Out with the old blood, in with the young blood

Rebalancing proteins in the blood is the single most promising strategy for age reversal in the present environment. There are two competing schools for how to approach this. I’m calling on both to put their heads together and develop a strategy that combines their insights.

Please forgive me while I rant for a paragraph before beginning this column in earnest. Len Hayflick demonstrated that senescence in many animal species, probably including humans, is promoted by lack of a simple, cheap enzyme (telomerase) that every cell knows how to produce. To anyone who hasn’t been indoctrinated into the selfish gene dogma, this would be a sure indication that the body is trying to kill itself. But fifty years on, Len is still saying that aging = entropy catching up to a body’s chemistry. An equally powerful discovery came from Irina and Mike Conboy, who have been at the forefront of experiments demonstrating that aging is centrally coordinated through signal molecules in the blood. In every context but this one, the Conboys will acknowledge that these molecules are subject to directional selection and are tightly regulated in the metabolism. But when the blood plasma fills up with pro-inflammatory cytokines during aging, the Conboys insist that this is an accident. The body made a mistake. They call it “deregulation”. And in case anyone misses the point, they add in parentheses, “(noise)”. These are exactly analogous to the directed changes that cause growth, puberty, cessation of growth, onset of menopause, etc. In those other context, the change in balance of plasma proteins are signals, but in the context of aging, they must be “noise”. 

And even more incomprehensibly, the “noise” to which they refer always goes in one direction, and that is producing too much of some signal molecules, and the “noise” always manages to emphasize exactly those signals that bring the body down in a hailstorm of inflammation. 

Evolution is a many-splendored thing, and natural selection is perfectly capable of producing well-regulated, interdependent communities. This has meant selection for Goldilocks rates of reproduction balanced artfully against death rates that are also well regulated under evolutionary control. 

And YES, it does matter whether you think of aging as signal or noise. (I apologize again as my rant spills into its fourth paragraph.) It matters because if aging comes from a set of signals, we know well how to block those signals, e.g., with drugs that jam their receptors. But if it’s noise, the task is so much more difficult because it unfolds differently in every individual. 

If you want to hear more of this kind of thing, please read my book, or just refer to the dusty archives of my blog.

It’s no secret to readers of this column that I think altering the balance of signal molecules in blood plasma is the most promising road to anti-aging in humans. There are now two competing approaches to this project. The Katcher school says that there are youthful factors missing in the blood of old animals, while the Conboy school says that there is an excess of pro-aging factors. Both are quick to say that yes, it is a balance of pro-aging and anti-aging factors in the blood that ultimately determines the animal’s fate. But Katcher says that if you deliver the right combination of youthful factors, they will reprogram the epigenetics so that the pro-aging factors retreat as a side-effect; while the Conboys claim that if you dilute the blood, removing equal proportions of pro-aging and anti-aging factors, that dilution is sufficient to reset the aging clock, and stimulate new production of the youthful factors. 

Problems with the Katcher protocol

Until last week, Katcher had the more compelling data (IMHO), because he demonstrated dramatic epigenetic age reversal in rats. But last spring, the disappointing results in a small lifespan trial (8 rats) makes us wonder if his protocol needs a lot of fine tuning before it’s ready for prime time. And another weakness in his protocol is that he doesn’t know what is in the blood-derived E5 elixir that does its magic. He tells me there are efforts underway to identify the active components of E5. I think this determination is a high priority with global implications for health, so, by my lights, the analytic work on E5 should be a top priority. But there is a financial incentive not to know what are the active components of E5. This is because Katcher’s Yuvan Research has a patent on the process of extraction, but the components themselves are natural proteins, and thus they cannot be patented. So as soon as the information about the active components of E5 become public, his process patent risks becoming worthless. Other, larger laboratories than Yuvan will be able to synthesize the chemicals and sell them. I fear that research is being held back, and for what? I don’t even believe that the strategy of secrecy can secure the patent rights for Yuvan, because the knowledge will inevitably leak out, and Yuvan doesn’t have the resources to pursue multi-million dollar court battles over patent rights.

Human trials of plasma dilution

Now there is a new article from the Conboys analyzing results of plasma dilution in three human subjects. They show improvements suggestive of rejuvenation in several biomarkers. They do not report methylation age. They do begin the analysis process, and offer suggestions about what may be the most important pro-aging components of blood plasma that must be removed or inactivated.

Why don’t they measure methylation age using any of the available clock algorithms? There is a short statement why they don’t believe in methylation clocks, and they express the opinion that another biomarker of aging, one not based on “machine learning or large data sets” is urgently needed by the community. I believe that methylation clocks are the best means we have at present to evaluate the effects of anti-aging interventions, and in this one respect I find myself (for a change) aligned with the majority view in the field. The Conboys owe us a better explanation why they have gone to such great lengths to report other biomarkers of aging, but they don’t offer us the simple one that most researchers rely on.

Accumulated DNA damage triggers genetic aberrations, senescence [26], and loss of cell function and leads to age-related diseases [24].

It’s a popular theory aging that DNA damage is an important driver of aging , but I don’t believe it.

Interestingly, the procedure of small animal plasma exchange to dilute the circulating factors in plasma effectively reset the age-elevated systemic proteome and restored youthful healthy maintenance and repair of muscle, liver, and brain, without any added young blood, young plasma, or young factors [15–17].

