Aging insights from heterochronic parabiosis models (Nature)

#1

Heterochronic parabiosis consists of surgically connecting the circulatory systems of a young and an old animal. This technique serves as a model to study circulating factors that accelerate aging in young organisms exposed to old blood or induce rejuvenation in old organisms exposed to young blood. Despite the promising results, the exact cellular and molecular mechanisms remain unclear, so this study aims to explore and elucidate them in more detail.

One study indicated that out of a total of 20 tissues and 122,280 cells, approximately 49 cell types are susceptible to the accelerated aging effects of parabiosis, while 51 cell types are susceptible to induced rejuvenation11. Circulating factors present in the blood of elderly subjects have been found to accelerate the typical changes of aging, contributing to various age-related processes. In contrast, the blood of young individuals possesses a remarkable rejuvenating potential, capable of reversing age-related profiles. Specifically, adipose mesenchymal stromal cells, hematopoietic stem cells and hepatocytes stand out as cell types that show increased sensitivity to the effects of parabiosis-induced rejuvenation and parabiosis-accelerated aging. At the pathway level, studies have indicated that young blood not only reverses established aging patterns, but also triggers the activation of new sets of genes. For example, in parabiosis-induced rejuvenation, there is evidence of enhanced mitochondrial function, as evidenced by the complete rescue of genes encoding subunits of the electron transport chain11,13. Similarly, it has been observed that many cell-cell communication networks, which are disrupted during the aging process, undergo alterations in response to heterochronic parabiosis13.

Open Access Paper: Aging insights from heterochronic parabiosis models | npj Aging

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#2

It is an interesting if challenging study area.

The big questions are what are the things in blood that cause this.

Here are some things that seem to have a major effect.

  1. EV - Extra Cellular Vesicles with mitochondria in them. The body shares around mitochondria in the hope that cells will get better mitochondria as a result. In one sense this is the big mechanism for making all the cells in a body equally bad. As the quality of mitochondria deteriorate then the quality of the mitochondria being shared also deteriorates. Although the body probably selects for the better ones they are not as good as when people were younger.

My own view is that mitochondrial quality and senescence are the changes that drive the aging phenotype (through effect on acetylation of the histone and splicing variation) and in fact also drive development in the sense of puberty and menopause (where relevant).

  1. Interleukin-10 - IL-10 is part of SASP that drives senescence by inhibitting NF kappa B which reduces the expression of SLC25A1. This is solidly evidenced as well.

  2. Citrate. I have not managed to find any studies on ages and levels of serum citrate. I would also expect it to be influenced by consumption of citrate (it clearly is) and hence to vary during the day. However, I think the body uses serum citrate as a more rapid mechanism for sharing energy levels. Interestingly low serum citrate is a good proxy for prostate cancer (where relevant).

  3. Melatonin. Younger mammals particular have more melatonin. Pineal melatonin is shared around the body once it has been through the CSF. It is a spectacularly good anti-oxidant and appears to hold back puberty.

There are, of course, other things. However, some of that will simply be how well organs like the kidneys work in terms of filtering the blood.

  1. above is something where it is both good and bad. Hence the EVs in old blood cause harm and those in younger blood create a benefit.

  2. is a bad substance in older blood that is not there in younger blood.

3 and 4 are substances that are good and helpful (up to a point there is a level at which citrate is toxic I don’t know about melatonin as it has not been seen, but there probably is a limit).

When it comes to things like plasma donation and although red blood cells can be an issue (older people have lower quality RBCs) that is a much bigger issue I think it can only be of a relatively minor benefit. In practice the circulatory system is circulating. Cells are putting things into blood/serum and cells are taking things out. A single pulse of this is going to produce a minor merit.

When it comes to EVs, IL-10, Citrate and Melatonin
a) EVs is all about mitochondrial quality. That is where Rapamycin and SOX2 activation has an effect (as does exercise, fasting, PEMF, RIR, HBOT, Yang Qi, Urolithin A etc). Interventions to improve mitochondrial quality in older people will make a major difference.

b) IL-10 is about clearing senescence as senescence is also about mitochondrial quality and stuck stem cells can be got over the hurdle of differentiation by various interventions (generally senomorphics such as HDAC inhibitors, but also citrate supplementation).

c) Citrate can be supplemented with good effects.

d) Melatonin can be supplemented with good effects.

Things like potassium levels and general gunk that is around in blood that is not helpful can be fixed by improving kidney function. Similarly glucose processing can be improved.

Hence I don’t see blood or plasma exchanges as being at the top of the list of anyone wanting to improve their health. There are also all sorts of complex issues with them although people have a lot of experience with them.

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#3

@John_Hemming Thanks for posting your thoughts. You didn’t mention iron overload as a problem to solve with blood donation. The older body doesn’t have good mechanisms for discarding extra iron that it allowed in. What are your thoughts about iron overload?

I am donating blood today! While I am doing my 5-day FMD (but I’m through the hard part…no hunger anymore).

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#4

There are many other issues such a lithium and iron. I dont see them as being the same importance.

#5

This idea is generally true but not with iron. Iron in red blood cells is recycled. Iron accumulates in the body over time. Iron overload seems to be involved in many chronic diseases.

It seems to me that blood donation has many advantages: keep iron from getting high (or get it down if high), help your community have blood for transfusions, AND, as a perhaps minor benefit….get rid of a little bit of “old blood factors”.

#6

I agree with you that reducing iron with blood donation is a good idea, but I don’t think it is a top priority issue.

#7

The related papers all seem to indicate platelet factor 4 (PF4) is doing all the heavy lifting in parabiosis. I see that PF4 is more available than Klotho for purchase. I wonder if anyone is trying PF4 injections and would be willing to discuss?

#8

Do you have any references on this?

#9

https://www.nature.com/articles/s41392-023-01716-w

https://www.nature.com/articles/s43587-023-00468-0
https://www.nature.com/articles/d41586-023-02563-z

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#10

Thank you for this. Clearly there is some reading to be done here.