Robust Rejuvenation with Exosomes

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A study out of Nanjing University last month brings exosome rejuvenation to the mainstream of researchers with broad new evidence and some speculations on mechanisms. The prominent publication in Nature Aging corroborates and greatly expands results from Harold Katcher’s Mumbai lab. Massive infusions of exosomes from young mice into old improve cognition, endurance, fertility, energy metabolism, heart function, immune function, bone density, cell senescence, and maximum lifespan.

History and context

This current research grew from the Stanford lab of Tom Rando 20 years ago. An old mouse and a young mouse were sewed together so they shared a common blood supply. The old mouse showed signs of rejuvenation and the young mouse showed signs of accelerated aging. Irina and Mike Conboy graduated and set up their own lab at Berkeley, where they demonstrated that it was not blood cells but something in the plasma that was responsible for the effect.

Aging is not something that “happens” to cells. It is centrally orchestrated and information about age is transmitted through the bloodstream. Aging at the cell level responds to signals in the blood, even to the extent that old cells can become young in a “young environment”.

The Conboys worked on removing old signaling from the blood. In cooperation with Dobri Kiprov, there is an ongoing human trial, simply removing blood plasma (but not the red or white blood cells) as a therapy.

Twelve years ago, James P Watson whispered to me, “exosomes”, but I was too distracted to listen.

Seven years ago, Harold Katcher made an inspired guess and quietly conducted research in Mumbai, infusing rats with a blood plasma fraction he would only identify as “elixir” or “E5”. In 2020, his team announced that they had turned two-year-old rats to one-year-old rats according to the Horvath multi-species clock. I wrote about it as a “breakthrough”.

From 2020-23, research proceeded slowly because Harold’s business partner, Akshay Sanghavi, had trouble raising funds for industrial scale extraction of “E5”, and no one else knew what was in it.

Then, last summer, a research group at Smidt Heart Inst in Los Angeles announced promising results rejuvenating rat hearts with exosomes from young rats. Akshay consented to reveal the secret that E5 was exosomes.

What is an exosome? All cells release tiny information packages, wrapped in fats like a lipid nanoparticle. They contain DNA, RNA, proteins, as well as lipids, that communicate both within the body and through the air to other living things.

Would the phenotypic and epigenomic rejuvenation that Harold and Akshay observed lead to dramatically longer lifespans? We had data from only eight rats (all female), and results are not as consistent as we might hope. Median lifespan increased ~20%, depending what you use for a baseline, but curiously the maximum lifespan seems to be extended by 60% or more.

The current paper adds lifespan data from only eight more rats (all male), but the range of metabolic and performance tests is greatly expanded.

Introduction

I predict that this new paper will bring exosome therapy into the mainstream. It begins inauspiciously.

“Aging is an inevitable, time-dependent process that eventually limits the capacity of cells to maintain efficient homeostasis and repair mechanisms…”

“Inevitable”? If they really thought so, then they wouldn’t be doing this research. My guess is that journal editors demanded this kind of language, both because I’ve experienced such editor arrogance myself, and because Chinese researchers are less hypnotized by the Selfish Gene ideology than biologists in the West.

They continue, “Mechanistically, the aging process is predominantly attributed to the progressive accumulation of stochastic damages in cells, organelles and macromolecules.” This is pure dogma. Despite this disclaimer, the method of their experiment is not to address stochastic damage in cells, but to adjust signaling in the organism as a whole.

The fact that aging can be reversed with system-level signaling is a sign that it isn’t just “entropy”, that the body is in control, and, of course, that aging is not “cell autonomous” but centrally coordinated. Harold understands this, and it has been central to his key insights. But the mainstream theorists can’t believe that natural selection would be so perverse, and they remain stuck in older paradigms. Perhaps these Chinese authors were compelled to make obeisance to old British dogmas as a price for being published in Nature. The paper was held up in peer review for an inexcusable 27 months.

