What is in E5? Harold Katcher’s patent

Harold Katcher’s patent was unveiled last week, and it’s not what I thought it would be.

I thought it would be a list of several molecular forms, together with recipes for how to make them and how to administer them intravenously for increased longevity. 

I hoped it would inspire laboratories around the world to replicate Harold’s results and to vary the formula with the intent of optimizing results and streamlining delivery. I imagined a quantum advance in parabiosis-derived experimentation. 

Instead, the patent seeks to cover a broad range of techniques for extracting proteins and entire exosomes from blood plasma. It may be designed to obfuscate. I am unfamiliar with patent law, and this may be entirely conventional; instead of giving explicit instructions that another researcher can follow, there are several alternatives at every step, with the claim that they are all variations on the basic technique, and the patent covers them all. I presume that Harold knows which of these options at each step are the ones used to create E5; but no one reading the patent could recreate Harold’s work without some inspired guesses.

Background

Ever since the Stanford parabiosis experiments of 2005, there has been evidence that aging is centrally coordinated and that the blood transmits information telling the body how old it is. Young tissues quickly deteriorate when exposed to the blood plasma of an old animal, and old tissues are rejuvenated in the presence of young blood plasma.

So the pressing question is: what is it in the plasma that transmits these signals? Is it predominantly pro-aging signals that need to be removed, or predominantly anti-aging signals that need to be enhanced? How many such chemicals are there? Are they proteins or active RNAs or something else?

These are difficult questions because blood plasma contains thousands of molecular signals in trace amounts. The quantities vary with activity and time of day, and many of them vary with age. We would dearly love to have a recipe for a handful of transcription factors that need to be added or removed, with the result that they would trigger readjustments in the rest. 

I had assumed until last week that Harold has this information, and that he has held it back from the public while his business partner secures patent rights and builds a distribution network for humans. 

But now it seems that Harold has general knowledge of the class of chemicals signals that is most effective, but that he does not know specific molecular formulas. Indication is that it is a class of proteins. 

Harold has told us that he has been building facilities for synthesizing E5. The patent seems to say that he has some techniques for extracting from plasma a cocktail of many substances that remain incompletely characterized. Akshay has told me that they get plasma from pig’s blood, discarded by butchers.

There are large proteins and short peptides and everything in between. A “plasma fraction” may contain a specific range of molecular weights. But in the patent, several different ranges are listed, so we don’t have the crucial information, “which range is the effective one?” I presume that Harold knows.

Perhaps among readers of this blog there are people well-versed in biotech patent law and others who know more about the biochemistry of blood-derived proteins. If so, please contact me and respond to this patent from a more informed perspective than i can derive.

Imperative for the near future

We know that the active ingredients are proteins, and Harold knows the range of molecular weights. Several different ranges are listed in the patent, and several fractioning techniques are specified for specifying them. I presume that one of these leads to successful rejuvenation and the others are decoys. 

So, the next step will require Harold’s cooperation, because even after publication of the patent, no one else will be able to replicate his formula. If he and Akshay are willing to subject E5 to laboratory analysis, then the protein constituents can be individually characterized. I personally don’t know how this is done, but I do know it is possible because biochemists generate pictures like this one routinely.

The number of chemicals in a given range of molecular weights is probably small, perhaps a few dozen; and of these, the active ingredients necessary for the formula to work constitute a smaller set, perhaps less than a dozen. Once we have the chemical formulas for all the constituents of E5, we can test different combinations of them and within a year of trial and error, we should be able to identify the minimal effective set. Then these can be synthesized in a modern factory and we won’t need a river of pig’s blood to rejuvenate humanity.

Harold is not the only or even the first to conduct research with blood-derived proteins inspired by parabiosis experiments. There is ongoing research at Stanford, Berkeley, Harvard, Alkahest and now Altos Labs. 

The next steps are crucial, and they will require more investment than Harold and Akshay’s Yuvan Research has available. I hope Yuvan will partner with a laboratory that has resources to analyze E5 and then test constituent ingredients to optimize rejuvenation effects with a minimal set of injected proteins.

120 thoughts on “What is in E5? Harold Katcher’s patent

  1. The Conboys have shown that blood dilution is as effective as young blood transfusions; and with much fewer issues. Blood transfusions can cause many problems.

    However donating blood and getting saline top up would fit for “old blood dilution” purposes one presumes?

    • Orion, blood donors live longer. It is most easily explained as iron reduction.

      One should also remember that blood transfusion is different than plasma. I learned that during the birth of my first child.

    • Yes, I understand that there is controversy in the field. Is dilution the most important thing or is addition of youthful factors more important? I respect both sides until we have more data.

  2. Josh, are you forgetting the partnership with Johns Hopkins? They should have all the resources you suggest are required.

  3. Let me precede this the following: I hold three utility patents, one at the USPTO and two of them were PCT filings – all approved and published. Of course I’m no expert on the matter but in general patent claims should be broad enough to cover various implementations, even some that have a lower likelihood of being realized. At the same time patent claims should not be excessively broad as to avoid having said claims challenged.

    Either way you look at it, the purpose of a utility patent for example is NOT an instructions manual on how to replicate a particular method or process. It’s sole aim is to establish a competitive hurdle that competitors would be forced to infringe upon should they seek to replicate that method or process. Almost all challenges to a patent are based on disproving uniqueness (e.g. via prior art).

    Manufacturing patents can be even more cryptic as the focus is on process and not on end product or result. The very same process may even be used to produce a diverse range of products or in this case biological compounds.

    I have not had time to study Yuvan’s patent but I suspect that it falls into the latter category. As much as I can appreciate your disappointment after reading the patent I feel that you may be jumping a bit to conclusions.

    The fact that no specific proteins or peptides were mentioned does not preclude the possibility that Harold and Akshay in fact have identified a number of them that seem to be promising. It’s very much possible that the competitive advantage lies not so much in identifying the actual protein or exosomes but in how to synthesize them in larger quantities.

    As I’m not a bioengineer or scientist I of course am at a distinct disadvantage in rendering an educated assessment of this patent. My goal in posting this was to focus the ensuing debate (which I’m sure will be heated) on the patent’s merits and its main purpose: to establish competitive hurdles and to justify future investment in Yuvan.

    • Well said Michael! Natural compounds cannot be patented, but processes can.