This is a crucial point. How strong is the evidence? The three references are all previous publications from the Conboy lab. Ref 15 describes results of delivering young blood into old mice, an experiment which cannot tell us whether dilution alone rejuvenates gene expression. Ref 16 is about plasma dilution in mice and humans. This study establishes that something in old blood inhibits satellite (stem cell) growth, necessary for healing and repair, and that dilution is sufficient to restore youthful activity of these cells. Some evidence is noted of changes in the global proteome toward a more youthful state. Ref 17 establishes that plasma dilution is sufficient to enhance cognitive performance and reduce inflammation in old mice.

There is a section of the paper documenting “proteome noise”, which the Conboys propose as an important biomarker of aging. I disagree, of course. I see the directed changes in gene expression as the important drivers of aging, and the random changes are secondary. Much of the Conboys’ paper is devoted to analyzing noise in the proteome of subjects, and interpreting this as an aging biomarker which moves in the direction of youthfulness after plasma dilution. I admit much of the biochemistry is above my pay grade. I can’t comment on the merits of their proposed components of a new proteomic clock. But from the vantage of scientific methodology, developing appropriate biomarkers of aging should be a separate endeavor, done in advance. Criteria for successful rejuvenation should be established ahead of time, and not developed on the fly with results of the experiment already in hand.

I would have liked to see methylation age before and after treatment. I understand that the Conboys have reasons for not giving credence to the methylation algorithms. But how about A1C or CRP? These are measures of insulin resistance and inflammation, respectively, that are standard blood tests, but are not mentioned in the Conboy paper. How about any measures of cognitive or physical performance? There are no phenotypic aging markers in the Conboy paper.

Breaking new ground

The Conboys identify two proteins, TDP43 and TLR4, that were previously unfamiliar to me, but are markers of an aging proteome. The former is associated with cancer, the latter with dementia, and both increase with age. Both are attenuated with the Conboys’ plasma dilution protocol. I recognize that it is labor-intensive work to identify specific protein targets and test them individually, but this is the kind of work I think is most valuable going forward.  

How I think about aging

My (tentative) model:   “Old” and “young” are always in the body’s repertoire of behaviors, and the body will choose according to the signals it receives. The age state of the body is stored in the epigenetic state of cells, and communicated through hormones and other signal molecules in the blood. Some of these molecules also act as transcription factors, and they can feed back to affect the epigenetic state of dispersed cells. This is the reason for hope that a younger environment in the blood can effect long-lasting rejuvenation.

The great task before the Conboys and Katcher and other researchers in plasma rejuvenation is to identify which of the hundreds of proteins that change with age are the few transcription factors that are capable of reprogramming expression of the rest. 


  • There is no guarantee that a small subset of proteins exists that can do the job, but we won’t know until we look. 
  • And there remains the possibility that a central clock in the hypothalamus is able to override records of biological age in the epigenetics of dispersed cells. If this turns out to be the case, then we have to find ways to breach the blood-brain barrier and reprogram the hypothalamus.
John OConnell - Old mouse.

John O’Connell

A modest proposal

Harold Katcher, Mike and Irina Conboy are at the forefront of anti-aging technologies today. Both labs are very close to having an effective treatment for humans, close in the sense that there remain no conceptual hurdles, but only the predictable quotidien work of expert lab biochemists. In other words, a lot of work remains to be done, but the map is drawn.

Aging is not a cell-autonomous function, but happens under system-level control, with information about the body’s age communicated by signal molecules in the blood. This is the key insight on which Katcher and the Conboys agree.

To those of us watching from the outside, it is clear that a rebalancing of young and old plasma components will have a dramatic effect on health and lifespan. The remaining task is to identify a minimal set of those factors that must be removed (or neutralized) and those that must be added to the blood of an old person in order to trigger a global resetting of the epigenome toward full youthful gene expression.

We, the consuming public, would benefit greatly if the Conboys would hire Katcher to come work in their lab. Their two conceptions need not be antithetical. Let’s call on them to work together to identify that minimal set of blood factors, resetting of which can accomplish robust rejuvenation.

The importance to humanity of this research agenda must override the personality differences, the philosophical differences, the legal and IP problems that must be overcome to make this collaboration possible.

110 thoughts on “Out with the old blood, in with the young blood

    • Could you give your opinion on the benefits of donating plasma or platelets as opposed to whole blood? Do you recommend doing all 3?

    • On ferritin depletion – I’ve been doing monthly plasma donations (800 mls per, about 25% of volume) since beginning of 2022 and several whole blood donations in 2021. My ferritin did go low, under 10 ng/ml. But my ferritin is on low side to begin with. 50 mls of whole blood is lost each plasma donatin so this can add up. Just check your ferrtin – its cheap. Going into 2023 Ill be hceacking several of the markers whoch showed changes in last Conboy paper (CD4, CD8 etc). At 68 I don’t have time for Katchers dawdling. All of this stuff should be open access – even Katcher could benefit from a group effort as he’s getting a bit old.

  1. I too am frustrated with the slow pace of research in this area and lack of investment.

    Globally speaking, we are blowing huge amounts of money on developing therapies that will be partly or wholly obsoleted by either the Conboy or Katcher approach.

    We should be throwing every resource we can at this. There should be concurrent trials on humans and various kinds of animals, in several variations, with other basic research also going on.

    Instead we have a single human trial with just 3 people.

    Given the inability to meaningfully protect IP in this area, it seems to be that the whole thing needs to be approached philanthropically instead.

  2. I realize that blood donation is not equivalent to plasma dilution, but similar benefits seem plausible. Add this to the already suspected probable benefits of blood donation, which include the prevention of the accumulation of toxic quantities of iron, possible reduction of the risk of heart disease, and the reduction of risk factors in patients with metabolic syndrome.

