Young Plasma from Pigs Reduces Epigenetic Age in Old Rats
One interesting question in the development of new epigenetic clocks to measure biological age, particularly now that a large consortium of researchers has published a universal mammalian clock, is how one demonstrates that a new clock is in some way useful enough or interesting enough to spend time on. There are, after all, many published clocks at this point, and we might expect that the research community will attempt to standardize on the new universal clock. Why use another novel clock? One answer might be that the clock is optimized to give a large signal under a particular set of circumstances. Hence we arrive at studies like the one noted here, in which researchers demonstrate that their novel clock performs in a potentially useful way when assessing the results of plasma transfer from young individuals to old individuals between mammalian species.
Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young pigs rejuvenates old rat tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=613 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=1366 human tissue samples to the training data.
We employed these six rat clocks to investigate the rejuvenation effects of a porcine plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro-to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging.
This and a few other other studies are definitely pointing to the extracellular vesicles of the young blood being the primary driver of the epigenetic age reduction when young blood is given to the old. That is approaching Yamanaka factors with the reduction and is something that could possibly be done on a mass scale since it worked between 2 different mammals. The implications for healthspan especially would be very big with this. Someone said young cows that just reached their milking age could be a large source of the EVs also in addition to young swine.
It is looking like the genetic cargo within the EVs is telling the recipient what age to be via changes in gene expression.
You forgot to mention that it restored cognitive function and strength almost to levels of young animals.
Need to do a lifespan study on these rats and recheck epigenetic age at death.
Does the clock catch back up without further treatment? Do they die of "old age" with a young epigenetic age?
Interesting that the treatment "wears off". Implies that EVs do a "hot wire" age reset and then the cellular mechanism (imo non-coding DNA) that actually controls age picks back up at whatever age it was at.
They did a lifespan study previously and the treated rats lived a little longer on average but apparently had quick dropoffs at the end and died. I believe they said the appearance and activity level difference between the treated and control rats was very striking up until the end though. One treated female rat supposedly broke a record for that rats lifespan.
Hi Lee! Just a 2 cents.
I concur with your view (about doing a study to find out if they die with a younger or older epigenetic age -- after was reset/reprogrammed or exposed to young plasma)...but I kind (of think) I know already what wil happen...
It may end up that the animal, rapidly, gains back the epigenetic age; like instead of gaining 'days' back...it gains 'years' back...in a record time/speed.
It was demonstrated that partial epigenetic reprogramming was only a 'temporary' thing...and not a permanent one. Meaning, once you had done the reprogramming -- if you did not reprogramm again (soon enough); it seemed to go back to the former 'old self'...quite fast. Faster...than 'regular aging'...as in, you would not go back to 'old self' 'slowly' ...like after all these years...of aging; no, it would be real fast...and in a few ***months*** or days**** you would 'gain back' your old self...not Years. So you might be back to 20 yeares old...but in a few days...you could be back to 60. If, you did not continue the 'repeat reprogramming'...or in this case, if you stopped exposing your blood/cells/organs..to young plasma.
Like, it seems, that the only way for it 'stick', is to expose yourself to in Continuously...or, to reprogram your cells...Repeatedly/continously too.
Partial epigenetic reprogramming (which is, the only possible one, that does not kill the animal; Full epigenetic reprogramming kills you..by 'erasing you/deleting you'...your cells lose their cell signature...and that is a death sentence; it was demonstrated in mice, that, 'full' epigenetic reprogramming killed them; only, partial created the 'reduction of epiclock' --- *without changing/losing the 'mature' state and the signature/phenotype of the (mature) differentiated cells).
They also showed that epigenetic reprogramming (partial one) is 'Temporary' thing...and so, from what I read/learned, it Seems 'as if' , if we would use epigenetic reprogramming - for it to 'stick'/be 'permanent' in effect' - we would have to do it DAILY....yes, daily.
Daily, you would need to expose yourself to this plasma...or to epireprogramm your cells...because, if don't the cells go back to their former 'old self'...and Quickly.
So quickly, that you miss 1 single day, 'of reprogramming/plasma exposure'...and that's it...you are 1 day 'behind..and 1 day closer to getting back to old self; like - 1 Single Day not doing any reversing...was enough to 'gain back' reallly quick the aging/old self...yes, 1 single day.
