Ambitious New Anti-aging Trial in Humans

Pre-announcement Announcement

Life Extension Foundation has just announced that next week they are going to announce a partnership with the Young Blood Institute for what is perhaps the most ambitious human trial of anti-aging medicine ever.  It’s a daring project, with what is IMO a most promising target.  But I find details of their protocol puzzling, and haven’t been able to get satisfying answers from LEF or from YBI about why they’ve made the choices they have, and how they will be able to learn from the project.

  • The principal treatment consists in 6 plasma transfusions scheduled over 4 weeks.
  • Extensive testing is planned, including telomere age and methylation age in addition to a full battery of standard blood tests like lipids and inflammation markers.
  • The program is self-funded by research subjects, with projected cost ~ $50,000 per participant.
  • In each transfusion procedure, red and white blood cells will be separated and cycled back into the subject.  Blood plasma with dissolved blood chemicals will be removed.  It will be replaced not by full plasma from a donor but by albumin and gamma globulin only.

“Rescue Elders” project of LEF

Last year, Life Extension Foundation announced a new and ambitious program of human experimentation at the edge of medical science, sponsoring high-risk trials to prospect for anti-aging breakthroughs in the near term.  (The project’s name, Society for the Rescue of our Elders, was taken from an 18th Century group in Amsterdam, Society for Recovery of Drowned Persons, that was formed after the efficacy of artificial respiration was first discovered.)  Their first project was a clinical trial of rapamycin, now ongoing.  This present program of plasma transfusions is their second project.

 

Target: Epigenetics

It’s my belief that the body’s primary aging clock is epigenetic.  That is to say, different combinations of genes are expressed at different times in life, and in old age the constellation of genes that is turned on causes inflammation, auto-immunity, and a preponderance of anabolism over catabolism.  The master’s tools are deployed in old age to dismantle the master’s house.

As a general concept, I think this is the best working hypothesis we have.  But if it is correct, it doesn’t offer an immediate key to rejuvenating the body.  The problem is that epigenetics is enormously complicated.  (The genetic code, in contrast, is as simple as it can be—a code of correspondence between triples of nucleic bases in the DNA with the 20 amino acids that are linked together, then folded to form proteins.)

Methylation of chromosomes is the best-known and first-discovered mechnism by which genes are turned on and off.  In addition to methylation, there are dozens of other epigenetic markers and signals that are applied directly to DNA or indirectly to the histone spools, beads of protein that around which DNA is coiled.

Different genes are turned on in different parts of the body.  This is the primary way that the body differentiates one kind of cell from another—they all have the same genes, but different combinations of genes are turned on in a nerve cell or a muscle cell or a skin cell.  Overlayed on these differences from one cell type to another, genes are turned on and off with age. This effect is reliable and consistent enough that Steve Horvath was able to construct a methylation clock based on 353 methylation sites that change consistently with age across all cell types in the body.

The connection to blood signals was supplied by research from Stanford, Berkeley and Harvard, in which blood from a young mouse is introduced into an old mouse, and is shown to rejuvenate its tissues, stimulate new growth, and promote healing.  With a small conceptual leap, I imagine that there is a self-regulating epigenetic clock distributed through the body.  On the one hand, epigenetic markers in each cell give each cell its characteristic age.  On the other hand, these same cells are sending signals though the blood (transcription factors) that are continually updating the epigenetic program and keeping it in sync throughout the body.  The hope is that (even if we don’t understand in detail how the epigenetics is programmed) the substitution of a young blood environment for an older blood environment will reprogram epigenetics in the distributed cells, and after a few cycles it will be self-sustaining.  That is, once the cells are reprogrammed to be younger, they will themselves send signals into the blood that maintain the younger state.

Criticism of the protocol

Here is a description of the proposed YBI protocol.  Six times over a period of 4-6 weeks, patients will be hooked up to a plasmapheresis machine.  Whole blood is removed from one arm, and a mixture is returned to a vein in the other arm.  The mixture that is returned will include all the patient’s own red and white blood cells.  But the blood plasma, clear liquid with all the dissolved signal molecules, will be removed.  The plasma will not be replaced by blood plasma from a younger patient, as in a standard plasma transfusion.  Instead, the return side will contain only albumin and gamma globulin.  These are the hydrostatic and immune components of the plasma (antibodies).  The theory is that auto-immune aspects of aging will be addressed in this way…but the antibodies are generated continually by white blood cells, so that the treatment will not last long.  Hence the rationale for frequent repetitions of the treatment, less than a week between treatments.

