Parabiosis Research Identifies β-catenin as a Target to Rejuvenate Bone Healing

Heterochronic parabiosis has become a growing line of research these past few years. It involves connecting the circulatory systems of two individuals, such as two laboratory mice, of different ages. Researchers have shown that the old mouse of the pair regains somewhat more youthful characteristics in stem cell activity, healing, neurogenesis, cardiac health and other aspects linked to tissue maintenance. It doesn't turn back the clock by more than a fraction, but the benefits are large enough in comparison to what can be achieved via other avenues in medical science for researchers to investigate further. An outcome of partial rejuvenation of function during parabiosis must be triggered by a different balance of factors that is present in youthful blood versus aged blood. Thus researchers conclude that some fraction of the decline in tissue maintenance and diminished stem cell activity that occurs in aging has signaling changes in the tissue environment as its proximate cause. The next logical path of action for the mainstream research community is to undertake a drug discovery program, aiming for treatments that can override age-related changes in signaling to at least some degree, and with minimal side-effects.

These age-related changes in the amount or type of proteins present in circulating blood are not a root cause. They are themselves most likely a reaction to the accumulating cellular and tissue damage that drives degenerative aging. So it is worth bearing in mind that any treatment focused on spurring greater stem cell activity by overriding the natural aged signaling balance is essentially a matter of pushing the accelerator on a damaged engine. These and other related studies in mice have not yet seen the potential threat of cancer that would be expected to arise from greater activity undertaken by damaged cells, but caution is still merited. It may well be the case that the evolved balance of stem cell decline is far from optimal, and researchers could turn the dial a way without producing a high risk of cancer or other issues as a result. The fastest way to find out is to try. Equally it would be nice to see more attention given to repairing the damage that causes aging rather than trying to compensate for the consequences one layer up while ignoring the damage entirely.

Researchers have recently reported another potential success for heterchronic parabiosis, claiming the identification of β-catenin signalling as important in age-related decline of bone regeneration. Note that while the popular press is focusing on the parabiosis portion of the research, the scientists involved also produced the same benefits with a more conventional transplant of young cells into an old individual. Given the recent news about GDF-11, however, it might be worth waiting a couple of years for firm confirmation and clarification of the mechanism involved before celebrating this advance.

Old Bones Can Regain Youthful Healing Power

Broken bones in older people are notoriously slow to heal. In studies using mice, researchers not only traced what signals go wrong when aged bones heal improperly, they also successfully manipulated the process by both circulating blood and transplanting bone marrow from a young mouse into an older mouse, prompting the bones to heal faster and better. The work builds on earlier research which identified an important role for a protein called beta-catenin in the healing process. The protein requires precise modulation for successful bone fracture repair. In older people, beta-catenin levels are elevated during the early phases of bone repair, leading to the production of tissue that is more like scar than bone, which is not good for bone healing.

Using mice as a surrogate for humans, the researchers found that they could manipulate beta-catenin levels by exposing older animals to the blood circulation of younger animals, essentially correcting the intricate formula necessary for healthy bone repair. "It's not that bone cells can't heal as efficiently as we age, but that they actually can heal if they are given the right cues from their environment. It's a matter of identifying the right pathway to target, and that's what's exciting about this work. The next steps are to figure out what's making beta-catenin go up in older adults, so that we can target that cause, and to explore drugs that can be used in patients to change beta-catenin levels safely and effectively."

Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin

The capacity for tissues to repair and regenerate diminishes with age. We sought to determine the age-dependent contribution of native mesenchymal cells and circulating factors on in vivo bone repair. Here we show that exposure to youthful circulation by heterochronic parabiosis reverses the aged fracture repair phenotype and the diminished osteoblastic differentiation capacity of old animals.

This rejuvenation effect is recapitulated by engraftment of young haematopoietic cells into old animals. During rejuvenation, β-catenin signalling, a pathway important in osteoblast differentiation, is modulated in the early repair process and required for rejuvenation of the aged phenotype. Temporal reduction of β-catenin signalling during early fracture repair improves bone healing in old mice. Our data indicate that young haematopoietic cells have the capacity to rejuvenate bone repair and this is mediated at least in part through β-catenin, raising the possibility that agents that modulate β-catenin can improve the pace or quality of fracture repair in the ageing population.

Comments

Reason, you remind us that this stuff isn't real repair and replacement on every post, but it's really starting to look like chemically simulating the youthful environment is a simple, logical, life-extending precursor to actually creating one.

They say it themselves: "The next steps are to figure out what's making beta-catenin go up in older adults, so that we can target that cause"

Posted by: Slicer at May 20th, 2015 9:55 PM

Agreed slicer and it is rejuvenation as its restores the aged phenotype and brings dormant stem cells back online. It's not total repair of all the damage but it is repair. This is why I think gene therapy will pay off because it can target the same pathways.

Posted by: steve h at May 21st, 2015 12:16 AM

"They say it themselves: "The next steps are to figure out what's making beta-catenin go up in older adults, so that we can target that cause""

Slicer, that is basically messing up with metabolism.

Posted by: Antonio at May 21st, 2015 12:56 AM

They are following it upstream to try to tackle the root cause. I have seen the phrase "messing with metabolism" used a lot and yet it does produce results and it does rejuvenate. Restoring the aged phenotype leads to resumption of Stem cell activity, this leads to restoration of tissue and function and in at least one study has been shown to restore Telomeres as well. I would say that is rejuvention in my book.