Results

Old mice, starting in late middle age = 20 months, were given weekly intravenous infusions of exosomes from young mice for as long as they continued to live.

Median lifespan was increased 12%, and maximum lifespan increased 20%. This reminds us of Harold’s exosome-treated rats, one of which lived much longer than the other seven. Usually we think that median lifespan is more malleable than maximum lifespan. For example, exercise increases median and mean lifespan, but not maximum lifespan. Here we find the opposite. More about this further down this column.

  • Exosome-treated mice scored much lower on a frailty scale than untreated mice, but were not fully restored to their young, “zero frailty” state.
  • Sperm counts and sperm motility were restored to young values, testosterone levels increased, and treated mice were as fertile as young mice. (all specimens were male)
  • Metabolic rate (oxygen consumption) was restored about halfway to youthful values. This reflected activity rates, which were improved but not as active as young mice.
  • Ejection fraction and other measures of heart performance were improved, but not to the level of young mice.
  • Parts of the brain that atrophy in old mice regrew toward youthful volume.
  • Memory, measured by a water maze test, was restored to youthful levels in exosome treated mice.
  • Treadmill endurance came back almost to youthful levels.
  • Treated mice had lower markers for cell senescence.
  • Glycation is a kind of molecular damage that increases in old mice and old humans. Glycation was observed to decrease in treated mice.
  • Treated mice restored bone density lost to osteoporosis.
  • The Nanjing group did not report results from the Horvath epigenetic clock for rodents, however they did their own analysis of protein expression in various tissues, and showed that the proteomes of treated mice reverted toward younger profiles.
  • As a control, young mice were infused with exosomes from old mice. Both their endurance and their memories were impaired. Exosomes from young mice have a rejuvenating effect and exosomes from old mice accelerate aging.

Mitochondria are electrochemical energy sources, and cells typically have hundreds to thousands of mitochondria. Mitochondria can reproduce and renew inside a single cell, but populations of mitochondria decline with age. We literally have less energy as we age. The Nanjing group documented restoration of mitochondrial populations in treated mice, and they assigned special significance to this, speculating that this could be a primary source of other rejuvenation effects. The title of the paper singles out mitochondria as a mechanism. Reading through the rationale, I don’t understand why the authors consider mitochondria to be the root of the exosomes’ anti-aging benefits.

My personal belief is that 20% increase in maximum lifespan — impressive as it is — is just the beginning. Exosome technology has not even begun to be optimized.

Dosage

What is the dosage of infused exosomes compared to the innate exosomes resident in the blood of the mice? The article does not offer this information directly; neither do we have specifications from Harold’s experiments. The best I was able to do was to make an estimate from the size of mice and from the provided information “200 microlitres in a weekly dose” and “1.8 micrograms total protein per microlitre”. From this, I guestimated that the infused exosomes are sufficient in quantity to overwhelm the innate exosomes, perhaps 10x the quantity. From some of Harold’s offhanded comments, I had roughly the same impression.

This large quantity underscores the difficulty of sourcing if this technology is to become widely available to humans. We might need 100 piglets per year per human patient, overwhelming the existing market for pork. Or we might need to develop in vitro technologies for growing stem cells that secrete young exosomes. Or we might be able to target a much smaller dose of exosomes to a part of the body that keeps track of time — my candidate is the hypothalamus.

Or, if it turns out that the activity is due to specific RNAs, we might synthesize them. See below.

Mechanism

“Given the above-observed phenotypes, it remains unclear which component is responsible for the rejuvenating effects of young plasma sEVs.” [sEVs are “small extracellular vessicles”, another name for exosomes.]

The assumption implicit in this statement is that there is just one chemical species in young-derived exosomes that is responsible for all the benefits. When will we absorb the message that living organisms are not like human-designed machines? The association of one protein with one function is vanishingly rare. Almost always, individual functions are not performed by individual chemicals. Rather, there are overlapping complexes of chemicals responsible for what we regard as a single function. Every chemical has multiple functions, and every function is accomplished by multiple chemicals in concert.

