It’s been shown that intranasal admin. of extracellular vesicles could normalize behavior and prevent reduction of PFC parvalbumin (GABAergic neural marker) in phencyclidine-treated mice. GABAergic neural function is often reduced in schizophrenia, and NMDA receptor antagonists like phencyclidine are often used to model this in rodents.
Couple thoughts…
Dr Katcher was mentioning that the brain-blood barrier might reduce the CNS bioavailability of E5, and it seems like intranasal admin. is a potential way to bypass this. It’s a little known fact that direct nose-to-brain transport can occur through the cribriform plate (this is how N. fowleri infects swimmers), and both microvesicles and exosomes are far smaller than N. fowleri trophozoites.
The extracellular vesicles used in this study were derived from cultured human mesenchymal stem cell. It’s in a limited context, but seeing that what works for humans can work for mice, makes me more confident that works for mice will work for humans.
Different modes of exosome entry can coexist within a cell. For example, ovarian tumor and melanoma cells primarily utilize cholesterol-associated lipid rafts for exosome uptake but also employ clathrin-mediated endocytosis, phagocytosis, and macropinocytosis simultaneously. Macrophage-derived exosomes use both macropinocytosis and clathrin-mediated endocytosis to penetrate hepatocytes and transfer interferon-induced resistance to the Hepatitis A virus. The uptake of exosomes by bone marrow-derived MSCs involves both clathrin-mediated endocytosis and macropinocytosis. In some cases, the roles of these pathways can be reversed, as observed in glioblastoma cells that stimulate exosome uptake through lipid rafts but inhibit it through caveolin-mediated endocytosis.
A recently discovered mode of entry is the filopodial pathway observed in fibroblasts. Filopodia are thin, actin-rich protrusions that allow cells to interact with their environment. Exosomes can surf on filopodia or encounter them through grabbing or pulling motions. This actin-dependent process facilitates the internalization and adhesion of exosomes, potentially mediated by transmembrane molecules like integrins.
Intracellular Signaling of Exosomes: Upon fusion with the plasma membrane or interaction with surface receptors of recipient cells, exosomes release their contents into the cytosol, initiating downstream signaling cascades. The fate of internalized exosomes follows the endosomal pathway, sorting into early endosomes, late endosomes, and multivesicular bodies (MVBs) that ultimately fuse with lysosomes for degradation. However, studies indicate that exosome cargoes can bypass degradation, leading to functional changes in recipient cells.
Gradual acidification in endosomal compartments can activate exosome cargoes, such as latent transforming growth factor beta (TGF-β1) and induce phenotypic changes in recipient cells. The fusion of late endosomes with lysosomes allows cargo uncoating and potential release into the cytosol. Some exosome contents may also passively diffuse across the cytoplasm, leading to potential leakage.
The endoplasmic reticulum (ER) can serve as a route for lysosomal escape and cargo release. Exosomes can be directed to ER-associated invaginations linked with late endosomes, allowing delivery of exosome components into the nucleoplasm. Other pathways for exosomal escape from lysosomal degradation include retrograde trafficking to the trans-Golgi network, the release of partially degraded materials from ruptured endosomal or lysosomal compartments, membrane fusion, or redirection back to the plasma membrane via recycling endosomes.
Exosomes possess a higher therapeutic potential for various disease spectra due to their ability for intracellular shuttling. Nanomedicine technologies have given rise to explore the usage of pathogenic importance of exosomal particles in various diseases. The targeted drug delivery system in nanomedicine focus on the sustained release of exosomes for exerting the biological activity in the targeted site. Exosomes are used as vectors or carrier molecules to elicit a biological response.
Under given physiological circumstances, exosomes demonstrate very low immunogenicity and the potential to circumvent the physiological blood-brain-barrier (86). With the help of a stable lipid bilayer, the cargoes loaded in the exosomal vesicles are guarded against the action of native immune cells and digestive enzymes. The engineered exosomal vesicles deliver the cargoes loaded to them to the site of action through various mechanisms of endocytosis or membrane fusion as shown in Figures 3 and 44 (87,88). EVs are derived from various cell types and tissues. On delivery to specific diseased tissue, under specific conditions, EV elicits tissue regeneration and homeostasis (89). Mesenchymal stromal cell-derived EV show cellular viability, trophicity, anti-inflammatory, immunomodulatory and therapeutic effects (90,91). They support neoangiogenesis and cellular proliferation (2,92-95). Exosomes demonstrate the homing effect of the parental cell type (2,96).
Sadly no, although I believe it has more to do with my physiology than the product. I did start a detailed thread and then felt like it may not have been all that interesting and so decided not to post it. Maybe I should. Long story short, initially it helped enormously and I was pain free for about four months. I was completely blown away, I’ve been in pain for about five years and being free of it was huge. But, the issue isn’t just my knee. It’s deferred pain from an overstretched tendon in my right ankle, which means that my patella doesn’t sit in the joint correctly. I had my knee injected because it was the thing that hurt the most. It’s an ever present incessant burn. Because I didn’t resolve the ankle issue. I’ve reinjured my knee and the pain is back. I made the mistake of treating the symptoms and not the cause.
Despite that, I’m still pretty positive about it. I think perhaps the problem was the dose and delivery. I honestly don’t believe the pain free period was a placebo effect. I think it was too small a dose in the wrong area to have a lasting effect.