      If E5 is a mix of substances, then the relative ratios of each can remain a trade secret as I understand the term proprietary formula. This may be another way Akshay and Harold can be justly rewarded for their efforts.

  4. Thank you Wayne and you are right. Which biotech has runs workshop for a 100 labs explaining how they make their therapeutic? It would be crime against the current investors. Also if those 100 labs were more proficient then shouldn’t they have invented E5 by now? Of the names mentioned Conboys are focusing on dilution, Altos as per announcements is focusing on cellular reprogramming so is Harvard start up. Only Alkahest is developing therapeutics derived from plasma and it is interesting to note and only they have 3 products in Phase II with FDA. No one asked Alkahest to give away detailed workings of their technology to a 100 labs. We are talking about handing over E5 development to bigger firms. But huge funds does not guarantee success. Otherwise Calico should have cured aging by now. They have funding in billions and been at it from a decade. And let us not dismiss transpecies invention of Harold. First of all it’s not possible to get blood from humans just after puberty and it would create major hurdles in mass production. This huge barrier has been demolished. We did not create the meat industry but it is there and it does have what us a waste product for them which they spend millions to dispose. It is not easy to make use of that which highlights the importance of this patent. Synthetic biology takes years if not decades to translate into a product that FDA will approve for humans. The mRNA vaccine technology was in development for 2 decades and were it not for a raging pandemic it would have taken another decade for FDA approval. The best possible team that understands the molecular mechanisms underneath these inventions is working on bringing this out as a product. If we have the results we would get the resources we need. It is good to be underestimated. We are very grateful for all the support given to us here by Josh and his readers 🙏 please continue to indulge us with your faith. Be rest assured the steps needed to be taken to make E5 available to everyone are clear to us and are being implemented one by one.

    • I’m watching intently from the bleachers.
      I’m happy to see progress coming out of the parabiosis observations as it seems like a fertile area to invest.
      Please update the community when you can.

      • Thank you Dave. If you read here often then you will see our first updates are here and we regularly update.

    • Thank you, Akshay. Well said. I’m glad for your presence on this forum, and I hope you understand that my position as a public advocate and yours as an investor might differ in details, but in the end we are after the same thing. We both want to see E5 get out into the world, and we both want to see you and Harold appropriately rewarded for an enormous gift to human wellbeing.

      • Thank you Josh 🙏 Harold and I are eternally grateful to you for being the first believer in us and for posting our results on your very popular blog. We won’t let you down.

    • Hi, Akshay:
      Have there been ANY animal plasma fractions injected to humans before?
      Are there no significant risks with such transfers?
      I am not a biologist, so I cannot know if and what potential risks exist. Being a layman, I would suspect possible infections & or cause of autoimmune deceases. Do you anticipate any possible problems?

      • Hi Zisos, There are xenographic organ transplants that occur all the time but they do trigger immune responses. Rapamycin in fact is used in high doses to beat down that response. In our case E5 components are purified to such an extent that they do not contain any material that would trigger immune reaction. Whatever we infuse is so highly conserved across species. Of course this is a novel step and Harold gets credit for discovering something so big. We have conducted 4 studies till now with zero immune issues. This works and it’s safe. If this becomes approved therapeutic that helps millions then he would deserve a Nobel prize.

        • Good to hear that you are confident there will be no risk.

          On May 14, 2020, in the “Age Reduction Breakthrough”, I have posted that “… if the success in human trials proves to be similar to those with rats, the two will be written in History as the Greatest Benefactors of Humanity.”

          I am even more convinced now that you and Harold will be written in History. And that is much more than a Nobel Price.

          • Thank you so much for your kind words Zisos! 🙏 You and your family are very special to us and to E5 in that rare category of being one of our early backers/investors. We continue to work on crazy stuff which all I can’t reveal now but while we work hard to make E5 available we are also working on the next version of E5 and pulmonary delivery of E5. Can you imagine taking 5 puffs everyday to continuously remain in a youthful healthy state?

          • That is true.

            On an individual level it is massive.

            But how will the earth handle 50 billion humans trotting about, is an entirely other matter.

          • With immortality, we’re not limited to the Earth. There’s a whole universe to explore and colonise. Overpopulation on Earth won’t be an issue.

          • Good point..but what if interstellar space travel is impossible?

            and if that is true..then you have to ask if there really are aliens
            flying around earth as the US military is suggesting

            Then where do the aliens come from? HAHA
            This is actually a question related to evolution….. are we to really believe that humans were the first intelligent species to evolve in the last 500 million years of animal evolution?? Carl Sagan pointed to the vastness of space and said how is it possible that we are the only intelligent species in all of this.. Maybe he should have pointed to the vastness of time and asked how is it possible that we are the only intelligent species to evolve? Just food for thought HAHA

          • I bet you can tell I watch a lot of ancient aliens on the History Channel

          • LOL You’re funny Jeff!
            Of course, there are MANY questions yet to be answered about our huge universe (which really gets to the point of why I want to live for a long time … there’s so much more to learn and discover!!)

            To address your points (which are just my own opinions):
            * I don’t believe there’s been any solid evidence yet about UFOs, so I proceed on the basis that they aren’t real (until evidence is provided);
            * We don’t require interstellar travel (yet) – Mars is already on the cards, and who knows, perhaps the ideal solution is artificial orbiting habitats with human biology being modified to support zero-G environments;
            * What you’re describing re: odds of us being one of the first conscious lifeforms to evolve in the universe is the so called “Fermi Paradox”. There aren’t any conclusive answers yet, so a lot of it is just speculation. It’s likely given enough time (again, there’s that pesky time thing which requires anti-aging cures to give us enough time) that we’ll eventually solve the paradox, but I confess, the thought of our species being the first or one of the earliest lifeforms to evolve is for me, super exciting! That would mean we’re the early pioneers and in the far future, other species might refer to us as “The Founders”. Who knows!

            So, first and foremost and immediately important is: we (those of us currently alive) need E5 if we’re ever going to enjoy a bright future (I refuse to accept that we’re so stupid to continue in our childish ways, so I assume we’ll grow up and our future will be bright).