Thus, I think it likely that no reduction of the exosome’s complexity will be discovered, and hence there will be no patented single-bullet solutions to aging forthcoming from these experiments. But again, read on…

Exosomes include proteins, RNAs, DNAs, and lipids. All these molecules carry information, and it may be that they all work together to whisper “young” when they are taken up by an aged cell.

The Nanjing authors nevertheless guessed that there might be a few RNA species that did all the heavy lifting and went looking for them with the tools of data mining that have become fashionable among molecular biologists.

They report limited success in identifying crucial RNA species. “Thus, miR-144-3p, miR-149-5p and miR-455-3p encapsulated in young plasma sEVs are the key rejuvenating miRNAs and have the potential to stimulate PGC-1α expression and improve mitochondrial energetic metabolism.” This claim is in fact an overstatement. What they succeeded in proving was that blocking all three of these RNAs with RNA interference was sufficient to negate the benefits of the therapy.

So, yes, the benefit seems to require at least one of these three RNAs, but it also may require a great many more RNAs that are “essential”. And it may be that if any one RNA is missing, others can substitute. After all, the reason that biology is evolved to use these complex, multipronged chemical mechanisms is that they are robust to disruption, much more so than human-designed machines which, typically, can fail catastrophically if a single part is broken.

The study also includes investigation of the role of RNAs in the age-accelerating effect of old-derived exosomes. They report several RNAs from old-derived exosomes that are potential culprits: “Therefore, miR-29a-3p, miR-29c-3p and miR-34a-5p in aged plasma sEVs are the key pro-aging miRNAs with an entirely opposite function to miR-144-3p, miR-149-5p and miR-455-3p encapsulated in young plasma sEVs.” They use RNA interference to block these specific RNAs, and find that the old exosomes lose their detrimental effect.

Questions for research

This work with specific RNAs that are pro-aging and anti-aging suggests that RNA therapies might be devised that bypass the need for animal-derived exosomes. These would be patentable, manufactured products which might attract capital investment. Creating a viable therapy from a combination of RNA and RNA interference products, presumably packaged in lipid nanoparticles, could be an attractive research direction for pharma companies.

As a first step, it would be useful to analyze RNAs of exosomes derived from young and old human donors and to quantify the differences.

Determining the natural source of the exosomes could be crucial. Are exosomes that carry age information generated from a “clock region” in the body, perhaps in the hypothalamus? Or are the most relevant exosomes created by many tissues, all over the body, so that we can think of the whole body keeping track of age and coordinating age information system-wide with exosomes in the blood plasma?

Can the treatment be made more effective if “old” exosomes are removed at the same time that “young” exosomes are added?

Certainly exosomes carry a variety of information unrelated to age. Are there specialized exosomes that carry age information? Or is age information one component of the information in all exosomes?

The authors suggest that a useful step would be labeling donor exosomes with radioisotopes so that they can be traced in the mouse who receives them, and tissues can be identified where they are absorbed preferentially. I would add to this the suggestion that different mice might absorb the exosomes in different tissues, and this might be correlated to the variable effect.

Is it feasible to tag different source organs, so we can determine where the age-relevant exosomes are produced?

Response to exosome therapy as currently conceived seems to be highly variable. Animals who respond best live a lot longer, while others die within the expected time frame. The limited data from Harold and from Nanjing both support this.

This makes me think of the mRNA vaccine technology introduced for COVID. Exosomes are lipid nanoparticles, and lipid nanoparticles are the delivery mechanism of the mRNA products. The present article presents evidence that RNAs are at least part of the mechanism of action.

Some people who took the mRNA shots got protection from COVID, while others got heart disease and still others suffered neurological damage. I think that LNPs and exosomes go everywhere in the body, and their effect depends on where they are taken up.

