Embryos reverse epigenetic clocks during their development

Madhavi Bhatia,NIPER Guwahati

The aging process is characterized by a progressive accumulation of damage, which leads to loss of physiological integrity, impaired function and, increased susceptibility to death. Earlier, it was thought that the aging process affects the entire organism except for the germline. Because the lineage is immortal in the sense that the germline has reproduced indefinitely since the beginning of life. However, some recent studies have proposed that germline cells may age and be rejuvenated in the offspring after conception. Thus, there must be a point or period of lowest biological age (ground zero) during the initial phases of embryogenesis.

To track this aging process, epigenetic clocks are utilized that can estimate the age of an organism based on molecular markers from the given data.

A study was conducted to assess epigenetic age dynamics during embryogenesis for which human and mouse DNA methylation (DNAm) were collected and subjected to various epigenetic aging clocks. During the study it was found that epigenetic age decreases during early embryogenesis, thus embryonic cells not only do not age during this period but also get rejuvenated at some point. In mid-embryonic development, it was observed that biological age begins to increase in almost all tissues. While localizing the minimum epigenetic age (ground zero) during embryonic development may lie in the range of E4.5 to E10.5, most probably at E6.5/E7.5. Aging of the organism begins after the rejuvenation event. The observed epigenetic age lies between E6.5/E7.5 during which gastrulation occurs. 3 germ layers are formed during gastrulation accompanied by the exit from pluripotency. Ten-eleven translocation (TET) enzymes (Tet1, Tet2, Tet3) play a vital role in gastrulation and cause demethylation by oxidizing 5-methylcytosines (5mCs).TET enzymes have a mechanistic role in the epigenetic age decrease which occurs in gastrulation.

DNA methyltransferases (DNMTs) have an important role in mouse development: DNMT1 is responsible for DNAm maintenance after replication, while DNMT3A and DNMT3B carried out de novo methylation of DNA during development. This methylation maintenance and de novo methylation play a vital role in the rejuvenation event. CpG sites which are associated with aging and lifespan may be hypomethylated and hypermethylated upon aging. It was found that global remethylation is associated with epigenetic age decrease, ground zero while global methylation maximum corresponds to the same developmental stage. So, to remove epigenetic damage, the genome should be first partially demethylated and then remethylated again. Cells that correspond to early embryogenesis (ESCs and iPSCs) do not age when cultured, while early passaging induces telomere extension and there is a partial reduction in epigenetic age.

 As epigenomic changes occur, it results in dysregulation of transcriptional and chromatin networks, which are crucial components of aging. Epigenetic clocks based on methylation levels of certain CpG sites turned out to be promising molecular estimators of biological age. Thus, a natural rejuvenation event occurs during early life and organismal aging begins during embryogenesis, approximately during the time of gastrulation.

Also read:  New species of parasitic fungus discovered in a fossilized ant

Source- Kerepesi C, Zhang B, Lee SG, Trapp A, Gladyshev VN. Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging. bioRxiv. 2021 Jan1 10.1126/sciadv.abg6082

• The Corrosion Prediction from the Corrosion Product Performance
• Nitrogen Resilience in Waterlogged Soybean plants
• Cell Senescence in Type II Diabetes: Therapeutic Potential
• Transgene-Free Canker-Resistant Citrus sinensis with Cas12/RNP
• AI Literacy in Early Childhood Education: Challenges and Opportunities