My principal fear is that the planned YBI protocol may be able to do only half the job.  My conjecture is that it is the signal molecules that actually maintain the epigenetic program.  The proposed protocol will remove the bad ones, and that’s half the job.  It may be that there are transcription factors from young blood that are deficient in the old and need to be replenished.  Full plasma transfusions from young donors would do both, fully replacing the blood environment of an old person with the blood environment of a young person.  But it is expensive and requires many donors for each patient.  It is to control expense that YBI has chosen to do do the removal, but not replacement of blood signal molecules.

Just last year, Tony Wyss-Coray headed a Stanford trial for AD, through a for-profit spinoff called Alkahest.  Alzheimer’s patients were given four doses of young blood plasma.  But the dose was small, a total of 1.5 liters of plasma, and the bad actors weren’t being removed.  Results were disappointing, but perhaps this is because the procedure was not bold enough.

 

Promising Precedent

Beginning in 1924, a Soviet Bolshevik named Alexander Bogdanov experimented on himself, receiving a series of 10 blood transfusions from younger donors.  He was 51 years old at the start of the experiment, and contemporaries report that he appeared physically ten years younger in the course of the procedures.  He self-reported prodigious health benefits and return of youthful vigor.  The experiment ended tragically in 1928, when he received blood from a student who had been infected with malaria, and died of the infection.  

Harold Katcher has been thinking about the rejuvenation potential of plasma transfusions for a long while, and here is the protocol he suggested five years ago.  He does not speculate about what schedule would be ideal, and he cautions us that extensive experimentation with mice and even in cell cultures would be useful before beginning human trials.

Unpromising Precedent

Two years ago, I spoke via skype with Jesse Karmazin (Stanford University and Ambrosia).  He told me that as a med student he had done an analysis of historic data from transfusions performed at Stanford University Hospital, and found that those who had received blood from young donors had better outcomes and better long-term survival rates than those whose blood had come from older donors.  I was very interested in this claim, and asked him for the data that supported it.  He told me it could not be released for reasons of patient privacy.  I never did get to see that data, and he never published his analysis.

Last year, a published study claimed the opposite:  that in a large database of Swedish and Danish patients transfused between 1995 and 2012, they were unable to detect any survival difference between those who received blood from young donors and a matched group of patients whose transfused blood came froun old donors.

 

Questions

Ideally we would like to learn many details from a trial of HPE (heterochronic plasma exchange).  Fundamentally, we would test the basic question whether circulating factors in the blood are indeed able to reprogram the epigenetics of cells throughout the body, and whether this will have a salubrious effect on vitality, appearance, metabolism and the immune system.  A well-designed trial might also teach us more

  • Which chemical components (proteins and RNAs) are most important to be removed from the blood of older people?
  • Which chemical components (proteins and RNAs) from young donors are most effective to be added back?
  • How long does the young plasma profile remain in the bloodstream before the body’s old cells take over and drag the proportions back down to where they were?  (At this point, the next infusion would be appropriate.)
  • How many transfusions are required before the body’s cells are reprogrammed, and the young plasma profile becomes self-sustaining?

Transfusions from young donors are a good place to start, but obviously not a practical solution for rejuvenating large numbers of people in the long term.  But if we can learn which chemical constituents need to be removed and which need to be added, it is possible that a core handful of such factors might be discovered.  Those that need to be added can be manufactured in bulk by vats of genetically modified E coli.  Those that need to be removed can be targeted with antibodies and removed in a simplified blood filtering procedure.  This is a promising research path—perhaps the most promising that is visible from where we are now.  But we’ll never know if it can work until we do an expensive and time-consuming series of experiments.

How many transcription factors need to be regulated in order to the job?  This is the biggest unknown.  When I spoke with Irina Conboy four years ago, she was optimistic that the number may be less than ten, but last year, she was less optimistic.  I take heart from the fact that just four Yamanaka factors can turn a differentiated cell into a zero-age stem cell.

 

Toward the future

Plasma transfusions are a safe, approved medical procedure, used for decades as treatment for (especially) auto-immune diseases.  No FDA approval would be needed for a clinical trial, using transfusions “off-label” to test rejuvenation potential.  However this is not a project likely to be picked up by venture capitalists looking to make a quick buck.  The first reason is that the process will be expensive and time-consuming, with a great deal of trial and error.  The second reason is that when it is all over, everyone will know what are the best schedules and procedures, and the most important transcription factors in our blood—but it is doubtful that this will be patentable intellectual property, or that the investors would be able to maintain a trade secret.  What we need is a substantial public investment or a middle-aged billionaire angel investor who is thinking clearly about his own destiny a decade or two down the road.