There is speculation that in response to certain exosomes, cells can sometimes decide, “this is an important message that I want to pass on”. Cells can create similar exosomes and amplify the message, like a virus or a “tweet that goes viral”. This is speculation, but not far from the edge of exosome behavior that has been established. Cells undergoing apoptosis emit exosomes that can signal other cells into apoptosis. [Apoptosis is cell suicide.] It is reasonable to regard viruses as exosomes that have gone rogue and evolved to maximize their own reproduction — to hell with intercellular messaging. It is likely that exosomes are an essential vehicle of cancer metastasis.

Exosomes for the Hypothalamus?

I have written about suggestions by Dongsheng Cai and Claudia Cavadas that there is an aging clock in the hypothalamus. We know that exosomes can sometimes cross the blood brain barrier. I wonder if the rejuvenating effect of exosomes is strongest if they reset an age clock in the hypothalamus. It is within current experimental technique to target exosomes to the brain and ask this question experimentally.

Whether or not the hypothalamus plays a central role, it will be interesting to discover whether animals rejuvenated with exosomes can transition toward producing younger exosomes, so that the rejuvenation becomes self-sustaining.

Directions for translational medicine

One of the (many) promising features of exosome intervention is that it seems to compress morbidity. In other words, healthspan is extended more than lifespan. Whatever our feelings about lifespan, we are all looking to remain healthier, longer.

There remains much to be done before exosome therapy can be widely distributed to humans. First on my list would be a factory scale source of young exosomes. Harold and Akshay have suggested that blood from the millions of young pigs slaughtered each year for meat could be a feedstock. Before this can be realized,

  • We need to confirm that exosomes from pigs are able to rejuvenate humans.
  • We should check that factory-farmed pigs are not impaired in the quality of their exosomes.
  • We need industrial scale separation and refinement techniques for extracting exosomes efficiently from blood.

Summary

These results corroborate a theoretical framework in which the age state of the body is communicated to somatic cells, which obediently can become old or young in response. Exosomes seem to be a prime candidate for the communication mechanism. Their lipid coatings enable them to slip easily through cell membranes, and their cargoes include a diverse array of active signal molecules.

It is my hope that with this new paper, the concept of exosome rejuvenation explodes into the mainstream of anti-aging medicine. There is much work to be done before we have treatments for humans available at scale.

It is extra-promising that healthspan seems to be universally improved, even in animals where lifespan does not change. Another auspicious sign is that maximum lifespan is augmented more than median lifespan in this study as well as Harold’s experiment.

Rejuvenation via exosomes appears to be quite variable across individual mice, despite the fact that these mice are inbred to be genetically identical. This suggests that a lot can be learned from studies comparing mice that respond well to mice that don’t respond at all.

If specific RNAs can be identified that do the heavy lifting, then these might be synthesized artificially. If, on the other hand, the whole package of DNA, RNA, protein, and lipid molecules in an exosome is found to work together, then we will need industrial-scale extraction from animal sources.

If we are really lucky, then targeting exosome therapy to the hypothalamus could greatly reduce the quantity per treatment and the cost of the treatment.

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42 thoughts on “Robust Rejuvenation with Exosomes”

  1. There is always the crude method for finding out what tissue creates the miRNA youth EVs. Sacrifice young rats for tissue samples, and check each for those miRMA products. The tissue that is generating the miRNA will have a much higher miRNA product than the other tissues.

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  5. Some time ago when I read Sandra Kaufmann I think she said “seems 90% of the effect from stem cell terapy seem to be in the exoxomes”. We have Akshay and Harold, to me this looks extremely promising. I dont understad how money into this is missing.

    Btw I think Kaufmann also praised spermidine (not on the same leves as exosomes of course).

    🙂

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  6. Josh, what are the best supports for aging being controlled as opposed to just continued malfunction/dysfunction (the wear and tear), in your mind? Top 2 or 3 reasons. I happen to agree with you and in a way, exosomes would support this, since the end result or transcription (in the case of exosomes delivering nucleic acids) of various factors still works if they are present.

