Dr Steve Horwath on Twitter about the paper
*Youthful blood induces systemic rejuvenation in older mice. Long-term heterochronic parabiosis lowers epigenetic age by up to 30% and enhancing both life span and health span.
The epigenetic rejuvenation effect was maintained even two months after disconnection.
Universal pan mammalian epigenetic clocks suggest relevance for humans.*
https://twitter.com/prof_horvath/status/1684841707702001665?s=42&t=zJMJ1xVdRJYEDYz-DHipTw
Does anyone have access to the actual Nature Aging paper (I seem to hit a paywall).
@RapAdmin I cannot commend you enough for this effort. This is timely and so important. We must figure this out.
Plasmapheresis is the most promising intervention to emerge so far. In terms of risk/benefit, it will probably end up coming right after diet, exercise and sleep. I am including below my own notes on the science behind it. Hopefully, it will clear up some stuff that has distracted the conversation in this thread. In particular: “young plasma” is completely irrelevant for our immediate purpose; and there is a specific mechanism being hypothesised, why only significant dillution will be effective (in contrast to small plasma donations). Following the scientific discussion, I will focus on the current status for obtaining the procedure and will end with a comprehensive review of current clinical practice.
Previously in 2016 (A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood | Nature Communications), blood was exchanged from young mice to old, and viceversa. It highlighted the fact that old blood appears to contain factors which actively suppress rejuvenation. One such example is the inhibition of stem cells: when muscle stem cells are cultured in old blood, they don’t proliferate; and when the plasma of the old blood is dilluted, they regain their function (see 2019 Conboy paper mentioned below). Transfusion of old blood had this effect even in otherwise young and healthy subjects. Conversely, young blood does not contain any instrinsic factors which can effectively mitigate the suppression, or otherwise stimulate rejuvenation again, if given to already aged subjects.
One theory for the accumulation of those factors in old blood is that they are being produced by tissue which gets damaged over time and then they propagate systemically in the rest of the body, having a negative effect on all other organs. This is partly suggested by the fact that tissue damage inflicted on young mice further amplified the systemic suppression caused by receiving old blood.
In 2019 (Undulating changes in human plasma proteome profiles across the lifespan | Nature Medicine), a study screened plasma proteins in people of all ages and tracked when the levels of those proteins had a strong variance across a +/- 5 years interval window. They identified three significant points when plasma composition shifts significantly, before stabilising again for a while in the new state (see Fig 3c). The first one is around the age of 35; the second, at 60; the third and most dramatic shift, at 78.
In 2020 (Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin | Aging), Irina and Michael Conboy discovered that plasmapheresis lowered numerous (most?) biomarkers of ageing in mice. The procedure consists of replacing between 1 plasma volume (60% or 40 mL/kg in humans) and 1.5 (75% or 60 mL/kg), with a neutral solution (saline + albumin). The consequence of doing this is a significant dilution of circulating proteins in the plasma. It is hypothesised that many of those proteins play signalling roles and that the therapeutic benefit emerges from interrupting signalling feedbacks. By having to secrete new signals following the procedure, the body has an opportunity to adjust their ratios and transitions spontaneously into a different steady state. Compared to manually tweaking individual signals, this process appears to be natural and self-adaptive. A simple mathematical model was also used to demonstrate how steady states can arise and how interrupting the feedback loops can trigger a state transition. A further paper by the Conboys in 2022 (Old plasma dilution reduces human biological age: a clinical study | GeroScience) showed through a small clinical trial that plasmapheresis once monthly for 6 months provided a cumulative improvement in ageing biomarkers.
Incidentally, participants in this trial had to pay out-of-pocket for the procedures! It appears there is very little funding available for this, probably because the IP prospects aren’t promising. A very pitiful situation that we see with D+Q trials, as well. So unfortunately, comprehensive clinical data might prove slow to come in.
There are currently very limited options for obtaining the procedure off-label. In the US, clinics such as the Maxwell Clinic (https://maxwellclinic.com/) offer it privately for an exorbitant price. The Conboys are working towards patenting a modified plasmapheresis method that they will offer through their startup, IMYu. Dobri Kiprov, the clinical consultant who collaborated with the Conboys, has been offering his consulting services to clinics, but it’s hard to tell whether his insight from applying it to longevity actually provides better results over standard plasmapheresis. He has his own upcoming venture, Lyfspn. So far, clinical trials have only accepted middle-aged (50+) volunteers. Plasma blood donations are inadequte, because the limit for one donation is way below the volume required by the protocol (40-60 mL/kg) and they also limit how often you are allowed to do it per week/month; therefore, it is unlikely that plasma donations, as currently regulated, will achieve a sufficient level of dilution that can reset the feedbacks.
