Human Trials of Plasma Exchange

Animal experiments demonstrating the anti-aging effects of exchanging young blood plasma for old have been prominent in the last two months. Several groups are saying it’s time to translate their findings into human trials. But I’ve recently learned that others have been doing this for several years. What can we learn from their results to guide the next steps in experimentation?


I had never heard of Grifols, the Spanish pharmaceutical company that is the world’s largest supplier of albumin. Since 2005, Grifols has been quietly funding world leaders in plasma exchange research in humans. Albutein® is their brand-name solution of human albumin.

Last month, the first results of the Grifol’s AMBAR trial were released. (AMBAR stands for Alzheimer’s Modulation BAlbumin Replacement). It was a much larger-scale phase 2.5 trial, with 496 subjects recruited from sites in Spain and USA, and treated for 14 months. A single treatment consisted of removing 2.5 to 3 litres of blood (more than half the body’s inventory) and replacing it with Albutein. Patients began with 6 weekly treatments, and thereafter there were 12 monthly smaller plasma replacements (0.7 litres), again with Albutein.

Subjects were evaluated with two standard measures, one of cognitive ability and the other of ability to function independently. Most subjects got worse over the year, as AD is a progressive disease. But treated subjects progressed less than half as fast as sham-treated controls. There was enough variation among individuals that even this strong difference in averages was only marginally statistically significant.

Subjects were categorized as “mild” to “moderate” in their cognitive loss. “Moderate” subjects responded a little better than “mild”, within statistical limits.

In the Conboy paper which I recently reviewed, albumin was considered to be just a passive replacement of proteins that every mammal needs. Albumin was replaced in the blood because when harmful signaling proteins were diluted out of the blood, albumin was removed along with it. The body needs the albumin, while the protein signals were doing damage. Henced they replaced the albumin.

But in AMBAR, albumin is considered an active part of the therapy.

[P]lasma albumin from AD patients is more glycated and nitrotyrosinated than plasma from healthy subjects, reducing its ability to inhibit Aβ aggregation Grifols theorized that replacing AD patients’ albumin with therapeutic-grade albumin should overcome this problem. Further, therapeutic-grade albumin should more effectively bind plasma Aβ and sequester it than plasma albumin from AD patients. Albumin may protect neurons by additional mechanisms, including anti-oxidant and anti-inflammatory activities.  [review, referencing  this primary source].

In one branch of the AMBAR program, ¼ of subjects also received intravenous immunoglobulin (IVIG). This consists of antibodies which identify challenges to which the immune system can respond. Grifols has a proprietary IG product called Flebogamma®. The AMBAR trial was unable to detect a benefit from IVIG.

Plasma exchange has a long history for treatment of auto-immune disorders. Some of the diseases of old age are related to autoimmunity (e.g., diabetes, arthritis, chronic inflammation). Older persons have a higher generalized autoimmunity, but a lower incidence of explicitly autoimmune diseases. Presumably, there are antibodies to self that accumulate in the bloodstream with age, and in recent years this has been related to leaky gut disorders. It makes sense to me that blood dilution would be a downstream or stop-gap treatment for autoimmunity, but that better approaches would be directed at the source of the offending antibodies.

Dobri Kiprov was a co-author of the Conboys’ plasma dilution paper. Kiprov’s clinic has been a site in the AMBAR trials, with experience in plasma exchange going back 20 years. Kripov has studied plasma exchange for a variety of diseases. In these treatments, a patient’s blood is removed and separated. The patient’s own red and white blood are returned to him, but his plasma is replace with saline, albumin, and possibly other ingredients. When I spoke to him, he described work which is soon to be published in Alzheimer’s and Dementia involving a proprietary added ingredient in these plasma transfusions. Benefits last at least 6 months, he said, which suggests that there is some epigenetic re-programming of the cellular sources of blood constituents.

Kiprov claims that patients who receive frozen blood plasma for a variety of reasons have fewer adverse reactions when they receive plasma from young donors (18-24) compared to middle-aged donors (35-45). He has seen patients’ immune systems improve, and arthritis symptoms decrease. He’s eager to see formal trials proceed for these conditions (but someone has to fund them).