This means, that reprogramming/plasma exposure...is a thing to do everyday..like breathing....
You cannot go on..without breathing a Single day...you have to breathe (air/O2) everyday, to survive...well it seems the same thing with epireprogramming or plasma exposure.
The effect 'wanes' quickly and, thus, back to 'old self'...in no time. I hope I am wrong and that this will be fixed/solved.
So, it has not been proven yet, that the effect 'will last'...Long,, as in be permanent (enough), and you would onyl Need to do a second reprogramming - some..,...30 years later...
No, it's more like..in the the Next 3 days or 3 hours?...you will have to 'fix your cells - again (and again, and again, rinse repeat...it's not too bad...we can do the 'looping/loopdloopdloop/rewind- repeat')'.
Thus, we would be in 'always-doing' reprogramming mode...like, breathing every second...
'to catch up' and 'never lack'...(like breathing..never lack oxygen for Energy/mATP in our cells).
I'm not sure that is super convenient, but, I mean...we do 'breathe every second'..to live.
It would become existential and subsistence-ial....you need to breather to live; you need to reprogramm or expose to plasma...to live/continue living ..... to do this - every day, every hour, every minute, every 2 seconds.
We age, we damage....all this...the 'epireprogramming' cannot Stop (neither young plasma exposure)...we RE-age, we Re-damage...the aging just 'restarts'...but from a 'younger self', younger 'point' in (our past) time....does not mean it stops the aging.
So, the aging 'restarts' again...from younger self. And, this is the important point, it Gains Faster...as in you may be younger (per epiclock) - but you are 'getting back' 'old'...faster.
Thus, you could be 'back to 60' (from your 'young epireprogrammed 20 self')...in little to no time.
Not in 40 years time (i.e. - 40 years gap between 20 and 60 - 40 Chronological Years....passed; not so, now you could be 'biologically' back to 60...in a few days, or few weeks/months...again, not years time). It seems, that we experience 'progeria' (fast aging) when we reverse cells epigenetic clock...and they 'reage again' from their young reprogrammed self...so you are back to 60..in no time.
Just a 2 cents.
PS: That's a bit what Mike is saying, it seems that their is a limit to this -- and so, the animal can experience 'morbidity compression'...you know, like centenarians..like 120 years...and then, from one day to the next...they die.
They were 120 years going Great...and then Boom...they die, suddenly, 'one day to the next'.
That is morbidit compression; where there is a 'plateauing'...of 'maximal longevity'...the centenarians are reaching the 'max'...(and I explained before why)...and there is no more 'to gain'...they reach the limit; healthy or not..and die suddenly, there; like 'hard limit'.
Healthspan - to the Maximum = 120-140. max.
It is most likely the reprogramming will only allow us to live 120; because of the rest (dna damage...etc; it was shown the reprogramming did not do much on 'already accumulated damage'...the animal waas stilll 'damaged'.,after reprogramming..); and the only way to solve this, is to fix that damage.
So we can live 'healthily (enough)', until we reach the 120 or so.
Yep if we got the optimal schedule down it seems what this would do for most people would be to allow them to maybe make 95 to 100 or so but would allow them to be like an in shape 50 year old at 80 years old or something similar as long as treatment started by like 50 or close to that. As far as what schedule would be needed I have no idea but I think one study the rats were given the stuff every 6 weeks or so but you could see the blood markers of some things had started to creep up and the next treatment brought it down again. When most people thought it was the young proteins doing most of the work one person made a pretty good argument that you couldn't convert mice time to human time for treatment times by their lifespan and that treatments would need to be about every 4 months to keep from falling back before the next treatment. Not sure what the thinking on treatment intervals for humans would be with EVs being what is doing most of it. How quickly would most of the effect on the cells wear off? In rats apparently it has worn off some at 6 weeks but is still clearly much better than before the initial treatment.
PPS: And (found) this (2014 study, already almost 10 years..ago)
:
''It was reported using various biological models that the administration of blood factors from young animals to old animals could rejuvenate certain functions. To assess the anti-aging effect of young blood we tested the influence of repeated injections of plasma from young mice on the lifespan of aged mice. One group of 36 CBA/Ca female mice aged 10-12 months was treated by repeated injections of plasma from 2- to 4-month-old females (averaging 75-150 μL per injection, once intravenously and once intraperitoneally per week for 16 months). Their lifespan was compared to a control group that received saline injections. The median lifespan of mice from the control group was 27 months versus 26.4 months in plasma-treated group; the repeated injections of young plasma did not significantly impact either median or maximal lifespan.''