          • Here’s a nice lifespan.io article discussing population dynamics in the context of increased longevity: https://www.lifespan.io/news/overpopulation/ As it turns out, eliminating senescence wouldn’t have that big of an impact, but even if it did, I think Aubrey de Grey first pointed out that if aging didn’t exist, surely, we wouldn’t invent it to solve a potential overpopulation problem as there are way better solutions that don’t involve killling people; and even then, aging isn’t a very efficient or “desirable” way of getting rid of billions of people. But enough rambling, the article is long enough on its own.

  5. My take on reading the patent was disappointment in realising that even Harold doesn’t know exactly what in the plasma is doing the business. Could explain the variable results.

    • Mark what you have read is our foundational patent. Wait till you get a chance to read our subsequent filings. You would be less disappointed.

    • Mark, as I understand it, Harold created his elixir based on targeting specific aging pathways. I am certain he knows more about what is going on than you or I ever will.

      • Harold’s previous papers only talk about the usual suspects: GDF11, Oxytocin, etc. If he didn’t have special knowledge then,.why now? What he had was an unshakeable faith that aging is a top down process and had the balls to run experiments to attempt to prove it.

  6. I happened to spend most of the week writing patent disclosures and editing the claims of an application, though none of it in the field of biology. The words “in one embodiment” are seen a lot in the claims. I don’t think it necessarily represents an effort to obfuscate. One wants to protect the intellectual property and not give an easy workaround to a competitor who may use slight differences in construction to beat your claims. So, you list all the variants that you can think of, as possible embodiments.

    • Can confirm Steve’s comment. I have literally studied hundreds of patents in my time and the phrase ‘in one embodiment’ is commonly used by patent attorneys. In fact I challenge you to find a utility or manufacturing patent where this phrase does NOT appear 😉

  7. Unfortunately my attempts at posting never go through for some reason. So I am entering this now just get the continuing comments.

    • I have a similar problem, to sign up for notifications to comments on new post, I must post a comment under it. There is no separate switch for this directly on a notifications management page.

      • I’m not sure if this is helpful, but Josh’s site is hosted on WordPress. Maybe go directly to WordPress, create an account and login, then check your Profile page.
        I know there are some options relating to which pages/posts you are subscribed to and if you want notifications (if I recall correctly).

      • Go to https://joshmitteldorf.scienceblog.com, then click on Subscribe (just under the Search field at the top right of the page … make sure you are on the Home page of Josh’s site).
        Then you’ll receive a confirmation email. Clicking Confirm will take you to subscribe.wordpress.com where you can manage your subscription and notification options.
        From that page, you can also sign up to WordPress for easier access (although, strangely, I can’t find a link back to the subscriptions page once I sign in, so it might be a good idea to bookmark subscribe.wordpress.com for future changes to your subscription settings).

        HTH.

        • Thanks Toby also for your insight. Perhaps with these tips you’ll see me chiming in to this incredible and historic on going conversation.

      • Thank you! For the tip. I have been following the blog for YEARS but could never get any “Comments” posted. I will try your advice the next time I want to post something.

  8. Harold’s first attempt was what I call the Kentucky Fried Chicken recipe. 10 herbs and spices that he administered to mice, designed to hit a list of molecular targets, that his broad knowledge and insights have identified over the last several years. He stated that it took four months to see the rejuvenation effects of this combination of agents. The rejuvenation effects demonstrated by these supplements provided confirmation that the targets Harold identified were in fact therapeutic / age regressive. Because the equivalent timeline in humans would translate to years on this regimen, he utilized the targets of these supplements to stratify the molecular weights of the corresponding pathways the supplements were addressing. I am sure that other insights were also incorporated into the stratification of the plasma fraction. Much of what I describe above is supposition on my part, but I don’t think I am very far off the beaten path.

    Yes the obfuscation in the patent is quite intentional and all modern patents incorporate the same (this or that) parameters to protect and broaden the scope of their patents. Harold and Akshay have a excellent patent attorney.

    The only way to reverse engineer the actual proteins would be to know the actual molecular weight parameters of the 12 fraction stratas they are filtering for. Then compare those weights against the mol weight of a list of known anti-aging factors. You would then be able to produce a list representing the constituents of E5. A requirement of all patents is that someone familiar in the art of the patent must be able to reproduce the same result. I believe that this is possible from what is disclosed in their patent, but it would take considerable laboratory resources, effort, and insight into the targets responsible for the benefits identified.

    Harold and Akshay have many hurdles to overcome and it will take several years to accomplish them. They have a lead process to formulate E5 that will need to be further refined. They have a regulatory process that will be hell given the xenogenic nature of the source(s) of the plasma fraction. This last problem resolves the largest problem of acquiring the benefits that young blood/plasma provides. The availability of young human blood is both a question of availability and ethics. Harold genius insight into the bioequivalence of all mammals’ proteomics aging factors, unlocks unlimited availability of these plasma fractions. This is a huge advancement for all medical science. Clinical trials after regulatory approval of the GMP production of the animal-derived plasma fraction will be long and protracted. An NDA is 7 to 10 years away. Last but not least, there are many patents that have claimed plasma fractions as disease and aging ameliorating inventions. I would not be surprised to see this patent challenged. Alkahest, a division of Grifols would be the company hot on the heels of both their patent and their research/technology pathway.

    In the interim, my suggestion would be to commercialize the supplements that Harold utilized to validate the targets of E5 and that demonstrated rejuvenation effects in the mice. If it tasks a year to start reaping the benefits, so be it. Lots of finish and fill contractors for nutritional supplements could have this product on the market in a few months. It would also help to fund the development process that as Josh indicates will be substantial, well north of 200 million.

    • MichaelatARC you have such a good understanding of patents and biotechnology process from idea to product in the market. Thank you for sharing your insights here.

    • The herbal mix was a completely separate experiment but was not taken forward as it was likely acting as a calorie restriction mimetic.

  9. His book the Illusion of Knowledge claims that he identified a single or a few agents that are conserved across species. He makes the claim that has become increasingly popular since the 2005 Convoy parabiosis work that aging is not entropy driven but programmed by evolution to increase the rate of turnover. The world patent looks just like my world patents where you are trying to cover a space. He will need to get far more specific in his embodiments in a US patent and disclose his preferred method. By the time he had that done human trials might be started although big pharma is going to throw a fit as at least in the short term people will need fewer symptom pills.

