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Recent Insight into the Processes of Rejuvenation that Act to Ensure the Offspring of Adult Parents are Born Young

Parents and their germline cells are biologically old, and yet developing offspring produced from the germline are biologically young. Therefore a form of cellular rejuvenation takes place somewhere between the start and the end of reproduction in multicellular organisms, whether they are nematode worms of a few hundred cells, or vastly larger and more complex species such as our own. New research on this topic from the usually secretive research groups at Calico was widely announced today; it is focused on the nematode Caenorhabditis elegans, but the findings are probably of relevance to the processes of rejuvenation that take place in mammalian reproduction. Aging is a matter of accumulated damage, of quite similar forms in nematodes and mammals: to make offspring young, all of this damage must be cleared away, or the germline shielded from it.

The rejuvenation that occurs in mammalian zygotes is not all that well characterized, though you'll find papers on the topic from recent years. It appears to overlap with processes observed to take place when cells are reprogrammed into a state of induced pluripotency: researchers have seen mitochondrial damage repaired, for example. This present work in nematodes is interesting for its focus on the lysosome and clearance of metabolic waste, as there isn't all that much work on what happens to such waste during induced pluripotency or in early mammalian embryonic development. Clearly it has to be successfully removed if present in order for offspring to be young, but this doesn't necessarily mean that the various mammalian processes of rejuvenation are anything like those of nematodes in their details and ordering, even if there are strong similarities at the high level.

The research here is intriguing for extending the findings in nematodes to frogs - give it a few years and we'll no doubt be seeing the study results for mammals. In mammals, early life rejuvenation must accomplish the same goal as it does in frogs and nematodes, regardless of how it is organized, which is to ensure that offspring are biologically young. Further, it must take place when those offspring are still a collection of just a few cells, as these processes would be highly disruptive and probably fatal if they took place throughout a more developed, complex organism. But perhaps such processes of rejuvenation could be selectively targeted to small and vital collections of cells. Perhaps it already takes place in some such cell populations as a way to maintain their function for a lifetime; consider stem cells, for example. This remains to be seen, as does how useful the rejuvenation processes that make offspring young might be as a starting point for the construction of therapies to slow aging.

Young Again: How One Cell Turns Back Time

None of us was made from scratch. Every human being develops from the fusion of two cells, an egg and a sperm, that are the descendants of other cells. The lineage of cells that joins one generation to the next - called the germline - is, in a sense, immortal. Over time, a cell's proteins become deformed and clump together. When cells divide, they pass that damage to their descendants. Over millions of years, the germline ought to become too devastated to produce healthy new life. "You take humans - they age two, three or four decades, and then they have a baby that's brand new. There's some interesting biology there we just don't understand."

Researchers have now reported the discovery of one way in which the germline stays young. Right before an egg is fertilized, it is swept clean of deformed proteins in a dramatic burst of housecleaning. The researchers discovered this process by studying a tiny worm called Caenorhabditis elegans. Most C. elegans are hermaphrodites, producing both eggs and sperm. As the eggs mature, they travel down a tube, at the end of which they encounter sperm. Researchers discovered that a worm's eggs carry a surprisingly heavy burden of damaged proteins, even more than in the surrounding cells. But in eggs that were nearing the worm's sperm, the researchers found far less damage. These experiments raised the possibility that the sperm were sending out a signal that somehow prompted the eggs to rid themselves of damaged proteins.

The researchers then created mutant "female" worms and observed that their eggs all became littered with protein clumps. When the researchers let them mate with males, however, the clumps disappeared from the eggs. They then carried out additional studies, such as looking for other mutant worms that could not clear out protein clumps even though they could make sperm. Combining these findings, the researchers worked out the chain of events by which the eggs rejuvenate themselves.

It begins with a chemical signal released by the sperm, which triggers drastic changes in the egg. The protein clumps within the egg "start to dance around." The clumps come into contact with little bubbles called lysosomes, which extend fingerlike projections that pull the clumps inside. The sperm signal causes the lysosomes to become acidic. That change switches on the enzymes inside the lysosomes, allowing them to swiftly shred the clumps. Researchers hypothesize that the worms normally keep their eggs in a dormant state. The eggs accumulate a lot of damage, but make little effort to repair it. Only in the last minutes before fertilization do they destroy protein clumps and damaged proteins, so that their offspring won't inherit that burden.