It is perhaps the case, that porcine plasma is more powerful (because pigs live much lifespans than mice...hence, it would make sense, to think, that young pig plasma would have more effect and protect that animal longer -- scavenge better/longer...after all, the pig lives longer - it Needs this 'type of plasma' to live 'this long'...hence, the old mice gain more benefit from young porcine plasma,...than young mice plasma transfer.
Also, I don't know how much 'more' lifespan did the old mice gain with the porcine treatmemt...it could be then compared to the young mouse plasma treatment...and tell us, taht indeed, if is the case (of living longer on porcine); than porcine effect is stronger (because they live longer and their plasma is made so...for them to live this long; hence, much more powerful effect); it would also mean, that young human centenarian offspring's plasma...-tranfered to mice..would be Even more powerful than porcine, because humans live longer than pigs; and centenarian' offsprings...live longer than the 'regular human population' (who live to 90 or so, or less; but don't reach 100 years old; centenarian's offsprings/youth/children', it was shown...age Slower than the regular children from regular aging parents...who do not have familial-inherited/family longevity genes/genetic advantage to 'reach 100+' years old with a great assurance (because of their centenarian parents' genes transfered to them/to their offspring))...
These studies, tell me all I need to know, that plasma transfer will improve health...and thus, epigenetic clock...but does not stop the 'maximal' barrier -- the 120-140 years old barrier will still stand (as was said, with the morbidity compression when people 'don't die anymore' and live to 120 - they hit a plateau limit/compression/'die one day to the next'); young plasma therapy (wether porcine, or human) or epigenetic reprogramming---or not.
Therefore, epigenetic reprogramming and young plasma exposure, will be health--improvement.
I mean it Does reverse the epigenetic clock, and they said the organs are younger/function better...so it has an effect, substantial (they also said the brain hyppothalamus was less in effect, and more 'resistant' to young mice plasma exposure - that's not good; it means the brain, might be the 'limiting organ'...the 'weak link' to beating 120...you need to preserve your brain to reach 120+..). And allow the animal to reach the 'plateau/max.' MLSP (Maximum Lifespan Potential); but not all that much above that (hence, reach the 120-140 max, for humans).
I asked Akshay on his blog about the hypothalamus not getting as big a reduction in age as the other things and he basically said he thought it was due to how it aged differently and how the cells worked there because they had real good results on memory tests and the rest compared to controls after the treatment. He also said the exosomes would have no issue crossing the blood brain barrier.
Hi Mike! Thank you for that (relaying their opinion), and that person, their opinion. That's a good thing, is reassuring. I mean, we don't know yet with 100% assurance, but he is on to something, that, probably, the hypothalamus, is its own thing'...doing its own thing (even aging as its own self-dictated pace) and quite separate from the rest of the brain (parts) and, of course, other organs; hence, seeing a substantial difference there. I just hope it does not end up 'another limit' (here, an organ)/another 'wrench' in the fig. cog wheel... to be able to reach above MLSP. I think (off the top of my head/like that, if memory is still sharp...(well, it needs to be..or I will never reach 120...obviousyl....my undle died of alzheimer's disease at 74...)), that, neurons in brain were capable of living up to a certain maximum; like, they can't be 'eternal'...if left in the brain; that, they would be good 'for 150 years or so' maximum...and then that's it -you die from dead neurons cell maximum life. Like, that was their (human) 'maximal neuron cell lifespan'....but, that's the thing; this is from a 'normal aging' view (of humans)....and cells that are Reversed in Aging and removed their damaged...do not 'stop' living...I mean, that continue to divide, or for non-dividing cells, they continue 'to be'/to exist....they don't die...well, that is, if we stopped 'the other stuff' (namely, telomere shrinking, dna damage accumulate, lipofuscin, progerin, residue..in them, etc).
it'S been shown in immortal cancer cells...even. So, neuron, are not 'different' or something (on that point), rather, they are 'different' cells, yes, but still, if we reverse them and repair them; then, I think/believe, that neurons cells..whether hypothalamus or frontal cortex, makes no difference much; rather, they Have to be reversed/repaired - and not 'resist' that...if no cells resists it...than All cells are reversed/repaired...than the '150 years neuron' limit...is not true anymore.
