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What if reversing aging is simpler than we think?


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#1
starspawn0

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Remember that scene in the film Avengers 4:  Endgame, where Iron Man snaps his fingers with the Infinity Stone glove, and completely ends Thanos and his armies?  All gone in a snap.  Maybe something like that is possible with aging, and even simpler than we ever imagined.
 
Ok... well I'm going overboard quite a lot here.  First of all, while this may, in fact, be true, what I'm going to present below might not be a path to do it; it's just some speculation.   However, it's possible that what I'm going to present has an "anti-aging effect", that partially reverses the aging process.
 
How?  What?
 
Before I explain, let me reinforce the "speculation" caveat:  I'm not a biologist, or gerontologist; so this is only speculation, and wild speculation at that.
 
Now that we have that out of the way, let me remind you of the result from last year, about partially reversing the epigenetic clock, through a combination of Human Growth Hormone, Metformin, DHEA, Zinc, and vitamin D supplementation:

https://www.nature.c...586-019-02638-w

(The usual skeptic comments should be noted: it's a small study; there was no control; the subjects were anti-aging fanatics, and could have done something else, outside the scope of the study, to bring down their clocks.)

Assuming that this is indicative of a genuine anti-aging process, one thing to note is that it wasn't complicated. The body knew how to reverse the clock already; all that was needed was a little jolt from the HgH and other supplements.

A subsequent study we heard about a few weeks ago, in which Horvath was also a coauthor (so far, it's only a preprint), also appears to have involved a relatively simple intervention, in rats this time -- again, it sounds like the (rat) body knew how to reset the clock, and de-age the rats (of course, assuming that the result is replicable):

https://www.biorxiv.....05.07.082917v1

A complete theory of how they think it works is not detailed in this paper (at least not that I could find, based on a quick scan).

Josh Mitteldorf mentions something interesting on his webpage describing the work:

https://joshmitteldo...cienceblog.com/
 

A question that remains unresolved concerns the location and mechanism of the aging clock. I have been undecided over the years between two models:

1. There is a central aging clock, perhaps in the hypothalamus, which keeps its own time and transmits signals throughout the body that coordinate methylation state of dispersed tissues

2. Information about epigenetic age is dispersed through the body, and the body’s clock is a feedback loop that is continually updating methylation age locally in response to signals received about the methylation age globally.

 
He brings up the possibility that the hypothalamus is responsible for "keeping time" and transmitting it to other parts of the body. He also has a separate blog entry about the role of the hypothalamus in the aging clock:

https://joshmitteldo...e-hypothalamus/

What I wondered was whether neurofeedback might somehow cause the hypothalamus, pituitary, or other structures to reset the aging clock.

I don't actually know whether neurofeedback is even possible directly with these structures; but it is possible with other structures they are connected to, such as the amygdala. So, perhaps through neurofeedback with the amygdala -- or other brain regions -- one can induce the hypothalamus and/or pituitary to reset the clock.

Interestingly, the brains of super-agers -- that is, people who live a very long time -- appear to resemble the brains of people several decades younger:

https://www.scientif...hat-look-young/

Maybe it isn't just that their young brains are part of the overall package of slowed-aging. Maybe that's backwards: their young brains cause the hypothalamus to slow down the clock for the whole body.

....

Now I want to talk about another aspect of this: several years ago, I was pretty skeptical of anti-aging research, and raised the possibility of "system-level aging" -- that "cellular aging" doesn't account for all the different types of aging in the body. What I meant specifically was that there could be a type of "aging" induced by the interrelationships among different cells in the body. That is, if you measured the age of each cell, individually, you might find that they were "young", and that none of them were too far out of place in their respective tissues; but that the collective error in their arrangement, and in how they communicate, caused a breakdown in their collective function.

What gave me the idea for this was a talk I saw online by the neuroscientist Chris Eliasmith, where he talked about how our "neural representations" of knowledge break down over time, and that half of it has nothing to do with the death of neurons; it's simply the result of the overall dynamics of the brain breaking down. That is an example of system-level aging. Here's perhaps another example, along with a fix:

http://www.thedoctor...ng/art5849.html
 

The researchers attribute this improvement to changes in synchronization and coupling within the brain. Basically, the electrical and information flow within networks and between different networks in the older brains was out of rhythm and mild electrical stimulation was able to get them back in sync again, at least in the short term. This was reflected in changes in the patterns of gamma waves and delta waves on people's electroencephalographs (EEGs).