54 thoughts on “Ambitious New Anti-aging Trial in Humans

  1. Very interesting, and kudos to the Life Extension Foundation for taking the bull by the horns and actually trying something.

    We badly need some machine learning to unpick all this for us however. Get some cells in vitro, passage them to senescence, map all the telomere length gene expression changes. Immortalise the same line with telomerase, see what genes are restored. Then passage the immortal cells, see what else changes. Try and control for the artificial environment by comparing such cells to similar (Horvath) age cells from an older donor. Then you can start messing with transcription factors. Some of this work, but not all, has been done by Shay and Wright.

    Until we do this kind of work, even if young or filtered blood helps, we won’t have the foggiest how.

    • I do machine learning as my day job, almost entirely supervised image processing.
      I would start out from Illumina480k (or even bigger resolution) datasets and would mostly concentrate on in vivo samples taken from people of different ages.
      If only I had the time (or financing) for this.

    • Excellent experimental suggestion. There are a couple of papers from the Shay-Wright lab (one by Joe Baur, who is now studying nicotinamide riboside in his own lab) that did a tiny part of what you propose… but that was back before there were gene-expression arrays.

    • There is another line of research that is slowly gaining traction: understanding how IPSC reprogramming works.
      Two interesting papers came out recently
      Chromatin Accessibility Dynamics during iPSC Reprogramming
      This one is available on Researchgate

      Transient and Permanent Reconfiguration of Chromatin and Transcription Factor Occupancy Drive Reprogramming
      This is unfortunatelly paywalled

      Both cam out in Cell Stem Cell Volume21 Issue 6

        • I am starting to doubt the scientific value of Belmonte’s research. There is no followup research, only marketing.
          They might have found something but that maye only work in progeroid mice only.

          That monkey cloning experiment is also interesting. They advanced the otherwise pointless animal cloning research from 20 year ago with the help of epigenetic reprogramming. They could ckone monkeys successfully only when then demethylated H3K9

          • Belmonte recently published a review paper entitled ‘Elixir of Life Thwarting Aging With Regenerative Reprogramming.’

            I haven’t read it yet and it’s not open access, but you can get it through sci hub.

          • There are factors of aging that cause epigenetic changes. The idea I would think is to find those factors and eliminate them. Even if we don’t know what are the factors, if we could find ways (agents) to stop/ reduce the epigenetic change that leads to aging, it will work as well. Forced reprogramming or transdifferentiation sounds way too risky IMO. I do not see how it’s going to work in vivo in a non progeria model.

    • I think there’s a place for high-risk research. You take a shot in the dark and sometimes you get lucky. But in case we don’t luck out on this first try, I think we should hunker down for the meticulous work of trying different blood fractions on different schedules.

      • Josh, in view of the difficulty in getting funding support for such a project, I suggest that the best way is to go for a methodology which has a very high chance of success.

        The proposal you outlined has a high chance of failure. And that will impact future funding possibilities.

  2. Could the aging factors in the blood be a plethora of miRNA exosomes produced by the hypothalamus? “Hypothalamic stem cells control ageing speed partly through exosomal miRNAs” in Nature 548, 52–57 (03 August 2017) doi:10.1038/nature23282

  3. Great article. How then about sending your book to a bunch of middle aged billionaires and explain how they can get involved in extending their own life?

    • Even young or very old billionaires would be OK… the important part is the “billionaire” 😉

      There are numerous new cryptocoin multi-millionaires… their sort might be very interested.

  4. Hi Josh, thanks for referring to my paper of five years ago, but I actually first proposed the procedure to Aubrey de Grey in 2010 and proposed it in person to those involved in the Young Blood Institute. I don’t believe the groups presently working on a variant of my HPE (Heterochronic Plasma Exchange) are doing it correctly and people will be spending large amounts of money to put themselves at risk for what I believe to be a short-lived effect at most. Note that I do believe that the path lies in the direction they think they are going – but I believe they are making some fundamental mistakes, and their approach seems more exploitive than scientific.

    • Professor Katcher,

      I very much enjoyed your Biochemistry (Moscow) article.

      Here, you write:

      “I don’t believe the groups presently working on a variant of my HPE (Heterochronic Plasma Exchange) are doing it correctly.” And: “I believe they are making some fundamental mistakes.”

      Could you please explain why you think they are not doing it correctly, and making fundamental mistakes?