    • A practical question I have is whether whole blood donation and plasma-only donation might optimally be done on separate schedules? Whole blood donation could be done at a pace that keeps ferritin at a healthy level. But are there any reasons to do additional plasma-only donations, and what are the markers that would tell you what amount of plasma donation is the right amount?

      • I think you might get more bang for the buck with plasma donations but a whole blood donation every so often would be good also. Do the whole blood donation a few days after a few weeks of plasma donations which is allowed twice a week but the 2 donations within 48 hrs of each other. When you give whole blood which donates much less plasma you can’t do any donations for 8 weeks not even plasma donation.

        • So to state the obvious, why don’t the Conboys do human experiments that combine plasma and whole blood donation instead of plasmapheresis? The point is that these services could be done FOR FREE, and therefore scaling up a human experiment to hundreds of individuals could be done at very low cost. While it might not have the same advantages as full plasmapheresis, it should result in measurable benefits and would be an extremely important result, because it could be immediately implemented by millions of people, without ridiculous levels of government approvals.

          • Not sure on that or if they ever tried bloodletting. I think maybe they believe all the accumalated bad stuff is in the plasma itself. I did see a while back some Chinese researchers saying their study showed that basic bloodletting in mice increased collagen in the skin and improved other tissues while reducing inflammation also. It cleared out a lot senesnt cells from tissues also they claimed.

        • Also people donating blood whole or plasma, frequently, should keep an eye on their Albumin levels.

          Low albumin levels, caused by anything, are associated with increased mortality rates in the general.

  3. Not to mention Dr. Horvath’s study from 9/2/2022: “Umbilical cord plasma concentrate has beneficial effects on DNA methylation GrimAge and human clinical biomarkers” https://onlinelibrary.wiley.com/doi/10.1111/acel.13696
    “We use data from a safety study (n = 18, mean age 74) to investigate whether human umbilical cord plasma concentrate (hereinafter Plasma Concentrate) injected weekly (1 ml intramuscular) into elderly human subjects over a 10-week period affects different biomarkers, including epigenetic age measures, standard clinical biomarkers of organ dysfunction, mitochondrial DNA copy number, and leukocyte telomere length.”

  4. Thanks Josh,

    The question may become moot in the near future. The horse race between the Conboy’s and Katcher groups has a dark horse rapidly advancing on aging’s holy grail. (If you want a few more metaphors, just let me know ;√))

    In 2006 Shinya Yamanaka Identified what are universally referred to as Yamanaka factors. He published his findings in 2007 and received the 2012 Nobel prize in medicine for an advancement that may shortly become the leader in anti-aging therapeutics. The distinction here is the real possibility of a therapeutic being readily available in the near future and without commercial limitations. The only limitation from my perspective is how knowledgeable, adventurous, reckless or desperate you are.

    Yamanaka factors originally consisted of four chemical factors that were capable of regressing /inducing cells back to a pluripotent state. In 2020 David Sinclair demonstrated that the sight of mice could be restored utilizing just three of the original Yamanaks factors introduced by viral transduction. He accomplished this safely by carefully controlling dose and interval.

    [2020] Reprogramming to recover youthful epigenetic information and restore vision [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752134/pdf/nihms-1640389.pdf]

    Now a group out of Switzerland led by Alejandro Ocampo has demonstrated that only two small molecules can accomplish the benefit of regressing not just cells, but whole organisms back to a more youthful state. By again controlling dose and interval the two agents can be utilized while reducing the risk of driving cell state into oncogenesis.

    The most amazing and compelling element of this research are the two chemical agents utilized to accomplish these results are readily available; a TGFbeta-1, ALK5 inhibitor (RepSox) and a prescription antidepressant; Tranycypromine, a monoamine oxidase inhibitor with a brand name of Pranate. There are a large number of effective nutritional supplement inhibitors of ALK5.

    There is a large body of research demonstrating the efficacy of utilizing inhibitors to the ALK5 pathway. A prime example is the Conboy’s paper:

    [2018] Rejuvenation of brain, liver and muscle by simultaneous pharmacological modulation of two signaling determinants, that change in opposite directions with age.[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710051/pdf/aging-11-102148.pdf]

    We do not currently know if this combination is effective or safe in a mammals. I would propose that the answers to those questions will come quickly, if not from clinical research, then from biohackers.

    Harold Katcher has already demonstrated a fairly fast and effective way to determine one level of efficacy by utilizing E5 topically. If the rejuvenative effects of two Ocampo factors (2OF) are effective then that simple, fast and effective experiment may provide us with our first insights into the human safety and effectiveness of a new leader in the race to effectively regress aging.

    [2022] Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan [https://www.biorxiv.org/content/10.1101/2022.08.29.505222v1]

      • Hi Josh: When you have a minute, please expand that thought. I assume that the goal of Ocampo’s work is/was systemic-cellular-rejuvenation. Isn’t that the goal of all anti-aging research that is not specifically disease directed?

  5. Hi Josh,

    A few years ago I proposed, and you agreed, that it probably does not matter that a good programmed theory of aging has not become a dominant theory of aging that informs the research directions because of the diversity of the volume of research and its momentum should result in near term breakthroughs without it. I no longer feel that this is the case, as you expressed above the dominant researchers seem all too willing to return to entropy as the foundation of aging and as a result slowing progress. What is your feeling on this now Josh, is significant progress likely without the adoption of better theory?

    Thanks Josh.

  6. It would certainly be nice to know the make up of E5 , and then perhaps the ITP could take a very critical look at it in terms of longevity .

