Just before getting my first session of plasmapheresis, I sent a sample of my blood to MyDnage labs for a before epigenetic test analysis. Well, UPS lost my package. By the time they find it, it will long be worthless. Oh well, not that surprising, especially in France…
I had my second session yesterday, all went well, just a little bit tired this morning.
In Part 1, I described an experiment I am starting, first on myself in the spirit of self-experimentation, then on other volunteers. Before having my first session of plasma dilution, I got a bunch of markers measured to evaluate my condition before. Here is myself in data:
34 years old
Epigenetic age (mydnage.com, derivated from Horvath Original 2013)
30 years old
Epigenetic age (mydnage.com, derivated from Horvath Original 2013)
I am pretty pleased with how it went. The doctor was interested in anti-aging research though not aware of the latest studies regarding plasma dilution. She has been doing this procedure for years and is very familiar with the risks and benefits. The regulations in France limit the quantity of plasma that can be replaced in one go to 800mL. However she found out that depending on the health of the patient, replacing double this dose is perfectly safe. Obviously she would never break the law, so she would never process more than 800mL, but if she did, hypothetically, she would remove a full 1600mL of plasma and replace it with a saline solution (NaCL 0.9%) and a few mL of Anticoagulant Citrate Dextrose-A as described in part 1.
The machine is a Hemofenix, russian made, but she was not able to give me the exact pore size, only that it was at most 80-100 nm. She will try to get the exact pore sizes.
My estimated plasma volume is 2630 mL according to this calculator and others. So I would hypothetically have had more than 60% of my plasma processed, though by the nature of the dilution process that would amount more to 50%. Pretty close to the study I’m trying to replicate!
The whole process took 75 minutes from start to finish.
I was able to keep the extracted plasma with me, to hopefully have more tests run on it.
As far as how I feel, there aren’t many sensations. You feel a few tingling sensations here and there, you’re a little bit tired for the rest of the day, but overall it’s pretty painless and uneventful. Which is good.
During the dilution, I chatted a bit with the doctor and she gave me a few very intriguing anecdotes: this 87 years old professor in Russia whose having wonderful results doing the procedure every month, this guy with a metastasized cancer having been “cured” with one 4-sessions procedure, herself and lot of other aged individuals getting a lot more energy after 1 procedure for months or years, and even this doctor in Spain having treated alzheimer patients for 6 years with very good results,… and so on and so on. This is just anecdotal data, and am not sure why there aren’t more published reports/studies if they are so good. But that’s why we’re here after all, aren’t we?
The next 2 sessions are on December 21 and 23, they will be run with the same protocol. One month after the last session, I will get new blood markers measured, as well as epigenetic age by mydnage.com.
A study made by the Conboys team made a lot of noise a few months ago: Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin . This is but one more evidence of a systemic regulation of the aging process by blood factors, but with the added and exciting bonus that merely removing “pro-aging” factors in the blood could have profound rejuvenation effects. This would be a game changer, allowing an greatly affordable and easily scalable anti-aging therapy to be developped.
Michael J. Conboy and Irina M. Conboy have started a company called IMYu to develop a commercial anti-aging therapy based on these latest findings, and they are keeping the details quite secret. Obviously they want to protect some sort of intellectual property, and considering that plasmapheresis has been approved and practiced around the world for decades, they have to hold on to some secrets or another. So when they declare publicly that it would be dangerous to try dilution of plasma for anti-aging yourself, or even that it would be unethical for doctors to try to replicate the experiment on volunteers, they are merely try to scare people and protect an ill-defined IP.
Unfortunately this means that we have to go by their published work to try and guess what works in plasma dilution, and ignore their attempt to muddy the water. At least until they publish more data on their human trials.
While we wait, there are a hundred thousands people dying of aging every day, so unlike them, I think the ethical thing to do is actually to try and advance public knowledge on the subject as much as as possible to allow people to make intelligent and informed decision and save lives that would be otherwise lost waiting for the approval of a bureaucracy that doesn’t recognize aging as a medical issue.
And it turns out that there are a few clinics are and there that offer a commercial treatment a plasmapheresis. For example, the only one in France is this one. On the description page of the procedure, they claim that it “detoxifies the blood”, helps with “aging”, “neuro-degenerative diseases including Alzheimer”, can help against “chronic fatigue”, “skin aging” and “hair loss”, etc… Sounds like typical crackpot sales pitch of the anti-aging marketplace. Except that now we have mice studies to back some versions of that up.