 
The old brains were just out of rhythm, and all it took was a simple intervention to correct it, at least temporarily.

Another example that is even more amazing:

https://www.nia.nih....ves-memory-mice

Simply by flashing light at a specific frequency -- flashes at 40 hertz -- at mice, one can induce their brains to clean up beta-amyloid and tau plaques (that occur in Alzheimer's), and other harmful debris, by activating microglia cells. The repair mechanism was there all along -- it just needed to be activated.

Could something similar be happening all over the body?

One possibility is that the way that we age is that our bodies have these extremely powerful mechanisms to prevent cellular aging -- they clean up junk, correct errors in DNA, flush out dead cells, recycle mitochondria, and so on -- but that, over time, the larger systems that coordinate them, break down; in fact, break down much faster than the smaller repair mechanisms themselves. In other words, we age much faster at the system-level than we do at the cellular level; but then that aging at the system-level is ultimately what causes the whole structure to fall, and even accelerates cellular aging.

It's kind of like having a world-class group of musicians being led by a bumbling, old fool conductor. They start to play, and play well in the beginning; but then make mistakes, because the conductor doesn't give them good direction, and it eventually all falls apart, and the curtain is pulled down to avoid further embarrassment.

....

What would cause the global systems to form in the first place, and why would they age?

Well, I recall reading various theories about whether and how the brain learns to do "gradient descent learning". One of these theories is that the brain is a meta-learner. e.g. individual neurons may use Reinforcement Learning to learn how to learn; and, since Gradient Descent is a method that might be near-optimal, among learning algorithms, the neurons learn to do that:

https://arxiv.org/abs/1906.00889
 
(I've not read this very carefully yet, actually... I'm mostly basing what I just wrote on a little lecture I saw by Kording, one of the authors of this paper.)

Maybe something similar happens all over the entire body. Instead of "learning to learn", maybe certain cells... certain structures "learn to coordinate". There would be some general outlines for how various body coordination mechanisms should work coded in our DNA; but then a large part of it would also be learned, somehow.

Everything would work fine... for a little while... until, like with the brain dynamics breaking down -- leading to our inability to separate concepts -- all these coordinating systems of the body stop doing their jobs. The conductors aren't able to conduct their world-class orchestras, and the shows all end in embarrassment.

But... like with re-synchronizing the brain as in that example above, and also the example with 40 hertz strobe light, maybe the conductors can be put back in rhythm, and everything works like new.

Maybe the conductors, themselves, have conductors... all the way up to some master conductor in the brain -- that, hopefully, can be re-tuned with neurofeedback.

Unfortunately, neurofeedback is still in its infancy. A lot of experiments would be needed to figure out just how powerful a technique it is -- and whether it can even be used to slow (or reverse) aging.
 
But it would be really cool if the only thing you needed to slow or reverse aging was a good brain-computer interface, and some software to run the neurofeedback (and, of course, a computer to run it on).

Stay tuned!

#2
Maximus

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Hmm, that's an interesting theory. One issue with this theory though is that some individual components of the body really break down on their own, and not as a result of erroneous communication with other cells. For example, telomeres located at the ends of each chromosome shorten with every round of cell division. These act as caps at the ends of the chromosomes, protecting genetic information inside our chromosomes from degradation due to replication. They are a ticking time-bomb inside your every cell. Eventually, they get so short that important genetic material begins to be lost, and cell function is lost. This process occurs internally in every cell, and can't be influenced by a method like you described, because it's independent of communication pathways between cells. 

 

I think the traditional understanding of aging as a combination of factors is more likely than just a single one-size-fits-all solution. Not to discount your theory though, it could very well turn out to be a big piece of the puzzle.