    The Conboy’s stated that the key player identified was toll receptor 4 . It’s interesting that the TLR-4 protein is inhibited by rapamycin, at least to a degree.

    I’m afraid that in terms of bottom line results, I’m more impressed with GlyNac at this point.

  7. You mean ask competing labs and scientists to collaborate and share their data and experience???? What a novel idea.
    If there is one silver lining in the Covid Cloud, it is/was the demonstration that scientific collaboration, scientists across the broad spectrum working together, can achieve great feats in amazingly short times.
    Seems so obvious.
    Josh, it is a great idea. I hope somebody listens.

  8. The aging process is connected with the control programs in the human Soul. Until the age of 16, a person matures, and then ages to death. This mode is set by the Creator for man. However, information space diagnostics ICD (diagtor.com.ua) established that the aging mode can be switched to the rejuvenation mode by changing the magnetic field in the mental body or in nerve cells. This rejuvenation technology is now used by ICD by taking water or malic acid YaKS-4, in which the strength of the magnetic field of hydrogen atoms is increased by means of informational activation. The speed of rejuvenation – one year of taking products is equal to 7 years of rejuvenation of internal organs. At the end of rejuvenation from 25-80 years old, skin, hair and teeth are rejuvenated by 16 years old.

      • У меня имеетсяI have the opportunity to ask questions and receive answers from the Creator. This technique is not always reliable, but in the treatment of various diseases, including viral ones, this works under 100%. 6 years ago I started an experiment on rejuvenation, while the experiment is going well, in a year I am waiting for the end of rejuvenation from 70 years to 16 years. Intermediate results show that at first there is a rejuvenation of all physiological systems, except for hair, teeth and skin. If the scientific community has a desire, I will give the results of the experiment. With rejuvenation, the reserves of the body increase. The path of rejuvenation through the Creator is the only one for a person, and this path proves that a person’s life is determined by the function of the Soul, which is controlled by the Creator.

  9. Josh what is being compared here? We have tested 30 biomarkers including functional. We have had 3rd party test at Horvath lab. We have given dose response curve – multiple times in smaller mammals. If I chose preferentially some proteins that go up with age and disappear with our treatment would that mean we have rejuvenated to teenage? In their recent paper they mention about another protein which also goes up with age but has only transient lowering through dilution and in month is back to original levels. No matter how many times they do the procedure. So if I measure with only this protein preferentially I will see now reversal in age through dilution. Time will tell us which strategy will give lasting reversal of systemic biological age. No drug has ever been created by giving away IP. In fact there are amazing natural products but because there is no financial returns no one funds their trials. There needs to be an understanding of how a therapeutic translates into a prescription drug. It is not any easy process no matter how good it is. Also it can not be hurried even by big money. Please track how long it takes for any therapeutic to reach the market. We must have patience. The branding of E5 having ‘disappointing’ results from female lifespan study is the price we pay for sharing all our research results whether good or bad as an open book. Alkahest too has studies with disappointing results, as does every lab in ther development process but they have 3 drugs in Phase II. There are no failures in true research only learnings. In this case we learnt that female biology has a different response to E5. We immediately launched a 5th trial which is mixed gender and again see the amazing response we always see in male rats but a lower response in females. It’s an anomaly that is quite common and will be resolved. Conboys have already done human trial even if only with n=3. We hope to do that next year with 10+ Volunteers. That is not slow under any biological development program. Major companies take many years before they can reach human clinical trial. I have respect for the Conboys and like them personally but regarding combining efforts: Harold had written about heterochronic plasma exchange – which is a combination in 2015. I reached out to him because of that paper. There will be multiple approaches to reverse biological age: Michael above mentioned about an interesting one from Ocampo group using two factor rejuvenation – although even partial cell reversal makes it dedifferentiate to some extent and can lead to oncogenesis. Time will tell which approach will safely and powerfully reverse biological age and allow us to maintain it.

    • Don’t worry Akshay. There are true believers who rationally understand the power of E5. We have a concept, a proof of principle. It takes time to perfect.
      As for Conboy’s intervention, the accumulation of any pro-inflammatory or pro-aging factors in the blood plasma is caused by retrotransposition of genetic elements and other genetic and epigenetic changes caused by disruption of nuclear architecture, therefore, their “filtering” will obviously give us a temporary rejuvenation effect, since the body has a temporary “clean sheet” to carry out cellular processes, but all this is quickly renewable. Recent studies also show that aging is not caused by mutations, but by inflammatory processes, which, again, occur through chromatin disorganization in response to DNA double-strand breaks. Why not compare the mechanisms of E5 and Conboy practices and why is the redistribution of pro-youth factors more important? Because it is important to reprogram the cell, either directly or indirectly (through blood plasma components). Of course, routine dilution will play a positive role in disease remediation, but I suspect it won’t help us push the limits of maximum lifespan.

        • Really looking forward to hearing about the clinical trial next year. I hope you have the resources you need to pull it off.

          Just FYI Akshay, I think you may now have enough subscribers (the minimum being 100 last I checked) to change your Yuvan Research channel URL to something custom. It could be some low hanging marketing fruit:

          Also, although this article says the form is youtube.com/c/thename I have found that youtube.com/thename also works.

    • Akshay – I hope I’ve made it clear how much I appreciate what you and Harold are doing. There’s a great deal that you have to offer the Conboys, especially in regards to their fundamental misconceptions about the origin and nature of aging. You have also developed technologies that they don’t have. What they have to offer you is well-developed micro-injection machinery, a platform for proteomic analysis, and knowledge about the worst blood components that may have to be removed or neutralized. My bet is that both removal and addition of blood components will be necessary before we have a cure.

