns using image texture analysis, resulting in multiparametric signatures of cellular states. Here, we took advantage of this technique to develop an image-based chromatin and epigenetic age (ImAge), a fundamentally different approach to studying aging compared to DNA methylation clocks.

We observed the emergence of intrinsic trajectories of ImAge using dimensionality reduction without regression on chronological age. ImAge was correlated with chronological age in all tissues and organs examined and was consistent with the expected acceleration and/or deceleration of biological age in chronologically identical mice treated with chemotherapy or following a caloric restriction regimen, respectively. ImAge from chronologically identical mice inversely correlated with their locomotor activity (greater activity for younger ImAge), consistent with the essential role of locomotion as an aging biomarker. Finally, we demonstrated that ImAge is reduced upon partial reprogramming in vivo following transient expression of OSKM in the liver and skeletal muscles of old mice and validated the power of ImAge to assess the heterogeneity of reprogramming.

We propose that ImAge represents the first-in-class individual-level biomarker of aging and rejuvenation with single-cell resolution.

Link: https://doi.org/10.1101/2022.10.16.512441