"The hypothesis is that it's not just a worm thing." In their new paper, the researchers reported that they had tested this hypothesis on frogs, which are much more closely related to humans than is C. elegans. The scientists exposed frog eggs to a hormone that signals them to mature. The lysosomes in the frog eggs became acidic, just as happens in worms. The germline may not be the only place where cells restore themselves in this way. Throughout our lives, we maintain a supply of stem cells that can rejuvenate our skin, guts and brains. It may be that stem cells also use lysosomes to eradicate damaged proteins. It might be possible, for example, to treat diseases by giving aging tissues a signal to clean house.

A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage

Although individuals age and die with time, an animal species can continue indefinitely, because of its immortal germ-cell lineage. How the germline avoids transmitting damage from one generation to the next remains a fundamental question in biology. Here we identify a lysosomal switch that enhances germline proteostasis before fertilization. We find that Caenorhabditis elegans oocytes whose maturation is arrested by the absence of sperm exhibit hallmarks of proteostasis collapse, including protein aggregation. 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 lysosomes. Sperm stimulate V-ATPase activity in oocytes by signalling the degradation of GLD-1, a translational repressor 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. Lysosome acidification also occurs during Xenopus oocyte maturation; thus, a lysosomal switch that enhances oocyte proteostasis in anticipation of fertilization may be conserved in other species.

Comments

Mmm this doesn't explain how eggs clean lipofuscin and other indigestible junk. Or is lipofuscin actually digestible after all?

Posted by: Antonio at November 23rd, 2017 2:23 AM

@Antonio - Stand back and look the bigger systems picture

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 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 aftre their discovery

Posted by: Ira S. Pastor at November 23rd, 2017 5:54 AM

Ira: Thanks, but that doesn't answer my question. According to SENS, the body doesn't have enzymes to break lipofuscin, and thus it accumulates in the cells. So, since newborns barely have lipofuscin, the germline must get rid of it somehow. If it can't be broken, then the egg must expel it or dilute it (by previous mitosis/meiosis). I'm wondering whether this paper opens the possibility that eggs do have the neccesary enzymes to break it, contrary to what was thought. That would be a big change to SENS.

Posted by: Antonio at November 23rd, 2017 6:51 AM

Quite a remarkable paper. And striking that Kenyon's group seems to be pursuing a damage removal (mitochondrial QC and protein aggregate clearance) strategy to treating aging.

It will be interesting to see if they can apply this method to (Human) aged somatic cells, iPSCs would suggest they can.

Posted by: Mark at November 23rd, 2017 7:07 AM

@Antonio

I don't know much about the oocyte or early embryo as it pertains to the dynamics of how they deal with getting rid of lipofuscin, but there are some papers (a few quite old) that exist in the literature in terms of what happens when things go awry -

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3455008/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943237/

https://www.ncbi.nlm.nih.gov/pubmed/899509

But suffice it to say that the dilution / elimination dyanmics will be very useful in developing alternatives to looking for small molecule scavengers of it

Posted by: Ira S. Pastor at November 23rd, 2017 7:14 AM

@Mark - not quite what some of us thought Calico were engaged in, i.e. more tinkering with metabolism to extend healthspan. This seems much more fundamental, if a long way from application. I did note how many times "repair" and "damage" were mentioned in the reporting.

Posted by: TheRage at November 23rd, 2017 8:35 AM

This also suggests that maintaining mitochondria in a fissioned state is sufficient to maintain their quality.

Posted by: Mark at November 23rd, 2017 8:41 AM

Its amazing how thousands of single-celled organisms manage to get rid of all their waste products and damaged internal organelles. I don't suppose that problem is so much different for sperm and eggs, which are also single-celled. Pretty amazing in any case.

Posted by: Biotechy at November 23rd, 2017 9:47 AM

This is intriguing...

This explains a few things.

-Aubrey's new role at AgeX. We suspected they were on to something, and now we know.
-George Church's confidence in his timelines
-Calico's secrecy. They know they aren't the only ones chasing this down (The race is on now, whoever develops this first will be richer than God).

This looks like a POWERFUL tool. But I think Aubrey is right on this... it might not fix everything, and we should still be researching other areas.

