Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction

Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young pigs rejuvenates old rat tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=613 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=1366 human tissue samples to the training data. We employed these six rat clocks to investigate the rejuvenation effects of a porcine plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro- to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging.

Competing Interest Statement

Several authors are founders, owners, employees (Harold Katcher and Akshay Sanghavi) or consultants of Yuvan Research (Steve Horvath and Agnivesh Shrivastava) which plans to commercialize the E5 treatment. Other authors (Kavita Singh, Shraddha Khairnar) received financial support from Yuvan Research. Gordan Lauc is a founder and CEO of Genos Ltd., a company specialized in high throughput glycomics. Sinisa Habazin, Mislav Novokmet and Frano Vuckovic are employees of Genos Ltd. The other authors do not have conflict of interest.

Full Pre-print paper:

2023.08.06.552148v1.fulls.pdf (2.7 MB)

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Even though the title refers to plasma fraction, this could broadly be seen as blood sharing via parabiosis or another method. The exciting part of the published research is that what is in the blood has been identified and used to REVERSE aging - exosome fraction of the plasma - that’s a big deal. In addition, the animal used to get the exosomes is pig blood, used in rats. Making it plausible that human blood would not be needed to manufacture it. Harold Katcher used this technique to extend the life of the longest living female rat. Katcher has a patent on the method he used, but I believe it was speculative about just what factors he used from the blood to get the results. This research clearly identifies it as exosome fractions.

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“The plasma fraction treatment used in the investigation described below, is based on the principle of Heterochronic Plasma Exchange (HPE) [39]
(https://www.biorxiv.org/content/10.1101/2023.08.06.552148v1.full#ref-39), which does not involve the physical attachment of the circulatory systems of two animals.”

“The plasma fraction treatment described here is a step change from HPE [, as it uses neither whole blood nor plasma, but the exosome fraction of the plasma, which we term as E5 (Methods ).”

“The plasma fraction termed “E5” was developed by Harold Katcher and Akshay Sanghavi at Yuvan Research. This fraction was derived from the platelet-free plasma of young pigs (6-7 months old), an age at which pigs are typically slaughtered by farmers. The selection of this age, immediately post-puberty, is reflective of the mammalian youthful homeostatic peak, with the anticipation that this would be represented in the regulatory cargo circulating within the secretome 63

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They have a way to test the epigenetic ages of tissue in vivo & candidates of gunk to put on it to test.

If I had their tools & a whole lot of money & grad students, aka motivated & affordable labor :smiley: I would start fishing in the gunk to pull out particular molecules to apply to the tissues, individually & in combination. The goal is to figure out what, in particular, is having this effect.

Something like the Ora bio worm bot might be useful to test a bunch of possibilities in parallel.

Hopefully, someone is planning to do something like that …

Once someone has figured that out, the next step is to apply it in vivo & see if it works in live animals. If so, very cool, bottle that thing & sell it.

Can anybody give me a simple theory of what the exosomes do? Do they turn genes on and off? Do they somehow facilitate communication from cell to cell?

So if I get the exosomes of a young animal, then my cells will think they’re young and invest in themselves in a way that makes the organism younger?

It seems like the exosomes of a domestic animal like a pig (while they are young and healthy) might not be the best mammal to use. Pigs have been bred to eat and grow, then be slaughtered.

Maybe I don’t know what’s going on here. Straighten me out.

Josh Mitteldorf’s blog post on Extracellular Vesicles (EV) and the most common type of EV, exosomes, can be viewed @ https://joshmitteldorf.scienceblog.com/2023/08/06/exosomes-and-their-potential-for-rejuvenation/

" Extracellular Vesicles (EVs) have only been studied in the 21st century. Think of them as natural lipid nanoparticles, or endogenous viruses. They transmit information around the body and they’re small enough to be exhaled and carried in the air to communicate with other individuals and even other species. EVs are encapsulated in fats that facilitate entry into cells, and inside they contain proteins, RNA, DNA, lipids — all of which carry information. EVs are a universal biological language, a barely-explored medium of communication."

" Exosomes are the most common type of EV, and probably the most relevant to aging applications. They seem to be a general vehicle for inter-cellular and inter-individual communication. The study of exosomes is in its infancy, but it is already known that exosomes are tagged in a way that recipient cells can distinguish and choose which exosomes to pick up and “read the message”.

As the least qualified person on this site to “straighten” you out - I found his viewpoint helpful to my limited understanding.

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Peer reviewed paper finally out:

Reversal of biological age in multiple rat organs by young porcine plasma fraction | GeroScience.

Extracellular Nanoparticles Sourced From Another Species Reverses Biological Age of Rats by More Than 50%

31 Oct, 2023, 20:14 ET

Peer Reviewed Publication: World’s first demonstration of cross species epigenetic transfer that significantly reverses biological age by Scientists at Yuvan Research.

MOUNTAIN VIEW, Calif., Oct. 31, 2023 /PRNewswire/ – In a groundbreaking research paper titled “Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction” published in GeroScience, scientists have unveiled a remarkable breakthrough in the field of aging biology. A therapeutic called E5 developed by Harold Katcher PhD and his colleagues was injected into old rats making them significantly younger within days. E5 consists of nanoparticles of complex structure, including exosomes, from young plasma sourced from another species.

