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.
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.
@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.
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?
@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."
@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 .
@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.
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?
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.
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 ?
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!
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.
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 :-)
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.
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."
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?
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.
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.
@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.
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? :-)
@Barbara,
Your friend is surely not donating half of his or her blood or plasma each time, or even a quarter. There may actually be a benefit, but it's not strong enough with only the donation of a pint or two each time for anyone to notice. It's not as though anyone has been testing your friend's blood chemistry before and after, right?
What occurs to me is that this suggests that hospitals are recreating the old-blood-to-young half of the experiment (and in humans, at that) every time they give blood donated from the old to young patients. Not having any idea that anything is going on, they simply aren't measuring the effects. I would think that they ought to be filtering it to prevent it from causing "aging" damage. It would be pretty ironic if the blood from older donors were causing aspects of "artificial aging"-- for example, inflammation-- in recipients who then might need interventions to deal with that problem on top of the problem they received the blood to address.
Dobri Kiprov (US) and Valery Voinov (Russia) are both experts in plasmapheresis since 20 years or so. As far as I know Voinov is doing plasmapheresis monthly on himself. He is over 80 years old and scientifically very active. There is a Russian membrane Plasmapheresis machine called Hemofenix.
Kiprov reports of anecdotical reports of rejuvenations after plasmapheresis. He is doing an Alzheimer clinical trial with plasmapheresis.
Both use plasmapheresis in a lot of different diseases since years.
So this is a low hanging fruit for rejuvenation enthusiasts.
I haven't found anywhere they take plasma if you're over 60
At first, it sounded like this was a new treatment. But it isn't. it is the notice of the effects on aging that is a new study.
If you google Plasmapheresis Therapy lots of treatment centers come up that are already treating humans. I don't know the exact amount of plasma they remove. Sometimes they use saline or albumen and sometimes plasma donated.
But this does not seem to be a new treatment at all. It is used to treat many diseases in humans including Lyme, MS, and other chronic autoimmune diseases. there are mainstream US hospitals that use this and also alternative health centers outside the US that use it for regenerative approaches for aging, cancer, etc..
On blood donation as a proxy for plasma exchange - It will take 6 or 7 donations to reach 50% turnover in whole blood, about 8 % of volume every 8 weeks. We don't know how quickly the "old" factors" build back in, or if there is a threshold for % removal at one time which sends a cascade of cell signals responsible for all the benefits. Need a lot more data. It does seem that if there were dramatic benefits to frequent blood donations there would be some amazing anecdotal stories by now. On the other hand, the medical literature indicates cardiovascular benefits as detrimental excess iron is removed by donations.
Since this Conboy report I have donated whole blood twice and had plasmapheresis 9 times at approximately 3 week intervals from June 2020 to April 2021 so far. I am 64 years old. Everyone in the center is young and donating for money. I have never seen anyone very old. Many of these folks donate 2x per week for years for income. There is no downside as long as you have a healthy liver to produce more albumin (no alcoholics). That's 825 ml each plasma donation and 285 ml plasma in whole blood donation out of 5500 ml total blood plasma volume. A 50% neutral blood exchange as per Conboy study is only 3-4 donations. What's the downside risk? This is a no-brainer. I certainly don't expect dramatic results, but feel great. I haven't done blood tests before and after but I just don't see the risk with this conservative donation schedule. Albumin filters through your intracellular and extracellular matrix and picks up proteins and Advanced Glycosylated End products. Yes your kidneys and liver should filter them but maybe they can't filter everything and need some help. You change your car's oil and oil filter.
Update on plasma donation. Plasma donation age has been raised at CSL Plasma to 75 so I, at 67, was able to try the center a month ago. It was busy and took a while on first visit. And as Neil said, most people are young and there for the money. Two weeks later I made my first plasma donation as local blood bank. Typically donate platelets, which I think makes blood bank more money and in short supply, but this time asked to donate plasma, which they allow every 4 weeks, unlike plasma-only donation centers, which can be done 2x per week. Don't know why the difference in frequency. But if you donate platelets elsewhere the plasma-only center requires 7 day wait before a new plasma donation can be made. In any case, Irina Conboy showed gene expression changes for humans a months after TPE (I assume about 50% of plasma exchanged for saline/albumin) which tells me that it is likely that doing an 800 ml plasma exchange (about 26% of my plasma) every few weeks will be beneficial. For normal blood work my liver function (AST and ALT) is now the best I've ever seen, and this is with only modest volumes effort, assuming casue and effect. 4000 mls exchanged in 2021 and 2400 mls so far in 2022. Plasma loss in 2021 was due to platelet donations. I'm trying for an average of twelve 800 ml plasma only donations this year and 12 platelet donations (about 300 mls plasma loss) for a total of about 12,000 ml or 4 volumes. On the 2 recent plasma donations approx 500 mls of saline was added back. No albumin.
The Conboys will win the Nobel Prize.
They were the first to ask if it's the garbage in the blood. Brilliant insight.
Albumin is like an old kitchen sponge with tons of crap (as well as essential molecules) stuck to it.
Throw out the sponge.
Another metaphor- in your aquarium, change the water, keep the fish.
Capitalist medicine will always choose the most profitable treatment.
There are many pharmaceutical billionaires.
There will never be plasmapheresis billionaires.
That's why it's not making it out of the lab.
It's already FDA approved, for crying out loud.