Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging

The notion that germline does not age goes back to the 19th century ideas of August Weismann. However, being in a metabolically active state, germline accumulates damage and other age-related changes over time, i.e., they age. For new life to begin in the same young state, they must be rejuvenated in the offspring. Here, we developed a new multi-tissue epigenetic clock and applied it, together with other aging clocks, to track changes in biological age during mouse and human prenatal development. This analysis revealed a significant decrease in biological age, i.e. rejuvenation, during early stages of embryogenesis, followed by an increase in later stages. We further found that pluripotent stem cells do not age even after extensive passaging and that the examined epigenetic age dynamics is conserved across species. Overall, this study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (the ground zero) marks the beginning of organismal aging. We remapped the raw reads of several available mouse datasets (ENCSR486XIX, GSE120132, GSE56697, GSE121690, GSE60334, GSE130735, GSE76261, GSE34864, GSE80672, GSE51239, GSE98151) to the mouse rDNA sequence, as follows. Raw sequences were downloaded and extracted using SRA Toolkit. Reads were trimmed and quality filtered by TrimGalore! v0.6.4 using the --rrbs option for RRBS. Methylation levels were extracted using Bismark v0.22.2. Reads were mapped to the mouse rDNA sequence (BK000964.3).