More Evidence for Dilution of Harmful Factors in Aged Blood to be the Primary Mechanism of Parabiosis Benefits

Heterochronic parabiosis is the name given to the linking of circulatory systems between old and young mice. The old mouse benefits, showing signs of rejuvenation of function, while the young mouse suffers early signs of aging. Initially it was argued that beneficial factors in young blood produce this effect, and a number of efforts moved ahead to produce clinical therapies based on this concept. Some companies like Alkahest have trialed plasma transfer from young to old patients, with so far poor results. Others, like Elevian, are focused on specific factors thought to mediate the effects, GDF11 in that case, and appear to be doing better in their preclinical work.

A presently important debate in the research community is whether or not the benefits of parabiosis are mediated by factors in young blood, or whether it is merely a case of diluting bad factors in old blood. Irina Conboy and Michael Conboy put forward a compelling demonstration a few years ago, using much more controlled method of exchanging blood between old and young animals. It provided very strong evidence for the "bad old blood" hypothesis. Yet there continues to be evidence on the other side suggesting that factors in young blood can produce benefits. Parabiosis is an interesting area of research in this sense.

In the open access paper I'll point out today, the Conboys report on their latest demonstration that parabiosis benefits are the result of dilution of harmful factors in old blood. They develop a means of diluting blood in animals without major disruption to metabolism, and show that it produces very similar benefits to a transfer of young blood. This is, again, quite a compelling argument for the primacy of harmful factors in old blood rather than beneficial factors in young blood in the matter of parabiosis.

Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin

Historically, the phenomena of heterochronic parabiosis and blood exchange remained unconfirmed with respect to the key assumption as to whether the addition of young factors is needed for rejuvenation, and if premature aging of young mice stemmed from the introduction of old blood factors or a simple dilution of young factors. To answer these questions in a well-controlled experimental set-up, we took advantage of our recently developed small animal blood exchange model.

Here, using our recently developed small animal blood exchange process, we replaced half of the plasma in mice with saline containing 5% albumin (terming it a "neutral" age blood exchange, NBE) thus diluting the plasma factors and replenishing the albumin that would be diminished if only saline was used. Our data demonstrate that a single NBE suffices to meet or exceed the rejuvenative effects of enhancing muscle repair, reducing liver adiposity and fibrosis, and increasing hippocampal neurogenesis in old mice, all the key outcomes seen after blood heterochronicity.

Comparative proteomic analysis on serum from NBE, and from a similar human clinical procedure of therapeutic plasma exchange (TPE), revealed a molecular re-setting of the systemic signaling milieu, interestingly, elevating the levels of some proteins, which broadly coordinate tissue maintenance and repair and promote immune responses. Moreover, a single TPE yielded functional blood rejuvenation, abrogating the typical old serum inhibition of progenitor cell proliferation. Ectopically added albumin does not seem to be the sole determinant of such rejuvenation, and levels of albumin do not decrease with age nor are increased by NBE/TPE.

A model of action (supported by a large body of published data) is that significant dilution of autoregulatory proteins that crosstalk to multiple signaling pathways (with their own feedback loops) would, through changes in gene expression, have long-lasting molecular and functional effects that are consistent with our observations. This work improves our understanding of the systemic paradigms of multi-tissue rejuvenation and suggest a novel and immediate use of the FDA approved TPE for improving the health and resilience of older people.

Comments

Parabiosys is an extreme change. It is like having an additional young set of many organs. Imagine kidney, liver, bone marrow, thymus and the list can go on. For sure there are some factors . but come on. You can not expect to have a bunch of signaling factors to be as effective as the whole body. The biggest takeaway from parabiosys is that the older organism deteriorates the young so much. Therefore, there are pro inflammatory secretions in the old body, harmful cell lines in the bloodstream, and summiting else that can cause a young body that corner readily handle the metabolic load if it was just the extra size and not the harmful secretions. In a way it is more important to identify those since that they are bad enough to deteriorate a young body.

I wonder if somebody tries parabiosys coupled with Senolytics. It would be interesting to see how the benefit /harm balance will shift if one of the harmful factors cold be eliminated, or at least reduced.