This also explains why George Church has said that the main issue with this technique is cell-targeting. I'm betting that's why Aubrey is at AgeX. He has a knack for thinking outside the box. His role is "VP of New Technology Discovery", a lot of that is going to be finding new targeting methods. I wonder if Ichor has something that can help.

Anyway, this is good news to see this method has promise. Once again, in a round-about way, Aubrey is vindicated yet AGAIN. It is about damage repair. But if we can coax our own cells to repair the body, we may have a shorter path to rejuvenation.

Posted by: Mark Borbely at November 23rd, 2017 10:06 AM

@Biotechy: They don't get rid of it. They push it onto one of the daughter cells, effectively a form of dilution.

Posted by: Reason at November 23rd, 2017 11:44 AM

Ira, Antonio: to be clear, the material cleared from these embryos is not lipofuscin, nor any other kind of "damage" in the strict SENS sense, but carbonylated proteins. They're quite easy to eliminate once the lysosome gets a hold of them: the oocytes just literally weren't bothering to clear them out until there was good reason to do so, possibly to conserve energy. Under basal conditions, the oocytes don't acidify their lysosomes (which is an ATP-consuming process) nor take up the aggregates (in a previously-unseen active lysosomal process that doesn't engage the macroautophagy machinery) until they are in close proximity to a sperm, at which point they "wake up" and clean house, just in time for The Big Moment.

Linking the quality-control switch to oocyte maturation may be biologically cost-effective. Otherwise, it would be energetically demanding for oocytes to continuously cleanse themselves of damage while 'waiting' for fertilization, especially in species in which oocytes remain dormant for long periods. ... We note that an initial relaxation of proteostasis may actively promote germline quality control, as driving damaged proteins into aggregates may facilitate their removal. In addition, consumption of aggregates could potentially help to provide raw materials to developing oocytes.

The analogy to aging is, then, a stretch: this is an unusual form of harmless self-restraint - a kind of "don't fire until you see the whites of their eyes." But they don't suddenly acquire some special ability to degrade the kinds of recalcitrant aggregates that accumulate in aging tissues.

Posted by: Michael at November 23rd, 2017 1:55 PM

.... accordingly, Mark, I don't see way to exploit this for combating aging, even if one is inclined toward messsing with metabolism as an approach to such problems.

Posted by: Michael at November 23rd, 2017 1:58 PM

Thanks Michael for your reply!

Posted by: Antonio at November 23rd, 2017 2:25 PM

Hi there ! Incredible study.

This is the kind of rejuvenation we are talking about, true biorejuvenation in the real sense, biogolical reversal to a young state. I think there is strong potential there, a la iPSCs like methods. I'm not surprised that this rejuvenation was all around specific areas like lysosomes and proteasome (where the accumulated damage residues stay). Clearing the junk is more important than we thought. Especially, protein aggregates, which have truly detrimental effect of lifespan, avg lifespan and maximal lifespan. That tells me they are onto something. SENS removal of lipofuscin with bacterial enzymes in nanorobots targeted capsules to lysosomes would only combine with this to make a total reversal of cell age. The fact that it aging can be reversed (through this way) by clearing out the crap, is a testament that aging can be Reversed not just slowed if only we can clear most types of damages. I would even say, thus, Death can be Cured from these results, it is promising. Protein aggregation and carbonylation and unfolding is incompatible with lifespan along with proteostasis loss. It is also why HSPs, HSF-1, LAMP and other lysosomal/proteasomal chaperones are so important for the maintain it in cleaned condition. Plus HSPs levels equals MLSP in mammals. And the protein aggregates and/or carbonyls have about the strongest effect on lifespan, which makes them target areas for rejuvenation. Until we can fix the lipofuscin, transthyretin, drusen, ceroid, tau,pigment crap etc problems. Mice experience protein aggregation extremely rapidly, while long lived rodents (like NMRs) don't. Same thing for dementia, mental degenerescence and alzh/park/huntin all have protein aggregations, or as they say 'we saw protein clumps/clumping'. Protein clumping = fatal. While the long-livest animal on earth (clam of 5 centuries), has little to no aggregation - yet experiences oxidative stress - but is oxidative stress resistant. But that'S just the tip of the iceberge; it maintains proteostasis by not accumulating protein aggregates/unfold proteins. HSPs damgaged protein folding/Refolding is extremely important. Maintaining a Continued Proteasome function, Lysosome function are Crucial; that means stopping protein aggregation while lipofuscine would be diluted somehow through cell cycling/mother to daughter cell dumping. I don't know how they will direct the Older cells to 'commit' to this big clean up (since it requires high energy ATP), if it even possible. But they found something Very powerful and could be a true rejuvenation allowing repeated age reversal by this cell clean-up; which would be amounting to eternal life. I agree that our body has the capability of removing/repairing nearly everything we just need to 'tell it' to do so just like at szygote/sperm/germline/egg stage (with advancing age). What I just hope is that this does not slip through the cracks (like so many study results) and ends up accumulating dust (like so many 'new discoveries')); there has to be a follow up and the community/large science bodies must act on it. I fear that this will just be 'another' story among calorie mimetics and 'lose weight fast' method...forgotten. Just a 2 cent.

