It is well established that early embryonic development involves a process of rejuvenation. As much as possible of the molecular damage characteristic of adult cells is stripped away. The development of cellular reprogramming to produce induced pluripotent stem cells has provided researchers with additional insight into some of this mechanisms of this process of embryonic rejuvenation, such as the resetting of epigenetic patterns and restoration of mitochondrial function. Using epigenetic clocks to assess embryonic cells at various stages of development produces interesting results, as shown here.
Aging is characterized by a progressive accumulation of damage, leading to the loss of physiological integrity, impaired function, and increased vulnerability to death. While the aging process affects the entire organism, it is often discussed that the germ line does not age, because this lineage is immortal in the sense that the germ line has reproduced indefinitely since the beginning of life. This notion dates to the 19th century when August Weismann proposed the separation of the ageless germ line and aging body.
However, being in the metabolically active state for two decades or more before its contribution to the offspring, the human germ line accumulates molecular damage, such as modified long-lived proteins, epimutations, metabolic by-products, and other age-related deleterious changes. It was shown that sperm cells exhibit a distinct pattern of age-associated changes. Accordingly, it was recently proposed that germline cells may age and be rejuvenated in the offspring after conception. If this is the case, there must be a point (or period) of the lowest biological age (here, referred to as the ground zero) during the initial phases of embryogenesis. Here, we carried out a quantitative, data-driven test of this idea.
We developed a 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 (ground zero) marks the beginning of organismal aging.