I mean (also), certain animals, like greenland sharks or bowhead whales - have brains (!) evidently...and they up 250-500 years old...so it'S complete bs...to say 'neurons are limiting us to 150'...I mean Yes they limit us 'in humans - that live normally..to 120 or so'...in that case yes; but Not if we Intervene in them and change that. To 'emulate/reproduce' the neurons - like in a greenland shark or whale's brain....they get to keep their brains way over that; proving, that neurons in their brain last this long - or - proving, that Replace their neurons/Make new neurons (neurosynthesis) to replace 'old dying neurons' with new ones...I don't know 'how' this would work (but I do know that BDNF, (brain-derived neutrophic factor) is capable of improving brain funciton/health and neuron cells function too; in fact, it was demonstrated that 'running/exercise' is almost (if not more) powerful that 'brain exercising through thinking 'education'...
I mean that Physical exercise triggers BDNF in the brain (so does 'education/learning/mental sharpening tests'..but physical exercise was seen as equal (or more) to regular education - on `BDNF levels production in brain (the reasoning behind is, is ancient hominins - that had to 'hunt', in cave age, we had to hunt and 'run' (from dangers)...and do exercise/be athletic and 'weary/wary' of some predatorial/danger..('fight or flight' response), a whole lot more than today.. and such, the brain was wired to 'physical exerice'..(via BDNF) ; with 100 thousands years later...our brain now is more wired for 'desk work on our behind/sitting' (especially, last 10,000 years, with the advent of 'cave drawing' or later 'paper writing' 'paper books' creating, books and reading and 'computer reading')...and sitting is bad for health over long time...so, phys. exericse as strong brain protection; just as much as 'learning while sitting' doing no physical exercise)))...and thart protects the brain; and possibly also increase new neuron formation or 'repairs' damaged/old neuron...and even CNS (central nervous system/neural system (BDNF, IGF, neurons, astrocytes, astroglial cells, microglial, other and CNS, work in tandem and help each other), connected to neuron, which need nerves for impulse signaling/transfer (brain neuron signal/impulse) to all over body/organs/muscles/body motricity. (via large CNS in whole body)).
Thanks again, just a 2 cents.
Do you know if the dialing back of epigenetic age with those Yamanaka factors resulted in the hypothalamus not reversing as much as the other organs and blood? That would likely tell us whether E5 itself is limited on the hypothalamus compared to the other stuff. If Yamanaka factors had roughly the same result then it probably is the difference with the hypothalamus like Akshay believes. I might try to find that paper but knowing my luck they didn't measure the hypothalamus reduction in epigenetic age.
I have a general question regarding epigenetic therapies (forgive me if it's been asked before):
If the body really can be restored so easily via switching epigenetic signals, wouldn't this imply that evolution is literally programming people to die? To believe that epigenetic therapies could solve many of the problems of aging...wouldn't one also have to come up with a plausible argument as to why evolution started this programming in the first place?
I don't see why evolution would do that, so therefor I don't allow myself to get too excited about epigenetic therapies, as a standalone solution.
I certainly think epigenetics will be a necessary tool, like crisper or something like that, but I just find it impossible to believe that you can make an old cell young again by telling it to "act young".
There seems to be 2 opposing camps on whether evolution purposely programmed most animals to die. I am in the camp that believes it purposely did this to make sure you died off after your reproductive age. Nature seems to have also made most mammals have a good period of senescence before they reach their lifespan limit. Animals like crocodiles and things like that have a much shorter period of senescence relative to their lifespans before they reach their lifespan limit. I read the arguments for why most mammals having a longer period of senescence is beneficial for the species overall but I cant remember what the arguments were right now.
PPPS: I did look, Mike, but, sadly did not find anything much; lots studies on Yamanaka/reprogramming, even (general, whole) brain....but not much (specific) hypothalamus (epiaging observation results) with Yamanaka factors/epigenetic reprogramming.
Hi Gregory! Just a 2 cents. That's a great question (if you have more, keep'em coming/don't hesitate to ask).