I don’t regret it, despite the cost and I don’t think it was a waste of time. I’m still pretty gung-ho on exosomes. In fact, the more research I do the more I’m convinced it’s going to have a huge role to play in regenerative medicine and healthy aging.
@Babster, I’ve been on Rapa for a year and couldn’t detect any difference between the before and after. At 75, I doubted I could benefit much and was thinking of letting it go. But then I recently suffered a compressed nerve in the lumbar spine, which caused me the utmost misery for months. I could barely walk, let alone run, which is one of those things that make me feel alive. The upshot is that I was able to run yesterday, and I have to wonder if the Rapa didn’t play a role in my recovery. I’ll never know for sure of course, but I wouldn’t bet against it.
Studies show that aging is associated with a decrease in EV production, although senescent cells and cells exposed to pro-inflammatory stimuli (age affects immune function and there is a shift towards inflammatory responses) produce higher numbers of EVs. However, there appears to be an increase in EV endocytosis, resulting in their levels not being elevated [108].
Eitan et al. examined the levels of EVs in participants divided into groups according to age (30–35; 40–55; 55–64 years) and found that EV levels decreased with age, whereas internalization of EVs by B cells increased. EVs endocytosed by monocytes increased MHC II expression, especially EVs from older donors [109]. There are specific changes in the cargo composition in aged EVs. For example, aged-cell EVs express a lower level of galectin 3 and mitochondria and their components [110,111]. Interestingly, expression of CD63 in EVs differs in the cerebrospinal fluid (CSF) and plasma with age, as shown by de Andrade et al. in a mouse model [112]. Whereas the expression increases in the CSF, it decreases in plasma. In plasma, levels of IL-1β increased with age. Geotzl et al. showed that platelets from older subjects express a higher level of alarmin HMBG1 (high mobility group box 1) [113].
Paul Tozour tried a higher dose of exosomes (though he paid like $3000 for it) and felt strong effects in terms of energy/etc
Why are they so expensive?
Stephen McCain’s are the least expensive
I tried 12.5b, and they didn’t make me feel different… It may have been worth luring me to Vegas for A4M, and maybe the negative result might still have been worth it for other reasons (testing), but…
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Exosome therapy cost $5,000
Exosome therapy is expensive. A survey I did of online prices from those selling exosome therapies yielded an average price of about $5,000.
Those selling exosome treatments are often charging thousands of dollars for something that likely costs only about $50-$100 dollars per dose to make. Talk about a markup.
It used to be that the cost of exosomes was far less than stem cell therapies, but now they aren’t so different. See my recent post on stem cell therapy cost.
He also did plasmapheresis, a series of 6 treatments like I did (but I think he did it in Texas or Tennessee or somewhere in that general direction) - and he said it made him feel great. I did it and didn’t feel a thing. So… who knows?
It turns out I got the real deal. $30,000 worth of plasmapheresis treatments (6 treatments of 3 hours each) over a 3.5 month period. And I didn’t notice any benefits. In fact I was very sure I was on the placebo arm of the trial given my results, but I was wrong. I’m hoping it at least reversed some biological aging metrics, but don’t have any visibility on that (and they won’t share individual results, just group results).
Apparently Dobri Kiprov announced some early results from his clinical trial at the A4M meeting last week, but I’ve yet to hear what he reported.
I think that means you’re a very healthy individual.
My father started Rapamycin and didn’t notice any effects except maybe a little fatigue. But he was doing intermittent fasting before (OMAD), going to the gym, and is a vegetarian. He may have been too healthy to notice anything just like you.
I at least had some euphoric fatigue and canker sores from Rapamycin. Since then I’ve gotten healthier (stronger?) and noticeable effects from Rapamycin have become weaker.
My theory is that the healthier you are, the less you will notice things that can make you even healthier because it’s hard to move the needle when you’re that healthy.
Now we just need to find a RCT of short-lived humans to test this theory on.
But that’s still from young adults, not neonatal, so for someone like me it would make no difference (esp b/c most Western young adults themselves are not that healthy)
Objective: The objective of this study was to investigate the effects and mechanisms of adipose-derived stem cell-derived exosome (ADSCs-Exo) in treating premature ovarian failure (POF).
Results: In POF mice, 3-MA treatment attenuated pathological injuries, decreased FSH, MDA, and ROS levels, and increased E2 and SOD levels. 3-MA treatment also inhibited GC apoptosis and autophagy. ADSCs-Exo alleviated pathological injuries, improved ovarian morphology and function, and reduced oxidative stress in POF mice. ADSCs-Exo inhibited GC apoptosis and autophagy. ADSCs-Exo downregulated the expression of AMPK/mTOR pathway proteins (p-AMPK and p-mTOR). In the POF cell model, ADSCs-Exo and rapamycin inhibited AMPK/mTOR-mediated autophagy.
Conclusion: ADSCs-Exo inhibits POF through the inhibition of autophagy and the AMPK/mTOR pathway. This study provides a potential target for the clinical treatment of POF.
“Conversely, Katcher’s intravenous infusion of exosomes (E5) has a dramatic effect on the Horvath rodent/human clock, reducing epigenetic age by half [39, 40], but thus far seems to extend lifespan less than the clock setback would imply [41].”
" 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.”"
