Large doses of young exosomes, delivered intravenously, have been shown to have extraordinary rejuvenation power in rats. We have known this for 5 years, but translation to human trials has been slow, not for technical reasons but because of trade secrets and intellectual property law and the inability to guarantee that he who funds the translation research will profit from the finished product.
In the interim, a cottage industry has developed around a weaker human therapy based on the technique that is so successful in rats. Plasma infusions are a well-developed, safe and approved procedure for trauma injury and other applications. It has been adapted by clinics in Texas as an anti-aging therapy. For some tens of thousands of dollars, an old person can buy two liters of blood plasma from a guaranteed healthy young donor.
For those with the money to spend, the limit of two liters comes about because the volume of the body’s circulatory system can be stretched only so much. Putting extra fluid into the system, with extra pressure on the arterial walls, can be dangerous. Typically, one liter of blood plasma can be removed and two added, for a net volume increase of one liter. (An adult might have 5 liters total, so this amounts to a 20% expansion of the blood volume.)
Some people report good results from this procedure, but no one has been restored to youthful appearance, health, endurance, and learning potential comparable to the rats in the laboratories of Harold Katcher or Xi Chen. I’m guessing this is because the exosome dosages in these rat experiments were far larger than the ~35% replacement that is achieved in the Texas clinics. I believe that Katcher and Chen both used exosome infusions large enough to overwhelm the reservoir of old exosomes in the blood of the old rat.
Proposal for infusing larger plasma doses in human trials
Blood plasma is 90% water. If it is the water volume that limits the dosage of young plasma, an obvious work-around is to concentrate the exosomes and other plasma ingredients before infusion. Freeze dried plasma is already a well-developed technology, in use for 80 years. Under a vacuum, the plasma is evaporated and the evaporation lowers the temperature. Over the course of 10-20 hours, almost all the water is removed, and the plasma is reduced to a slurry.
This technique has been developed for the convenience of long-term storage only, so that, in hospitals, plasma is routinely reconstituted to full strength before administration. But by adding less water, the plasma could be reconstituted at triple strength or more. In this way, a much larger dosage of young plasma could be infused in the old patient.
Refinements
Platelets are miniature cells responsible for blood clotting. It will be necessary to remove platelets from the plasma, because blood with 3 or 4 times the healthy concentration of platelets poses a danger of clotting, heart attack, and strokes. It may be advisable to remove albumen and some other elements of the plasma to keep their concentration within normal limits.
There is an experimental anti-aging clinic in California, where old blood plasma is removed and replaced with albumen. It probably makes sense to remove old exosomes as we add young exosomes
We do not yet know
The principal uncertainty is whether the young exosomes are able to reprogram the body’s epigenetics, with a result that is self-sustaining. If we are lucky, then the reprogrammed body will produce its own young exosomes; if we are unlucky, then infusions of young exosomes will have to be repeated, perhaps as often as the blood turns over, which is a few months; if we are very unlucky, then the infusions will have to be repeated as often as exosomes are cleared from the blood, which is less than one day, and the treatment becomes completely impractical.
But results with rats suggest that the rejuvenation has some staying power.
Discussion
111 reader comments
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Last year I started donating blood.
This time they asked if I could donate plasma instead and so I did. Since that is less invasive I can do it every month. So I was thinking about it in the context of Health. What is the latest ? Is it healty to "thin out" old plasma or do you need input of Young plasma (exosomes) to get benefit. ?
My understanding is that's it's helpful, but trivial. Lots of people give blood, and if memory serves, there's a lot of data, which has been analyzed, on the health impact of donation, and the result is that it's only a tiny bit helpful - perhaps not even due to the actual blood work, but rather community engagement or something. That makes sense to me - the plasma your body will make to replace what was lost will have the same age profile.
I think your points are valid and if there were any large differences they would have been derived by now. BUT:
What about plasma-donation only, I would guess empirical data are less?