You are very close to the (real) truth (I believe, 2 c), that, yes, evolution is really 'rigging us'...and, as such, we have a 'master plan/blueprint'....ours, is about 120 years old...that's 'the program' (blue print) for us...I mean, that we forget the word Genetic -- in epi-Genetic.
That'S the key word, genetic, and thus, the Genes --- DNA (mostly, if not all, the nuclear DNA - genes; and, a little bit, the mitochondrial DNA genes; but, these ones are (way) not as impactful; they are mainly for mitochondrial ATP production 'assurance/guarantee/stability' (they maintain mitochondria 'functioning well' and producing energy, for the cell.....well too; they are the mitochondrias' 'safe/mini-control tower'); ...they don't have much say, on what happens in the (nucleus) nuclear DNA - genes (nuclear chromosomes), there...that's where the 'bulk' of stuff happens and 'forms you' how you are/look/function...them nuclear genes... etc...as human; it's also there the 'telomeres' are - Telomeric DNA - caps on the chromosomes that dictate aging/replicative aging); Nucleus and Mitochondria, 2 different compartment...far from one another (well..not 'far'..but 'around the corner', as separate, floating things)...all inside the cell.
Evolution (C. Darwin's Natural Selection too/adaptation/survival of the fittest/survival of the specie; the most adaptable/adapting to new environments/dangers/resources lack...);
is all about the 'genes'...genes transfer, recessive genes and 'playing the gene lottery'...
or as you hear sometimes: ''removed from the gene pool''.. (extinct).
So, in that sense, what you said about 'so easily turn on/off epigene switch'...to kill you/age you or make you live....is true...that, because, your body is a genetic controlled entity...it makes sense to think that these 'Switches' on genes (mostly 'methyls', acetyls and the histones) would dictate which genes would be expressed/activated/Active...or unactive/unexpessed/deactivated.
With age (you guessed it), it's mostly the 'inflammaging' one that get 'Activated'...and anti-inflammaging, vice versa. We go from an 'Anti-inflamma-ging' state...to an -- Inflammaging state.
Now, why would evolution 'program us' to a certain death....because, animals have different blueprints/master plans...depending on their lifestyle and environments and 'ways of living/feeding/maturing/reproducing...etc'' 'Living'....in other words...some animals live fast, some live slow...we (clearly) don't live all the 'same' (way) or at same speed....also, metabolistically, speaking (fast/slow metabolism..).
And so, For Evolution, the primordial thing, is specie (or individual) survival; specie survival means that the animals in that specie..must live/survive (evidently);...and so, that means Reproduction (babies/kids/sex....) to make offspring..and Continue the Survival of this specie.
If mating/sexual reproduction lowers...than, you can assist/see...a denatality and a death of the specie. Because, no more 'kids' are popped...hence, the specie dwindles by attrition from lack of birthing/natality...number. No more 'new kids (on the block). Demographic death.
So, who's left...well the 'elders' the 'already alive' and the 'Getting Old'...until, dyying....that is the attrition of the specie....beucase no new animal is birthed to replace the oldies...(on that point, I have a POV...but it'S a long story...for another day (about 'replacing old ones'...with, new ones, of course...'the cycle of life/rinse-repeat'...so far...));
Another reason, why we are programmed to dying...is complexity (and entropy)...it is Hard to keep a complex being 'immortal'...vs a 'simple organism'...and it's why, for example, a jelly fish will be 'quasi-immortal'...while a human only lives barely a century...that jellywish is was less complex (anatomically/organ-ically/cells...etc; we share a lot in common, but we're more complex 'machines''; the human body is some of the most complex...for Evolution = that's problem..);
Evolution is forced to make a 'trade-off'...with us..and that trade-off (for complexity)...is mortality.
So, we could become 'simpler'...and funnily (but makes sense), then we woul reach immortality...
Our complexity...is not 'fault-free'..it is 'error-prone' and 'mutation-prone', 'damage-prone'...etc..
Simple organism = Easy = Immortality (no adaptation..no need to, Perfect already).
Complex Organism = Not Easy = Mortality (mutations, cancer, adaptations, 'not perfect'...machine; ''complex systems mean more 'errors' in the fray/bound to happen - entropy and random sht...happening..'bugs' as said in 'complex games and software....' the more complext and hard...the more 'new' bugs 'pop up'...)