  10. I have always suspected that somehow Harold is extracting something similar to Yamanaka factors from the plasma..the big clue is his injection protocol

    2 injections on day one then 2 injections 2 days later and no more in the short term?
    this seems like he is trying to avoid the point of no return that occurs when animals are injected for more than 5 days in a row and then all their cells start turning into embryonic stem cells then they die.. People who use transient expression of Yamanaka factors for aging reversal adopt similar injection protocols to Harold’s.. But I was under the impression you could only get a meaningful amount of Yamanaka factors out of embryos.. So maybe Harold has found a way to get them from older individuals? If it truly is some sort of novel plasma derived factors unrelated to Yamanaka factors then I don’t understand why he chose a protocol of 4 shots over 2 days…why not everyday for 6 months?

    • Hi Jeff it’s 4 injections given every alternate day. So a total of 4 injections over 8 days. It’s not yamanaka factors. There was mathematics in arriving at the dose.

  11. Really amazing and interesting.

    My only concern was that the lab I saw in one video just looked rather common and un professional and truly Indian standards.

    After having lived in India for almost two decades, I was just concerned that under such casual lab conditions, anything could be manipulated or fabricated to stimulate hype and investment.

    Regardless, the reported results and potentials of such a venture are unfathomable and magnificent.

    All the best and many blessings.

    E5 = Sat Chit Anand 🙏🌺💚

    • I think the experiment that was the study reported in the preprint where aging was rev was reversed by 54% carried out in California by Steve Horvath’s lab probably at UCLA..Harold brought him the E5 I believe…So I have question for Ashkay…what would happen if you gave the rats E5 for say 8 days straight? everyday have you ever tried that?

      • Thanks Jeff. 8 straight days is possible but subject to the approval of a IACUC committee. We do think similarly. I will email you privately on this.

  12. It boils down to one question. A full reveal or not . What serves humanity better. I believe either decision has its merits and problems. Which would provide the better timeline and effectiveness. I trust in Harold and Akshhay’s decision.

  13. Sorry to post a secondary post so quickly. What comes to my mind are the lyrics from a song.

    Look what they’ve done to my song Ma. They’ve picked it clean like a chicken bone and it’s turning out all wrong Ma.

  14. The patent uses the same figures as in Katcher’s book, Illusion of Knowledge”. He claims that it turns out the aging mechanism is very simple and conserved from fish to humans. He further claims that E5 is a very simple youth promoting agent that decreases with age. In other words, proaging agents only respond to a lack of E5. If you remove the pro youth agent all the inflammation agents become dominate. It seems almost too good to be true but from an evolutionary standpoint it makes a whole lot of sense.

    If you are say, 80 years old and have only 2-5 years left of poor quality life shouldn’t it be your right to by pass the the feds who will drag this out for a decade or more?

    • I think it must be more than one factor, or a mutant could easily emerge that lacked the appropriate lifespan. If it is one factor, the cell population that produces it must be under the control of many genes to atrophy or many check points for its production must exist to make it very difficult for mutation to escape aging.

  15. I suppose it’s nice being reassured that Harold and Akshay aren’t trying to lead any other researchers astray, that their intentions are good, and they are just navigating the exigencies of patents and the concerns of their investors in a way that assures continuation of funding and furtherance of their work. But I never suspected otherwise, so the comments here speaking to that mostly just make me yawn.

    Let’s take a step back instead, and openly state what ought to be obvious: Science struggles under onerous sociopolitical structures that do much to hold it down. Science should have nothing “obfuscatory”. There should be no “decoys”. Everything should be an open book, and it should be like so from the get go. We waited years to see this patent with next to no information?!

    It would be highly desirable not to have to answer to investors and more broadly, the oligarchs behind them. They think not of the public interest, but only their own pecuniary well-being. I’m not a researcher myself, and while I’m fairly knowledgeable and clever, I may never make a contribution to a cure for aging myself. But if I were in charge of a central bank, the funding landscape would be very different and I could totally bring about a cure.

    Of course, getting me in charge of a central bank is not a practical objective. But might there be some other way to shake off the yoke of the plutocrats – some way to allow science to operate in a different context, where it might flourish? I have in mind a grassroots approach. Are there not communities of bio-hackers? Are there not DIYbio facilities? Are there not further ways to take advantage of waste? (Kudos on obtaining pig blood from butchers. I know someone who trash picked an electron microscope being discarded by the University of Chicago. (Yes, an electron microscope.)) Are there not websites where one could obtain crowd funding? Can we not knit all this together in a grassroots, wisdom of the crowd sort of Manhattan project and cure aging? Who out there can be such a knitter?

    The more options/avenues/pathways we have, the better. It’s great that we have different labs working on different approaches. We have the parabiosis, blood plasma signal approach. We have Greg Fahy’s work pertaining to the thymus. We have people working on clocks… Who knows, maybe even the ‘aging as damage’ people might come up with something useful. But there’s a sense in which we still have all our eggs in one basket; this milieu of proprietary nonsense. Let’s open source and crowd source the heck out of this. (All the while still rooting for Harold and Akshay, and everyone else.)
    One more time: Who out there can be a knitter?

    • So Fred as far as E5 is concerned I have some good news for you: Subject to us getting great results in our topical E5 human trial we may be able launch it without needing the full regulatory approval. Disclaimer: this still needs to be confirmed by our regulatory attorney. But if we can then I dont know what biohackers will do with it (wink).
      Second: thanks to our Medical Director we might get an IRB approval for a human clinical trial of E5 as early as end of this year which would set us up for a trial early next year. We may be conducting all the tests on the volunteers here in US at Stanford Medical or Johns Hopkins but the E5 infusion may be off shore at a licensed high quality medical clinic under US doctor supervision. If this trial succeeds on all counts including safety and efficacy the clinic may continue to offer this to customers who want to fly in. Knowing Harold and me it would be available at a reasonable cost for the E5 treatment itself. How is that? 🙂

      • I’m Waiting for Harold to come play tennis with me.

        I mean you guys should at least prioritize getting Harold to look and feel twenty eight again, not only for his health, but also promotion of E5 and further research and discovery.

        All the best.

        • Yes that would be pretty irrefutable (especially if he beat you)!

          Although personally I’d like an offshore option Akshay, I’d have thought that the FDA would not be too happy with that approach.