The bottom line

As a treatment for AD, these results are not impressive. Patients were already quite disabled, and the results were essentially to prolong their end-of-life institutional existence. There are no effective drugs for AD, so compared to any pharmaceutical, AMBAR looks good. But compare these results to Bredesen’s RECODE program, which aims to improve cognition, and in some cases has returned people to productivity from a non-functional state. RECODE works better the earlier you start it, whereas preliminary results suggests that AMBAR is more effective in late stages.

Inflammation is a driver of all the diseases of old age. Pro-inflammatory signals (cytokines) in the blood were among the elements diluted by AMBAR, and it may be that reduction in inflammation fully accounts for the program’s successes.

As a proof of principle, the results are quite informative. A benefit was demonstrated from plasma exchange in humans for the first time. Subjects did not become dramatically younger, despite much more dilution than in the Conboy mouse experiments (reviewed in this space earlier this month). They suggest that simple dilution as pioneered by the Conboys in mice might be effective in slowing senescence but not reducing biological age.


Two plasma exchange doctors were kind enough to help me with this column. I’m grateful to David Haase (TX) and Dobri Kiprov (CA) for offering background and providing direction to my readings.

54 thoughts on “Human Trials of Plasma Exchange

  1. This is amazing, I first published heterochronic plasma exchange in 2013, and I’m really disappointed that you didn’t credit me Josh

  2. I still question whether the Conboy 5% albumin plasma replacement was truly neutral. Here we are led to believe that albumin alone can be therapeutic. I might also once again remind folks that both the Levine and aging.ai clocks have albumin as a not inconsequential factor.

    • Albumin matters, see:
      Low serum albumin, aspartate aminotransferase, and body mass are risk factors for frailty in elderly people with diabetes–a cross-sectional study
      https://doi.org/10.1186/s12877-020-01601-z
      Blood Albumin as a Prognostic Factor Among Unselected Medically Treated Inpatients https://pubmed.ncbi.nlm.nih.gov/31475857
      Risk of Acute Respiratory Failure Among Hospitalized Patients With Various Admission Serum Albumin Levels: A Cohort Study
      https://pubmed.ncbi.nlm.nih.gov/32118775/

      • Plasma albumin can be lowered by both kidney and liver decline, so low albumin is associated with mortality. But is it just a correlated marker rather than a cause?

        • A quick and imprecise check led me to believe it is causal based on Mendelian Randomization ( in my opinion the savior of epidemiology as a science).

          • Plasma albumin is lower in Covid and HIV patients and predicts mortality.

            I suspect chronic viral and other infections lowers it which may be why albumin is lower in the elderly.

            “Hypoalbuminemia Predicts the Outcome of COVID-19 Independent of Age and Co-Morbidity”
            https://pubmed.ncbi.nlm.nih.gov/32406952/

          • Scientists – pay attention. When implementing the information doctrine of rejuvenating people at 70, the concentration of albumin increases in the third year from 20 grams / liter to 50 grams / liter, and in the fourth year of rejuvenation to 65 grams / liter. This applies only to man, when rejuvenation is carried out through a change in control programs in the human soul.

  3. My question is how long does the effect last? Can one do weekly or monthly plasmapheresis just to slow down progression? Is it safe to repeat procedure for weeks, months, years. Would appreciate answers from those knowledgeable in this area. My bet would be on a therapy that reverses Alzheimers, hopefully cures it with an annual dose at reasonable cost.

    • An epigenetic age test before and after should allow us to quantify exactly the benefits.

      But it looks like this is not enough to rejuvenate. And we’re back to the need for young factors in the blood.

    • Hi Akshay, What are your thoughts around the potential effectiveness of the Elixir to combat AD? Would you expect it to improve cognitive function given what you’ve seen so far?

      • Howald I would think that potential is there to reverse AD but till we have completed a trial in a rat model of AD or human we cant confirm. Personally I am positively inclined based on the complete reversal we have seen on the chronic inflammation markers to youthful, healthy levels.

