Questions about parabiosis

This question is for RapAdmin. However, everyone else is welcome to give their input.

Hi RapAdmin

I have seen in another thread that you are currently involved in a parabiosis trial and I hope you don’t mind if I ask you some questions about it.

Firstly, I would like to state some of what I currently know about parabiosis. This will become relevant for some of the questions I want to ask.

When I first came across the concept of parabiosis, it was on the Internet and was in the form of two mice (an old one and a young one) whose blood streams had been connected together. The result of this experiment was that the old mouse became somewhat rejuvenated and the young mouse aged quicker.

The initial provisional conclusion was that there was something in the young mouse’s blood which rejuvenated the old mouse.

A second experiment was performed involving just an old mouse which was connected to an albumin saline drip. This had an even more powerful effect.

This suggests that the old mouse in the first experiment was actually befitting from a dilution of bad stuff in its blood instead of benefiting from something good in the young mouse’s blood.

My first question is this. I presume that for ethical reasons, you are not being connected to another human. Am I therefore correct in thinking that you are being connected to an albumin saline drip?

If yes, is it synthetic albumin or real human albumin?

If it is human albumin, do you know if the quality of the albumin depends upon the age of the blood donor?

If yes then could the quality of the albumin effect its rejuvenative ability?

I think that these last two questions are possibly very important. Can I therefore suggest that you mention them to the people who are running the trial?

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My personal view is that it is the removal of IL-10 that is key. I don’t think the quality of the albumin is that important, but it is best to replace with some albumin rather than just saline.

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Hi, I’m participating in a plasmapheresis clinical trial for aging, not parabiosis. They are somewhat similar in concept, but in the parabiosis they are connnecting you to another living human/mammal (I think this is only done in mouse and rat experiments, not yet in humans).

Plasmapheresis is also called “Therapeutic Plasma Exchange” by some groups. I think they are synonymous, anyway. Plasmapheresis is a procedure that removes plasma from whole blood, swapping out unhealthy plasma and replacing it with healthy donor plasma or a plasma substitute.

You ask a good question regarding is is “synthetic albumin or real human albumin”? I have no idea. I’ll ask the next time I go in. I’ll report back when I learn more!

The clinical trial is explained here: Plasmapheresis Startup Looking for Clinical Trial Participants SF Bay Area

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Hi RapAdmin

Thank you very much indeed for your answers.

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Can you also ask if the plasma is synthetic or real?

Thank you very much.

EDIT: It has just occured to me that maybe the plasma contains albumin so my question about plasma may be unneccesary.

EDIT2: I have just found the following article that states that with Plasmapheresis, the plasma is replaced with an albumin solution.

EDIT3: It does not say if the albumin is synthetic or human.

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Related to this, a good article on albumin and aging:

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Thank you very much for the link.

There is an interesting graph in the article. I have just checked my last three blood reports in order to compare my abumin values with the graph and it seems that I have abnormally high albumin.

My values are as follows:

Year: 2012 Age: 42 My albumin: 54 What it ought to be according to graph: approx 44
Year: 2013 Age: 43 My albumin: 53 What it ought to be according to graph: approx 44
Year: 2022 Age: 52 My albumin: 45 What it ought to be according to graph: approx 43

The first two albumin values were somewhat higher than the peak of the graph.

The last result is a little bit elevated.

I am doubtful that these results mean that I am biologically younger that my chronological age. I am wondering if there is another reason for my high albumin values.

Albumin is problematic. (as are most biomarkers) on CR Albumin will be reduced. That does not mean the outcome is bad. Albumin has a U shaped curve for mortality. Over 50 is bad news.

On this topic, I can foresee a lucrative market for new mothers to sell their child’s umbilical cord and amniotic sacs to groups of old people in search of eternal youth.

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Hi John

Thank you very much for your reply.

What is “CR”?

Calorie restriction…

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Hi John

Thank you very much for the info.

FWIW…

Plasma is a Bu$ine$$ a very large Bu$ine$$.

From Dec 06, 2019

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Does anyone here know what effect it has on your health losing the amout of blood these donors are giving as frequently as they are?

I’m not sure of all the details, but there seem to be some benefits to donating blood (beyond the humanitarian aspect):

Here: Blood Donations improve Skin Aging

Here: Does plasma donation or blood donation also lead to "plasma dilution"?

Also discussed in this thread Here: Young Blood: Heterochronic Parabiosis Rejuvenated Adult Stem Cells Across Mouse Tissues

and

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Thank you, RapAdmin, very much for the info.

