Unlike what has been suggested since the 19th century, the germ line isn’t ageless and does accumulate damage over time – new study explores what this means.
A new study from researchers at Brigham and Women’s Hospital and Harvard Medical School on epigenetic clocks has uncovered that the germ line rejuvenates during gastrulation, an early stage of embryogenesis, thus allowing for new life to begin in the same young state.
We usually measure our age by the years we’ve spent on Earth, but our biological age, through specific molecular markers, can tell us something different. Epigenetics is a booming area of research: epigenetic clocks, DNA methylation (DNAm) based biochemical tests, can quantitatively determine the biological age of tissues by measuring the levels of methylation of age-dependent cytosine-guanine dinucleotides (CpG) sites [1].
While the application of aging clocks to human foetal blood samples from various tissues is possible, the entire prenatal development and its clinical utility remains unexplored [2,3].
Longevity.Technology: Steve Horvath is the founder of the first epigenetic clock. GrimAge, PhenoAge and iAge represent some of the latest aging clocks. Although the exact mechanisms behind the clocks is complicated, and biomarkers are still being refined, talking about rejuvenation is no longer a novelty. Cell reprogramming has shown us that it is possible to “turn back time”. The discovery of a natural rejuvenation event is even more thrilling – it widens the possibilities towards better and longer lives for organisms.
Human and mouse prenatal DNAm datasets were explored for tracking biological age using multiple existing epigenetic aging clocks and a newly developed multi-tissue ribosomal DNAm (rDNAm) clock [4].
Can embryonic cells stop aging?
The rDNAm clock applied to mouse early embryonic datasets showed at days 6.5 and 7.5 of embryogenesis a mean epigenetic age lower than in earlier stages – from zygote to blastocyte [5]. The use of four existing genome-wide aging clocks with high accuracy in age prediction displayed similar results. This demonstrates that during early embryogenesis, embryonic cells stop aging and rejuvenate at some point.
The specific analysis of human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) with the Horvath multi-tissue clock showed a near-zero epigenetic age [5]. Even under heavy physiological pressure – i.e., increased oxygen exposure and extensive passaging (the transfer of cells from one culture vessel to another) – these cells of early embryogenesis did not increase, or did so only marginally, similar to Horvath’s findings [6]. This suggests that early-stage embryonic cells do not age.
During early embryogenesis embryonic cells stop aging and rejuvenate at some point.
When do embryonic cells resume aging?
Organismal aging was quantified using the rDNAm clock on mouse samples at both early and late embryonic stages. The epigenetic age turned up significantly lower at days 6.5 and 7.5 than at 13.5, time point representing the stage of primordial germ cells – the progenitors of sperm and oocytes [5]. The genome-wide aging clocks revealed that epigenetic age undergoes a consistent increase from day 10.5.
A similar increase in epigenetic age was also observed on human prenatal datasets when applying the Horvath multi-tissue aging clock [5].
Together, these results show that at some point the biological age during embryonic development resumes its increase and that ‘this dynamic is conserved between species’ [5].
The gastrulation stage could mark the beginning of aging with ground zero playing the role of a biomarker of this starting point.
The minimum epigenetic age – ground zero – was determined using the genome-wide aging clocks and the rDNAm clock on mouse datasets at all embryonic stages. It was estimated to lie between days 4.5 and 10.5 of embryogenesis and most likely 6.5 or 7.5, corresponding to the time of gastrulation, the second step of embryogenesis marking the germ-layer specification period [5]. The gastrulation stage could mark the beginning of aging with ground zero playing the role of a biomarker of this starting point.
What perspectives?
The early stages of embryogenesis are accompanied by multiple other molecular changes, such as the extension of telomeres [7]. Telomeres play a pivotal role in aging by regulating cell response to stress and growth stimulation [8]. Initial passaging of mouse early embryonic cells – i.e., ESC and iPSC – induces telomere extension. Mice generated from these rejuvenated cells ‘live longer and are better protected from age-related diseases’ [9].
The Ten-eleven translocation (TET) enzyme supporting demethylation [10] and the DNA methyltransferases (DNMT) responsible for maintenance and de novo methylation [11] during embryonic development seem to also play a role in the epigenetic age decrease of prenatal cells [5].
Ground zero and the roles of TET and DNMT in rejuvenation were investigated in mouse embryos. Further explorations could help increase the accuracy of the epigenetic age dynamics during embryogenesis. But even as results stand here, ground zero could become a clinical target that not only helps organisms age more slowly, but improve their healthspans and extend their lifespans.
[1] https://pubmed.ncbi.nlm.nih.gov/29643443/
[2] https://www.nature.com/articles/s41598-019-39919-3
[3] https://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1068-z
[4] https://genome.cshlp.org/content/29/3/325.short
[5] https://advances.sciencemag.org/content/7/26/eabg6082
[6] https://genomebiology.biomedcentral.com/articles/10.1186/gb-2013-14-10-r115
[7] https://www.nature.com/articles/ncb1664
[8] https://pubmed.ncbi.nlm.nih.gov/18391173/
[9] https://www.nature.com/articles/s41467-019-12664-x
[10] https://www.nature.com/articles/nature20095
[11] https://www.annualreviews.org/doi/abs/10.1146/annurev-biochem-103019-102815