  4. I’m not doubting the results by Grifols / AMBAR but I wish to point out that they consider the only component that makes their treatment proprietary (their version of albumin) as crucial.
    The strongest proof of plasma exchange would be an extension of *maximum* lifespan. It would also obviate the questions around causality of the epigenetic changes (and the associated clocks). Does anyone know whether Katcher/Horvath and/or the Conboys are working on such an experiment (mice/rats)?

      • Do you mean blood donors?

        IIRC, blood donation does not dilute, and blood reconstitutes at similar nature. You have to do the plasma exchange, wherein blood is taken out and replaced with the simpler solution with albumin.

  5. According to the informational space diagnostics of ISD (diagtor.com.ua), the cause of Alzheimer’s disease is due to a decrease in the work of the Center of Knowledge, which is in the Soul Consciousness. The problem is eliminated through the implementation of the information doctrine of IDR rejuvenation, which helps to restore the work of the Soul Cognition Center and telomeres of all body cells. Evidence. A girl in 30 years lost the ability to navigate in space. After the implementation of IDR, all abilities were restored.
    Ermakov P

  6. I know this column is about plasma dilution but this DNase 1 treatment for Alzheimer’s caught my eye a while back. I am surprised it hasn’t gained any traction.

    DNase1 is a human protein that is used for cystic fibrosis as a mucolytic. In this single person experiment it was taken orally.

    “The patient was unable to remember his name or family members, among other things, and had been diagnosed as terminal when his family agreed to try DNase I. Just two days after treatment began, improvements were seen. And he was soon able to recognize family members, dress himself, tie his shoelaces, feed himself and walk and ride an exercise bike.”

    “Treatment with DNase I allowed the patient to withdraw from a terminal state and resulted in significant improvements in cognitive and behavioral function, including the ability to walk and perform everyday tasks with near independence,” said Victor Tetz, scientific advisor at HMI.,”

  7. The age of the donor albumin has to matter. From what I could gather, it seems to be separated from a huge pool of donor plasma so it must be the average age of the donors.

    I wonder about the detrimental things in commercial albumin that are not filtered out during the manufacture.

  8. well, in the Conboy paper they just evaluated the plasma dilution with some biomarkers, didnt they? no disease free survival, no age extension effects were studied.
    in that sense the result from AMBAR fit nicely. some small improvement in cognitive function. true rejuvenation is hard.

      • Hi Steve. If you say “this is not how they (the Conboys) work”, do you mean they are not even interested in answering this central question? Even if a family office or HNWI gave them the funds to tackle this?

  9. From the leaky gut link:

    “Growing evidence shows that the gut microbiota is important in supporting the epithelial barrier and therefore plays a key role in the regulation of environmental factors that enter the body. Several recent reports have shown that probiotics can reverse the leaky gut by enhancing the production of tight junction proteins; however, additional and longer term studies are still required”.

    It seems to me that origins of most of the problems is a gradual dysfunction of the epithelial layer of the gut. Probiotics may mitigate the problem but eventually the layer ceases to function correctly, possibly because of some limit in the epithelial stem cells.

    • If you’re interested in leaky gut stuff and haven’t already seen the work of Martin Kriegel at Yale, check it out. According to his research, diets high in resistant starch may prevent leaky gut and ameliorate autoimmune diseases. Who knows what other health parameters could be improved by reducing leaky gut as we get older.

      • Thanks. I’ll take a look.

        It seems leaky gut is one of the best measures of age and best predictors of death.

        Rapamycin may work in part by repairing the leaky gut and apparently does not need microbiota to do that, although it also seems to have effect on microbiota too which might be indirectly through effect of intestinal wall cells.

        From study with fruit flies:

        “Similarly, intestinal barrier dysfunction is more accurate than chronological age in identifying individual flies with systemic metabolic defects previously linked to aging, including impaired insulin/insulin-like growth factor signaling, as evidenced by a reduction in Akt activation and upregulation of dFOXO target genes. Thus, the age-dependent loss of intestinal integrity is associated with altered metabolic and immune signaling and, critically, is a harbinger of death.”