          • Mark that’s what I thought too but we are submitting our protocol to FDA in advance and will incorporate all their recommendations. Apparently many Pharma/biotech firms do their Phase I offshore to save a year. Since we comply with FDA recommendation and our IRB is FDA approved if our safety data holds up we can enter FDA application straight to Phase II. We will have experienced regulatory consultants and lawyers guiding us every step of the way.

          • Amazing….

            So at the very least you hope to have this available for human use within ten years.

            So basically every ten years we would just get a series of treatments and hopefully return to youthful bodies…. with up to three rounds of this working.

            I better start taking better care of my teeth so that I still have them sparkling at 250.

            Akashay, it must feel incredibly exciting and fulfilling to be part of such a revolutionary new chapter for humanity.

      • Thanks for the wink Akshay. I’ve had similar thoughts.

        I find it difficult to believe you and Harold will have the ability to set the price of E5, but I hope you do. I wasn’t thinking about price at all when I wrote my comment, but I have before at times. If a cure for aging ever comes to be, I wonder how I would access it. DIY seems like the best possibility to me. That’s another reason I’d like to see the grassroots, citizen science type efforts I outlined.

        I was speaking to the pace of science in general. Thanks for the good news about bypassing a regulatory hurdle, but that’s chump change – I think the pace of science could be 1,000x greater without the commercial influences. And that matters a lot because I think there is still much science to do here. Maybe you disagree. Do you believe E5 is a cure for aging? That all we need do now is dot some i’s and cross some t’s? Last I heard, most of your treated rats had died, presumably of old age. (If you accidentally stepped on them, don’t be embarrassed to tell us of your clumsiness. We’d all be delighted.) I don’t like being pessimistic. E5 strikes me as a monumental achievement, but insofar as it is, that serves to emphasize how much further we have to go.

        • I must again agree with you Fred … you are indeed quite pessimistic.
          The response to your previous post was in fact quite positive (thanks Akshay!).
          I suggest you go back and re-read Akshay’s and others’ posts – you might start to see things in a more positive light.

          • Thank you Toby you are a True Believer 🙂 Hopefully we will please you soon.

          • Thanks Akshay – out of all the different anti-aging research currently being conducted, I believe Dr. Katcher’s (and yours) research has the greatest potential for success. I am hoping to travel to the USA in 2 years time to participate in one of your E5 trials, if I am eligible for that.

            Also, as I asked in another comment, do you have a direct way (say, email) that I contact you? I wish to ask you a private question off the forum.

            Thank you again Akshay.

            Best, Toby.

        • Fred you do have reason to be pessimistic. The system of regulatory approval is a very difficult one. It takes years and costs a lot. A professor at a major University in US told me he thinks 95% of the research papers do not have replicable results! He thought some of them are outright fraud. We share our lower results but atleast we can assure you they are real. We did a mix gender study and female rat results were lower than male rats so our lifespan study was based on a gender that is less responsive. We have not yet conducted lifespan on male rats. We should get better results as the age reversal seems to be deeper. If 50% age reversal holds up in larger mammals including humans it would be unbelievable. So E5 is ready to that extent. I personally wouldn’t be satisfied and would want to go to 70% reversal or 80% reversal. My goal is to for us to reach to us reaching our biological state of our 20s and maintain it. So we will keep chipping away till we reach that. Lifespan should increase multifold but I do not underestimate Nature as we may find some weapon may get revealed at 125 regardless of youthful health. But on its own safely reversing biological age is a big jump in science. It may help prevent many painful chronic diseases. Apart from disease regaining youthful energy, sleep, metabolism, arousal, appetite for the years we live too would be a great blessing. In my previous reply to you I have shared with you some plans which may be give early access to E5. Let’s hope for the best.

  16. I just read the patent thoroughly, and personally, if I were an independent observer/scientist looking to replicate earlier E5 results, I think I’d be pretty pleased with the level of detail provided. I had two main take-aways from the patent:

    First, the three tetraspanins — CD9, CD63 and CD81 — are called out and highlighted so often in the patent (see sections 23, 98, 108, 190 and 198, and also the Claims paper), that it seems likely that the inventors believe that these three, together or individually, play a primary role in the effectiveness of E5. Not sure if Akshay or Harold will ever comment on this now that the patent is out, but I’d be curious to hear their thoughts on this.

    Second, the patent provides very specific instructions on how to make E5. Specifically, sections 191 through 199 describe in detail how to collect, process and prepare mammal/pig’s blood to produce E5, and sections 200 through 215 describe specifically how to administer it to rats for experimentation.

    It would certainly take resources and time to do all of the above, but if I had lab access, funds and the inclination, I’d think it would now be pretty straightforward to replicate Harold’s E5 experiments, and see if similar results could be obtained.

    So personally, I’m pretty pleased with the patent. Congratulations to Harold and Akshay for getting this first E5 patent written and published!

    • Thank you Brian. You are probably the first here to have fully read it and great and accurate observations. You are good.
      Josh hope you read Brian’s post.

      • Thanks Akshay. You guys really provided a tremendous amount of detail in the patent. Literally, the last third is a detailed, step-by-step description of exacty how to go about creating E5 and replicating Harold’s experiments and results. Personally, I was pretty pleased and impressed.

    • I agree with you, Brian. Once you wade through all the necessary legalistic boilerplate, and get to section 191, things get very interesting!

      After purifying the plasma to remove cellular components, and some further processing, the plasma fraction is sent through a chromatography column to restrict the components to a certain range of molecular weights. Since lower molecular weights are more mobile, the first 10 ml fraction is presumably the lowest molecular weight, and subsequent fractions get progressively higher. We are told that a total of 12 such fractions were taken, and then ¨clubbed¨, and concentrated using PEG 20000. I was confused by the word ¨clubbed¨, but checking Webster Online, I think they simply mean ¨combined¨.

      The material was then placed in a dialysis bag with a molecular weight cut-off of 12-14 kD, and the fluid was allowed to ooze through the membrane into a beaker full of PEG 20000. The concentrated material is basically E5. Presumably, it is a mixture of proteins, with a molecular weight in excess of 12 kD ( lower values would have passed through the membrane). The upper limit is known only to Harold, but since he states that it contains CD81, we know it´s greater than 26 kD.