#3
starspawn0

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Well, I thought of that.  But the body can and does automatically lengthen telomeres, and furthermore, they change in lock-step with the brain -- the brain might can direct their lengthening:

https://www.scienced...90927103248.htm
 

Recent studies suggest that telomeres can change faster than previously thought, possibly taking just one to six months of mental or physical training to elongate. The exciting premise is that telomere lengthening may represent a reversal of biological aging processes. However, it remains unclear if telomere elongation actually reflects any improvement in a person's overall health and aging trajectory.

....

The result: "Across systems, our biological aging appears to change more quickly than we thought. Indices of aging can vary together significantly in just three months," says Puhlmann. If the telomeres changed in length, this was associated with structural changes in the brain. In a period when participants' telomeres lengthened during the study, it was also more likely that their cortex had thickened at the same time. On the other hand, telomere shortening was associated with reductions of grey matter. This association occurred specifically in a brain region called the precuneus, which is a central metabolic and connectional hub.

The above results suggest that even short-term changes in telomere length over just three months might reflect general fluctuations in the body's health- and aging status. Many other questions, however, remain open. "We do not know, for example, which biological mechanism underlies the short-term changes in telomere length," explains the scientist, "or whether the short-term changes really have a longer-term effect on health."

 

However, meditation and similar practices might not be the way to get the brain to lengthen telomeres, this study shows.  Neurofeedback has yet to be tried, as far as I know.

 

One thing you have to consider is:  why would naked mole rats appear not to age, compared to other rodents?  If it's so very complicated, surely requiring an immense number of genetic tweaks, evolution would not have selected for it, as there wouldn't have been enough time (naked mole rats are not that genetically distant from similar rodents).



#4
kjaggard

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Well, I thought of that.  But the body can and does automatically lengthen telomeres, and furthermore, they change in lock-step with the brain -- the brain might can direct their lengthening:

https://www.scienced...90927103248.htm
 

Recent studies suggest that telomeres can change faster than previously thought, possibly taking just one to six months of mental or physical training to elongate. The exciting premise is that telomere lengthening may represent a reversal of biological aging processes. However, it remains unclear if telomere elongation actually reflects any improvement in a person's overall health and aging trajectory.

....

The result: "Across systems, our biological aging appears to change more quickly than we thought. Indices of aging can vary together significantly in just three months," says Puhlmann. If the telomeres changed in length, this was associated with structural changes in the brain. In a period when participants' telomeres lengthened during the study, it was also more likely that their cortex had thickened at the same time. On the other hand, telomere shortening was associated with reductions of grey matter. This association occurred specifically in a brain region called the precuneus, which is a central metabolic and connectional hub.

The above results suggest that even short-term changes in telomere length over just three months might reflect general fluctuations in the body's health- and aging status. Many other questions, however, remain open. "We do not know, for example, which biological mechanism underlies the short-term changes in telomere length," explains the scientist, "or whether the short-term changes really have a longer-term effect on health."However, meditation and similar practices might not be the way to get the brain to lengthen telomeres, this study shows.  Neurofeedbts).

1) telomeres getting shorter doesn't lead to the loss of genetic code, last I checked. Telomeres split between each half of a dna strand when it divides. When it gets too short to divide the telomeres the cells stop dividing. 2) as stated there are ways to re lengthen the telomeres. some dietary options as well as supplementation of Telomerase 3) RNA repairs and Mitochondria failures are more often than not where failures of old cells come into play. 4) There are a ways to replenish mitochondria as well, again aincluding dietary and supplementation options. 5) there have been mixed results from studies done with young plasma, suggesting that it may still be possible that some component of systemic chemistry may provide maintainable youth. 

 

in all likelihood it will be a combination of things that gets us there. and much like any recipe it will likely feel like a hell of a lot of blind hard work to get there, but once we get there it may look as stupidly simple to us as washing your hands after an autopsy and before delivering babies as a way to reduce deaths in childbirth does now.


Live content within small means. Seek elegance rather than luxury, Grace over fashion and wealth over riches.
Listen to clouds and mountains, children and sages. Act bravely, think boldly.
Await occasions, never make haste. Find wonder and awe, by experiencing the everyday.