As usual, it could be worthwhile to find clinics in developing countries who will provide the intervention at a considerable discount; but also with the downside of travelling costs and the risk of dangerous incompetence.
Plasmapheresis is old and well-established. Complications are minor, self-limited and easily treated. The bottom line is that deaths have occurred in 0.09% of cases and even then, the majority were attributed to underlying medical conditions.
The procedure consists of blood being passed to a plasmapheresis machine, then centrifuged to separate plasma from cells (or, rarely, a less efficient filtration mechanism is used) and finally reinfused into the patient, with the original plasma removed, plus a replacement fluid.
Low-cost, portable plasmapheresis units have been known to be resold occasionally on secondary market. One such manufacturer is Haemonetics; but, as @RapAdmin pointed out, the caveat with the low priced models is vendor lock-in for compatible consumables
The replacement fluid is required in order to restore the missing volume; insufficient fluid replacement (e.g via oversight or technical failure of the unit) will cause hyperviscosity and is very dangerous. There are several alternatives for the fluid. The most common one is combination 0.9% saline plus 5% albumin on a 50%:50% (volume-for-volume) basis. It must be properly warmed, otherwise it can cause hypothermia. Fresh frozen plasma is also used as a replacement fluid, but as explained before, irrelevant for us; besides, for every type of complication, the risk is much greater when using fresh plasma, but particularly so for hypersensitivity (allergic) reactions. Allergic reactions (typically itchy skin, wheezing) are also possible with albumin (contingent on the quality and purity of the manufactured product), as well as to the equipment through which the blood passes; but those reactions are exceedingly rare. Premedication with an antihistamine can help, but not always. If the allergic reaction becomes intolerable, the procedure should be stopped. Perhaps a silver lining of immunosenescence due to old age is that those allergic reactions in response to foreign antigens will be less common in old vs. young. In rare cases, watch out for respiratory difficulties, because they can have causes besides allergy and might constitute an emergency.
Replacement of removed volume with other colloid solutions that don’t contain albumin, or even containing just saline would be much cheaper; however, based on clinical data from fluid management and resuscitation, unfortunately this appears associated with a higher incidence of adverse reactions, compared to the use of albumin. To do: need to look into this specifically in the context of plasmapheresis; especially the saline-only alternative should be considered, as it can offer a substantial reduction in cost. Besides, in mice the Conboys have proved that the benefits of the intervention do not actually depend on the addition of exogenous, “fresh” albumin at all (“young” or otherwise).
The main danger now remains that of coagulation. Due to blood leaving the closed-circuit of the circulatory system, making contact with the artificial surfaces of the device and going through centrifugation, it can trigger clotting (and transient inflammation). Hence, this needs to be mitigated by adding an anti-coagulation factor to the returned blood, with “acid-citrate-dextrose (ACD) solution A” being the preferred choice. The apharesis device controls its administration automatically. Citrate is rapidly metabolised, however it has the main downside of chelating blood minerals. Electrolyte complications are due to hypocalcemia etc. and symptoms begin with tingling and can escalate to vomiting. However, serious complications are actually extremely rare and typical only of drastic protocols (i.e long sessions done on consecutive days, etc). Either way, an isotonic sports drink or prophylactic adiministration of a calcium supplement will mitigate citrate toxicity. Citrate and its metabolism also transiently disturb the pH balance of the blood, but I couldn’t find any recorded data of this leading to adverse effects or symptoms.
There is also a converse to the above: the procedure dilutes endogenous coagulation factors present in the plasma, thus increasing the risk of coagulopathy. However, this dilution is only partial and typically recovers within 2 days.
Low pretreatment hematocrit and other hetmatological issues are an important risk factor for complications and should probably be checked through a routine CBC blood test, if you have suspicions. A coagulation test is also a good idea, to identify any pretreatment abnormalities in coagulation factors (i.e thromboplastin, prothrombin, fibrinogen): as plasmapheresis will change the balance of those factors (see above), plus reduce your platelet count by up to 50%, it could leave you at increased risk of hemorrhage. Paradoxically, spontaneous blood coagulation after the procedure has also been reported; perhaps due to disproportionate loss in anti-coagulation factors, but it only happened a few times in the 90s and wasn’t fully elucidated.