From what I have understood from the debates som far:
It has been speculated (Conboys ?) that getting rid of old plasma in the body will get rid of bas substances which delay degeneration (aging ?) in the body
Then "the other school" (Katcher Aksay) "flood" yong exosomes into the plasma which have produced some results in mice.
All stems from the original parabiosis case, where is was obvious that that there are effects of conneting old and young bloodstreams.
I think there are many years since this was started reported and Josh have written about it, BUT, one would think that the would have found out more on this since the last time Josh wrote about it, but I guess not...
I'm unable to count the number of mouse studies with pictures showing grey lackluster hair turning into dark shiny hair. From what I can see, the effects are primarily related to a reduction in ROS by switching on Nrf2 and SIRT1, which can be achieved by other substances like e.g. sulforaphane. I'm pretty sure we would have heard about psilocybin long ago, if it had any dramatic effect on aging. But thanks for posting the article.
Josh, I'm not certain where to put this, so I'm putting it on the current thread. This sounds like a joke, but it is published in the July 8 issue of Nature Aging. Psilocybin as an anti-aging drug? (Hey man, look at the colors on that bird . . .)
https://www.nature.com/articles/s41514-025-00244-x
And, now, for something entirely different: https://grundvilk.substack.com/p/the-u-shaped-curve-polyamines-and
Epidemiological evidence that dietary polyamine mix international determines about 90% of average longevity at birth.
An adjunct to this post. Don't know how to edit so posted as a reply
Brian Packard's recent interview on YouTube Modern Healthspan channel is interesting and pertinent. Awaiting updates on his work.
I am a simple man. So Dr Harold Katcher knows what to do. It would seem do-able. If Dr Katcher wishes to have a treatment. Then could it not be a achieved via scientific and philanthropic support. Liz Parrish gets her stuff done. People are free to die in Geneva. So ethically to balance the scales of justice, they should have rights to whatever they wish medically later in life.
One more thing.
In reviewing the comments, it seems Tom Casey probably has the most straight forward and realistic approach: just use healthy, sex matched plasma with the exosomes.
I would think you could get donors all over the world for that as an older person with some money, and a future that isn't so economically bright for many of the younger people. Especially if it doesn't hurt the younger people at all, why shouldn't they get paid by the older people who have all the money and assets currently? I'm not that old, but I would pay decent money for a plasma exchange from a 20 year old, if it had been tested/evaluated and safely administered like Tom says.
Eric, how expensive do you think such a therapy would be?
Josh, have you seen the paper on the "waves of aging"? It's a type of punctuated (anti) equilibrium that states that greater aging happens in mid 30s, around early 60s, and late 70s. Any comments on that?
Thanks
Immunis, a company run by Hans Keirstead is kind of growing EVs in bioreactors through young human stem cells. This would be ethically better than counting on human donnors (I refuse the idea of young donnors).
And something that amazed me, I came across the list of the X prize candidates and there is a big bunch of them working with exosomes. Even some of them using bovine plasma.
So now that it is understood where the parabiosis trick was, many teams are chasing after a way to destillate/harvest those EVs and infuse in humans. Harold Katcher is just one more of them. For sure the pioner, but science races are often merciless even with former leaders.
I wish the best to Harold.
I think the best experiment moving forward is a combination of the Conboys technique and the Harold Katcher technique but with a human-derived E5.
The human-derived E5 would require taking dozens/hundreds of 18-25 years olds' plasma, and running it thru Harold's instruments to generate a large volume of heavily-concentrated young EVs.
Every 3 months, replace 50%+ of plasma with a sodium water + key proteins (eg. Albumin) plus the EV concentrate in 60-year-old participants for several years.
I'm confident we'd see rejuvenation and ultimately life extension.
Hey Josh...
I've come to believe that we've all been missing these studies' bigger picture point.
About the Xi Chen study.
---> It found that PGC-1a expression is required for the Younging Effect to occur.
Meanwhile, Harold Katcher's E5 patent clearly states that polyethylene glycol (PEG) is key to processing the porcine plasma extract before its administration.