#5
Erowind

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This presents a greater issue. My understanding of all this is very rudimentary so excuse me if what I'm about to say is foolish. I can't remember where I heard this but it can't be my original thought. Cancer. That perhaps aging itself is the bodies primary defense mechanism against cancer. By preventing smooth functioning with age and frustrating the bodies processes the body also alienates and frustrates the growth of cancer cells. So, if we could just redirect the body to conduct its systems properly how would we also combat the rogue cancer cells that stop listening due to executive breakdown from cell mutation?

#6
starspawn0

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I've heard that theory; however, naked mole rats almost never get cancer, and live a long time -- over 30 years, which is 10x that of similar rodents; and scientists still don't know exactly what kills them (maybe mostly accidents or infections unrelated to aging):
 
https://en.wikipedia.../Naked_mole-rat
 

In 2013, scientists reported that the reason naked mole-rats do not get cancer can be attributed to an "extremely high-molecular-mass hyaluronan" (HMW-HA) (a natural sugary substance), which is over "five times larger" than that in cancer-prone humans and cancer-susceptible laboratory animals.[24][25][26] The scientific report was published a month later as the cover story of the journal Nature.[27] A few months later, the same University of Rochester research team announced that naked mole-rats have ribosomes that produce extremely error-free proteins.[28] Because of both of these discoveries, the journal Science named the naked mole-rat "Vertebrate of the Year" for 2013.[29]

In 2016, a report was published that recorded the first ever discovered malignancies in two naked mole-rats, in two individuals.[30][31][32] However, both naked mole-rats were captive-born at zoos, and hence lived in an environment with 21% atmospheric oxygen compared to their natural 2–9%, which may have promoted tumorigenesis.


Elephants, also, don't get cancer, or rarely do, and live almost as long as a human (lifespan of 60 to 70 years).  Furthermore, they have 100x as many cells as humans -- meaning there are lots of potential mutation sites.

 

Some whales live 200 years and don't get cancer.

 

Chimps, also, are said not to get cancer very often; though, I'm not sure how good the evidence is.



#7
kjaggard

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my understanding of cancer is that they are damaged genetically and we all get single cells that could be called cancer from time to time. They are essentially immortal in many cases. They are also resource hungry to fuel their unrestrained dividing.

 

Our own bodies are reasonably good at finding isolating and killing those cells before they can replicate and spread too far. It's as the body gets older that it's defenses and protective forces become less effective and fewer through aging, that they cannot keep up with accumulating damaged cells.

 

Any good anti aging system will need a way to replenish and maintain a robust system of finding and fixing genetic damage, including killing cells that go 'off'. Even with that there are things that will slip through, and if you think about it like any gamble, the more rounds you are in the game the greater the chance that a negative scenario will occur.

 

Fortunately there exists tech even now that could radically change cancer treatments. Things like ultra-sonic cavitation therapies that are essentially sonic blowtorches that can pass through tissues and focus on microscopic points within a person exist already. If we can increase detection  ability it could change those gambles that inevitably, given enough time in the game, drop something like this in our laps, into something that is just a regular preventative maintanance.

 

edit to add Aubrey De Greys master list of hurdles to longevity and proposed solutions.

editedDe-Grey-table.png

 

I think the only thing I'm unsure if I'm comfortble with is the 'suicide genes' for cancers. I favor something a bit more external to the gene. medications, or ultrasonic options seem like doable options in the near term, with nano tech augmentation a bit further out.


Live content within small means. Seek elegance rather than luxury, Grace over fashion and wealth over riches.
Listen to clouds and mountains, children and sages. Act bravely, think boldly.
Await occasions, never make haste. Find wonder and awe, by experiencing the everyday.

#8
starspawn0

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Immunotherapy is another approach to cancer treatment.  

 

My brother is actually a cancer expert and medical doctor (double board-certified), and has helped run clinical trials of cutting-edge cancer treatments.  I asked him once about immunotherapy, how good it is, and he said something like, "Well, it has a large effect on about 20% of cancers.  If you have such and so mutation [when he talks cancer, he starts talking like `AP2-onc-beta mutation' or whatever, that's what I mean by `such and so'], and we're talking about carcinomas [or whatever], then there's a good chance it will work.  But if you have this other mutation [whatever he says], then there's not much we can do."  