      I must admit that I was surprised in reading the patent. I expected the components of E5 to be smaller peptides, such as the GHK which is the active ingredient of NEEL. GHK is also reported to change gene expression to a more youthful profile. It would appear that E5 works at a higher level, perhaps instructing cell to produce GHK and other signaling peptides.

      I would like to conclude this post with a humble suggestion for a future experiment. Take a sample of E5 and use HPLC to obtain peaks corresponding to molecular weights of its various components. Then apply the same procedure for obtaining E5, but this time using blood from OLD pigs. Those peaks which are prominent in the ¨young¨ E5, but much smaller (or absent) in the ¨old¨ E5, are good candidates for the youth factors. Conversely, peaks which are much higher in the ¨old¨ E5, might be age-promoting factors.

      • > would like to conclude this post with a humble suggestion for a future experiment.
        >Take a sample of E5 and use HPLC to obtain peaks corresponding to molecular
        > weights of its various components. Then apply the same procedure for obtaining
        > E5, but this time using blood from OLD pigs. Those peaks which are prominent in
        > the ¨young¨ E5, but much smaller (or absent) in the ¨old¨ E5, are good candidates
        > for the youth factors. Conversely, peaks which are much higher in the ¨old¨ E5,
        > might be age-promoting factors.

        Yes! This is just the kind of analysis we need. Maybe somewhere in the world, someone is already doing it. But it would all be so much more efficient if the process was out in the open and Harold were working closely with others who can cross-fertilize his thinking and supply lab resources that Yuvan currently can’t afford.

      • That may not hold true. The aging factors may have a different weight than the youth factors, and not end up included in the fractions you are looking at. To truly find them, you would have to process old pig’s blood and to the same process to find the aging molecules that was done for the youth factors.

        Yes, this is important, but there aren’t enough resources to do this yet. Katcher and Askay are doing their best with the resources they have available. Get E5 tested, and in a Phase 1 trial somewhere for something (not aging) that meets the FDA requirements. This priority number 1!

          • Again there is underestimation of what we are doing with E5 and assumption that if multiple labs work on it there may be some benefit. There is not just characterization but functional characterization happening on amazing equipment- functional characterization means what each of the active components in E5 are doing in the cell. Also the there is no technology available for the improvements we plan to make – our brilliant collaborators are developing cutting edge new methods and technologies to achieve certain goals we have for enhancing the power of E5. To give you a glimpse: for one part of the new technology we need a genius scientist working in a quaint Govt agency (that has nothing to do with aging or health) is helping us develop it and set it up for us in our collaborators lab. Big money can’t buy such guys-only friendship and scientific excitement can recruit them. Our 4th study of mixed gender already reconfirms the same systemic age reversal capability of current E5. Now we want to test on larger mammals and on diseases recognized by FDA while we continue to improve and standardize E5. A great multinational team is working on all of this. Fingers crossed we will all be getting some exciting results over the next several months. I have mentioned earlier that from past events observed in our field huge resources and funds does not guarantee cure for aging – such things have better chance to happen with scrappy outliers. Results will get the needed resources.

          • Just trying to provide other ideas. Josh requested some “out-of-the-box” thinking; I and many others here responded as best we can. It’s all “we who follow” can do to help. You, Harold, and the brilliant people working with you, are doing far more than we can. I wish you great success – I won’t say luck because, as a favorite writer pointed out, lick is the bonus for continual hard work – and the E5 team is doing that hard work.

  17. I agree with Don.

    In the USA, around 367,000 people die of old age (over 55) every DAY, i.e. 134 million per year! I don’t have the worldwide stats available, but it must be huge. Note: 367,000 is my estimate, and even if I’m off by a large factor, everyone must agree that aging is the #1 cause of death globally.

    Is it the ultimate irony that all of us alive today must wait for the next 5-10 years for an FDA approved cure for aging to “ensure it is safe”, and yet during that time 650 million to 1.3 billion people will die (in the USA alone) … but hey, at least they were kept “safe” from any adverse effects of E5, right?

    Surely, Akshay and Harold could do a deal with a company or a Billionaire in a non-regulated country to produce and administer E5 to anyone who accepts the personal responsibility and liability, allowing them to travel to that country for the treatment.

    If it’s a matter of protecting income and commercial interests, surely there’s a way to physically manufacture and store E5 in a highly secure facility in that other country and administer it to customers without ever revealing the formula of E5?

    As Don said, give 80 year olds the OPTION to take E5 *now* before it’s too late, and hey, as a bonus, you get human trial data immediately. Worst case, E5 causes some adverse effects (or deaths), but that was the risk the customers were willing to take i.e. it isn’t Harold’s fault.

    And if all of the above is simply “wishful thinking” on my part, at the very least, can we please get primate testing NOW to allow human trials within the next couple of years? I mean, let’s at least prove that E5 is safe NOW, not 5-10 years in the future.

    Bottomline: a LOT of us are close to death and E5 is tantalising close. Give us the option now or very soon to survive, because even if we miss out on E5 by just one day, we’re still going to be dead forever!!

    • HI Toby what you can try now is tot take Ca-AKG and vit c throughout the day to try and reactive the 36 genes that get shut off with aging that Horvath discovered I am 62 but prematurely gray have noticed after one year on high dose AKG and Ca -AKG my arm hairs ae growing in dark brown again like crazy and my legs and the bottom of my stomach is starting lots of other great things also there was a study by Ponce de Leon company that taking just 1 gram of Ca AKG time release reversed DNA methylation age in older people by 8 years in just 7 months. Human AKG levels decline dramatically with age and AKG is needed to activate the TET enzymes which keep the 36 anti aging genes turned on. Vitamin C also helps this process and is a TET cofactor. That covers the mostly male aging system.. then there is the mostly female aging system which can be reversed or slowed down by taking high dose melatonin at bedtime ( it is the height of the nighttime peak that is important) and maybe DHEA and pregnenolone.. Should tide you over until get E5

      • Hi, Jeff:
        You have had phenomenal improvements with AKG regimen.
        a) With respect to “high dose AKG” :
        Do you mean you take AGK in acid form?
        Can you please be specific as to the form you take AKG, method of delivery, dosage, and frequency?

        b) With respect to Ca -AKG
        What dose you using?
        When do you take it?

        c) Vitamin C
        Can you please be specific with dose, delivery method, and frequency?