    • Hi, Akshay, I am a big fan of what you and Harold are doing, I was wondering if you might be interested in getting funding for your R&D activities from crypto-native communities like Vita DAO.

  10. One small correction, it was Leonard Hayflick that discovered the limitation on the passaging of human cells – now termed the Haflick limit – not Leonard Guarente. It was later found to be due to a lack of telomerase. So in this particular case, it is a case of too little of a good thing, no too much of a bad thing.

    Most likely we are looking at a ratio of blood borne factors, not absolutes. Hence why adding concentrated young pig plasma has benefits, as does simple dilution (albeit with albumin).

  11. The patent secrecy risks not finding out quick enough whether and how exactly to bring meaningful rejuvenation in humans. Quick enough for Harold himself.
    I think he stands to lose big time from what he thought would benefit him (the patent).

  12. Unfortunately, the Conboys still to be of the opinion that aging is the result of ‘wear and tear, and hence aging is the result of the accumulation of toxic products of metabolism etc. That was the point of showing that simply replacing a fair proportion of blood plasma with saline plus albumin removes many of these anti-aging factors. The assumption is that diluting these aging factors reverses aging – but their ‘proof’ is based on a few measurements, nothing physiological or cognitive and not DNAm age, and would require frequent replacements with human serum albumin. (And a bioRxiv paper from China showed young serum albumin to be an anti-aging factor which sort of invalidates the paper’s thesis.) Well, certainly better than nothing, but their basic thesis is wrong – there are anti-aging factors in young blood and they are apparently able to markedly rejuvenate male rats. Female rats are not as greatly affected which is why our previous study showed But we are working on it as well as the possible problems dealing with life span extension. In my 2013 paper (Studies that shed a new light on aging.) Where I proposed that complete plasma replacement with young plasma (plasma exchange) ought to both rid the blood of aging factors and provide the pro-youth factors present in young plasma. There is plenty of proof of pro-youth factors and they seem to dominate the pro-aging factors.

    • Would we not know by now if plasma dilution/removal was all that was required for marked effects from those who gave plasma regularly?

      • I met someone today who has been doing plasma donations every 2 weeks since 1986! Nice guy, but looked normal for his age. I started doing regular plasma donations myself a few months ago. You’re right, regular long term donors need to be studied.

      • Well we know there is no financial incentive to find that out as less people would be willing to pay the crazy prices for some of those exchange procedures. Also you have the opposite issue of whole blood donors because many of the donors are not leading very healthy lives and are there for the money they get paid for donating. A few are young healthy college kids however just trying to get a quick buck.

        • Here in Australia we don’t get paid for donations. The donation centres are very particular about the health status of donors so it’s generally a relatively small group of healthy people who are allowed to donate. I do understand it’s a different situation in the US

          • Neither in Spain. A bare sandwich and a drink is all you’ll get. And the gratefulness of the receptor and the spanish society in geneal.

  13. It just so happens I recently read an article by Josh published in 2015 that looked forward to heterochronic blood plasma research. Interesting contrast to this blog post.
    He described it then as “an opportunity for creative science, using large databases with computerized screening, but also applying basic science of transcription factors with their hierarchy of actions. Applying a broad knowledge of biochemistry, aided by statistics for gene expression changes with age, it should be possible to arrive at candidate blood factors in the near future.” I take it that hasn’t come to pass? But then I also vaguely recall some work by Tony Wyss-Coray where he had data on like hundreds of plasma-borne molecules, tracking the changes in their concentrations over time. Perhaps this is where the notion that there are a couple of key inflection points came from; one in our thirties and another in our seventies. Pardon me if I’m conflating some things. Have there been any developments off of that?

    • Fred yes there have: Alkahest, Tony Wyss-Coray’s company is the only anti aging company I know that has reached 3 drug candidates in Phase II with FDA. Using young blood plasma fractions. This is the key litmus test: unless one is on track to get regulatory approval all the peer reviewed papers and conferences and news articles are meaningless as they do nothing for patients who are suffering everyday. The research groups that follow this path do succeed in getting prescription drugs available. I remember in 2011 Dr. Carl June from UPenn was working on a radical treatment for cancer called CAR-T therapy and in a couple of years astounding results were coming from patients with some cancers. Like Alkahest did a deal with Grifols Dr. June did a deal with Novartis. Even for all the money power of Novartis only recently their cancer drug KYMRIAH has been approved by FDA and helping so many cancer patients live longer. Dr. June did not go about distributing their IP to hundreds of labs or collaborate with a competing lab. Neither did Tony Wyss-Coray or Alkahest. When their drug development and their results reached certain maturity big investors-in their case strategic investors-stepped in to take it to commercialization. One day you will also see E5 achieve the same.