    My current theory is that we have a general set point, as some of the fitness industry have suggested, that can only be deviated from with extreme discipline or abuse, regarding pretty much everything in lifespan, but also in healthspan. And that is also particular to an individual, who is an inherited mosaic of many ancestors’ DNA.

    Also, would you presume that there might be a cost to pro-growth and recuperation signalling (with exosomes) much like there is with HGH and testosterone supplementation? That is, you get many youthful benefits but also you are generally advocating for growth, which can hurt you in terms of a higher percentage of cancers popping up? Thanks.

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    • Best 2 or 3 reasons for believing aging is programmed? Read my book Cracking the Aging Code, or this blog post https://joshmitteldorf.scienceblog.com/2013/07/01/the-demographic-theory-of-aging/

      The default perspective should be that everything that appears broadly across many species in nature must have an evolutionary purpose. The reason that many biologists resist this idea is that they believe the Selfish Gene version of evolution.

      Cynthia Kenyon’s “one line proof” is that lifespans vary from one day to hundreds of years, and yet the same biochemical mechanisms cause aging in both yeast cells and bowhead whales. Any genes that evolution has preserved for a billion years must have an evolutionary purpose.

      My own one line proof is that animals who eat more have shorter life expectancies. With all the caloric energy they need, of course animal metabolisms could avoid aging if they wanted to. This shows that the metabolism does not want to live as long as possible.

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      • The problem with Cythia’s ‘one line proof’ of programmed ageing, is that she’s looked for ageing and only found growth. Of course when you slow down the mechanism of growth you extend out lifespan (in a non-competitive environment), because you’ve slowed the whole life cycle mechanism. Find a mechanism of ageing that has nothing to do with growth rate, and then I’ll know we’re getting somewhere.

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    • About “extreme discipline” – I think that even with healthy eating and minimal calorie intake and maximal exercise, we are just tinkering at the edges of a programmed lifespan. If we want to change our programmed lifespan, we have to hack our epigenetics. Exosomes can do that.

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    • Will we find a down side to exosomes? Only time will tell, but I am hopeful that rejuvenation will turn out to be general and robust. There are plenty of examples of interventions that improve quality of life and simultaneously extend life expectancy, including exercise and social engagement.

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      • By the way, do you think the eventual attempts at (mass) production of the exosomes will be porcine? Will cost be a bigger hurdle, or safety trials?

        Thanks for all the great posts, JM.

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  7. Thanks very much for the reply. I agree with you, and I see that you think that we’re just “tinkering” around the edges regarding longevity, at least, by employing various protocols or hacks to try to lengthen life. You know from previous posts I’m far more interested in healthspan, as I see longevity as an idol, and interestingly this is somewhat confirmed if you (we) are correct about the programming that all men must die (a maxim indeed).

    Does anyone even have a theory about the production/aggregation of exosomes? It seems that, as you have stated, we downregulate mitochondria over time and thus program energy loss and the ability to perform or overcome challenges as we get older. I think some people have identfiied viral mRNA or DNA in exosomes that are expelled.

    One final thought that hit me, as I read your earlier link about population balance, which I hadn’t come across but is very interesting, is that it seems unbelievably applicable to the modern day with these human population bursts. We also seem to have a social/elite factor that also doesn’t want larger numbers of humans (see three letter agencies and the covscam as an example), but oddly the world has put forth systems (like monetary and debt systems) that promoted huge increases in the numbers of humans, but with relative dysgenics since survival became (at least for a while) easier. Either that or the families in the picture of all of this pop boom become increasingly destabilized, and now we’re looking at a multiplicity of crises coming up. A lot of the “developed world” has clearly initiated the behavioral sink that was described in rat experiments last century. That of course is going along, hand in hand, with dropping fertility rates. Do you have thoughts on that, too, Josh?