Posted by: Cuberat at June 8th, 2020 9:27 PM

@cuberat
I think you might be missing the importance of this paper. The Conboy's did only one single procedure where they replaced 50% of the plasma in mice. This was not parabiosis. It was
Plasmapheresis .

To me this means that there could be a way to filter our own blood, like dialysis, to remove the harmful contents and return it to the same person. No donor needed.

Posted by: Lee at June 9th, 2020 6:33 AM

If I understand this correctly, does it contradict Katcher or others in claiming to reset the Horvath clock? As opposed to just diluting bad blood?

Posted by: Eighthman at June 9th, 2020 6:51 AM

@Eighthman
This paper did not check the Horvath clock. It does partially contradict Katcher. The main theme of the paper is that the dilution of bad blood is what is important.

"Our data demonstrate that a single NBE suffices to meet or exceed the rejuvenative effects of enhancing muscle repair, reducing liver adiposity and fibrosis, and increasing hippocampal neurogenesis in old mice, all the key outcomes seen after blood heterochronicity."

"This work shifts the paradigm of blood heterochronicity away from dominance of young blood factors and establishes that replacement of a large volume of old blood with a neutral age physiological fluid (saline supplemented with 5% purified albumin), is sufficient for most if not all observed positive effects on muscle, brain and liver."

"This study does not exclude the possibility that factors that are present in young blood, as well as sharing of young organs and environmental enrichment, might also contribute to the rejuvenative effects of heterochronic parabiosis."

Posted by: Lee at June 9th, 2020 9:02 AM

@Lee
For sure reducing the harmful factors helps but it is hard to believe that only neutral dilution helps so much. Of course, it might turn out that parabiosys brings some undetected conflicts and also brings harm with it .

Posted by: cuberat at June 9th, 2020 7:33 PM

@cuberat

"it might turn out that parabiosys brings some undetected conflicts and also brings harm with it ."

It is not parabiosis they are using, it is next generation plasmapheresis and quite honestly, removing the pro-inflammatory factors from blood (similar to how senolytics works) is likely to be beneficial as animal studies so far suggest.

Posted by: Steve Hill at June 10th, 2020 5:35 AM

To the untrained mind (i.e. mine), this study seems to be pretty remarkable. How complicated a procedure is "next generation plasmapheresis"? What risks might there be for humans in replacing say 25% of blood with such a mixture (or 50%)? What before and after tests/readings would be helpful in illustrating the impacts on health?

Posted by: Michael Nuschke at June 10th, 2020 1:21 PM

I'm wanting to know the same as Michael Nuschke here. I can't see what harm there is in making this procedure available to humans who want to experiment, especially those suffering from age related conditions and illnesses. Transfusions have been done on humans with the right blood type for decades now and with little complication and risk. This procedure doesn't even risk the wrong blood type as a factor. It's a neutral solution and unless someone is allergic, there's no reason why we shouldn't move to trying this on volunteer humans. I'll certainly volunteer. Supposedly if you lose more than 40% of your blood you can die, but that is likely due to the loss of albumin for nutrient transport and pressure that keeps you from going into shock. I can't imagine a 50% replacement being a huge risk in that case.

Posted by: Nate at June 11th, 2020 8:14 AM

Conboys´ and Katcher ´s approaches could well be complementary though Katcher doesn't say yet what his "Elixir" is made of. And from rodents to humans: as proven not an easy step to say the least.
All those experiments are "after-the-facts" ones. Do we need another/additional longevity research paradigm that might be successful in a shorter time than obviously endless waiting ?

Posted by: Art Finch at June 14th, 2020 2:44 AM

Let's just assume for a moment that there are no errors in either Katcher's, Conboys', or other similar work. If so, adding new blood to an old animal, replacing old plasma with saline/albumin, or adding Katcher's mysterious Elixir all rejuvenate, AND adding old blood to a youthful rodent causes aging. I am no biochemist, but logic suggests that maybe young blood, Elixir and saline/albumin stimulate reversal of a pro-aging signal and cause natural mechanisms to restore youth; and that youthful mechanisms are unable to efficiently clear the pro-aging signals in old blood. This might be measured by looking at the epigenetic profile of certain brain tissues before and after administering the various treatments.