Also SENS does fund work by Irina Conboy who is one of the primary investigators "messing about with metabolism" so I would be interested to hear what ADG makes of it and if he considers it rejuvenation at any level. I admit I am not a scientist just a layman but clearly pathways can and do repair some damage of aging.

And yes it does not address all the damage types but other technology is being developed that does. So is investigating signalling really as much of a red herring as thought or is the amount of knowledge people like Irina and Michael building up leading to something we can use?

Posted by: Steve H at May 21st, 2015 3:28 AM

"have seen the phrase "messing with metabolism" used a lot and yet it does produce results and it does rejuvenate."

AFAIK, there is no working rejuvenation/LE treatment for humans yet (or primates). CR improves some health biomarkers, but there is no proof of rejuvenation yet.

Posted by: Antonio at May 21st, 2015 3:45 AM

Rejuvenation of the Systemic Environment is the project and appears in the 2014 SENSRF newsletter.

"Additionally, the team will
perform in vivo imaging of aged mice exposed continuously
to young plasma using one of two advanced new
imaging platforms to ongoingly monitor the effects of
interventions, giving scientists the first opportunity to
witness tissues being progressively rejuvenated in vivo.
And along with their mouse work, the Berkeley group
will be performing a pilot experiment examining proteins
present in plasma from young and old humans, to
explore translatability and identify important components
of the plasma that either help or impede
rejuvenation of old organs and systems."

Sounds like SENS is interested in this too but how does it fit into the SENS strategy/model for aging? Genuinely curious about this.

Posted by: Steve H at May 21st, 2015 3:45 AM

@ Antonio no rejuvenation in humans no you are correct but that would be because it has not been tried in humans yet (besides Alkahest who are doing so now).

However there is evidence that signals can and do rescue the aged phenotype, can even repair the ECM and all kinds of rejuvenation has been demonstrated.

Even Androgens in the blood have been demonstrated to increase Telomerase expression and lengthen Telomeres so there is without a doubt power in the factors. Of course the complexity is in working out those factors and balances but if anyone can do it it's Irina and Michael.

Posted by: Steve H at May 21st, 2015 3:49 AM

PS I hope I am not coming across as having a go at SENS but I am somewhat confused on what I see a contradiction of it being messing about with metabolism on one hand and on the other supporting research into the very same messing about with metabolism. Mixed signals for me, no pun intended :)

Posted by: Steve H at May 21st, 2015 3:53 AM

Hello everyone - my attention was just drawn to this thread. Quite right - the relationship to SENS is not obvious. It is as follows:

1) Changes with age to the circulation occur as a result of changes that are within the seven SENS strands, because the circulation is after all only a highway between places.

2) The beneficial effects of heterochronic parabiosis, plasma exchange and also transplant experiments show that some parts of the body transmit aging effects to other parts that would not otherwise age so severely.

3) Therefore, we may end up having less work to do with SENS than one might think (not fewer strands, but fewer examples within some of the strands, especially cell loss) if we can elucidate which tissues are the key culprits, and rejuvenate those, and thus rejuvenate the blood stream.

4) More exploration using parabiosis etc is a really promising way to achieve that elucidation. We don't propose that parabiosis (or even plasma exchange) would be a SENS therapy in the long run.

I hope this clarifies the matter somewhat.

Posted by: Aubrey de Grey at May 21st, 2015 5:42 AM

Perfect thanks Aubrey that really clears it up.

Just to clarify about point 2 by transmit aging effects to other parts assume you mean things like the endocrine secretions and things like SASP?

To address point 3 I would suggest the first port of call would be the Endocrine system eg, spleen, Pancreas, Hypothalamus, thymus, and Thyroid etc... these areas seem to be key based on the parabiosis and HPE studies I have read. Once they age they start sending out the aging signals to the rest of the body. One of these is GDF-11 which is Miyostatin and could contribute to the muscle wastage we see with age. Just a thought anyway I am just a layman.

But thank you very much for the clarification on this I was struggling to see how it fitted into the SENS strategy.

Posted by: Steve H at May 21st, 2015 6:30 AM

"The next logical path of action for the mainstream research community is to undertake a drug discovery program, aiming for treatments that can override age-related changes in signaling to at least some degree, and with minimal side-effects." NO. This was the first logical path - and one totally missed. Researchers have pissed away decades of time and resources researching the symptoms of the genetic default (signaling) process that begins with sexual maturity - rather than the genetic default and signaling processes themselves. The current logical path would be seek to control default genetic codes that produce the cascade of aging symptoms.

Posted by: Mason Hamilton at May 24th, 2015 8:18 AM

Agreed with above poster. Dr Fossel believes an upstream point of intervention are the telomeres which regulate gene expression via the postioning effect. I think he is right that if we change telomeres we can make epigenetic changes to the cell age phenotype.this has been demonstrated in various studies to be the case. About time we tested it and Dr fosell plans to do so.

Posted by: steve h at May 25th, 2015 2:01 AM

The main drawback of parabiosis-the ageing young animal. The aging factors are in the General circulation. You want to filter old blood and to remove these substances. There is also a natural filter of the placenta. Pregnancy is the parabiosis. If you connect the vessels coming from the fetus to the pregnant woman (old) female, rejuvenating factors will directly get into the bloodstream of the mother. This "ideal" experiment preclude the aging of the young organism.

Posted by: Anatolij at January 31st, 2016 11:35 PM

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