It’s a great idea and I was thinking along the same lines. We have Biolife med director at this forum, so it could be a good food for thought for him. I have an appointment with a local Biolife next week, will ask if they could do plasma dilution vs plasma donation.
1 Like
1 Like
As you can not post on a thread when you have three consecutive postings.
I am adding to my last posting, on this thread.
On 06/16/2023 at 11:40 EST I added;
FWIW
A copy of:
“Principles of Blood Separation and Apheresis Instrumentation”
Dobri Kiprov, M.D., H.P.
Chief, Division of Immunotherapy, California Pacific Medical
Center, San Francisco, CA
Medical Director, Apheresis Care Group
Shamelessly a PDF copy of;
“Transfusion-Medicine-Technical-Manual” Second Edition 2003
I do not think we have much interest in this subject.
2 Likes
Yes - it doesn’t seem too many others are interested in this yet. But - as the research progresses I suspect many more people will be interested. I will continue to slowly move ahead on the research into this, and work on identifying source and pricing for all elements of the therapy, and I’ve reached out to the Russian Biohacker team and have an intro from Leon Peshkin at Harvard so I hope to hear back from them soon.
2 Likes
Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner
As we age, our blood changes. These changes are a consequence of alterations in hematopoietic stem cells (HSCs) that reside at the apex of blood production and have fundamental implications for our ability to replenish blood. Aged HSCs lose regenerative potential and shift their production of white blood cells to favor more myeloid cells and fewer lymphoid cells. 1, 2, 3, 4, 5 In addition, mutated HSC clones begin to dominate blood production by outcompeting other cells in the HSC pool (clonal hematopoiesis). 6, 7, 8, 9, 10, 11 Ultimately, these mutated HSCs can degenerate to myelodysplastic syndromes and leukemia. 10, 12, 13 However, the physiological processes that drive age-related HSC dysfunction are poorly understood. Mechanistic understanding of HSC aging might enable us to mitigate the degradation of blood production with profound medical benefits.
https://www.cell.com/molecular-cell/fulltext/S1097-2765(23)00419-7
It is clear that alcohol (and I thought it was through aldehyde) drives up the MCV. Its a good argument for people who drink alcohol to also take Pantethine. (Or not to drink alcohol)
2 Likes
@RapAdmin Did I see on the forum you were participating in Kiprov’s clinical trial? Any updates from them or if they are still recruiting?
They quickly filled the participant list - and I think they had something like 300 applicants (at the time I asked) for about 60 participant spots (I forget the exact numbers, but this was almost a year ago).
They have 3 month long “arms” and a 6 month arm. They finished the 3 month arm back in January timeframe, and I guess by now they’ve probably finished the 6 month arm, from a treatment perspective. They say they are going to invite me back this month or so to do a blood test followup - but it hasn’t been scheduled yet.
They won’t tell me if I’m in the treatment or control group until after all the study components and evaluation are completed - so I think sometime in the next 6 months.
So - right now, not much to report.
1 Like
That’s interesting, Thanks for the reply. I had applied for the Apheresis trial also, but they informed me: " After discussing your case with Dr. Kiprov, we decided that your participation in the Pearl Trial could be contradictory with our study.
As of now, I cannot recruit you to our study."
I know it can take one to several years before results of a clinical trial are formally released. But, hopefully Kiprov may have something by the end of this year.
I sure would like to see costs come down. I could afford 1,000-2,500 but 5-8K is too much. Maybe we could suggest they offer a volume discount to RapaNews members. 
1 Like
FWIW count me as among the interested in this — I’d love to be kept in the loop on any progress you make in researching feasibility. It sounds like the consumables are the first bottleneck. There’s probably much cheaper alternatives in emerging markets but we’d need to be much more informed in the field to recognize the parts and ascertain if they’re 100% equivalent.
2 Likes
A team of scientists has extended the lives of old mice by connecting their blood vessels to young mice. The infusions of youthful blood led the older animals to live 6 to 9 percent longer, the study found, roughly equivalent to six extra years for an average human.
While the study does not point to an anti-aging treatment for people, it does hint that the blood of young mice contains compounds that promote longevity, the researchers said.
“I would guess it’s a useful cocktail,” said James White, a cell biologist at the Duke University School of Medicine and an author of the new study.
New Scientist article on this topic:
Research Paper:
Published: 27 July 2023
Multi-omic rejuvenation and life span extension on exposure to youthful circulation
Heterochronic parabiosis (HPB) is known for its functional rejuvenation effects across several mouse tissues. However, its impact on biological age and long-term health is unknown. Here we performed extended (3-month) HPB, followed by a 2-month detachment period of anastomosed pairs. Old detached mice exhibited improved physiological parameters and lived longer than control isochronic mice. HPB drastically reduced the epigenetic age of blood and liver based on several clock models using two independent platforms. Remarkably, this rejuvenation effect persisted even after 2 months of detachment. Transcriptomic and epigenomic profiles of anastomosed mice showed an intermediate phenotype between old and young, suggesting a global multi-omic rejuvenation effect. In addition, old HPB mice showed gene expression changes opposite to aging but akin to several life span-extending interventions. Altogether, we reveal that long-term HPB results in lasting epigenetic and transcriptome remodeling, culminating in the extension of life span and health span.
2 Likes
6-9% is barely above resveratrol levels.
True - but this was only a three month test: “Here we performed extended (3-month) HPB” - so if its proportional, you might experience 4X that 3 month result, i.e. 24% to 36%, for a year-long treatment. And perhaps more if it was multi-year…
1 Like
Yea, this is kind further backed up by the different epigenetic clock studies they did:
“drastically reduced the epigenetic age of blood and liver based on several clock models using two independent platforms. Remarkably, this rejuvenation effect persisted even after 2 months of detachment.”
“Altogether, we reveal that long-term HPB results in lasting epigenetic and transcriptome remodeling, culminating in the extension of life span and health span.“
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
1 Like
Does anyone have access to the actual Nature Aging paper (I seem to hit a paywall).
1 Like
@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.
Scientific background
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.
Practicalities
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.
The procedure & standards of clinical practice
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.
4 Likes
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.