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  8. I’d like to include two new terms to studying anti aging. Life Span 50 (LS50) and Heath Span 50 (HS50). They are like ID50 and LD50, only to describe effectiveness of anti aging methods. LS50 would be described by taking the median average age of the trial group at death and dividing that with the median average age of the control group at death. For Heath Span you do the same, only you have to define the breakpoint for measuring the end of health span. This way, you have a standard method of comparing different methods and procedures, as well as a yardstick to compare the relative effectiveness between different species. I note that so far, all the different methods (E5, Yamanaka factors in AA9, and EPOCH) all seem to fall into a range of LS50 of 1.1 to 1.2, even if they improve the health span markedly. Food for thought.

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    • It’s true that we don’t have spectacular increase in median lifespan from exosomes yet, but the technology is barely new, and has been tried on a total of less than 20 rodents, with no optimization. We’re at the beginning of the learning curve, and exosomes are already doing as well as any mature technology.

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      • The current testing shows that the portion of aging affect by exosomes is not all that is needed to increase the LS 50 to 2 or greater. What is needed? We don’t know. The exosome process seems to only affect actively dividing tissue cells. Neurons, thymus, hypothalmus, and who knows what else, don’t seem to be affected. Neurons seem to be activated for regeneration by Platelet Factor 4 (PF4), the others? Who knows. I suspect it is not a matter of fine tuning, but of discovering other blocked pathway. (That is consistent with aging being highly conserved and aging death being a “first to die” pathway contest.) Exosomes being necessary but not sufficient.

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        • It shouldn’t be that hard to test if exosomes are merely masking the problem (of harmful excretions from damaged, old cells), or are in fact the signalling that tells such cells to be old. We can take cells from people of various ages, as well as passage replicating cells in the dish. We can expose such samples to exosomes from the young and see how they respond and see if when the young exosomes are removed, if the old cells deteriorate again, or if after sufficient exposure they can be made robustly young. Personally, I think that it is just masking harmful signalling, and therefore old cells will most often return to being ‘old’ but I’d like to be proven wrong and actually see some serious lifespan extension from these techniques.

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          • We can agree that there’s much we’d like to know about the effects of young and old exosomes, and that a broad research program in vitro and in vivo should be a priority for the community of aging medicine.

  9. Since Christiaan Barnard performed the first heart transplant in 1967, organ donations rely on a recipient match, preservation, and time, just as blood bank cells and plasma are collected, tested, bio-preserved and recipient matched. Banked eggs and sperm are cryopreserved. Ex-vivo autologous tissue-specific stem cells and gene-edited cells are alive and efficacious. Nematodes revive and reproduce after being frozen alive for 46,000 years (and Ted Williams won’t). All are examples of the essential properties and benefits of quantum biology, as only life begets life. The problems with proprietary magic molecules are that synthesized drugs and sterile biologics are binary, not quantum, and that the plasma from a biologically peaked and sex identified 18-25-year-old donor contains not only 1.84 billion exosomes per ml, but also the 10.5K proteins, 5K peptides, 50 sex-specific hormones, 45 cytokines and various minerals needed to act on that signal. “We never noticed the complexity of mother nature because we were too busy trying to recreate it”.

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      • My guess is that plasma infusions aren’t large enough to have optimal effect. What we really want is to replace ALL the old exosomes with young exosomes. This would require a plasma replacement.

        Is it feasible to do plasma transfusions in mice?

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        • Just spoke with a friend who told me that “The word on the street” is that young blood plasma really work, but there is a risk to it.

          30-50% of the positive effect one gets by just getting rid of old blood-plasma, which is risk-free.

          Then the our best option at the moment seems to be to to start by extracting blood-plasma and then wait for the exosomes (Harold, Akshay), and fill on young exoxomes.

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  10. Hi Josh:
    Your comment seems to underscore the potential of Young Plasma, as mentioned by Tom Casey. It is currently the only age-regressive therapy that addresses the entire signaling milieu necessary for resetting the biological age. Your thoughts, excerpted below, strongly imply this comprehensive approach is essential:

    “The association of one protein with one function is vanishingly rare. Almost always, individual functions are not performed by individual chemicals. Rather, there are overlapping complexes of chemicals responsible for what we regard as a single function. Every chemical has multiple functions, and every function is accomplished by multiple chemicals in concert.”