      Thanks,
      Brian

    • Hi Harold,

      I read your paper and must say you are pretty convincing about aging being imposed on cells via external signaling rather than it being intrinsic, irreversible damage.

      Did you read the news published about a year ago about a clinic in Greece using platelet rich plasma to reverse menopause? I read it in New Scientist but haven’t seen a peer reviewed paper on it yet. Perhaps this is further evidence of some fraction of blood regenerating old organs, in this case the ovaries?

  5. I don’t know if any other countries are practicing this procedure in hospitals. But I know from personal experience in China if someone is dying, if they have money or connection, they will be given albumin, which might help boost their energy. If album doesn’t work, they will then be given blood transfusion. In my grandmother’s case, she was dying because she was 92 and very tired, they gave her some albumin, it helped her to stay awake longer, she felt less tired. The effect only lasted 2-3 weeks. In my mother case, she was dying of lung cancer. Albumin didn’t do anything, but blood transfusion worked. Doctors I talked to believe blood transfusions can extend life of the very sick in a matters of days. They were trying to keep my mother alive for me to rush back from Ecuador to China (it took five days for me to get back as I needed a Visa), plasma did boost her energy even though she was not dying as they thought, she lived 17 more months. Unfortunately I didn’t pay any attention as what type of blood transfusions were given. I only know it was not whole blood nor was blood plasma.
    Just thought I share the experience in case it might help.

    • Albumin is often low in ill or elderly patients due to kidney issues, cirrhosis, heart issues, malnutrition, or inflammation.

      In those cases Albumin will help, temporarily.

      Elderly or chronically ill patients are often also anemic due to low EPO (Erythropoietin) levels, iron deficiency, or just anemia of chronic disease.

  6. I agree that life extension deserves some credit for trying something for those who are elderly and may not have time to wait until the next best and proven therapy arrives. On the other hand, I can easily see this failing and the approach labelled as quackery by a bunch of ” crazies trying to live forever”. That could really set us back.
    Just look at a very proven drug like rapamycin, where we know a great deal about both its effects and side-effects, but the vast majority of medical professionals view it as very dangerous and unproven. Most patients refuse to even try it. Labels are very difficult to overcome.

    • Hence why we need a billionaire who is immune to reputational damage. We’re getting there in terms of treatments that might actually work, so I think there’s a good chance an older billionaire will want to try to push a treatment across the finishing line.

      Anyone know how much Libella Gene Therapeutics are changing for their telomerase AAV gene therapy?

      • I don’t know how much Libella is charging and neither do I know why they don’t disclose that price on their web site.

        The only comparison point that I have in mind is the price tag that Spark Therapeutics wants to charge for LUXTURNA, the first ever FDA approved gene therapy, which is 850K for two injections (in both eyes).

        https://www.aao.org/headline/spark-unveils-850-000-price-tag-luxturna

        Obviously, I don’t expect Libella to charge that much. Spark Therapeutics need to generate more money than what they have paid for all the trials to get the FDA approval, which is not the case for Libella. But the point I want to make is that gene therapy is still in its very infancy and by no way a routine procedure.

        • Apparently producing all the adeno associated virus vector is the expensive part, at least for the Libella Therapy – I don’t know, but expect this will be a similar limitation on all gene therapies using this vector. I hope this can be overcome so these type of therapies become accessible to all.

          • My day job used to be making lenti vectors… they were easy and cheap to make. Just a little hazardous if they ever got their gag and pol back…

      • There are innovative doctors specializing in aging that may prescribe it for you.

        The drug and doctor’s visits for follow up, most likely will not be covered by insurance simply for anti-aging purposes.

        You can do an internet search for a doctor.

  7. Regarding the Swedish Transfusion study: Perhaps results from one emergency hospital transfusion is not enough to influence the recipient’s health.

    From Josh’s post: { “Full plasma transfusions from young donors would do both, fully replacing the blood environment of an old person with the blood environment of a young person.” }

    If this turns out to be true, I think it would be interesting if people could store their own frozen blood plasma while young, in a blood bank, similar to the way they store umbilical cord blood, then transfuse it back when older. This would avoid any rejection or unknown disease issues.

      • Josh:

        There are adverse reactions to blood transfusions. They may be rare but there is always a risk with whole blood transfusions.