---> And it turns out that PEG is a significant promoter of PGC-1a expression.
---> Really!
Meanwhile, backing up to get a better view of the whole scene...
Shai Efrati found in 2020 that HBOT therapy increased telomere length and reduced senescent cell expression.
-- And it turns out that...
---> HBOT is a profound promoter of PGC-1a expression
---> and PGC-1a competes with NF-kB within cells to control p65 and its impact on inflammation and telomerase expression.
WHO KNEW? HBOT is a Blood Plasma Intervention!
-------------------
I now believe that
- we haven't yet grasped the size of the puzzle we need to assemble for true understanding
- the interventions we think of as comprising the entirety of "Blood Plasma Interventions" all require needles.
- Meanwhile, the needle-required-interventions are just a subset of all the puzzle pieces
Until we grasp how large the puzzle actually is, we don't have much hope of profound progress.
In the bigger picture, you are correct. However, I suspect that the puzzle is a bunch of "first to kill" pieces. Solving any one of them may extend maximum lifespan somewhat. Better a little than nothing. There are some fixes to be considered that are in the "pipeline".
IL-11 antagonists. They are in Stage II trials not for longevity, but for stopping degenerative fibrous diseases, such as primary lung fibrosis, and chronic kidney disease. However they have shown about the same life extension in rodent models as E5.
Anti lipoprotein alpha blockers. Lipoprotein alpha is believed to be the primary cause of arterial sclerosis, rather than cholesterol, but until recently there was no way to alter the level by any means. Now there are drugs that radically lower the blood levels. Stage III trials are about to get underway to see how effective it is on lowering heart attack and stroke rates. (In addition, a mutation of this protein is highly correlated with Alzheimer's.)
And not to leave out the AOH1996 Stage II trial for cancer treatment. It may dramatically increase cancer lifespans. The code is going to be cracked in 2026.
Things to consider.
This is really interesting and new to me, George. Can we have links for IL-11 antagonists and for lipoprotein alpha?
Here is another paper you might find of interest. The title is "Exosomal miR-302b rejuvenates aging mice by reversing the proliferative arrest of senescent cells". The link is - https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00481-9
Also, here is the latest on thymus regeneration coming out of cancer research - https://www.news-medical.net/news/20250203/Researchers-discover-key-to-boosting-thymus-regeneration-after-damage.aspx
How applicable this will be to anti aging is still to be determined.
Josh, you have voiced an opinion that the hypothalamus may be the "master switch" for aging. Here is a recent paper on overexpressing neuropeptide Y in an early aging mouse strain. It wasn't setup to determine total lifespan increase, but the results are most interesting. https://link.springer.com/article/10.1007/s11357-025-01574-0
Yes, Claudia Cavadas is the main person pursuing the idea that NPY is a rejuvenating agent. She is the senior author of this new paper. I have never seen independent replication, and I don't understand why others are not motivated to follow up on NPY.
https://scienceblog.com/joshmitteldorf/2022/06/20/is-there-a-master-timekeeper-upstream-of-the-methylation-clock/
There is a close relationship to the work of Dongsheng Cai
https://einsteinmed.edu/faculty/11603/dongsheng-cai
Josh here is the link to the Nature article on IL-11 - https://www.nature.com/articles/s41586-024-07701-9 . For the link to the lipoprotein a (alpha), here is an overview link - https://pmc.ncbi.nlm.nih.gov/articles/PMC4253862/ . This is closest to a published paper link - https://jamanetwork.com/journals/jama/fullarticle/2811935 . Hope this is useful.
Strikes me that besides using a more concentrated plasma, the water volume problem might also be addressed by administering the plasma more slowly. Given adequate time, kidneys are efficient disposers of excess water.
Time may also serve another purpose as more is learned about just what components of the plasma exosomes are doing most of the anti-aging work. Plasma administration may turn out not to be the end but a stepping stone.