    Your insights suggest that Young Plasma’s ability to rejuvenate the signaling environment aligns with the complexity of biological functions.
    Another site detailing the history, science and benefits of young Fresh Frozen Plasma, (yFFp) https://www.age-regression.com/young-plasma

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  12. why not try to treat human iPSCs from an aged (or diseased) person with young human plasma from an compatible donor and try to give them back to the aged in a targeted way.

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  13. I believe a good test would be to combine the Conboy’s plasma dilution (replacing >50% of plasma with saline + albumin) approach, along with processing copious amounts of Young Human Blood as Dr. Katcher did to Pig’s Blood to create E5. Thorough testing for disease beforehand, and using purified human sEVs & Exosomes in a concentrated form, should reduce some risks while providing a solid proving ground of these anti-aging methods. Repeating the treatment every 30-90 days for a year or two, with all the biological age testing available today, should put this approach to the ultimate test once and for all.

    I, like Josh, am surprised there is not much funding to pursue this research. I would raise my hand to participate in this trial.

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    • You’ve hit upon a promising and direct path. There was already an injection trial of concentrated umbilical cord plasma into elderly human muscles with safe and significant results. Doing this with plasmapheresis or intravenously would be straightforward. The concentration is key, vs. saline and 1x albumin plasmapheresis. This approach captures the complex interplay between EV components while avoiding figuring out which specific fraction is essential, by using a concentrate of the whole thing. Concentrated umbilical cord plasma seems to be readily available, but I don’t know about sourcing it. BetterHumans would know.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9577957/

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  14. Josh, I read your recent paper, and I got to thinking about the nature aging paper. I would like to quote the last paragraph of that paper, just before the discussion section. “Conversely, we investigated whether the miRNA cargoes in aged
    sEVs could facilitate PGC-1α loss and drive age-related mitochondrial
    impairments. As expected, aged sEVs exhibited considerable inhibitory
    activity against PGC-1α expression in the hippocampus and muscle of
    young mice (Supplementary Fig. 18f). Likewise, direct transfection with
    miR-29a-3p, miR-29c-3p and miR-34a-5p mimics led to reduced PGC-1α
    expression in NE-4C and C2C12 cells (Fig. 7a), which was accompanied
    by loss of mitochondrial activity and mtDNA content in these cells
    (Fig. 7f–h). We then co-administrated antisense oligonucleotides of
    miR-29a-3p, miR-29c-3p and miR-34a-5p and aged sEVs to NE-4C and
    C2C12 cells. Aged sEVs strongly inhibited PGC-1α expression, caused
    impaired mitochondrial activity and reduced mtDNA content and
    promoted cellular senescence marker p21 in NE-4C and C2C12 cells;
    however, co-treatment with antisense oligonucleotides significantly
    rescued the detrimental effects of aged sEVs on mitochondrial bio-
    genesis and metabolism, recovering PGC-1α expression, mitochon-
    drial function and p21 level to a normal state (Supplementary Fig. 21),
    further proving that the pro-aging effects of aged sEVs are carried out,
    at least in part, through their miRNA cargoes. Therefore, miR-29a-3p,
    miR-29c-3p and miR-34a-5p in aged plasma sEVs are the key pro-aging
    miRNAs with an entirely opposite function to miR-144-3p, miR-149-5p
    and miR-455-3p encapsulated in young plasma sEVs.” The use of antisense RNA for the 3 most effective pro-aging RNAs to block the pro-aging RNAs, in simultaneous infusions, makes me wonder if using those artificial antisense RNAs by themselves along with E5, might have a positive effect on the LS 50, by blocking the aging RNA natural production. Adding youthifying agents along with aging block agents as a cocktail. Attack the clock aspect lower down in the genetic expression chain.