E5 Reverses Biological Age of Rats By More Than 50%

E5 a young plasma derived therapeutic resets the epigenetic landscape of the older recipient cell to the lifestage of the young donor thereby making the recipient younger.

Steve Horvath, PhD, formerly a Professor of Genetics and Biostatistics at UCLA played an instrumental role in this study with his invention of epigenetic clocks, which determine biological age using DNA samples. Horvath remarked, “Initially, I could hardly believe the profound epigenetic rejuvenation effects of E5. However, our findings are robustly supported by parallel rodent studies from different labs.” Upon final analysis by Horvath and his team, there was a remarkable 67.4% average reversal in the epigenetic age of treated elderly rats. If these results translate similarly to humans, it could equate to an 80-year-old reverting to the age of 26.

Two unlikely co-founders Harold Katcher and Akshay Sanghavi embarked on an impossible quest 5 years ago to ‘cure’ aging. Sanghavi, having lost his mother to diabetes, was researching aging from 12 years and had set up trials to upregulate repair pathways that go down with age. He came across Katcher’s 2013 paper on Heterochronic Plasma Exchange and reached out to him to join his small team. The rest, as they say, is history. Their venture Yuvan Research is in Mountain View, California.

Another aging clock confirmed Horvath results, GlycanAge developed by Professor Gordan Lauc also showed age reversal of around 50%. Lauc said, “Human studies clearly demonstrated that glycans are very responsive to different interventions, but changes are usually relatively slow and not too extensive. Dramatic reduction in glycan age of rats treated with E5 is fascinating.”

Michael Snyder, Chair of the Department of Genetics and Professor of Genetics at Stanford University who did not participate in this study but sits on the Scientific Advisory Board of Yuvan Research said, “The results are stunning and have enormous potential, not just for humans, but also for animals including pets.”

SOURCE Yuvan Research Inc.

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This is amazing and not the direction my gut said it would go. I thought they had fooled everybody including themselves.

Will there be human trials next? How soon?

Sadly, I think they are still struggling to raise a reasonable amount of funding for their company… dogs next it seems:

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It seems like if you are injecting something that will tell your cells that they’re younger you would need to get rid of the ones that are already telling them they’re old. So you’d need to run the blood through something to take out the E5 in the old animal first.
I’m using logic which may not apply. Has nobody else ever explored this mysterious fraction of the blood? Exciting times! Like Pons and Fleishman are back!

A story on the company…

“The real point of our experiments is not so much to extend lifespan, but to extend youthspan, to rejuvenate people, to make their golden years really potentially golden years, instead of years of pain and decrepitude,” Katcher said at the time of the announcement.

“But the fact is, if you manage to do that, you also manage to lengthen life, and that’s not a bad side effect.”

E5 has already been patented by the company. In the formula, plasma can apparently be taken from apparently any animal. The platelets are removed by centrifugal force as they can cause an immune reaction. The plasma can apparently be taken from any mammal, with the patent mentioning humans as well as livestock, cats, dogs, and even wild animals like deer or dolphins.

Full story:

The Yuvan Patent: WIPO - Search International and National Patent Collections

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Is Yuvan publicly traded? Is he doing this publicity for money?

Thanks for the article. I’ve been working 12 hour days for so long… only a few days left.

He said only a couple years to human trials.

bookmarked for further research/digging. sounds interesting!

No, its a small (poorly funded) private startup company right now.

I tried to post the paper a few days back but for some reason I wasn’t able to post it. I’m not sure if it’s my internet or browser.
I can’t understand why this isn’t receiving more attention and funding. I was wondering if Yuvan maybe have rejected overtures from big companies because they want to own their rights. It seems to me that this should be all over the news.

They’re also working on a topical that they think they can bring out much sooner as they can bypass the FDA ad expensive trails. Harold rubbed some on his hand and it ‘seems’ significantly younger.

I spoke to Ashkay and he told me that that use a very concentrated amount of E5 to overcome transcription, they’re essentially flooding the system, which is why I think they don’t need to remove the old plasma. Maybe with more research they may discover they can get a more potent effect if they remove old exosomes

It seems like they really don’t have a product that can’t be copied. Can’t anybody with a centrifuge start making this stuff for themselves? I suppose you could stop them from selling it.

I guess the guy that does my PRP has a centrifuge and needles and stuff, yet he charges me for a kit. He gets it from a company that sells kits and I suppose paying for it makes it legal.

I suppose you could invest in a company that makes high grade medical centrifuges. My experience with PRP has been really good too. Anybody know a good name?

Yes - I’ve heard that. This is, I suspect, why getting funding is harder than we might think. If IP protection isn’t well established in a biotech company, its hard to sell the idea of a good return on the investor’s money.

Harold is strange. He was always pushing his idea on GRG.org. Asking for belief without providing evidence.
Years ago he was bemoaning a lack of funding to continue his research.
I offered funding.
Never heard from him again.

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If the topic is pan-species extracellular vesicles, then Royal Jelly is a great source:

Royal jelly extracellular vesicles promote wound healing by modulating underlying cellular responses - PubMed (nih.gov)

Extracellular Vesicles derived from Apis mellifera Royal Jelly promote wound healing by modulating inflammation and cellular responses | bioRxiv

Honey bee Royalactin unlocks conserved pluripotency pathway in mammals | Nature Communications

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