      • L glutamine can help with age-related, or other types of gut health decline, also, if the user has no health or medicinal contraindications to its use such as glutamate intolerance (think MSG), epilepsy or liver/kidney disease, etc.

        Also, if taken at night, it is capable of stimulating natural Growth hormone release.

        Something to consider, along with resistant starch, and probiotics, until Plasma exchange becomes commercially available and affordable to most.

        • Thanks, Heather.

          I guess I will add some glutamine to my supplement mix.

          I decided to write a fairly long post on my blog trying to sum up my views.

          https://broadspeculations.com/2020/07/06/aging-and-the-gut-brain-axis/

          The more I think about it the more I think the gut (or maybe gut-brain) is most directly tied to aging. C. elegans ages. Fairly quickly it turns out which makes a good species for aging research. Yet about all it has for organs are reproductive organs aside from the gut. If there is any common mechanism for aging across animal species, the logical place to look would be what is in fact most common to all animal species.

  10. To me this just shows that the Conboys were correct in their assessment that albumin plays a minimal role in the benefits of plasma exchange.

  11. I am a little disappointed that the results weren’t greater for the trial participants, but not surprised.

    I think a large part of the improvement from parabiosis is from the sustained corrections in the blood by the younger animal.

    I’ve wondered for awhile if the benefits of young blood might be partly due to something as simple as the correction of the blood’s amino acid profile in the elderly.

    Studies have shown that amino acids in the blood change as we age, ie: in aging some amino acids go up and others down.

    That might explain why single blood extract treatments appear to be insufficient.

    Studies have shown supplementation of specific amino acids have reversed muscle loss in the elderly, for example creatine ( a non-protein amino acid ).

    What would happen if the entire amino acid profile were corrected to match a younger age? Some amino acids would need to be lowered and others increased. Perhaps that is what we are seeing in the parabiosis experiments?

    How would our cells’ epigenetics respond to a younger amino acid profile in the blood, being made available for their use?

    I am hoping that reversal of the epigenetic age studies coming up will see a correction in the amino acid imbalances, as the gut, etc.. start working better.

    • Very interesting point – I have often wondered the same thing. There are significant benefits to cysteine (or hydrolysed whey) and glycine supplementation for controlling oxidative stress parameters in the blood and reducing chronic inflammation in muscles (which prevents the benefits of weight lifting in the elderly). I suspect there are also benefits to the liver and to glucose control.

      Most people think the benefits of autophagy inducers like rapamycin and coffee come from organelle turnover (i.e. mitochondrial quality control), but equally the benefits might be from amino acid release into the blood. Some amino acids can block autophagy, as they indicate sufficient availability. But if the AAs sensors are not sensitive to all AAs equally, then problems might build up. I can’t find any studies that show definitely how AA concentrations change with aging in human blood. Let me know if you do any better.

      • Hi Mark,

        Here are several age-related studies on amino acids.

        Muscular Atrophy and Sarcopenia in the Elderly: Is There a Role for Creatine Supplementation?
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921011/

        Use of Creatine in the Elderly and Evidence for Effects on Cognitive Function in Young and Old
        https://pubmed.ncbi.nlm.nih.gov/21394604/

        Age-related Changes in Serum Amino Acids Concentrations in Healthy Individuals
        https://pubmed.ncbi.nlm.nih.gov/22628330/

        A Comparison of Fasting Serum Amino Acid Profiles of Young and Elderly Subjects
        https://pubmed.ncbi.nlm.nih.gov/1770195/

        Age-dependent Changes in Plasma Amino Acids Contribute to Alterations in Glycoxidation Products
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298480/

        • From Wulf Droge, a distinguished German researcher sadly no longer with us
          (note the mention of albumin):