There are a few differences with the original study done on mice, which might make this flavor of the therapy completely ineffective for rejuvenation. As a quick reminder, in the study, 50% of platelet-rich-plasma was removed by centrifugation, and replaced with a saline-albumin solution. Here are the specifics of what the clinic offers:
Membrane plasmapheresis (mTPE) (the machines are Hemofenix), which is less efficient than centrifugal. I couldn’t get the pore size of the filters they use but from what I understand it will remove most but not the biggest proteins. The solution used for replacement is physiologic saline solution (0.9% NaCl), with a few mL of Anticoagulant Citrate Dextrose-A as needed by the machine to operate.
The procedure is done in 4 sessions separated by 48 hours minimum, during each of which you usually get 800ml of your plasma replaced (~30%). Note that because mTPE is less efficient, less of your plasma will be replaced than the volume of plasma extracted.
So I decided to use their service to test the rejuvenation effect of plasma dilution. I am starting with me as the first test subject, and depending on data will move on with others.
To evaluate the efficiency of the procedure, which is the whole point of this experiment, I will take measurements of various useful (and less useful) biomarkers. The first session is booked for December 17, 2020, and will be described in the next blog post, along with the first data gathered.
Edit from December 24, 2020: I was able to get a bit more information on the machine used for this procedure:
In part 1, I gave an overview of the current anti-aging research with a focus on what I think is the most promising approach. Now I want to turn to the obstacles to our progression toward a post aging world.
Obviously predicting the future is impossible, and I’d be foolish if I thought I had any insights into what’s going to happen. So instead, I will focus on what trends I perceive today and what they might lead to. My main goal is to think about the best strategy to navigate these obstacles.
There are some narratives among longevity enthusiasts that I think are not quite accurate and it’s worth exploring the whatifs. What if things are not happening as we think they are?
The first obstacle is related to the strategy to defeat aging. Funding in the longevity space can be divided in two type of strategies:
The first is finding ways to tinker with the metabolism to slow aging. We now knows of several metabolic pathways that influence aging, like mTOR or AMPK. Playing with this pathways has been shown to influence lifespan in primitive organisms like worms or small rodents. Since these lifespan extension effects seems to scale down as the “natural” lifespan of an organism scale up, there is few theoretical ways that any such interventions could produce any more than a few years of additional life. Furthermore, these pathways can naturally be influenced by interventions like exercise or fasting. That dozens of millions are spent to try and develop a pill that will might give you the benefit of a good diet and exercise is rather telling of the society we live in, and a waste of money as far as rejuvenation is concerned.
The second strategy, the consensus among the more “radical” anti aging crowd, is that aging is a multifaceted process, the Hallmarks of Aging, resulting from the normal “wear and tear” of metabolism or from some sort of programming, depending on who you ask; To cure aging, we’d need to target each hallmark. This is a strategy that has been championed for years by Aubrey De Grey. And that is a very good strategy. It makes no assumption about what causes aging, it simply target all the changes happening to the aging body to push the body back to a younger state. According to this strategy, it doesn’t matter whether for example beta-amyloids are the cause of Alzheimer disease or not, we need to get read of them because young people don’t have such high levels.
Not only is this strategy very sound, but Aubrey De Grey has made more than anyone to bring public awareness to the cause of longevity. It may be his peculiar long beard or his powerful charisma, but we would probably not be so far ahead today would it have not be for him.
While it is a very good strategy strategy, it might not be the most effective one, as we reviewed in part 1. As much as it is a good thing to diversify the development of anti-aging therapies, the weight of evidence should move us to put more funding and energy on those targets that seems upstream of most hallmarks of aging. Nonetheless, there so far seems to be enough funding for a few approaches to epigenome reset, enough so that we can reasonably expect some of them to reach the clinic in the medium term.
A second narrative widely shared is that public opinion, at some point in the future, will be vastly suddenly swayed to the cause of life extension after which everyone will get to work to democratize anti-aging cures so that we can all live happily forever and after. All it would take, it is thought, is a convincing enough study. Whether it is robust mouse rejuvenation or an impressive human study, one of them will be a catalyst for profound change.