  14. Regarding your recent post Out with the old blood in with the new blood.
    I agree with you that interfering with signals in blood, especially in plasma, is by far the most promising current approach toward delaying human aging and even possibly reversing aging and causing at least some degree of rejuvenation. In particular, Harold Katcher’s recent work is extremely interesting.
    One of the interesting aspects of Katcher’s approach is that it is not necessarily essential to identify which components of young plasma are causing or preventing youth in order to produce a beneficial anti-aging effect. Considering aging as a programmed feature of mammals, there are multiple blood components (e.g. hormones) that appear to be either pro-aging (i.e they increase with age increasing aging effects) or are pro-youth (they decrease with age causing increased aging effects). An initial treatment protocol could be based on either or both.
    As you suggest, many of those working in this field are still unable to accept that aging is purposely programmed because aging, per se, creates an evolutionary advantage. This directly results in ignoring more or less obvious research paths such as described above because they have difficulty imagining that blood could contain agents that purposely cause aging. In addition, the huge medical/healthcare/pharma establishment and associated regulation is largely based on the idea that aging is a normal, untreatable aspect of life. This leads to difficulties in administering or even human testing of agents that require injection as would be the case for most plasma elements. Notice that the NIH/NIA interventions testing program only considers oral agents. Efforts to sell “anti-aging” agents such as by Guarente (TA65) involve oral precursor agents “activators” even though the effect is caused by telomerase.
    These issues are described in more detail in my recent article: Aging is controlled by an evolvability-based adaptive program.

    • it’s the simplest thing for a patient to swallow a capsule. There are a growing number of substances that are digested by enzymes, but now through micronized coating and/or pairing them as salts more and more of them could be taken orally as they now survive stomach acids. TA65 is one of them, but there is a growing list of others like SOD (coating), AKG (salt), GHK-Cu (salt), epitalon (salt), BPC-157 (salt), hydrolized elastin (breaking into short pieces).

  15. Is anyone else disappointed that the best the Conboys could do is a human study with N=3? Does this maybe suggest that it is impossible to get funding for larger human trials, and the simple reason for that is greed? No one can make money from plasmapheresis, which is easily copied by anyone, and which already has FDA approval. So instead billions of dollars flow into risky proprietary approaches like Yamanaka factors, which in the very best case have a 15-year runway before a widescale FDA approval.

    It is incomprehensible to me that the San Francisco Bay Area – without all of its high-tech billionaires – does not have a single person willing to fund widescale human trials using the Conboy approach.

  16. I wonder how these rats/mice are dying that have been treated with the young proteins and/or had the bad stuff reduced with plasma exchange etc. Are they usually just reaching what would be considered an older lifespan age for themselves and then the body just starts shutting down with the usual age related problems like it might at that age despite acting way younger previously.? I haven’t heard that addressed much or I missed it. Just curious how these E5 treated rats eventually died and was it a very rapid decline at the end or not. As far as the possibilities having a healthspan anything like that is suggested with some of these studies would be a game changer regardless if some unknown master switch was still limiting most people to say 90 – 95 years old especially if the decline at the end was pretty rapid.

    • Completely unknown at this stage. The dead rats are being preserved for later analysis, which will be doe after the last rat dies.This is reasonable, it prevents interim data from pre-disposing a particular outcome before all the data is in.

      Proper science. (believe me, I want to know as well, but all in the proper order.)

  17. If removing plasma and/or whole blood really affected aging in a positive way why do we not see ‘healthy’ plasma/blood donors living longer than non donors?

    • Not sure if there has been a study on that. Studies have shown whole blood donors being more healthy as far as certain aging conditions and the most frequent donors being healthier than the less frequent ones. Like I said to someone above the typical plasma donor is probably leading an unhealthy life so I doubt a study with them could tell you a lot.

      • I would think there are ‘outliers’ in the plasma donating community that are healthy and donate for charitable reasons. I would think an efficient way to determine if this theory has legitimacy is to locate them and study it – doesn’t ‘seem’ like that would be that difficult.to do.

        • There might be a few but I think it would be rare to find many that weren’t donating whole blood also but maybe the ones that donate both could be compared to the whole blood only donors. My own personal hunch is we would find better healthspans through old age and a lot less things like heart issues and diabetes etc. A younger appearance on average but nothing crazy. I doubt it leads a lot of people to making 100+ though as I think there is some other switch involved with max lifespan

  18. “it does matter whether you think of aging as signal or noise. (I apologize again as my rant spills into its fourth paragraph.) It matters because if aging comes from a set of signals, we know well how to block those signals, e.g., with drugs that jam their receptors. But if it’s noise, the task is so much more difficult because it unfolds differently in every individual. ”

    I loved this statement, Josh, because if you link this to most if not all the experiments done where you can check the epigenetics before and after, any logical thinker would conclude that aging is a matter of signaling (how would Dhea+HGH+limiting insuline get some results as spectacular as kidney and thymus regeneration!)
    To me it is a mistery why the Conboys have never checked:
    a)lifespan in mice or rats after series of plasma replacement. They just work with the mice tissue samples and proteome to prove rejuvenation.
    b)epigenetics, specially when they are accepted by mainstream science and repeatedly tested and improved. I think no one dismisses Horvath/Levine works in the field, but they seem to ignore them.

    How can they quantify the advantages of their treatment? Science works with measurable items, Time is one pretty easy to measure, you just need patience. Why don’t they proceed with a lifespan study in mammals before jumpintg to humans? And there Katcher has an advantage. He has measured nont only biomarkers, but epigenetics, and he is checking on lifespan and gender. Yuvan seems to cover more ground than the Conboys.
    On the other hand on summer 2021 Grifols started a protocol in Barcelona, in order to treat mild to moderate Alzheimer patients: The protocol is the following:
    Six weeks of intensive plasma replacement:
    During 6 weeks the plasma of the patient is replaced weekly by an albumine solution, in order to eliminate any trace of Beta-amiloid (so to get rid od the trash in the plasma). After this heavy shock (I don’t think Kiprov has ever done such intensive treatment in any patient), the second phase consists of a partial plasma/albumine replacement, this time replacing the 50% only, and monthly.
    Alzheimer’s patients can expect to slow the progression of theirr disease by 61%. But I am so sorry, there are no traces of rejuvenation. And it is obvious that the heavy treatment has not only cleaned the beta amiloid, but some other hundreds of kinds of trash.
    So the evidence is there.
    What is in the Conboys protocal that is not in Ambar protocol? Because the second only provides temporary relief. Why would someone expect a redical rejuvenation an life extension?

