Stem cell-derived extracellular vesicles/exosomes [MSC-exosomes] can reduce epigenetic age by 15 years - anyone tried them?

#41

for those who might have missed it, the links discussed things such as

It is hard to understate just how big a deal it would be if we could edit thousands of genes in cells all over the human body. Nearly every trait and every disease you’ve ever heard of has a significant genetic component, from intelligence to breast cancer. And the amount of variance already present in the human gene pool is stunning. For many traits, we could take someone from the 3rd percentile to the 97th percentile by editing just 20% of the genes involved in determining that trait.

Tweaking a few hundred genes might be able to halt the progression of Alzheimer’s, or cure untreatable depression.

The same could apply to other major causes of aging: diabetes, heart disease, cancers. All have genetic roots to some degree or other. And all of this could potentially be done in people who have already been born.

And

Based on the model, we can come to a surprising conclusion: there is enough genetic variance in the human population to create a genome with a predicted IQ of about 900. I don’t expect such an IQ to actually result from flipping all IQ-decreasing alleles to their IQ-increasing variants for the same reason I don’t expect to reach the moon by climbing a very tall ladder; at some point, the simple linear model will break down. But we have strong evidence that such models function quite well within the current human range, and likely somewhat beyond it. So we should actually be able to genetically engineer people with greater cognitive abilities than anyone who’s ever lived, and do so without necessarily making any great trade-offs. [and the article focuses on the potential of doing these types of things in humans who are adult today]

interesting read

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#42

Paul Tozour on grg reports negative (harmful) results from the highest dose possible (the $5000 one)

I think they were the evovex exosomes, WE NEED TO CONTROL FOR QUALITY

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#43

mb not stem cell derived but w/e

You may already be doing single cell RNA sequencing to study the transcriptome but did you know that there are over 3,000 proteins that are predicted to be secreted and are currently understudied? These include antibodies, cytokines, growth factors, proteases, and extracellular vesicles that are often washed away before scRNA-seq. Moreover, the first step in scRNA-seq is to lyse or fix the cell, making it impossible to ask these cells additional questions. With Nanovial technology you can isolate single cells along with their secretions, retaining that paired information, while keeping the cells alive. This lets you:

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Sr. Product Manager

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EVsNature

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Researchers sorted stem cells based on the level of secreted vesicles, and used these on a mouse model of myocardial infarction. Learn how they got more insights into cell to cell communication and how imaging cytometry confirms measurements from Nanovial Assays. Read the publication

PNAS

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Paired Secretion and transcriptome904×644 257 KB

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#44

https://www.nature.com/articles/s41467-024-49123-1

#45
  1. Zhang, X. et al. Plasma extracellular vesicles carry immune system-related peptides that predict
    human longevity. Geroscience (2024). Online ahead of print. doi:10.1007/s11357-024-01454-z.
#46
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#47

I’m late to the topic, but let’s maybe address the very first question here on plausibility of MSC-exosomes actually making a difference.

Your blood has around 10^10 EVs per ml Redirecting

You have, let’s say 5 litres (5,000 ml) of blood in total; thus 50,000,000,000,000 EVs in circulation at any given time. Those originate from all sorts of places, including endothelial cells lining the vessels, the blood cells, and of course your tissue cells, including stem cells.

So if we take some therapy and administer an exogenous dose of 100 million EVs. That is adding 0.000199% onto what is already in your blood, secreted by your own cells. You already have lots of MSC-EVs in your blood. Why would adding a tiny fraction more make any difference?

Furthermore, exogenous injected EVs have a half life of less than 1h, and we still have absolutely no idea what cargo is important or beneficial, and the nature and activity of the cargo itself is still controversial.

I’m just incredibly sceptical of this whole idea.

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#48

You make a good point, however, we do know from several animal studies that intravenous EVs do have significant effects on health.

I haven’t double checked your numbers above, but they don’t tell the whole story. As an example, if you add MSC derived exosomes to your blood, that may not add much to the total amount of exosomes in the blood, but it might markedly increase the percentage of exosomes that are specific to MSCs. MSCs are after all just a tiny portion of the cells in the body, so whatever exosomes you have in your blood normally, probably only a tiny portion of those are derived from MSCs.

In any case, this is all very complicated. Exosomes are far from a uniform entity. Different types can contain a different set of cargo so this is not something we can just work out with simple math on the number of exosomes.

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#49

Hey @Olafurpall this is a good point… but, I honestly think there is a massive amount of publication bias, and probably a good amount of fabrication, falsification or methodological problems in this research area. And I say this as somebody (hopefully) credible in the field, have spoken at ISEV before, invited to give talks on this topic etc.

Of course it’s about more than just raw numbers. You’re right that most EVs in the blood aren’t from MSCs (they’re from blood cells, endothelial cells, and smaller amounts originating from organs). However, I am just use that as an example to illustrate why I find the whole “idea” to be lacking credibility.