Resistance to change is great
It might be so. Public opinion is unpredictable, and it seems like internet has made it quite volatile, and as irrational as it has ever been. Information overload means it’s likely gonna get harder and harder to get public attention. And conformity bias ensures social homeostasis toward the status quo.
But there are more compelling reasons to doubt this narrative: There are already some really good studies showing rejuvenation in mice. The 2016 landmark study showed a 20 to 30% life extension in mice following the destruction of senescent cells. Another 2016 paper showed that partial reset of the epigenome turn back the clock of aging. But that is not all. We now have a study that showed actual rejuvenation in humans! Each of these studies generated some buzz (mostly online). But each time, the buzz died down and the public at large is none the wiser. The ranks of the longevity community grow a little, bringing in more scientists, more physicians, more enthusiastic people, more money. That is bad at all. But it still marginal. Aging research is as ignored by the mainstream as it ever was.
And yes, we could argue that none of these studies were enough. Not enough sample size. No controls. Just a mice. Or maybe it just misses the key ingredient that might catch public imagination. But here I will argue that none of that matter. No study will ever convince the public because the public doesn’t listen. And if the public doesn’t listen, neither do the politicians. And the money will continue to be hard to come. We have had outrageous headlines claiming the fountain of youth has been found for years now. If a good study is enough to catch the public attention, it would already have happened.
The only way we might possibly get the public attention is if a therapy is officially approved by an authority like the FDA against aging. But that would suppose that authorities recognize aging as a medical target, which is not the case and can not be the case as long as the public consider aging to be in the order of things….
Ok, but there are already numerous potential therapies in clinical trials right? Surely when they are approved things will change? Let’s examine how things might change. We will talk about the FDA mainly as it is the locomotive of the regulatory system of healthcare development.
In our current market-based system, the development of therapies to the clinic is carried out by the private sector, with varying level of involvement of governments around the world. The only incentive of private company is to be profitable. Patent laws have been designed to increase the possibility for a company to make money out of a product whose development cost dozens or hundreds or even billions of dollars, most of this cost coming from the regulations they have to follow. Discussing this system is far outside the scope of this article; I just layed out the foundation for what comes next.
So the only choice for a company willing to get its therapy approved on the market is to target officially a specific disease. Fortunately, aging is the root cause of a plethora of ailments like sarcopenia, dementia, cardiovascular diseases,… Plenty to choose from. But already, the incentives start to diverge from the goal of a comprehensive cure for aging. Take Alkahest for example: instead of developing a single therapy targeting the aging process as a whole, which we hypothesized to be possible in part 1, they are trying to bring multiply therapies to match the numerous individual diseases of aging. At the end of the process, we will have numerous therapies that individually will not do much against aging. It takes mission oriented individuals to focus on the bigger picture and fight against the pressure to maximize revenues. And considering how arduous is the process of getting FDA approval, let’s just say that the odds are not good.
Fast forward a few years. You have a bunch of therapies officially approved on the market. Each for a specific disease. The longevity community is ecstatic. Longevity escape velocity is here! Is it, though? By law the companies behind will not be able to advertise the anti-aging effect. And if you go to your doctor and ask him to prescribe one of this therapy, you will likely have a blank stare and a polite goodbye. Ever tried to get metformin, one of the safest and most used drug that has a positive impact on longevity? Why would it be different with a newly approved therapy? And even if you find the right doctor, you’ll have to pay for each of those therapy the price that has been designed to extract maximum value from health insurances. In short, these interventions will be available for the few that are rich and connected enough. The public at large will ignore life extension as still a pipe dream.
If you think I am being pessimistic, consider our current situation: We could already quickly and cheaply add at least a decade to the current healthspan in developed countries! A third of americans are obese, another third are overweight (link), a third of americans have prediabetes, and so on and so on. All of these can be classified as metabolic syndrome, and though age is a factor, by far the biggest factor is lifestyle. It is costing billions of dollars in healthcare every year, and millions of healthy years of life lost. And it is completely reversible. And yet, its prevalence is still on the rise worldwide. The causes are multiples, and if you are interested in reading more about it, Food Fix by Mark Hyman is a very good place to start. But whatever the reasons, here we have interventions that are available today, are free, would add years of healthspan, save trillions of dollars to society, and yet is not implemented.