Hi RapAdmin

Do you have a rough idea of the quantity of new albumin you receive per plasmapheresis session.

How many sessions are you having per month?

I’m curious. What is your reasoning for thinking removal of IL-10 is key here?

IL-10 is part of SASP, it operates though the Janus Kinase to inhibit NF kappa b. NF kappa b regulates SLC25A1 which feeds tricarboxylate to the cytosol. ACLY converts some of that to Acetyl-CoA some of which migrates to the nucleus which influences the splicing of RNA by being available to HAT/KAT as part of RNA pol II. Without the Acetyl-CoA, RNAPII stalls and you get alternate splicing. This is linked to gene size.

There is also a research paper which demonstrated that IL-10 caused cells to enter the senescent state.

All of this is linked to the research on my web page.

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I think it’s a complicated issue and that the benefits of parabiosis may be partially explained by removal of some harmful factors in the blood but also by addition of youthful factors. Fresh albumin may have some benefits. Here is something I wrote about it elsewhere a while back:

The study below is interesting and suggests that injection of recombinant mouse serum albumin increases median lifespan of mice of both genders. Importantly the injected albumin was fresher and less damaged than endogenous albumin and this may be important.

I haven’t read the study in detail but going through it very quickly it appears that they didn’t measure albumin levels in the blood of the mice so it is not certain whether the injections led to a significant rise in blood albumin levels or if the blood levels remained relatively constant due to downregulation of endogenous production. Whichever is the case is important to know since it matters with respect to knowing whether the benefits in this study were caused merely by elevated albumin levels or by the infused albumin being “younger” and less damaged than the endogenous albumin or some combination of the two.

My immediate thoughts when I saw this study were that the results obviously have potential implications for interpreting the plasmapheresis experiments where saline with albumin was infused into rodents (anyone know how pure and undamaged that albumin was relative to that used in this study?). I also thought it has implications for the value of plasma albumin specifically as part of a blood biomarker for assessing biological age (albumin is if I recall the strongest predictor in the aging.ai formula) and whether higher plasma albumin is a causal factor in any health benefits or merely a marker.

If the benefits in this study were caused by the mice having higher proportion of less damaged albumin not by higher levels of albumin in the blood per se then one cannot expect to gain these benefits by raising albumin levels by any means but would require infusions of fresh albumin to get the benefits. Another thing one can do is to attempt to minimize the damages to the albumin (glycation, homocysteinylation etc.) that one already produces and is found normally in the blood.

If on the other hand the benefits in this study were caused by higher albumin per se and the freshness of that albumin relative to the endogenous one is not of much importance then one might be able to get the same benefits by attempting to raise blood levels of albumin.

These are my quick thoughts on this. Perhaps someone can look into the study in more detail.

Young and Undamaged rMSA Improves the Longevity of Mice

Jiaze Tang, Anji Ju, Boya Li, Shaosen Zhang, Yuanchao Gong, Boyuan Ma, Yi Jiang, Hongyi Liu, Yan Fu, Yongzhang Luo

doi: Young and Undamaged rMSA Improves the Longevity of Mice | bioRxiv

Abstract

Improvement of longevity is an eternal dream of human beings. Here we report that a single protein recombinant mouse serum albumin (rMSA) improved the lifespan and healthspan of C57BL/6N mice. The median lifespan extensions were 17.6% for female and 20.3% for male, respectively. The grip strength of rMSA-treated female and male mice increased by 29.6% and 17.4%, respectively. Meanwhile, the percentage of successful escape increased 23.0% in rMSA-treated male mice using the Barnes Maze test. The rMSA used in this study is young and almost undamaged. We define the concept “young and undamaged” to any protein without any unnecessary modifications by four parameters: intact free thiol (if any), no advanced glycation end-product, no carbonylation, and no homocysteinylation. Here “young and undamaged” rMSA is much younger and less damaged than the endogenous serum albumin from young mice at 1.5 months of age. We predict that young and undamaged proteins altogether can further improve the longevity.

Quote from the full text:

“rMSA used in this study is not only “young” but also almost “undamaged”, which endows rMSA to offer more protection against unnecessary modifications and damages, and suggest that the four parameters could monitor the aging process. Here, “young” means that the rMSA is much fresher than the endogenous albumin from young mice at the age of only 1.5 months analyzed by the 4 parameters (free thiol, carbonyl, AGE, and Hcy).”

Olafur