''A micro-loose screw or part....willl falll... from a complexifying system/in the cog wheels''.
It's (analogically) a bit like, the Titanic boat...it's impressive, it's Huge..and a Wonder...it's complex...you will need 1000 'workers' on the boat...that 'plug holes' to not sink....as in, bigger boat...bigger problem will happen at some point...'some hole' will happen...then you sink, like Titanic. You make it sturdy and 'invicible'..but, we are not 'invincible'...we are 'fragile/error-prone' complex systems...that are 'Bound to Fail'...by 'some bug/mutation/damage/'error'...'...at some point. So complex systems are Not always 'better'. More Difficult/More Complex....you want more problems down the line - you offer 'more possibility/Chances of 'sht happening/hitting the fan..'...?...sometimes, KISS is better (Keep It Simple Stpid..). Don't do 'bloat/overbloat' or 'giant complexifying stuff'..bound to fail...
bound, to mortality.
Your second question (great commonsensical question too), probably, you're right, someone should come up with a reason why we have this epiprogramm in the first place...(And I kind of answered it already); but, it'S really, a 'shuffling of genes' and 'blueprints' and 'masterplans' or 'specie masterplans'...evolution is just 'playing/juggling the gene lottery'...and testing stuff - stuff (I mean animal--istic) that 'lives' or stuff that dies. Animals Have to survive, for specie/theirs to survive; and that means Living - on and 'reproducing' to keep specie surviving/thriving and prospering - so,,, living..on. It is called the 'Biological Imperative'...which means, you are forced to live...to make the specie continue...a biological imperative is on you..'to live'..and not die/disappear. Becaue, if disappear/die....you do not reproduce/did not (unless, you (did) reproduce(d) Before your death and thus 'continued your offspring/lineage/branch/specie..').
That is what dinosaurs experience (about 75% of dinosaurs were wiped 'dino extinction' around 66 million years ago at the yucatan peninsula and the asteroid (a K-impactor) blasted there and wiped them; not entirely.. but only 25% of dinos survived...). So, extinction is the biggest worry for evolution. You are not Supposed to go extinct...you are suppose to live (on)....and evolution/mother nature..does not Really Care...as in, if you disappear...you disappear you are just a # in the list...and as such, it is primordial upon the specie 'to adapt' and 'survive'...to Carry On/Live On and 'make the biological survivance' (of that specie). Evolution/Natural Selection puts pressure on those to adapt/to survive...those That Do...Continue' 'to be'..those that don't disappear. The epigenetic programming - in regards to that - is that if the specie does not survive, then, its 'master plan/epigenetic 'grand program'...is one of a short life...because 'not surviving'...so, you could say, that evolution is 'fine tuning us' and WE fine tune it too...for a long while..we did not; like evolution dictates - Us...but in the last century..no, not anymore...that is due the advent of 'medical research/biological science'..and Especially, BioGerontological study...this changes the human, body, and thus, WE are changing 'evolution', we are changing the trajectory that evolution had for us...because, normally speaking...humans...would live only about 25-30 years lifespan...but, we 'upgraded' things...and so we live to 120...the major reason is the 'grand-mothering' hypothesis, that grand-parenting and grand-mothering Helped us to live long lifespans (by women, grand-mas...who live Very long..and transfer this gene longevity advantage..in children; think the supercentenarians offspring kids...who live as long as their grand-parents...100+). So, in the case, of humans, longevity because more important than Making 1 million babies...unlike mice..they live only 2-3 years..they 'blast' babies out...and reproduce 'sex crazy'....and it's obvious..having 2-3 years..is short; and so they must 'make up' somehow...making 'tons of kids'...that'S how...and thus, when mice only live 1 or 2 years....they die...and that reduce numbers of hte specie...thus, they Reproduce fast/numerously to compensate - that denatality 'by short life'...it's the same thing..with certain insects that have short life...they pop 1 milion eggs....1 million new kids...they compensate (their short life) via ultra-reproduciton 'to make up - for loss of insects - due to short life). Humans, no need for that, we live 100...no need 1 trillllion humans...we Already Live very long...so we don't 'to replace everyone' - because (almost/many) people Can reach 100 years....thus it is a sort of trade-off between 'longevity vs reproduction'...for specie survival. In general, it was even demonstrated in centenarian women..(in genearl) centenarian women had LESS children...than younger dying women/mothers...like centenarian women (that lived this long..to 100); only had 1.5 child..or none, even.