Similar is the case with the few interventions like Metformin, as we mentioned earlier, which are cheap, safe, widely available, have been shown to increase lifespan and yet are never prescribed for this purpose outside a small circle of connected people. Why would anything change just because more interventions become available?
Hostility is worse than apathy
The lack of public enthusiasm for healthy longevity can be disheartening. If only we had a few hundreds of millions of dollars, we’d be immortal already. Or so the thinking goes. So a lot of effort in our community goes toward advocacy. And that is the right thing to do. We want to touch every people on earth, because every life is sacred and everyone deserved to be spared the sufferings of aging.
Still, there is a scenario worse than apathy: hostility. As said above, public opinion is a volatile and sometimes irrational beast. It can be hard to predict where it will lend on a subject. Nuclear energy is virtually carbon free, cheap, abondant, the radioactive waste are objectively a trivial issue to manage (because there is so little of it), so it should be the darling of an eco-conscious society, especially because the lack of storage option makes it the only scalable clean energy so far. And yet it is quite tabou especially in environmental movements, for some reasons. That’s an example among others that mainstream opinions not always coincide with reason.
Who knows how the public will react. The development of the first therapies that have a real impact on aging will influence this reaction, among other factors. The most advanced therapies are senolytics. If for example those drugs have a short term benefit, but end up decreasing maximum lifespan in the medium term, as some fear, the backlash could be severe. I don’t think this hypothesis is likely though. The data we have on the few self-experimenters that share their experiences hints to a beneficial effects that last for years. And even if the aging process does end up been accelerated eventually, it is unlikely the link can be definitely proven in the public mind.
Another reason would be that the first therapies becoming widely publicized will be expensive enough to anger people, and misguided anger can end up thwarting further development in the name of equality rather than letting the rich fund the development of cheaper therapies, as happen for lots of technologies.
There can be many reasons why the public will start to become hostile to the research against aging. And if that happens, that will make progress will crawl to a stop.
The good news is that, as I speculated in part 1, the research against aging is already very advanced. We shouldn’t need much more fundamental research now. It might not take long to have a true anti-aging therapy available to the public. If it is affordable enough, that could be enough to win the public heart. Because it is one thing to prevent research against an hypothetical cure, it is another thing to prevent billions of people from trying to stay young if the means to do so exist already. If just one clinic open in a third world country somewhere, the tide of clients will be too hard to stop.
This is where I want to end this part 2, on an optimistic note. I think the best chance for universal anti-aging therapies is to present the public with a “fait accompli”, a therapy already available, affordable enough for the majority of people to benefit from it right away.
In part 3, I’ll conclude with what I think the best strategies are for the “average person” like you or me to make a post-aging society a reality as soon as possible.
In this series of posts, I want to speculate on the future of human longevity. I will start with the current state of anti-aging research and move on to what is possible from there.
I am trying to assess the current state of life extension research. Obviously that is only my interpretation, as a layman person with only a high level understanding of the science involved. If you the reader spots a fault in my reasoning, please correct me in the comments. What I will expose here does not represent the consensus in the longevity community, if such can really be defined.
After the discovery of the yamanaka factors in 2006, which can induce pluripotency in any cells, it has been shown in severalstudies that transient expression of all or some of these factors can rejuvenate a cell, or an organism, without loss of cell identity (by “resetting” the epigenome). By rejuvenate, I mean that most hallmarks of aging are reversed. “most” does not mean the others are not reversed, it means they have not been properly studied in this context. There is a case to be made that all hallmarks are actually reversed if most of the cells of an organism is rejuvenated by way of epigenome reset.
Furthermore, numerous studies about parabiosis shows that exposed to an young environment, an old organ becomes young again. Infused in young blood, an old mice become young again.
If a cell becomes old, it means they “chose” to do so. Which means they are programmed to do so, and must follow some sort of program. Parabiosis experiments hints strongly to the fact that the “age appropriate phenotype” instructions come from the blood.
This is very good news for an anti-aging cure. Even now, we know how to rejuvenate a mammal. It is at the moment very hard and risky, as it involves manipulating our genes to reset the epigenome. But it is not unreasonable to think we would sort out the issues if we choose this road, this is simply a matter of engineering.