  19. This notion has been around for a while. I see it as more likely than not that rich old folks have there own plasma exchange program with healthy 20 year olds, working their way through college or whatever. There’s no particular reason for them to let the secret out to the great unwashed. A former President comes to mind along with others in their late 70s and 80s who seem unusually hale and hardy.

  20. Ines unbiased and thoughtful evaluation. I always like your posts. You said time is easy to measure: I agree and not just with lifespan: how can one say ‘lasting rejuvenation’ without giving information about how long it lasted in time?

    • The concept of lasting time also applies in a different manner. Until there is experimental data in long lived mammals, we don’t know how long E5 will last in those long lived mammals. There is no certainty of the scale up time. It may scale according to the same dose to lifespan ratio, it may not scale at all, or it may be in between. No data yet. . .

      • Has anyone even done a lifespan study that validates methylation-age as a strong correlate? GrimAge has been retrospectively applied to stored tissue and have strong ‘predictive’ power for mortality. But to be honest, I won’t trust it until a mouse or rat lifespan study is done with methylation-age of various tissues taken straight after death of each animal. Only that way will we see if it really works. Then we can start to make rapid progress that isn’t dependent on long-winded lifespan studies where if you get your animal husbandry wrong, you lose all your data.

  21. Agree that “altering the balance of signal molecules in blood plasma is the most promising road to anti-aging in humans”. Somewhat disagree that “rebalancing proteins in the blood is the single most promising strategy for age reversal”.

    IMHO small molecules are more promising than proteins because small molecules are:
    – the main components of cells
    – the main regulators of protein function
    – the main drivers of the pathogenesis of many diseases
    – the main actors in cell signaling.
    – the main elements of current anti-aging arsenal

    The reason why in the 2 studies that we plan to carry out in 2023 we will focus on the discovery of a molecular signature of aging in small molecules and not in proteins. The main challenge we face is that we don’t expect that the molecular signature will consist of a few molecules only, at least not like the only 4 Yamanaka factors, meaning that the study should be powered enough (in the few thousands of subjects) to discover a pattern shared by a large number of molecules. Working hard these days to get the necessary funds to complete the 2 studies by end of 2023.

  22. I would like to know the SOURCEs in the body that sends anti aging signals
    to the blood. Also like to know the body SOURCES that sends pro aging signals to the blood.

    • I am definitely not an expert like many people commenting here but I believe the thinking is an accumalation of certain proteins in plasma as you age signal the cells to be old and cause inflammation etc. while having less of other proteins ages you also. I assume E5 is a combination of some signaling proteins that are at low levels as we get older. Are you actually asking what signals the proteins to change in numbers? Maybe someone else has a good answer for that.

  23. Before we get too carried away about the benefits of therapeutic plasma exchange we should consider that there are already people in America that are “donating” plasma up to 120 times per year (according to the NY Times). If there were any significanct health benefit of doing so, one would expect someone to have noticed by now. Not everyone donating is in poor health. I think we need to be warry of claims that the elixir of life lies in donating your blood. I think that Josh and others make a good point that the Conboys have yet to show any functional improvements – as opposed to indirect “indicators”- in health and performance associated with plasma dilution. Where are the 90 year olds winning Chess tournaments, running 4 min miles or even looking like 30 year Olds?

  24. I think you make a compelling case for a deliberate biological program as the cause for aging. However, my question is, if aging is the result of a deliberate biological program of self-destruction, why does the program never fail? Considering everything that can and does go wrong with the human body during development, surely there would have been at least one person out of the approximately sixty billion that have lived during Earths history that was born with a broken ageing mechanism that failed to activate, thus granting immortality to the person affected.

    • Lets assume it did happen.
      Then the person and offspring was also immortal, and population increased exponentially due to “the advantage” of having not only one generation having offspring, but also their parents, grandparents, etc. This soon could result in complete depletion of resources after a few generations, and eventual death to all, not due to programmed death, but due to resource limitation. So maybe it did happen, it but failed in the long term.

      • Which is why a simpler theory may be that there is rising damage and there are repair mechanisms that are themselves degraded by the rising damage. Together these two phenomena have never failed and cannot fail to kill the organism because they are leveraging a principle more fundamental than biology, that of entropy. The species lifespan is determined by how much the genome invested in repair mechanisms, a fact of contingent evolutionary history.

    • the simplest answer is that there are at least few of them (independent of each other) and/or they are based on physical process that the body cannot repair, and positive positive feedback loop of all of them causes all systems failure in the end. The long it was thought to be telomere attrition, then due to widely popularized measuring of white blood cells only for telomere length where telomeres have little (if any) correlation with life length, it was thought to be discredited by some. Then came the discovery of mechanism by which some white blood cells donate up to 3k length telomere chains to other white blood cells, and paired with discovery how much destruction in the body senescent cells (their main cause being replicative senescence) causes come back of the telomeres. Add to it natural process of glycation and lipofuscin accumulation and you have three separate physical independent procesess which combine together into this always destructive positive feedback loop. Which list isn’t exhaustive, because then came multitude of another similar processes, where still there is little known on their relative interdependence.