Other risks being reported in the literature are due to vascular access (e.g thrombosis, infection, even pneumothorax), but competent phlebotomy and using peripheral access (i.e not usuing the jugular and instead inserting the catheter into the arm, provided the vein is strong enough) will avoid that. The needle for drawing the blood is placed in a larger vein (typically in the antecubital fossa) and for return, in a smaller one (basilic or cephalic). A 17-gauge needle is used for drawing and an 18-gauge for return. Narrow catheters (i.e size 7 on the French scale) must be used. They must be short, to reduce the distance that the blood travels over the extracorporeal circuit. Damaged/kinked tubes or equipment failures can lead to ruptured cells (hemolysis) as they pass through the circuit: use rigid catheters and observe the plasma collection lines for pink discoloration, which is a sign of hemolysis; if that happens, stop the procedure. Sudden disconnection of tubes causes air embolism, which is dangerous.
Dizziness, hypotension are somewhat common, but never critical. It is recommended that your systolic blood pressure before treatment is 100 mmHg or greater.
One of the conditions that plasmapheresis is FDA-approved for, is chronic auto-immune disorders. In that case, it works via the periodic clearing of immunoglobulin antibodies. This is also the reason why it comes with a theoretical increase in the risk of opportunistic infections: severe septicemia was reported on a few rare occasions and the antiboties of a vaccine will also be cleared by the procedure. However antibodies will return, slowly over the next few weeks, back to levels associated with protection from infection.
Plasmapheresis is also recommended for acute intoxication and poisoning, when the toxin has a high rate of binding to plasma proteins and the volume of distribution is low (i.e, not when the elimination half life of the toxin is short anyway; or, when the toxin levels are much higher than what the procedure could clear). But note that, in the same way, plasmpaheresis dilutes any systemic drug that you may have taken and which binds to albumin and it will thus result in subtherapeutic levels of your medication. Any biomarkers/diagnostic constituents in the plasma will also be artificially reduced and unreliable following the procedure (kind of the point, tho).
Other risk factors: renal insufficiency; concomittant use of ACE-inhibitors.
In conclusion, the procedure requires at the very minimum access to a plasmapheresis machine, consummables and a nurse trained in phlebotomy. It is unknown how long the benefit of the intervention persists afterwards, but as mentioned previously, the Conboys showed that the effect of doing it monthly accumulates for at least the first 6 months.
If you find this useful, please consider furthering our efforts. I live in Europe. If you have any idea in mind for how to accomplish this, please get in contact.
I give you my five cents (Euros) regarding where treatments with therapeutic plasma exchange can be started, and who could start such treatments in a cost-effective way.
My mind landed on dialysis clinics. For them, the threshold is lower than for a novel start-up focusing only on therapeutic plasma exchange. They also already have expertise in place that are well versed in similar procedures.
To bring the price down, I would look for clinics in Turkey or Romania, where the regulations might be less strict compared to the northern countries or the core European countries.
Its an interesting area… but I also think there needs to be some more data to make sure that the mouse data translates to benefits for humans.
I’ve been in this clinical trial for plasmapheresis (TPE) from this San Francisco-based startup, but I’ve not heard anything back from them over the past 5 months… they had said they’d be inviting me back for followup blood draws and testing, but they have not contacted me, and when I contacted them they said “later…” Plasmapheresis Startup Looking for Clinical Trial Participants SF Bay Area
Also - as you may have heard, Bryan Johnson has been trying Young Blood plasma using his son’s blood, and other’s at a clinic near Dallas. But - he said they had no good / positive results with it, so now he’s stopping it.
So - I still think the data needs further human validation right now.
the problem really isn’t expertise; with such an old and common practice, expertise is plentiful. the main obstacle is convincing them to go around the rules and offer it off-label for a sane price (instead of being available only to the super-rich).
Thanks, I am currently looking into this actually. The concern is stuff like: Journalistic investigation reveals disinfectant fraud in Romanian public hospitals | Romania Insider. Perhaps one approach could be to negotiate with the medical team that they procure the consummables (e.g albumin) from Western suppliers.
If anything, Bryan’s results validate precisely what we already know about this “young plasma” nonsense. But no point repeating myself – life is too short lol.
I do not feel you supported that statement. Further up in this chain there is support for young blood / young / young plasma blood factors potentially having meaningful impact. How come you feel that it is irrelevant - logistics? Or are you saying that it scientifically is not a meaningful hypothesis (whether complementary to plasmapheresis or the main driver of a lot of the heterochronic parsnips results - I’m personally not saying that plasmapheresis is not helpful)
I have read the entire thread and am ready to move forward and get this started. I will buy the plasmapheresis equipment and set up a clinic. People may come to the clinic and use the equipment cheaply.