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  15. While investigating exosome therapy in Washington State, I found a treatment called ExoFlo, which is an EV/exosome product, recently cleared by the FDA for treatment of long COVID:

    https://directbiologics.com/exoflo/

    Apparently, a mL contains 10 billion exomes. An IV drip is available. I’d think an experiment of n=1 could be accomplished, of therapeutic plasma exchange (TPE) coupled with an ExoFlo drip.

    With the recent news of HBOT therapy, I’d also sit in an HBOT immediately following, to enhance these therapies.

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    • One needs to crawl before you can walk. First test for rejuvenation in a replication of a mouse/rat trial to check the simple grip testing and blood work. If that works, human ho. . . .

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  16. I just had a little bulb lit in my head:

    since it’s shown that tissues through out the body influence each other via blood plasma,
    then by improving the health / rejuvenaing even a part/organ/tissue type in our body, the rest of the body should benefit as well, at least a bit.

    In particular – our skin, the largest organ.

    Perhaps this is an important reason why women outlive men: they take better care of their skin, and also tend to avoid stresses better.

    (This occured to me after watching several of Brain Johnson’s video, how he does intensive care for several of his body parts, even small ones.)

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    • There was a study a few years ago showing you could give old people a nice all over body moisturiser and it decreased whole body inflammation. The skin the is barrier to the body and it is under attack constantly…
      https://pubmed.ncbi.nlm.nih.gov/30835878/

      My advice is to avoid Brian Johnson or any of his advice like the plague. The downside of greater public awareness of efforts to intervene in ageing is that we have to put up with people like him.

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      • Hi Mark,
        thanks for your advice, but what do you find so wrong with B.J. ?
        He seems to exaggerate a bit his results, but I still apreciate him sharing his experience and protocols.

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        • Its just the general culture of ‘influencers’ entering this space and degrading it.

          For example, claiming he had a ‘world record’ young epigenetic age when he first appeared on the scene, when if he’d even bothered to look into results reported by self experimenters present here and on Longecity for instance, he’d know he was no where near the record and had nothing significant to report. Of course, that would never stop a self-promoter.

          Perhaps someone with a genuine contribution to make will come into this area because of him, but its hard to credence at this point.

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  18. Some more interesting items from the paper.

    “Cancers are a common cause of death in old mice44, and gross autopsy
    data revealed fewer macroscopic tumours in mice with Il11 deletion
    (pooled sexes: wild-type, 49 out of 84 mice had tumours; Il11−/−, 3 out
    of 25 mice had tumours; P < 0.0001) or on anti-IL-11 therapy (pooled
    sexes: IgG, 22 out of 36 mice had tumours; X203, 3 out of 19 mice had
    tumours; P = 0.0013) (Supplementary Tables 6 and 7)."

    "Mouse
    mortality in old age is often cancer-related44 and our end-of-life autopsy
    data support the notion that inhibition of IL-11 significantly reduces
    age-related cancers. Of note, IL-11 is important for tumorigenesis and
    tumour immune evasion and clinical trials of anti-IL-11 in combination
    with immunotherapy to treat cancer are planned22."

    So whatever the mice died of, most likely it wasn't cancer. Most useful information, implying there is another "first to die" blocking, after the E5 (or similar) age extension treatment.

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  19. I think that the reason why Akshay and Harold showed us the best yet result is the fact that they somehow caught the connections between the process of ageing and specific characteristics of the exosomes and other factors controlling our machinery, for example, the length of transcripts. Otherwise, if we aren’t able to find this kind of specificity, it will be far harder to track and discover all the secretome that control ageing and to isolate, concentrate and inject/infuse, because of the possible infinite number types and combinations. In this case, rejuvenating all types of cells and organs through gene therapy to regain the youthful and specific order of the chromatin to make them remodel ECM, affect mitochondria and produce young secretome, seems to be a wiser and more achievable way.

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  20. I think there’s not just one magic chemical in young exosomes. The whole package works together. It will be a long time before we can untangle the biochemistry but if we’re willing to experiment at a higher level and just see what works, we should have exosome rejuvenation much sooner.

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