          “The various beneficial effects of
          cysteine supplementation on top of the normal diet
          suggest by analogy: (i) that there is an ageing-related
          deficit in body cysteine and glutathione reservoirs and
          (ii) that a deficit in cysteine leads to a decrease in
          muscle function, a decrease in immune function, a
          decrease in plasma albumin concentration, and an
          increase in TNF-a concentration. As all these changes
          are hallmarks of the ageing process, it is concluded that
          the age-related decrease in body cysteine and/or
          glutathione level may be a major driving force for
          multiple ageing-related degenerative processes”

          Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1569588/

          Later work work tying this in with redox regulation of the insulin receptor and therefore autophagy: https://www.liebertpub.com/doi/abs/10.1089/ars.2007.1953

          Wulf Droge also has a book.

          More recent work adding glycine to cysteine to reverse oxidative stress in the elderly: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155927/

        • The body can easily dial up the production of the non-essential amino acid glycine, but it decides not, even though we certainly need even more glutathione during old age, than when we were young.

          I wonder, if Harold’s and Akshay’s elixir show any improvements in endogenous production of non-essential amino acids?

          • Thanks Akshay. As all 3 building blocks for glutathione synthsis are non-essential, I think it is fair to conclude, that the Elixir does indeed raise the endogenous production of non-essential amino acids.

          • It’s not that simple Ole. In glycine’s case it is what is called conditionally essential. The body can make it from serine catabolism but the rate is set by the requirement for 1 carbon units and it’s not reversible in the glycine direction (whereas glycine can always be cleaved for more carbon units). From this you would expect a fall in glycine with age, and in fact collagen levels do fall in all large land mammals. But surprisingly from one of Gerald’s references above, glycine actually rises in the blood in old age. Maybe this is a consequence of mitochondrial dysfunction, a fall in cell turnover, or a fall in collagen turnover. In any case supplementation is clearly beneficial for both antioxidant defence and collagen synthesis.

          • High Blood glycine levels may indicate that it is not being absorbed and utilized intracellularly

        • Whey protein isolate is more processed than Whey protein concentrate.

          The isolate is a product with a higher protein content, less lactose, fat and carbs and therefore fewer calories.

          Both the concentrate and the isolate can be hydrolyzed

          If you are lactose intolerant the isolate may be better. It still contains lactose but at a much lower level than the concentrate.

          However, isolate is more expensive, and the concentrate is thought, by some, to taste better, likely due to higher fat content.

          Hydrolysates/hydrolyzed are absorbed faster due to a process that breaks down particles similar to a pre-digestion process.

          Whey protein in general is easily absorbed by most people, though

          Some studies show that hydrolyzed protein stimulated muscle protein synthesis by a larger degree. They also show a higher leucine content.

          Whey isolate processing, however, removes. lactoferrins, beta-lactoglobulins and immuno-globulins). The concentrate still contains those factors.

          • Could be Heather, but in the last of my references we see that glycine levels in the blood fall between youth and the aged. This is what I was talking about with Gerald; it’s hard to get reliable data on age related changes in amino acid levels.

            We do know the body uses up more glycine in collagen synthesis than antioxidant defence, so dependent on the needs of the body one could easily imagine the aged body having to prioritise. With knowledge of the glycine synthesis pathway, and how it is rate limited by the requirement for 1 carbon units, it seems inevitable that aged humans will suffer from a lack of glycine without significant supplementation. The ‘elixir’ correcting gluthathione levels most likely must be acting by increasing 1-carbon requirements, i.e. re-establishing cellular (and organelle) turnover.

          • Thanks, Heather for this in-depth information about whey protein.

            I take pure whey isolate after my gym workout, but also a teaspoon of leucine dissolved in water and lemon juice towards the end of my gym session. Seems to be right.