 

People often say that cancer is many different diseases, so it's going to be a long time before it is "solved".  But if one class of therapies can make large progress 20% of the time, that makes me think there might be single, simple approach.  It's even possible that a single immunotherapy will eliminate almost all cancers, without the need to upgrade our genome.  The brain might even be able to initiate the cleanup by itself -- it's intimately linked to the immune system.

 

And the neat thing about immunotherapy is that, once again, it leverages the body's own repair and defense mechanisms.  The body has all these incredible mechanisms that are under-utilized.



#9
Zeitgeist123

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i personally dont think it is that simple because if it is then we would have at least one genetic outlier in history who could have reversed their aging indefinitely. no such accounts related to it whatsoever has ever happened in the history of mankind


“Philosophy is a pretty toy if one indulges in it with moderation at the right time of life. But if one pursues it further than one should, it is absolute ruin." - Callicles to Socrates


#10
starspawn0

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And yet, like with the discovery and use of Penicillin, sometimes you can prevent a lot of death (temporarily) with a simple trick.  Some immunotherapies are also like that.  

 

Aubrey de Grey's SENS project is basically saying "you only need take care of a small number of things".  7 things, in fact.

 

Genetics is completely different matter.  I'm not claiming you just need to tweak a single gene, or even 10.



#11
starspawn0

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Here's another thing to consider:  last year, there was an experiment that showed that human-growth hormone,  in combination with metformin, DHEA, vitamin D, and zinc supplementation, caused the reversal of the epigenetic clock -- and the regeneration of the thymus.  Now, the body is capable of producing and secreting more HgH than it ordinarily does; and that secretion happens in the pituitary gland at the base of the brain.  For example, during exercise people secrete several times more HgH than they normally do.  A few hours after exercise, however, and it drops back down to normal levels.  

 

What if one could "overclock" the pituitary to produce HgH a lot more during the day -- more than would be produced during exercise?  And could it be done through passive neurofeedback?  (say, by being exposed to stimuli in the background that selectively trigger the release of HgH).

 

I can't rule out the possibility.  However, I may be overlooking something here -- e.g. just how much HgH would be needed to regenerate the thymus -- but assuming I'm  not, then the outcomes of that experiment might be repeatable just using some method to stimulate the pituitary.  

 

The body can synthesize that DHEA, too.



#12
Maximus

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This presents a greater issue. My understanding of all this is very rudimentary so excuse me if what I'm about to say is foolish. I can't remember where I heard this but it can't be my original thought. Cancer. That perhaps aging itself is the bodies primary defense mechanism against cancer. By preventing smooth functioning with age and frustrating the bodies processes the body also alienates and frustrates the growth of cancer cells. So, if we could just redirect the body to conduct its systems properly how would we also combat the rogue cancer cells that stop listening due to executive breakdown from cell mutation?

With respect to telomeres specifically this is very true; the human body actually does possess an enzyme that repairs telomeres. However it's not expressed in most of our cells; only gametes, stem cells, and significantly, cancer cells. Evolution probably made sure telomerase wasn't active in all of our cells to avoid cancer.

 

I'm not expert in all this stuff either, but I do believe we'll have to conquer cancer before we conquer aging, as there seems to be a fine line between immortal cells and cancer cells. 



#13
starspawn0

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According to this, the reason we have telomeres has to do with the fact that our DNA comes in linear strands, and that we would lose genes every couple replications if we didn't have an end-cap:

https://www.khanacad...eres-telomerase
 

Telomeres act as caps that protect the internal regions of the chromosomes, and they're worn down a small amount in each round of DNA replication.

The end-replication problem

Unlike bacterial chromosomes, the chromosomes of eukaryotes are linear (rod-shaped), meaning that they have ends. These ends pose a problem for DNA replication. The DNA at the very end of the chromosome cannot be fully copied in each round of replication, resulting in a slow, gradual shortening of the chromosome.


So, it doesn't sound like an evolved mechanism to prevent cancer.  And perhaps the same is true of restricted telomerase use in the body:  Cancer cells, it turns out, often have shortened telomeres and turn telomerase back on.  So, how could it make it any worse to turn it back on in other cells?

In fact, there are organisms that don't get cancer very often, and live a very long time.

 

....