      • Multiple genetic programs to destroy the organism has a whiff of Ptolemaic epicycles. Why would evolution bother when the external world is full of bacteria, viruses, predators and accidents always available to do the job? You just need to let repair mechanisms decay.

        • 1. Nature is not an engineer, and she doesn’t think like a human trained to separate functions cleanly, one signal to one response.

          2. In my book, I argue that regulating animal lifespans is essential to the stability of ecosystems. It’s not optional. Of course, there is always going to be individual selection pressure to escape from any death program, and nature has made it difficult to do this with any small number of mutations.

          • Josh, appreciate you responding to my comments. I own your book but never got around to reading it. I will correct that oversight and reply soon!

        • The problem with entropic arguments is that entropy doesn’t care if you decay in 10 years or 1000. And looking at the difference in lifespan of animals, it seems entropy is not the driver (just the executioner). It is more like animal bodies are being driven to destruction. Blagosklonny may have come closest to explaining this with his growth is aging argument. You can look at a young man, maybe only 18 years old, strong jaw, muscular – and already you can see the receding hairline. Fast forward to 45 years old and in many men you can see the bloating; the redness; the incoming stroke or heart attack. The problem with Blagosklonny’s argument is that you can’t turn mTOR down very much without the human body just not working properly anymore. We need to find some more fundamental mechanisms to the way our cells operate that radically reduce the effect of these aging signals whilst still permitting us to live a normal, active life.

          • Not just entropy, but the loss of repair that keeps entropy at bay. I just got done reading Dr. Michael Fossel’s The Telomarase Revolution, and he makes a lot of sense. He sees repair processes slowing down on a pattern that seems tied to the shortening of the telomeres and he thinks the relationship is causative, not just correlational.

            His book is an exhaustive description and analysis of how the most common diseases of aging can be explained by slowed repair processes and therefore increasing damage. He also declares any intervention other than lengthening telomeres to be pretty much useless.

            In this context I find interesting that alternative thinker Morley Robbins considers copper deficiency to be at the root of most of the aging hallmarks and sure enough there is a study that points to a significant association between copper intake and telomere length – “Dietary Copper Intake and Its Association With Telomere Length: A Population Based Study.”

    • Interesting. Well when that E5 cream hits the market I guess we will find out what is in it. Hopefully they do the work with cats and maybe Katcher himself will take it once they have produced enough of it to start that work. It sounds like he would anyway.

  25. The future E5 research on the Sprague Dawley rats should only be by prior dilution of plasma.

    You need to contact the Conboy lab and have another Plasmapheresis blood cell separator manufactured.

    There is no need to further research male and female Sprague Dawley rats combination unless, you remove the old plasma first, which is likely to further reduce Tissue Necrosis Factor on both sexes.

    For human trials, do email me on [email protected], my father is 86 years old and an ideal candidate.

  26. Has anyone had a look at this recent paper in rejuvenation research? At first reading, it suggests that the hope that plasma exchanges will result in significant rejuvenation are slim. Seems we can make young animals old but not old ones young.

    Three Month Heterochronic Parabiosis Has
    a Deleterious Effect on the Lifespan of Young Animals,
    Without a Positive Effect for Old Animals

    • Parabiosis is hard on both animals that are sewn together. They don’t live long. I’d say that Katcher’s findings are a significant update to anything reported on parabiosis. Likwise the Conboy/Kiprov results.

      • The study by Yankova et al appears to have been well conducted using appropriate controls and adequate numbers (~50 individuals per treatment). Mice were connected for 3 months then disconnected and survival monitored for up to 800 days after disconnect. The fact that some mice survived so long after disconnect strongly suggests that the results can’t simply be attributed to the stress of treatment. Also, statistical comparisons were made between groups that had all been connected parabiotically. Difficult to simply dismiss these results. We need to be careful that we don’t fall into the trap of wishful thinking. It would be nice if something as simple as therapeutic plasma exchange would lead to rejuvenation. But these results and the lack of significant rejuvenation of regular plasma donors – which number in the millions- suggests it probably is not the case.

  27. Re: my last post about recent evidence that plasma exchange does not benefit old mice. Here’s a preprint showing the opposite. As far as I can tell this manuscript has not yet been published in a peer reviewed journal. What is one to think?

    Mpulti-omic rejuvenation and lifespan extension
    upon exposure to youthful circulation

  28. Akshay, still some questions that came to me after watching the video Josh linked recently.
    In first place, after watching Harold’s video, there is a moment in which he states that depending on the complexity of E5 there may be a chance to synthesize it, so people wouldn’t be depending on cattle for its production, but he adds that what is seen in the electronic microscope is far from being simple. He says that in the context of the source you’ve been using. Where you able to identify the molecular cocktail that forms E5? If you cannot answer this, of course, I understand. I am just curious.

    Second question. E5 acts locally, This local effect is also the approach Vittorio Sebastiano is taking for his ERA platform, to act locally on the patient stem cells that are to be infused later in any organ, younger and improved. By now it seems to work pretty well in vivo (rodents by now). After thinking of the topical E5 treatment on skin, which Harold tried on himself, did you consider the approach to deliver E5 in an organ (any organ inside the body), be it muscle or any other?
    Still concerning the skin. Do you expect any paracrine effect after the topical E5 is acting in skin? Young cells and old cells have different secretomes, changing the age of the cells would change their secretome too. Skin is the largest organ of our body by far. This alone could have an effect.
    And another one. Did you consider the possibility to use E5 together with other different techniques to solve the female problem? Or are you pursuing another version of it?
    And how is the last of the rats doing? I had to ask this one:)

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