I'll be waiting to hear from the Nobel people. Haha!

Posted by: Walter Crompton at June 14th, 2020 1:25 PM

I hope LEAF does a journal club on this one. It is a bit involved, also I find the figures hard to make out - even when using the PDF and zooming in.

It seems they are saying that removing pro-aging factors will restore youthful function in signalling pathways. Providing increased levels of some factors that are repressed in aging may provide benefit, but removing pro-aging factors which cause the repression in the first place (which seem to be mainly TGF-beta family proteins?) is more effective.

One thing that occurs to me is that the dilution will probably stimulate production of erythropoietin (EPO) [I think it did but I'm not sure I'm interpreting the figures correctly] and that will have effects on iron homeostatis. The authors mention EPO -
"an increase in erythropoietin is likely to improve the numbers and health of erythrocytes, attenuating age-imposed anemia" - I think that statement underplays the effects of EPO.

Posted by: CD at June 16th, 2020 11:35 AM

So, how is the Conboy NBE any different than donateing blood or just plasma? Seems to me it's exactly the same except the Conboy's have discovered a NEW Anti Aging benefit. That of flushing out years of accumulated garbage (maybe broken components that the liver/kidneys can't filter out?). You don't replace 50% of your plasma at once but donating 1 pint of blood with 8 weeks between donations should add up :-)

Posted by: gary dale at June 26th, 2020 12:06 PM

In the US, you can donate blood plasma up to 2x per week. Shouldn't regular plasma donors already see these benefits?

I'm not aware of any reports of better health or rejuvination of regular plasma donors.

Posted by: gene at June 27th, 2020 5:46 PM

gene
That's what i'm saying. Maybe the parabiosis people and the phlebotomists just haven't compared notes yet. For example, here is a quote from a healthprep.com article about blood donation not realizing they are confirming the Conboys anti aging findings :-)

"The body replaces the volume of donated blood within forty-eight hours, a process some individuals describe as an 'oil-change' for their body because the surge in new blood allows muscles and organs to function more effectively."

Posted by: gary dale at June 28th, 2020 3:41 PM

Seems to me the Conboys are saying they believe health benefits come from flushing old & damaged particles out with the old plasma. Maybe there are ALSO health benefits from the surge in new blood after a donation?

Posted by: gary dale at June 28th, 2020 3:55 PM

Anecdote: I know a person who donates blood and / or plasma 3-4 times a year and never looks a day younger than he is. If results were so radical someone would have seen something a long time ago...
I mean come on, there are millions of regular donors in the world and many are in their fifties and sixties, when rejuvenation - if at all meaningful - should be visible to the naked eye.
This sounds too good to be true.

Posted by: Barbara T. at July 2nd, 2020 11:30 AM

Barbara
Maybe those people are actually in their 70's and 80's and just look like 50's & 60's...huh? :-)
Just kidding.
I don't think a fix for aging will be a magic pill. Since multiple systems are failing there will probably need to be multiple approaches to maintain permanent health. Flushing years of accumulated garbage from the blood system as the conboys propose seems like a good simple, minimally invasive and relatively safe approach. Worst case scenario is that you save someone elses life with your blood donation.
I doubt any of those millions of regular donors tested for anti aging biomarkers before and after several donations.

Posted by: gary dale at July 2nd, 2020 3:09 PM

@Gary

I am not against it at all but think that expectations should be kept very low.
Unless the Conboy protocol is drastic - which would in itself be a major obstacle to implementation - if the regular dilution of pro-aging factors were any more rejuvenating than a good diet we would definitely know by now.
I agree that those millions of regular donors don't get tested for biomarkers, but if they still die on schedule or with a delay of a couple of months then why even waste the lab assays.

Posted by: Barbara T. at July 2nd, 2020 4:04 PM

Barbra
Do you remember back on Dec 16 1903. You had the same attitude about the Wright Brothers. And the next day it was laughable that they put all that work into that piece of junk that only flew for 12 seconds and a pathetic 120 feet. But, it turned out to be a "groundbreaking" event didn't it? :-)

Posted by: gary dale at July 3rd, 2020 9:58 AM

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