 

At least if you keep telomerase on a short time, it doesn't cause cancer in mice:

 

https://www.drugdisc...t-cause-cancer/

 

Also, as stated above, the body does periodically re-lengthen telomeres in the body.  That could be through a dose of telomerase, or some other yet-to-be-discovered mechanism.  This is a new and unexpected discovery. 



#14
starspawn0

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Just thought I would mention another breakthrough here:
 
https://twitter.com/...037664885084163
 

The Conboy lab reports the ability of young blood transfusions to reverse Mouse aging is mimicked by a simple replacement of blood with a neutral age fluid [saline + 5% albumin] with benefits in muscle, liver, and new brain cell formation (image)Flexedbiceps #aging



It's even simpler than the previous breakthrough about using "young plasma". In fact, it's so simple that it should be cheap and easy to perform on humans -- assuming it works in humans -- without even needing any young blood.

The fact that it induces new brain cell formation is a sign that it might also fix problems with brain aging -- e.g. dementia.

Even if this doesn't fix all the problems of aging, if it fixes most of the problems, you can probably expect to live a lot longer, and will look and act young and healthy right up past the age of 100.

#15
starspawn0

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I wonder about the FDA restrictions on this.  I mean, people can donate blood... and I'm sure there are limits.  Extreme athletes often remove a lot of their blood volume, keep it cool in a refrigerator, and then load up some time later.  

 

As far as I can tell, the procedure would not need any drugs of any sort -- just a saline IV drip.  One could imagine a clinic, where you go and they remove, say, 25% of your blood, and pump you with saline and maybe a little albumin (or maybe the albumin isn't even necessary).  You'd be light-headed, so would have to spend a couple days at the clinic to recover.  When you're done, you will have set the clock back a couple years (every couple years you'd have to go back for a new treatment).  The diluted bad stuff in the blood isn't able to do its thing; and so the body's rhythms reset back to a youthful state.  Perhaps the epigenetic clock also resets.  

 

This could be like "tanning beds" -- simple to set up pretty much anywhere in the world, even in places with the most rudimentary medical care.  

 

Just imagine what it would mean if it cures most of the major diseases, like heart disease, diabetes, dementia, and so on -- at least if you start early enough.  It would cause the collapse of the medial system and insurance industry as we know it.  Large pharma companies would also collapse, as too few people would need their pills!  Trillions of dollars will go **POOF**.



#16
tomasth

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There would still be medical problems, the industry will shift its business to those directions.

Do long lived creatures have a different blood clearing system ?

#17
starspawn0

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Two things:
 
* In the Conboy Labs's paper on rejuvenating mice, they claim that the closely-related human procedure, called "Therapeutic Plasma Exchange (TPE)", has shown a crazy number of health benefits in humans, including that it resets the blood proteome back closer to youthful patterns.  I looked up a recent TPE clinical trial to treat Alzheimer's, and the results so far are jaw-dropping:
 
https://www.grifols.com/en/the-results
 

Grifols presented the first AMBAR results at the 11th CTAD in Barcelona, Spain, in October 2018. The primary efficacy endpoints – the ADAS-Cog1 and ADCS-ADL2 scales – showed a 61% reduction in disease progression for both measures in the cohort of patients with moderate Alzheimer's.


and

The CDR-Sb scale – which assesses memory, orientation, judgment, community affairs, home and hobbies, and personal care – showed a 71% reduction in clinical decline with respect to placebo in patients treated as a whole and in all three clinical trial treatment arms analyzed separately.


* And the other thing is that the Conboy Labs procedure sounds pretty similar to "blood plasma donation", which works as follows: they put an IV into your arm, filter out the red, white, and platelet cells, giving you those back, but then they keep a lot of your plasma, and give you saline to replace the lost volume. According to this:

https://health.howst...ma-donation.htm

if you are 175+ pounds (I weigh about 200 pounds), you can donate around 1 liter of blood plasma at a time. The human body typically has between 3 and 5 liters of blood, total, 3 of which is plasma. So, 1 liter out of 3 would get replaced by saline; a third is not too much smaller than the half fraction from the Conboy Labs study for mice!

And the best thing is, many place will PAY you to donate plasma! They pay you to do something that might ultimately make you healthier!




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