This demonstrates the 'cost' of sexual reproduction to a human; espeically, women; it was demonstrated that women witth 'high gravidity' (mainy 'repeated' pregnancies over years) suffered mitochondiral burden Higher than low gravidity women (that birthed less kids and had less pregnancies). So, it's not 'free' to a woman..to have child.. there is a substantial sexual resources cost...AT the cost of 'DNA somatic resources'...so there is sort of 'retranslocation' of 'somatic (DNA) repair resources' --- towards, as sexual resources -- for multiple sexreproduction.
So, basically, the body is 'juggling' the resources...depending; if you want to live longer; it's clear, sexual reproduciton is costly; and should not 'be abused' of ...because there 'sexual resources' are 'taken' 'from the Other resources' (which are mainly somatic tissue repair resources); which you need if you want to live longer. Mitochondrial (DNA) lesions will accelerate death...it's also been shown..with men, that 'overdoing it'..is costly, in men too. Maybe slack a bit on the family jewels...
Anyway, sorry for the long post...I hope it (somewhat (in part) answered things).
I understand that you would have reservation(s) about epigenetic reprogramming..totally understandable...it's not a standalone solution...it's a 'à-côté..'/a supplement to add to the rest...
On your point of not believing that you make an old cell...to act young...I understand; the thing is (I believe) that you can 'tell it' act young...because you are reserving 'its clock(epiclock)'...and this is important element that determines the 'age' of the cell. But, you are right, in the sense, that because 'of the rest' (damages...etc); the cell is not Totally 'reversed' or 'young'...Truely young.. I mean; it's more an illusion (again); but it does not meant it has no effect...when you epireprogramming it -- you are changing its 'state/signature'..so there is something happening; it's a bit like removing a tattoo on your body...there may be some damaged done by that tatoo/tag on your skin...but you removed the tatoo...there's still some 'lingering effect' of it (as said with the term: ''epigenetic memory (lingering memory)'', tjhat's the 'signature/phenotype'..your cell is 'different' 'matured'...it's a 'state/signature/type')...but, the tattoo is gone. Is this True?...well, it's subjective; you could say it's 'half-true'... Aging is veryyy nebulous/ambiguous; if not the most ambiguous thing ever.. it can interpreted (or mis-interpreted) in so many ways...that 'we thoought' we were right..but all long, were not. (in my case, I have changed my mind about aging/the processes of it.. about a billion times ,..'I stood corrected an infinite amount of times'.
Just a 2 cents.
I think that morbidity compression offers a valuable insight into what might be happening.
You have a master timekeeper that controls an organism from development to death. This resides in the non-coding DNA and lifespan is predetermined. I think it must be sort of like a quartz oscillator in that at conception it starts counting and is independent from light/dark cycles or magnetic forces. OSKM can reset this timer but EVs don't.
This timer controls gene expression via epigenetic marks. Sort of like if all the genes had a volume knob on them where their output can be turned up and down. Extracellular vesicles are used to synchronize the animal's gene expression and thus its operation between cells.
When you do plasma or EV therapy you reset those epigenetic marks (and gene expression) closer to the age transmitted within the EV genetic cargo. You have just reset those knobs for a short while until the master timekeeper gets all the cells synchronized again at the "correct" age.
@Gregory Shulte
"I just find it impossible to believe that you can make an old cell young again by telling it to "act young"."
That is precisely what they did. Physical and cognitive function were almost at young levels, for a while. The catch is that it doesn't last, you don't really get more time and the effect wears off.
Not my first choice but better than a slow then fast decline to death.