        Of course w
        “The most common immediate adverse reactions to transfusion are fever, chills and urticaria. The most potentially significant reactions include acute and delayed haemolytic transfusion reactions and bacterial contamination of blood products.
        Blood Transfusion : Adverse effects of transfusion”

        https://www.rch.org.au/bloodtrans/adverse_effects/Adverse_effects_of_transfusion/

        Also adverse reactions to albumin and packed platelets only are possible.

        In an emergency it is always a risk benefit.

  8. Hi Josh,

    The immortality of the individual, if it would be achieved, would mean the extinction of the human species in the long run.
    It is obvious by a thought experiment why.

  9. They are going to charge people $50K to participate in their research? Doesn’t that violate all kinds of research protocols and create bias in their population sample? This smells of “we are doing this primarily for profit, not for research”. For me this just ruins the entire project.

    Why isn’t someone doing this study on animals? The animals can be sacrificed, and we can measure actual changes in brain tissue and muscle tissue. I don’t understand why they would make humans the first target.

    The right way to do this is to fund animal research until they locate the actual substances that need to be removed from the blood of old animals. Then – applying that to humans – it could be done as immunoadsorption of those specific proteins. That would be a much cheaper and much safer procedure for humans as well.

    • No, the plasma study violates nothing, because it is a private study.

      Also, because as stated in Josh’s article: “No FDA approval would be needed for a clinical trial, using transfusions “off-label” to test rejuvenation potential.”

      In the end, the only really valuable studies will be studies on humans.

      Animal research is tantalizing but the results do not always translate to the same outcome in humans.

      I think the people doing the research are interested in acquiring real and useful answers, so, no, I do not think it will continue primarily and only for profit.

      It will only likely continue if it works as expected.

  10. Stimulating SIRT4 gene activity lead to a 20% increase in healthy lifespan in fruit flies
    Jason Wood . Proceedings of the National Academy of Sciences. 2018.

    Sirt4 is inhibited by mTOR. So bring on the rapamycin ( yet again)

      • Yes. And growth is bad. I remember my grade school teachers telling us to stop doing something because it would stunt our growth. Wish I could remember what that was!

          • ” The average lifespan of a ( Lord of the Rings) Dwarf is 195 years which is a bit lower than one would expect considering that the age of the oldest Dwarves exceeds 250 years”.

            They probably never eat.

      • Eating is not a negative. It’s eating too much that will kill you.

        Short people tend to gain weight more easily with fewer calories.

        Remember it’s “calorie restriction with adequate nutrition” that shows the life extension benefit.

  11. Has anyone looked at CohBar Inc. (presumably contraction of Pinchas Cohen and Nick Barzilai, two founders of the company), the first private company to explore mitochondrial derived peptides to treat age related diseases?

    There was an interesting post from Josh recently about mitochondrial peptides, mentioning Dr. Cohen as an expert in Humanin (a promising mitochondrial peptide for neuroprotection):
    https://joshmitteldorf.scienceblog.com/2017/07/25/mitochondria-in-aging-ii-remedies/

    It is interesting to note that the startup has already quite a decent market cap of 250M despite its very early stage and almost no revenue. They are planing to start human trial in 2018 to target NASH and obesity using a MOTS-c analog. Their next targets should be Neurodegeneratve diseases and cancer.

    • I like the science, i like the people, i have not had an opportunity to review their economics, but purely from an financial side of things, i dont like the fact that: only 0,76 of outstanding shares are hold by institutions. I will have to check insider ownership also.

      Longevity wise i love that we have scientist looking into mitochondrial peptide sciences. Look at the peptides on the market today, the potential are HUGE.

      • Yes you are right that less than 1% of shares are hold by institutions and most of them (0.7%) have been purchased by “Optimum Investment Advisors” during this quarter.

        However, the stock price has tripled since last October and volume has picked up, which I see as a positive sign. It looks like some people have started to get interested in the story. Hopefully institutional ownership will slowly pick-up with the beginning of human trial on NASH and collaboration deals.

        I don’t own any stock of CohBar (but obviously I wish I had bought stocks 4 months ago). My interest is mostly in their science. It looks like mitigating the aging process is starting to be seen as a viable investment!

        • Let’s hope that something comes of it. I also read a science news report that Blagosklonny is testing rapamycin for a longevity effect in marmoset monkeys.

          • In the same kind of lines, have you seen the recent study of Matt Kaeberlein?

            “A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs”

            One interesting finding is about a possible improvement of heart function, which you said could have happened in your own case after taking rapamycin:

            “Echocardiography suggested improvement in both diastolic and systolic age-related measures of heart function (E/A ratio, fractional shortening, and ejection fraction) in the rapamycin-treated dogs. “

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