I will say that I find a lot of the animal studies hard to believe, and in my lab we’ve actually tried replicating a few key findings from some big studies, and we’re almost never able to. Let me give you a concrete example (Just note, this relates to plasma EVs, not MSC derived EVs, and should be more generalisable). There’s a Nature Aging paper here: Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism - PubMed which claims taking EVs from the blood of young mice and injecting them into old mice basically fixes almost every pathology of aging. They show better sperm counts, heart function, physical performance etc etc. They trace it down to a few EV miRNAs, targeting mitochondrial PGC-1a.

Well, a couple years ago got some old mice, (~90 weeks old), and some young mice (8-12 weeks old), and we took blood samples, isolated EVs from the plasma, and we tested them in a bunch of in vitro models. We found almost no statistically significant differences at all across the board, so we actually gave up on the project. (See how the publication bias comes into play). When I saw this paper, we dug out our cell cDNA samples and looked at PGC-1a expression (the hallmark discovery of this paper) - no change in 3 different cell lines. We also tried measuring the miRNAs miR-29a, miR-34a etc in the EVs from young and old, and didn’t find any differences. In fact, I seem to recall that at least one of them wasn’t even present/detectable, using multiple primers.

So maybe what they report in the paper is true, but perhaps it only works in their lab, in their mice, in their hands. So is the finding/hype applicable to anything outside of that? Who knows.

You can also find other papers, like this one in Aging Cell (
2020 - Alibhai et al. - Cellular senescence contributes to age-dependent changes in circulating extracellular vesicle cargo and function.pdf (1.6 MB) that reports different findings, different upregulated miRNAs etc. If you look at what they say is higher and lower in the cargo, it has no resemblance to the other study.

So you’re right about exosomes being far from a uniform entity, and that’s part of why I find it so hard to get excited about any of this stuff. There’s also the apparently massive gaps in our knowledge. For example, all the hype about miRNAs, but apparently they are extremely rare: https://www.pnas.org/doi/10.1073/pnas.1408301111

With small molecules like Rapamycin the findings are mostly reproducible because we can at least standardise the compound and the dose. So personally, until somebody can explain what the active substance is, what the dose is, and roughly how this works, I remain extremely sceptical of exosomes.

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#50

Thanks for the informative reply and for sharing your research!

You raise some very important points. The potential for publication bias is a serious concern. It’s so true what you said that standardizing exosomes is a big problem. Their content can vary so greatly and they are basically a soup of tons of things like miRNAs and various other factors. Therefore, any kind of approach based on simply isolating exosomes from a particular animal or cell type and using that is highly problematic because of the variety of the contents.

I think one of the more promising use of exosomes going forward is going to be based on designing the cargo to contain a lot of some specific factors intended for treatment. As an example, using MSCs that are genetically modified to contain extremely high amounts of a specific miRNA and isolating exosomes from them would allow for an exosomal product that might act as a delivery vehicle for significant amounts of that specific miRNA. If such a product would have some desired effect we would at least have strong clues as to what is causing the effects.

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#51

Yes, I agree. Personally, I’m sceptical that exosomes will ever “make it” as a drug. To me, they’re more like a supplement or a natural extract. Plus, it’s very difficult to commercialise unless, as you say, you have some unique edited cell line or some sort of intellectual property to protect.

I think about this in the same way that a green tea extract or pine bark extract won’t be a drug - but the purified active molecules from those sources could be. What we might end up with is lipid nanoparticles (already used - ie. covid vaccines) containing the key active cargo, and potentially targeting proteins to help with delivery.

Looking at the Nature Aging paper for example, this is relatively easily tested. One could make a lipid nanoparticle containing the 3 miRNAs they identified, test it on various in vitro cells to see whether PGC1a is boosted, and do some animal injury/disease/longevity experiments. I would bet that it won’t work, but if it did, that would be some really strong evidence and it’s a “product” with a proper formulation that could actually move forwards. Just my thoughts - I might be completely wrong, haha!

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#52

I mostly agree with what you said above.

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#53

Exploring extracellular vesicles in TDP-43 proteinopathies: in this review article, Elizabeth Dellar, Alexander G. Thompson at University of Oxford and collaborators studied evidence linking TDP-43 to extracellular vesicles in post-mortem tissues, in vitro models, and human biofluids. They explored how EV-associated TDP-43 may contribute to disease pathogenesis, either by aiding in the clearance of aggregated protein or by facilitating its spread through templated aggregation. TDP-43, a 43 kDa transactive response DNA-binding protein, forms pathological aggregates characteristic of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and related proteinopathies
:link: LinkedIn
The secretion of TDP-43 via EVs may thus have both protective and harmful effects. The authors also highlighted the potential of EVs in biomarker discovery, not only through detection of TDP-43 but also by analyzing alternative protein or RNA cargoes. However, current EV isolation methods remain time-consuming and often lack reproducibility, presenting a major obstacle to clinical application. Rigorous validation of these techniques is therefore essential for advancing EV-based diagnostics. An article co-authored by Lara Nikel, Steph Fowler, PhD, Björn Vahsen, Ruxandra Dafinca, Emily Feneberg, Kevin Talbot and Martin Turner