    • It has long been known that: The ageing systemic milieu negatively regulates neurogenesis and cognitive function. https://doi.org/10.1038/nature10357
      “…..exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines—including CCL11 (also known as eotaxin)—the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory.” Also: β2-microglobulin, a component of major histocompatibility complex class 1 (MHC I) molecules, is a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529371/ And such factors are still perhaps not a few

  12. Numerous studies have been done on the neuroprotective benefits of Lithium. Problems arise with high doses, but with low dose Lithium supplementation throughout life as naturally occurs in regions where lithium is available in drinking water and soil (food crops), or seafood is a daily part of diet, neurodegenerative diseases and psychiatric problems are reduced. A minimum daily requirement for Lithium, as suggested by numerous researchers, needs to be established.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710473/
    Findings: In this Danish nationwide, population-based, nested case-control study of 73 731 patients with dementia and 733 653 control individuals, the level of lithium exposure was lower for patients with a diagnosis of dementia than for controls. Similar patterns were found with Alzheimer disease and vascular dementia as outcomes.
    Meaning: Exposure to higher long-term lithium levels in drinking water may be associated with a lower incidence of dementia.

  13. Based on my pretty rudimentary understanding of AD it’s not surprising that we’d see minimal improvements from albumin treatment. AD leads to massive neuron death and build up of various byproducts. So to expect to rebuild the brain with this therapy seems intuitively to be a missapplication of this therapy. Slowing progression of the disease, sure, but anything more than that would seem to require more proactive therapies. Perhaps with plasmapheresis on a weekly or monthly basis in patients starting around 50 we’d see far less progression into AD, through a more preventive approach. But that kind of study will take years and decades to complete.

    • According to the information of space-based diagnostics of ICD, intelligent processing of information in animals occurs at the level of high-frequency electric fields. Man has a Soul, which is based on the information field. In the Soul of a person, information is processed on the information field and then an information signal is transmitted to the nervous system to the Schwanian cells of the myelin sheath of nerves, and then enters the entire nervous system. Therefore, man and animal have a different structure and approaches to rejuvenation are completely different. Using the information doctrine of IDO rejuvenation for the fourth year, experiments are conducted to rejuvenate people aged 32-90 years. In experiments, a significant increase in the relative telomere length of almost all body cells is detected.

    • It sounds like there is a small negative effect.

      From the Conboy’s paper:
      “Interestingly, a single NBE does not significantly worsen the examined parameters in young mice”

      NBE= neutral blood exchange

  14. My company (Alpha Sciences) is preparing to initiate human trials for young donor plasma exchange. We believe it may provide significant regenerative effects (akin to the mouse/rate studies), but might also treat a host of age related diseases and conditions. We have already received IRB approval. We hope to put this uncertainty as to whether it will work or not to rest once and for all.

  15. I have just finished reading Harold’s paper, and I was very impressed.
    One thing I noticed was there was no mention of the Thymus.
    Was it simply not examined or did it not show any regeneration ?
    I ask this simply because Thymic involution leads to the eventual collapse of the immune system and death, you only have to look at the horrific death rates of elderly Covid 19 victims to otherwise see our eventual fates.

    • Michael,
      A very good point indeed. We have not been able to test it in first 2 trials but will be able to in our upcoming trials with Dr. Fahy who is an expert in thymus rejuvenation.

  16. Information space diagnostics of ISD (diagtor.com.ua) allows you to immediately get answers to many questions of the existence of man and space, since information is taken from the information field and from the Creator. A lot of information has already been received about this. If you have a desire, I can conduct an assessment of the state of longevity, for example, Josh Mitteldorf. The main characteristics of aging will be presented. I think it will be useful and interesting for you. This requires your consent.
    Best regards, Ermakov Petr

  17. Information about the coronavirus. I think it will be interesting for you to know.
    According to the information space diagnostics of ICD, there are seven types of coronavirus.
    Type 1 – multiplies in the respiratory system
    Type 2 – multiplies in the heart
    Type 3 – multiplies in the respiratory system and nervous system
    Type 4 – reproduces in the nervous system
    Type 5 – multiplies in the heart
    Type 6 – reproduces in the digestive system
    Type 7 – reproduces in the reproductive and hematopoietic-immune systems
    Dangerous are coronaviruses 3 and 4, which make up 6% of all viruses and they lead to death 31 days after entering the human body. other viruses are not dangerous.
    Best regards, Ermakov Petr

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