Posted by: CANanonymity at November 23rd, 2017 3:23 PM

PS:

DAF-16 CR and HSPs -> lysosome acidification (- pH) -> vATPase-lysosome activated macroautophagy/degradation of protein aggregates -> lifespan extension

Azh/park/huntin/aging -> incomplete lysosome acidification/lysomembrane permeabilization/defective HSPs -> dysfunctional atutophagy, accumulation of protein aggregates /amyloid/pigments/clumps -> lifespan shortening

In a study below (4.) proteasome dysfunction is compensated through an autophagy-lysosome pathway; demonstrating that autophagy and the lysosomes (degrading the aggregate proteins) are at the heart of it.

'' Here, we demonstrate that loss-of-function mutants of the Caenorhabditis elegans proteasome subunit, RPN-10, exhibit moderate proteasome dysfunction and unexpectedly develop both increased longevity and enhanced resistance to multiple threats to the proteome, including heat, oxidative stress, and the ***presence of aggregation prone proteins***...
Consistent with a critical role for this pathway, the ***enhanced resistance of the rpn-10 mutant to aggregation prone proteins depends on autophagy genes atg-13, atg-16.2, and prmt-1.***''

Regulation of Lysosomal Function by the DAF-16 Forkhead Transcription Factor Couples Reproduction to Aging in Caenorhabditis elegans
1. http://www.genetics.org/content/207/1/83

Heat Shock Protein 70 Promotes Cell Survival by Inhibiting Lysosomal Membrane Permeabilization
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211935/

Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans
3. https://www.nature.com/articles/ncomms14337

Graded Proteasome Dysfunction in Caenorhabditis elegans Activates an Adaptive Response Involving the Conserved SKN-1 and ELT-2 Transcription Factors and the Autophagy-Lysosome Pathway
4.http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005823

Posted by: CANanonymity at November 23rd, 2017 4:20 PM

Heat Shock Protein 70 is a protein folding chaperone that is important in maintaining the integrity of proteins in aging. The important SNP goes under the gene HSPAIL rs2227956 AA. The A allele is a longevity allele and thankfully I am homozygous for, as are the 114 year old man and woman whose DNA was analyzed in a longevity study be Sebastiani in 2012 titled Whole genome Sequences of a male and female supercentenarians greater than 114 years old. About 50% of Caucasians are homozygous for the AA allele.

Posted by: Biotechy at November 23rd, 2017 5:17 PM

If lipofuscin can only be dealt with through dilution, as Reason and Michael suggest, then we should be able to see evidence of this by comparing proliferating and quiescent iPSCs generated from old or senescent human cells. Has anyone done thus experiment?

Posted by: Mark at November 24th, 2017 2:30 AM

@Mark

The answers may not just be in the cell reprogramming dynamics, but more importantly in how the developing groups of cells undergo their respective cooperative dynamics to remove what will be detrimental / useless to the embryo

https://www.nature.com/articles/ncomms11165

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714589/

https://academic.oup.com/humrep/article/17/3/760/642328

It is in studying these tiered physiologic dynamics that a more complete picture will be found where interventions can be developed

I am a big fan of the Levin group at Tufts; one of the leading labs on integrating these different tiers of biological control

https://ase.tufts.edu/biology/labs/levin/research/newdirections.htm

Posted by: Ira S. Pastor at November 24th, 2017 7:01 AM

So the eggs clear aggregates, yes... Part of me worries, however, that the aggregates being cleared are the 'easy ones' which the body already knows how to control.

Posted by: Patrick Deane at November 28th, 2017 9:03 AM

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