PPPPS: The longer period of senescence in mammals...is due to (mostly) as cancer-prevention mechanism...senescencen is a 'negative (feedback)' protection mechanism; it's the 'fight fire with fire'...(normally, you fight it with water..not fire); cancer is very large threath -- mutational load; somatic DNA mutational load...cause; /rogue cells/mutant cells; tumors....tumorous/metastatic cells...(immortal cancel cells, that want to take over -- beceause they 'behave wrong - mutated'...per the epigenetic program - they hijack it...for their survival -- they MUTATIONALLY change the genome...to their advantage (nature seleciton/evolution -- Competing to Survive);
these cancer cells...are Competing to Survive...ebcause they don't want to disappear; thus, they Mutate Even More....a fc....the whole thing inside -- the normal '(epi)program'; they use inflammation (hijack inflammatory genes) to cause 'damage' - but Not Enough..to kill them; you could say they do 'hormetic damage'..just a bit enough to make cancer....work -to their advantage. Because, the protection against that- is the Tumor Suppressor Genes (p16, p21, p53); in fact, elephants and other long live mammals - are much bigger...'cellularly speaking' 'in fill'...yet...they do not get dcancer...why?..because they (for example, elephants) have more 'copies' of these cancer-fighting genes/tumor suppressors; so senescence, that period being longer is a Negative Protection - against formation of tumors/mutations; so, your body 'goest to senescence' - to prevent mutation or cell death; and in that period, the senecent cells are 'fighting the mutation' namely activating the 'tumor suppressors' genes...that Counter the possibility hat the senesecent cells 'would turn cancerous'...thus, a 'negative protection' 'evoluted/evolution' mechanism --- against cancer. Because, cancer, is the largest killer and destroyer of specie (besides, cardiovascular, atherosclerosis, brain alzheimer's, diabetes, lung/breathing loss (pulmonary ischemia or blood-clot strokes), or immunosenescence...etc).
Tumors were found on bones of ancient apes ...like it was demonstrated, that melatonin (the pineal hormone for sleep) protected against cancer...but was not enough; and the ancient apes/cave age animals...succombed to cancer - too. Like us , today, million years later...cancer/tumors/malignancy/metastasizing/'mutation load'...has been since dawn of animals.
PPPPPS: I should add - it is a cancer-mechanism protection BECAUSE we Live Longer...that'S the reason why; humans live longer -- More Chances/MOre Long Period of Life....that Gives the Possibility..to Obtain Cancer...I mean, if we live 100 years...that's Long Time..that It Could be Possible To Get Cancer...that's why we are in such a long period of senescence - to try to twarth mutation load/cancer/tumor formation - during this Long Life/Long Period of human life.
And it's why, animlas with short life...may not 'invest much' (blueprinting/genes) in 'tumor suppressor genes' -- like humans, or elephants (elephants have more copies of cancer genes than humans - Elephants live up to 80-some90 years....so they live long...Cancer-Free...and evolution solved it/tuned-it in them--they have more copies...to withstand cancer even if they are cellularly 'immense' (large mammal) and live up to 100 years...; like humans; we, as humans, are a bit less protected then them; same thing for bowhead whale mammals...they too have more copies or better 'tumor suppressing' gene mechanism...hence, they Also will have a longer senescence period...if they are 'in a dire position' of malignancy happening...malignancy or 'damage' = immediate 'exit' to senescence - to Twarht 'mutation/cancer' formation.
Negative protective mechanism...against cancer/tumor formation (when senescent cells...would turn from senescentg..to litterallt cancer); you could say, the body/evolution is trying to remove the 'bad weeds' (tumor) from a garden (body); our garden must always be prottected against bad weeds 'popping up' (tumorous/mutation load) and 'taking over' the garden (killing it..if they do).
Animals that do not obtain cancer...AND are quasimmortal...have found a way' 'jackpot' to Never let 'rampant cancerous rogue cell/mutation' formation take over..they keep 'damage/mutation' very low to none...thus No damage, no cancer,... immortal life..a possibility. But, as said earlier, complex beings (like us humans) it is Harder to make 'fault-free' 'no mutation' for 100 years...it 'just happens' and 'mutations pop'...and elephants sort of had an answer to that..with more tumor cancer suppressor genes that destroy cancerous cells. This is, also, in tandem, with improved or fined-tuned 'immunity' because the immune system 'phages' kills cancer cells (macrophage, T-cells...etc..immune cellls kills/eat pathogens..& cancer too). It's why the most powerful way to defeat cancer...is via the immmune system rejuvenation or reversing some of the epigenetic changes..caused by tumors, on the epigenome. This way you 'starve' the cancerous cells of 'access to inflammation genes'..et.c..
thanks for the answers everyone! Much appreciated. I'll be re-reading and thinking them over.