        Thank You

        • For those feeling unsafe about taking Ca-AKG due to lack of long term human studies, switching to a ketogenic diet and practicing CR/IF can help increase endogenous AKG. Choosing AAKG is tempting, due to lower price than Ca-AKG, but I’m unaware of any studies using AAKG.

        • HI there for the first 6 months or so I was taking just AKG 2 grams 2X a day….and with that I would take 1 gram of vit C 2x a day and 500 mg ascorbyl palmitate 2x a day then I heard about Ponce de leon using CaAKG where the calcium makes it absorb better they say so I bought a kilo of that from peter at vitaspace (CHEAP) and would add 1.5 grams to a large cup of water and sip throughout the day….maybe 2 or 3 times but I kept taking the regular AKG too. You can read about Peter at JeffTbowles.com check out the save 90% blog post

          • Thanks for the tip Jeff. I’m sure you are already aware of this, but with the relatively large amount of Vit. C you take daily, it’s important to maintain a consistently high glutathione status, or otherwise Vit. C will start to act as a pro-oxidant. Good for cancer treatment, but certainly not something a healthy person would want long-term.

    • I tend to agree with all of the sentiments of your post, but the numbers you cite in the first paragraph are complete nonsense. If 134 million people died per year in the US, the country would be depopulated in less than three years. The actual number of deaths per year in the US is about 2.5 million, which increased to about 3 million during the two years of Covid .

      https://www.cdc.gov/nchs/nvss/vsrr/covid19/excess_deaths.htm

      • To quote my own post: “Note: 367,000 is my estimate, and even if I’m off by a large factor, everyone must agree that aging is the #1 cause of death globally.”

        No need to call it “nonsense”, just say I got the figure wrong and I’ll be the first to agree with you.

        The truth is, when I googled the figure, I couldn’t find a definitive answer so I needed to calculate it as best as I could, hence why I added the note to cover myself.

        Bottomline is that aging is the #1 cause of death and the sooner E5 becomes available to the masses, more lives that will be saved.

  18. Hi Akshay

    Do you have a way (such as email) where I can contact you privately? I wish to discuss something with you.

    Thanks

    Toby

  19. I got an exosome IV about a year ago and the effects are very subtle. So subtle I didn’t get a second one. The doctor I got the from has done two maybe three by now. I am very fit for my age and maybe the exosome treatment played a part. If this leads to a better exosome mix, then I will get another treatment.

  20. Wish Harold and his team much success.

    Separately, has anyone read recent paper by Conboy lab.

    https://www.nature.com/articles/s42255-022-00609-6.epdf?sharing_token=UYmJFfOkCCEVzGI50HP3WtRgN0jAjWel9jnR3ZoTv0MM4Ysh4mn4RLp4AGGAgbbGs8jhEffmu_2GzTblOVqLqQZOdB8UA77wXKsZFukXiHFRwnxFHOvf5DAl-AShVELGa7g4LuivNIky29A7eHx9Vm5KD9yTyzDv1VBF8TGg_tg%3D

    The aging/senescence phenotype has nothing to do with youthing factors, but dilution of aged factors. One could argue possibly, Harolds work is possibly also a dilution??

    Let the debate begin…

      • The net effect is still the same, supporting Conboy…attenuation of aging factors. You are familiar with Conboys albumin replacement experiment, showing a rejuvenation phenotype, also an aging factors attenuation.

        • If you use the age related changes in hormones as a guide….it suggests that the increase in the senescence promoting factors is more important than the decline in youth promoting factors in causing aging…so if you r3emvoe both of them you get a net de-aging effect.

          • @Jeff Bowles Conboy just looked the senescence factors and shows youthing is not a pathway agent, only attenuation of old. Youthing is NOT in play biologically or mathematically (ie dilution).

            So can Harold’s work lead to the same net effect…dilution of old “senescence” signalling factors, and not via youthing?

          • HI there
            Yamanka factors are definitely “youthing” factors but they tend to be high in embryos and take the age of the cell back to 0….. short blasts of them in older cells has been shown to reverse the age of the cell …as measured by DNA methylation….so the question is are Yamanaka factors floating around in plasma of young individuals? If so then the Conboys are wrong.. I have a feeling that E5 is working along the pathways that Yamanaka factors are

          • Did you read the Conboy paper? Separately, Ashkay already said their protocol has nothing to do with Yamanka like factors.

          • Yeah I looked over the Conboy paper and sent ti harold when it came out and he initially said BS!!! And I am not sure they are at liberty to speak freely about E5

          • Well I look forward to Harold’s full manuscript so we can assess ourselves. Would welcome Harold’s comments without having to disclose yet his pathway.

            Look I’d much rather take an injection than rinse my blood volume, but biology does not care about human impediments, just want to see rejuvenation translated from mice/rats to human.

          • well if you want to see what the other anti aging researchers a doing …search the different yamnaka factors for recent studies like OCt-4 c-myc Sox-2 and or
            KLf-4
            this is a big area of research by Altos a Jeff Bezos investment in an aging cure

            Sinclair just reversed aging damage in mouse eyes with some of these factors

            the reason I am pretty sure there are both aging factors and youthing factors is due to Horvath’s amazing new study he found in all mammals they have 36 gene that get turned off with aging and 12 that get turned on

        • RE: Conboy’s paper. Yes, they are diluting away all the aging factor. They are diluting away everything. If there are youthening factors, they too are also getting diluted, to the same amount. The ratio between the two would remain constant.

          What turns on/up the aging factors? Are those “switches” manipulable? If so, how? That leads us back to youthening factors. The data certainly implies that there are competing factors in play. Consider the rapid aging caused by using “old blood”. Normal “wear and tear” of the young animal didn’t cause them; aging factors did. What causes the creation of aging factors? Are they always present, and being counteracted by youthening factors?

          Think insulin. Insulin does not exist in isolation, it is in a tight regulatory “dance” with a counteracting hormone, glucagon. Both are being regulated by a third factor – glucose. I suspect that aging has a similar pattern, only with multiple simultaneous “dances”; failure of any of them could cause aging. (Think of tell me “X” times logic. Any failure of the “X” elements causes the shutdown (aging).) And what causes the third party regulatory control? Unknown.