The main issue is where to establish this clinic. I think a major city in Texas might be best for the first clinic. Because I plan to sometimes replace my plasma with just saline and albumin as shown by the Conboys, but other times I might want to replace my plasma with young plasma which for older people I speculate is possibly better. Texas is the only state in the country where I know how to get young plasma so I would like to be there.
If I start such a clinic in Texas do you think that will be useful to people such as the members of this group or is that too far away from where people live?
FWIW
I see you just joined.10/15/2023 around 10:30pm
If you are serious, you can count me in.
Any location is acceptable to me.
As we know, there are some clinics in this segment in Texas but overly priced! Therefore, i think if someone establish w/ low price and good/safe equipment “costumers” showed up. Iam one of them.
Plasmapheresis alone is promising and as we learn more, we may find that its effectiveness is enhanced when used with other interventions. The one I’m thinking about now is E5, whenever it finally gets into human trials.
In rat trials, the exosomes that constitute E5 have to exceed the old rat’s natural exosomes by four to one to get its dramatic effect. Manufacturing enough volume seems to be a hurdle Harold and Akshay are trying to get over. What if the old exosomes in the plasma were removed by plasmapheresis first? Maybe much less E5 would be needed.
If your planned plasmapheresis center were located in a city where aging/longevity research is already being pursued in a major way, future collaborations could be in the picture. Houston has a big medical center, but I’m not sure if any aging research is done there. I’ve never heard much about Dallas or Ft.Worth as medical centers. I’m pretty sure there’s not much of that going on in Austin. San Antonio has the Barshop Institute and the UT Health Science Center, with the associated San Antonio VA Medical Center that all research aging/longevity and run clinical trials.
Good to here others are on the same page, I was thinking about buying the machine and doing it in flordia, but Texas is good. Please count me and 2 friends in.
@Lankheet1 @davidjhp if you really want to make a positive impact to the community, please, please share with us advice for how to procure the equipment (particularly without a licence) and any other practical information.
Yes, myself and 2 others are definitely in, please keep me posted. We have capital available to help underwrite the venture
Having gone through a series of 6 TPE sessions over 4 months as part of the clinical study, I have to say I’m currently on the fence with this therapy. I summarized my results / experience here: Plasmapheresis Startup Looking for Clinical Trial Participants SF Bay Area - #51 by RapAdmin
But, generally, I did not notice any benefits from this treatment process. If anything I actually felt worse during the 4 month period and few months afterwards. I had paused my rapamycin a month prior to the clinical trial, and I have to say that I think the benefits / results I’ve noticed from 3 years of rapamycin far exceeded anything I’ve noticed from a series of 6 plasmapheresis / TPE treatments. I’ve been saying for the past year that I thought I was in the “control” group that didn’t get any actual treatments… but just recently found out that in fact I did get the treatments.
And the results were actually extremely disappointing for me. I had read all the research and have been very, very hopeful about plasmapheresis. If anything, my strong bias towards the TPE type therapy would seem to suggest that I’d at least get a strong placebo benefit.
So - I await more research on this topic. I hope that the Kiprov / Buck Institute / startup collaboration in the clinical study I participated in, results in a paper that demonstrates some significant effect size. Perhaps it provides benefits that you don’t feel. I really hope this works, but right now I’m not yet convinced.
please share with us advice for how to procure the equipment
My preference is the Fresenius Kabi Amicus Separator. I am still researching the options. If there are any problems trying to buy it without a license then you have to find a doctor to buy it for you.
Yes, myself and 2 others are definitely in
Thanks, your words of encouragement mean a lot to me.
please keep me posted.
I changed my mind about Texas, because I find the laws there too hard to deal with so I will not move to Texas. I am currently planning to move to Florida soon to set this up. I am currently leaning toward Tampa FL but still studying the location options.
We have capital available to help underwrite the venture
This could help a lot, please contact me at david10@davidjpotter.com and let me know a little more about your thoughts on this.
But, generally, I did not notice any benefits from this treatment process.
I replied on the other page
Dr. Kiprov’s latest lecture and the preliminary results of the plasmapheresis clinical trial for aging, which was presented at the A4M Longevity Fest last week in Las Vegas.
I was in group A or B (they haven’t told me which one).