But, and this is where it gets better, as we saw earlier we know that the aging regulation is at least in part made into the plasma. So another plan would be to find out those “aging instructions” and find a way to synthetize them cheaply rather than relying on young plasma, the production of which can not scale, and which has strong ethical concerns attached. There is actually a team of scientists who claims to have found the solution and have a therapy only a few years away. How this will pan out remains to be seen.
Whether by trying to directly reset the epigenome or trying to emulate a rejuvenating plasma, the plan is pretty straightforward, the science quite mapped out, as we will see below.
According to this review, there are four ways to reset the epigenome:
Strategy 1: Somatic cell nuclear transfer (SCNT) experiments. SCNT involves transplantation of a cell nucleus into an enucleated egg/oocyte in order to generate a “cloned” animal with an equivalent genetic composition as the donor individual.
Strategy 2: Extract cellular components (“reprogramming factors”) from pluripotent cells. Presumably the cytoplasmic “reprogramming factors” from the pluripotent cells can be isolated and concentrated to achieve a higher reprogramming efficacy.
Strategy 3: A third strategy involves ectopic expression of defined transcription factors in somatic differentiated cells to generate induced pluripotent stem (iPS) cells. Delivery of the ectopic transcription factors can be achieved by viral approaches, such as the use of retrovirus, lentivirus, adeno-associated virus or Sendai virus, or by using episomal vesicles, or by direct mRNA or protein transfection.
Strategy 4: iPS cells can also be generated by using combinations of microRNAs (miRNAs) or small chemical molecules without the needs of ectopic expression of reprogramming factors. We could argue that using plasma from a young organism falls into this category: the environment (the plasma) is acting as a signal to rejuvenate to the cells. Although the fourth item, it might be the safest and most powerful approach.
There are already several enterprises that are working on direct epigenome reset:
Turn.Bio. They use the Strategy 4 (miRNAs). They are using several delivery POC to target various tissues, with the first therapies expected to target skin and lung. Delivery methods to some tissues is still to be defined.
David Sinclair’s lab used gene therapy (Strategy 3). They showed a proof of concept, regenerating a damaged mouse’s eye. A stealth company, Iduna Therapeutics, has been spun out of it to translate the concept to the clinic.
Strategy 4 is also explored by Harold Katcher and his company Nugenics. They have shown impressive age reversal on rats in a (not yet peer reviewed) study.
The publicly traded AgeX Inc. seems to be working on a drug that can reset the epigenome (Strategy 4)
Alkahest is capitalizing on parabiosis studies (Strategy 4) to bring multiple therapies to the market. Instead of trying to find a common plasma fraction that would act on aging as a whole, they seek to find separate factors (that are either too low or too high in old plasma), so as to be able to bring differents therapies each targeting a specific disease of the old, in order to maximize revenue. I’ll come back to that in the second part.
I also need to mention that various anti-aging interventions already exists which might or might not actually rejuvenate us. For example, stem cells and exosomes systemic delivery. These therapies are already available to paying customers in some countries around the world, and are associated with exceptional claims and anecdotal reports. Unfortunately, as far as I am aware, their anti-aging effect has never been investigated properly: no one has yet studied the effect on epigenetic age, which is the best marker we have of biological age. So we can only ignore those until they are properly vetted.
As you can see, if we actually take into account the recent progress made in understanding aging, we have a straightforward path toward actual rejuvenation. There is every indication that a therapy that can induce epigenome reset will be able to keep us biologically young indefinitely. We don’t even need the concept of longevity escape velocity, because we only need to develop the right type of anti-aging therapy once. Or at the very least the damages not cleared by this type of therapy would not be a problem for a long time.
We are past fundamental science, far into clinical translation. How much funding until the clinic? Ten millions? Fifty? One hundred? Maybe. But all of it can be provided by investors, and it’s really a drop in the bucket to bring the end to the suffering of hundreds of millions. How many years? Ten could be a reasonable estimate. That is, if the development of these companies goes full steam ahead.
That’s the state of longevity research. Technologically wise, we are very close to a cure. But of course, technology and science are the easy part. There are a lot of obstacles standing in the way of a post-aging society. We will explore them in the second part.