          E5 seems to be either a youthening factor in itself (actually multiple factors) and/or that third party regulator that control the “dance” between the aging/youthening pathway.

          On hint for the Conboy experimenters. Track down the aging proteins, then use them to create a mouse antibody(ies) and inject those in to mouse to kill those protein producing cells. Sort of like inducing type 1 diabetes in a mouse by killing the beta insulin cells.

          An aside: I wonder how the last three rats are coming along. . . .

          • Georg 2 of the treated are still alive at 42 months age. Avg lifespan of SD rats is 36 months.

        • What I would like to see is how long does the benefit last – dose response curves and test on the Horvath clocks. If any of the dilution experiments have these please point me to them.

      • There have to be both youth promoting and senescence promoting factors …just look at the hormone changes that occur with age….Aging promoting hormones KH and FSH and hCG shoots up sky high sometimes 1000% after age 50. AND youthful hormones like melatonin DHEA pregnenolone progesterone decline up to 90% a little after age 50.. And one thing I do know…melatonin suppresses LH and FSH!! >>>> the youth factor reduces the senescence factor….

        not sure if LH and FSH in turn suppress melatonin and dhea etc…that is a good question

        • Exactly Jeff. What your research shows is that high dose melatonin brings down the harmful rise in LH and FSH. So it represents youthing factor in this conversation. Now one could also achieve benefit by diluting LH and FSH but it will also dilute the already depleted melatonin. One can decide which is better based on individual choice. I would personally choose an option that brings back down the harmful rise of hormones but also upregulates the wonderful benefits of melatonin. This is a great example because it also alludes to my belief that there are no bad factors. LH and FSH too are valuable and so is melatonin but aging disrupts their ratio. Idea is not to eliminate anything but to bring back the homeostatic balance amongst them.

          • Yes, in fact, you are very right Akshay, a little FSH and a LH pike are good and cause happiness (estral cycle in female mammals, and its consecuences), when they are tuned in a young body but when it is out of control causes terrible effects, and it is the cause of death in some species with a single reproductive cycle (cuttle fish, for instance). Or premature aging if those hormones are high in young bodies.
            Anyway I had another question also concerning the parabiosis experiment and the current male/female lifespan experiment:
            As far as I know, in a longevity parabiosis experiment, mice were conjoined for three months, having the expected effect of rejuvenation in the old mouse and ageing in the young mouse. After they were desconjoined and free from each other, the aged young mouse died prematurely, but the aged and rejuvenated mouse didn’t lengthen his lifespan a single day and died in an average mouse lifespan (I presume they were male, as most of times are).
            Why do you expect a dramatic increase in lifespan there (I have to say that I expect it too, as the epigenetic clocks results were really impressive, and I do believe they a lot to do with lifespan, but still, in the basic parabiosis experiment the lifespan never increased).
            In the current experiment (the one with females only), lifespan has increased mildly compared to the control group and did better than the Rodolfo Goya experiment, at least three rats survided the whole control group and two of them are still alive.
            As Harold pointed in a previous post, the ovary is key in female ageing, but it seems not to respond to E5 spontaneusly. despite that, there are a bunch of tecniques to wake them up.
            Are you planning in the double gender experiment to act on the ovary of some of female rats? Or giving them something like estradiol and prg? A functioning ovary prevents the massive release of FSH and LH. And keeping those hormones within reasonable limits is basic to prevent ageing.
            Thanks beforehand Akshay.

    • Having only scanned the new Conboy article, I probably am incorrect as to the following:

      1. The new experiments were with whole blood replacement.

      2. The main point of the article is that removal of senescent cells in old blood via in vivo treatment by senolytics produces improvements in old animals when used for replacement.

      3. It has little, if anything, to do with plasma fractions.

      Please explain how badly I’ve misunderstood, because right now I’m becoming more positive about senolytics.

  21. Ines, totally agree with all your observations. As I have said before we should not underestimate Nature. There may be some embedded kill switch that we may find out after reaching a youthful 125. Will we overcome that too and cross into big jumps in youthful lifespans? Yes. I have no doubt. It’s all a matter of time. We are working with the assumption that if we can reverse biological age systemically to a youthful one and are able to maintain it in a stable manner we should be able to hope for crossing maximum known lifespan for some us. At our peak there is very little that can kill us. I mentioned some of us because each human based on their genetic fingerprint will show variances in their response. Currently gender is showing the biggest variance but knowing Harold he will soon resolve that. You already liked his observation about ovaries as being one of the key differentiators. The 54% reversal that we all were astonished by (including Steve, Harold and me) was average of 8 rats. In the female lifespan study which showed mixed response in biomarkers for 3 of the treated to live to 41 months when avg lifespan of these SD strain is 36 months is remarkable. One of them died on 42nd month but 2 are still alive! So imagine what the results can be if we reverse their biological age by more than 50% and keep them at that age continuously without testing for dose curve and with great consistent results in the 30 biomarkers we tested. But we have not set up Yuvan to increase maximum lifespan. That may be a happy side effect. We set out to move the biological age dial backwards and hold it there to make us young again safely and maintain that youth in stable state.

    • Thanks for your kind reply. I am sure Harold found (and was able to demonstrate) a new paradigm of aging process based on signaling. There is a long way to go and I also believe that there are a bunch of “bottle necks”, o check points, once the body has reached them, they act as a trap that prevent the body to come back to a younger phenotype, in a way forcing to it to die. But I am pretty sure that with medical/biological intervention most of them can be overcome. Just like carthilage regrowth, some years ago it was thought impossible and now some health care providers can do that pretty simply and routinely. All I can say is that I hope you persevere. My best wishes. Please, update us when some data about female rats epigenetics is released.

  22. My mind keeps returning to why we have these 2 rats still living . Do you already have strong theories on that. If so, not suggesting you make them public. Not read any comments regarding this yet.

    • Derek hopefully the reason is that since they were treated with E5 they reversed their biological age to some extent thereby improving their healthspan and thereby their lifespan. Why only these 3 (and now 2) could be because they responded better to E5 in their group.

  23. Apologies Akshay. Re read your last post regarding genetic finger printing. So could E5 be applied following some future crispr type intervention to break that barrier ?

    • In breakthrough technologies anything is possible. But as we learn more and more about E5 dosage and responses we can keep improving outcomes for everyone.

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