On the Aging of the Germline and Rejuvenation in Embryos

It is clearly the case that cells and tissues are in principle capable of rejuvenation. Individuals age, but their offspring are born young. The germline in adults is protected in comparison to other cell populations, but it nonetheless accumulates forms of stochastic damage over time. Yet that damage is not apparent by the time later stage embryonic development takes place. Somewhere between conception and that later stage of embryonic development, a form of rejuvenation takes place.

The authors of today's open access paper consider this topic in some detail, and the relevance it might have to future efforts to produce rejuvenation therapies. In recent years, scientists have become interested how and why reprogramming cells into induced pluripotent stem cells turns out to mirror much of what takes place in the developing embryo. Many of the marks of age are removed, and cells are rejuvenated.

An unexpected development in this field of research is that reprogramming cells in vivo appears to be beneficial, rather than very disruptive to tissue structure and function, and this approach is consequently now under development as a form of rejuvenation therapy. This makes it much more interesting to better understand exactly what is going on in the developing embryo.

The Ground Zero of Organismal Life and Aging

One of most profound revelations of recent advances in science is that biological systems can be completely rejuvenated. Indeed, just a few years ago, reversing the deleterious changes that accumulate with age in their entirety was simply unimaginable. Yet, we now know that this is possible, whether we consider the conversion of somatic cells to induced pluripotent stem cells (iPSCs) or the natural reversal of age of the germline with each generation. These two processes converge somewhere during early development at the point here proposed to be termed the 'ground zero.' It is here that both organismal life and aging begin.

It is often discussed that, because the germline is immortal, it does not age; this notion dates to the 19th century, when August Weismann proposed the separation of ageless germline and aging body. However, at the time of conception, the contributing human germline has typically been maintained in a metabolically active state for two or more decades and must have accumulated damage, such as metabolic by-products, epimutations, and modified irreplaceable proteins. In other words, it has become biologically older than its earlier, embryonic state.

Although the germline biological age at the time of conception is expected to be much younger than that of somatic tissues of the same organism, and although some of the accumulated damage may be removed by designated molecular systems, rejuvenation in the prezygotic state could only be partial because, in the absence of cell division (as in the oocyte), there are always more damage forms than the means of protecting against them. Also, although some germ cells may accumulate more damage than others and therefore may lead to early mortality and abnormalities in the offspring (this damage will also increase with the age of the host), all germ cells unavoidably accumulate some damage. Thus, for the new life to begin in the same young state as in the previous generation, the zygote must somehow remove this damage and decrease its biological age to the level of the germline age in the previous generation. In other words, it appears that the germline ages during development and adult life, and then it is rejuvenated in the offspring after conception.

All this leads to a model wherein early embryos are gradually rejuvenated, for example, by extending their telomeres, erasing epigenetic marks, and clearing up and diluting molecular damage, and this continues up to a particular time during early development. Conception represents a starting point for this process, culminating in the state of the lowest biological age, the ground zero of organismal life and aging. In effect, the period from conception to this stage may be viewed as a preparatory stage, which is associated with damage clearance and rejuvenation, for subsequent development of the organism.

The ground zero model extends and modifies Weismann's notion of heritable immortal germline and noninheritable aging body by positing that (i) both body and germline can age; (ii) both body and germline can be rejuvenated; (iii) body and germline can be brought to a common state characterized by the lowest biological age, ground zero; and (iv) age can be reversed without the need to have a separate body and germline. The proposed model is currently based on in vitro experiments and application of epigenetic and other clocks to assess biological age and should be extended to experimental organismal biology. Understanding the nature and mechanisms of rejuvenation, defining the exact point of ground zero, and discovering ways to manipulate the lowest age may provide opportunities for dramatic advances in human biology and medicine

Comments

@Reason or anybody. If germline cells "accumulates forms of stochastic damage over time", and the cell cannot revert some forms of damage (like mitochondrial disfunction or intracellular agregates), how can it be young again in the embryo? Thanks

Posted by: Josep at October 2nd, 2020 4:21 AM

@Josep

Below are some links to nice reviews on the general theme of regenerative micro-environments (embryonic, epimorphic, and symplasmic) and their ability to organize in / out, and well as modify the diseased phenotype

As a subset of this re-organization theme, there are also some papers on the topics of revertant mosaicism (primarily seen in tissues with an active regenerative niche) and cellular competition (seen in both development and the maintenance of tissue fitness)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706275/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735296/pdf/v040p00721.pdf

http://jcb.rupress.org/content/200/6/689.full

The seminal work on embryos and teratocarcinoma was done by Mintz et al in Philadelphia in the 1970s:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC433040/

Similar dynamics also occur in the plant kingdom:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC335936/

The baseline summary is these micro-environments have a lot to teach us about rejuvenation

Posted by: Ira S. Pastor at October 2nd, 2020 8:34 AM

Ok Thanks Ira! I'll take a look

Posted by: Josep at October 2nd, 2020 11:20 AM

Cynthia Kenyon wrote a paper on a similar topic. Before fertilization lysosomes in egg cells acidify and clear cellular debris to reset proteostasis.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936623/ - A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage

... "Remarkably, sperm-secreted hormones re-establish oocyte proteostasis once fertilization becomes imminent. Key to this restoration is activation of the vacuolar H+-ATPase (V-ATPase), a proton pump that acidifies lysosomes3. Sperm stimulate V-ATPase activity in oocytes by signalling the degradation of GLD-1, a translational repressor4 that blocks V-ATPase synthesis. Activated lysosomes, in turn, promote a metabolic shift that mobilizes protein aggregates for degradation, and reset proteostasis by enveloping and clearing the aggregates."

Posted by: Benas at October 7th, 2020 7:50 AM

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