The SENS Research Foundation Comments on Calico's Research into Apparent Rejuvenation in Oocytes

The normally secretive California Life Company, or Calico, recently shared some of their investigations into the rejuvenation that takes place in the earliest stages of the reproductive process - parents are old and children are young, so a form of rejuvenation must happen at some point, or reproductive cells must be exceptionally well protected from aging. The Calico team showed that in nematodes and frogs, egg cells, or oocytes, undergo a burst of cellular housekeeping when they are used, clearing out damaged proteins. It is thought that something similar happens in mammalian early embryonic development, a process that also seems to be triggered in part by induced pluripotency. Is this all useful and relevant to efforts to produce rejuvenation therapies? Here is a lengthy commentary from the SENS Research Foundation, whose founder has been one of a number of researchers very critical of Calico Labs in the past:

Some readers got the impression that this study had uncovered a special molecular mechanism that allows these nematodes' oocytes uniquely to stay "young," even as the body as a whole grew old. This impression may have been reinforced by a quote from one researcher, contrasting the aging of the human body with the (seeming) "immortality" of the germline (the "line" of sperm and egg genes that actually passes from generation to generation): "You take humans - they age two, three or four decades, and then they have a baby that's brand new."

Taken together, some readers came away with the suggestion that the fact that babies are born young implies the ability of oocytes to "sweep themselves clean" of their adult parents' lifetime burden of deformed proteins, and excitedly hoped that the tricks that oocytes use to execute this feat could somehow be engineered into aging cells elsewhere in the body to keep our muscle and brain cells young. Unfortunately, no such tricks emerged from this study, nor are they likely to. This study adds substantial insight to a body of work on nematode (and later frog) oocyte biology sparked by a discovery made by French scientists in 2010 and prior work in yeast and in mouse embryos. However, there is nothing here that can be exploited for developing anti-aging therapies.

The real finding of the paper is better captured by its own title than the newspaper headlines: "A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage." The key word in there is not "immortal," but "renewal" - renewal of "proteostasis," the somewhat equivocal concept of the young cell's dynamic maintenance of stably low levels of damaged proteins. As it turns out, the "renewal" in question is a reactivation of the normal "proteostatic" activity of the lysosome - the cell's recycling center, where old and damaged proteins are broken down into raw materials that can then be reused to build new proteins.

While oocytes are held in storage, they adopt a metabolically dormant state to conserve energy and reduce the production of metabolic wastes. This much is just as true in mammals as it is in the roundworms and frogs studied in this new report. What the new study uncovered is a particular energy-conservation strategy these animals' oocytes use. No special rejuvenative power is involved in this process: other cells clean up these same wastes routinely, as a matter of day-to-day housekeeping, instead of letting them build up until it's absolutely necessary to get rid of them.

Despite the lengths to which the body goes to maintain only viable, "young" eggs, oocytes do still manage to degenerate with age, which is part of the reason why older parents are less fertile. The silver lining in all of this bad news: because the nature of the degenerative aging process in the reproductive system is not different from the aging of the rest of the body at the cellular and molecular level, the "damage-repair" heuristic of rejuvenation biotechnology can be applied to rejuvenate the aging reproductive system just as it can to the rejuvenation of the rest of our bodies.

We're not going to solve the degenerative aging process by borrowing any special tricks from the oocyte. The oocyte doesn't really have any tricks for us to profitably exploit - and more importantly, no cell in the body is naturally able to remove or repair many of the kinds of damage that accumulate in aging bodies and ultimately lead to age-related disease, debility, and death. The oocyte has no way to clear beta-amyloid from aging brains, or TTR amyloid from aging hearts - nor to cleave AGE crosslinks from aging arteries, as they are subject to none of this damage. It has no internal means to replace cells that are lost to aging damage, and is no more able to degrade the truly stubborn intracellular aggregates that accumulate in aging cells than any other cell type. For that, we need a new class of medicines that can do what we can't do on our own: remove, repair, replace, or render harmless the cellular and molecular damage of aging in our tissues. It is when we develop rejuvenation biotechnologies and deploy them comprehensively that we will finally be able to effectively "turn back time" for aging bodies as a whole.

Link: http://www.sens.org/research/research-blog/question-month-16-any-rejuvenation-relevance-roundworm-reproduction

Comments

The interesting point for me was that oocytes do not experience certain kinds of damage. On the other hand they and sperm cells do experience some aging and all of this is effectively cleared out during the process of conception. So I'm still not convinced there is nothing to be learned from this. In addition, immortalized human cell lines seem to live up to their name. Again, I can see the argument that cell lines may not be subject to some forms of damage that occurs in vivo. Still I would like to know what forms of damage they are and are not susceptible to before I conclude the mechanisms they do employ would not be useful in application to real aging.

Posted by: gabor at December 14th, 2017 12:10 PM

I think the idea is not that there is nothing to learn from Oocyte damage. But that the damage that occurs to Oocytes is the same damage that occurs to the fully developed body and that there is nothing special or unique about the damage that occurs to the Oocytes.

Posted by: Abelard Lindsey at December 14th, 2017 1:34 PM

As mentioned in a previous post, the oocyte and early embryo have a lot more to contend with than realized - oxidation, inflammation, infectous insults, senescent cell dynamics in patterning, DNA repair, etc. to name a few

But more / very important to the task at hand, are the dynamics occuring at the tissue remodeling level, (i.e. the inherent ability of these multi-cellular niches to organize in "the good" / and out "the bad"), which this type of work in another example of.

This type of work, and other historial precendents, are important to incorporate into a complete model of rejuvenataion

As previously mentioned:

The seminal work on embryonic fields and teratocarcinoma normalization was done by Mintz et al at U-Penn back in the 1970s:

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

The regenerative biology space is full of related papers on dynamics in blastema fields, and their ability to get rid of "junk tissue insults" of all types:

downloads.hindawi.com/journals/tswj/2010/742904.pdf

Similar dynamics also occur in the plant kingdom in such symplastic fields:

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

Here are also some links to nice reviews on the general theme of regenerative micro-environments and their ability to modify the diseased phenotype, as well as a subset of the tissue re-organization theme, related to 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

http://precedings.nature.com/documents/6045/version/1

Nature and evolution have developed elegent solutions to these issues that are, in our opinion, worthy of re-exploration decades after their discovery

Posted by: Ira S. Pastor at December 14th, 2017 5:18 PM

Then we have to ask; just what the hell is Calico for? Is there something more under the hood of this organization than humdrum basic research?

In which case, why the secrecy around it?

Posted by: James Corbally at December 14th, 2017 6:55 PM

Why is this research being referred to as Calico's research? I don't even see it among their press releases on their website.

https://www.calicolabs.com

Does Cynthia Kenyon work for Calico exclusively? I don't think so.

Posted by: NY2LA at December 14th, 2017 9:33 PM

@NY2LA: The original articles covering it made it clear it was coming out of Calico.

Posted by: Reason at December 15th, 2017 5:23 AM

I remember that there was a thesis from Sweden (I think, at least it was a nordic country; I have read it) about 5-10 years that already demonstrated that a set of transcription factors and genes are extremely active at the blastocyst stage and that it clears the damage of the cells. Isn't it the same thing?

Posted by: edebonneuil at December 16th, 2017 4:21 PM

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