Non-Canonical Autophagy in Aging

Autophagy is the name given to a complex collection of processes that recycle broken and unwanted proteins and cell structures. Autophagy declines in effectiveness with age, while upregulation of autophagy is a feature of many of the approaches shown to slow aging in laboratory species. The ability of calorie restriction to slow aging appears to depend on autophagy, for example. So far, little meaningful progress has been made towards therapies that can greatly improve on the ability of exercise to improve autophagy, though mTOR inhibitors could be argued to be somewhat better than exercise on this front, given their greater effect on longevity in short-lived mammals. As mentioned, autophagy is complicated, and the paper here is an example of that complexity, diving into what is known as non-canonical autophagy, some of the less well explored interactions taking place during cell maintenance.

Macroautophagy requires the conjugation of members of the ATG8 family, ubiquitin-like proteins including LC3 and GABARAP, to phosphatidylethanolamine (PE). This enables double-membrane vesicles termed autophagosomes to recruit ATG8 proteins, which mediate loading and maturation of cargo. More recently, autophagy-independent functions of ATG8 proteins have been discovered. Several recent studies have highlighted these additional roles of ATG8 proteins leading to alternative fates of their cargo in degradation and secretion, together referred to as non-canonical autophagy (NCA). With age, there is a general decrease in efficiency of degradative autophagy, both canonical and NCA. Additionally, in what is likely a response to age-associated decreased degradation through the lysosome is the shift to "secretory autophagy" (SA), release of material into the extracellular space. However, owing to the overlap of the initial steps of autophagosome formation, SA also decreases with age. Understanding the mechanisms that differentially initiate and regulate NCA will help identify how defects in these pathways contribute to aging and disease.

One of the defining hallmarks of aging is altered intercellular communication, with a prominent example being "inflammaging", or the chronic inflammation that further amplifies the aging process. Growing evidence identifies inflammaging as the driver for NCA in aged microglia. SA has been shown to maintain proteostasis when autophagy is inhibited by blocking fusion with the lysosome in vitro. However, the downstream effect of this is the release of cargo into the extracellular space, and, depending on what was targeted for degradation but is now in the extracellular space, can itself induce an immune response. Hyperactivation of macrophages will lead to increased phagocytosis of the discarded cargo, bringing it back into the cell to attempt to be cleared. However, if the limitation is at the lysosome, the effort is futile and will lead to deposition of aggregated proteins both intracellularly and in the extracellular space. Thus, chronic inflammation seen with aging is a likely driver for aggregation-associated diseases, including many neurodegenerative diseases.

The role of NCA in aging and age-related diseases is still under intense investigation. It is still not clear how cargo is recruited for NCA, whether NCA and canonical autophagy coexist, if differential signals direct the decision to complete canonical versus NCA, and whether the cell has a preference for either type. Alternatively, NCA may only be initiated when canonical autophagy cannot meet cellular requirements, and thus becomes the dominant response for cargo clearance. Furthermore, the molecular pathways and vesicular trafficking in SA are not fully described, but canonical autophagy machinery is required for the initiation. So, if the same machinery is needed, but there are different outcomes, what determines if degradation occurs in the lysosome or if SA is induced? Moreover, with so many pathways to deliver cargo to the lysosomes for degradation, does everything come down to functional lysosomes? This seems to be the case, since the switch from degradation to SA does not solve the overall problem in neurodegenerative diseases.



Hi erasmus, just a 2 cents. TL DR: exososomes (the link you provideD) are good thing, but yes, it will be healthy span/health improvement mostly; and keeping you younger, to posisbly reach 150; I think exososomes delivery will give about 15-30% extension; not more; because the person is 'already aged/damaged' but if Combined with it starts to add up and could do 50% possibly...

Thank you for the link,

Exosomes delivery of young DNA/nutrient/stem cell is akin to parabiosis or young serum delivery to old mice; of course, it does rejuvnate, it seems it does slow the aging in old animal.
But, the key word, is partially (once again); I am seeing/betting that this exosomes delivery will give 15-20% extension of lifespan; just like stem cell injection in mice; it will renew the stem cell niche; and you need to keep it young/quiescent; to rebuiild tissues; with age, the stem cell niche exhausts and their telomeres shrink/accumulate DNA you can't rebuild tissues anymore, by lack or too aged adult stem cells...

So, it could be possible that exosomoe delivery would allows us to reach 150 years (as they say in the link you provided); but, I would not get my hopes to high about it; because, the effects were decent in mouse...and will be/translate as lesser in humans. They will do something, as they said, it makes the hair thicker and it reduces the graying of the hair...and it reverst some of the collagen loss with age; so more plump skin (like young; they said that young people have more exososomes...and it'S why they keep bettter/younger looking skin; obviously, being yougner; but it's having more exososomes...that 'deliver' this 'load' to the young age; with age exososomes reduce in numbers; so less 'deliverers/'delivery men'...'to your door'; and that means the cell is deprived for dysfunctional/less numbers of them.

But, this is just a small % in the equation..just like 'stem cell injection' was....or now that epigenetic reprogramming (partial) only gives 10-15% extension in mouse...yet supposedly the clock is back to someone half or more younger in age...

This, means, that there is a huge contribution to the 'rest' Ira Pastor had said, it's the 'microenvironment' the milieu...and, especially, the nucleus/DNA; no matter how much we try to circumvent this area, I'm nearly 100% sure the results will be underwhelming. Because, aging, is Literraly, in the DNA (not just that of course...a major one); and DNA repair studies have been lackluster or just fails...they tried to boost 'Helicase/Lyase' DNA repair enzymes...again, it only makes like 10-15% extension in mice....and 'deciphering' DNA/ extremely hard (it's like untangling an spaghetti mess/ball of billions of cords...); and it is why, DNA damage/fixing studies all lacking a lot. They don't what to do, when we know, that the DNA/Chromosome domain is a major reason of (regular) 'physical aging' as time pass.

If we cannot reverse the epigenetic clock (partially only....) repeatdely...and even loses its effect over time...and we cannot repair these other damages because it is Needed so....then, it is nearly certain we will live to 120-130...maybe 150. But, not that above that. As MLSP.

Stem cell injection, exososome delivery...but, possibly, 'nanorobots working on us daily to fix DNA damage'....they will not make huge gains in Maximal specie lifespan; they will improve Healthspan. and Average lifespan. So, instead of living to, 100-110 will be the
'new 80'.

120 wil STILL remain a very very very rare thing, despite these therapies.

Sometimes, I think, that if we cannot repair DNA damage, we cannot make epirejuvenation matter, we cannot make exosomome that useful (altogether), stem cell helping a bit, senolytics like in fruits we eat, than I guess we will be dying at 120 or less.

If we cannot do these things and it takes an eternity to get a therapy...yeah; and that link you provided the People commenting in UK are very negative all fatalists...they all are like :'' why bother...we die anyway, I want to die at's too long and boring'' heck, the comments and people that are --51-- years old say: ''I lived too long...I want to die.''..

That'S teh state of things in Europe. (And Nothern America ttoo). Fatalists -- planet wide. Humans have never realized that it Might be possible to live above 150, so it's unacceptable in theri minds; and, like to go 'against the 'grain' of 'living..dying' wrong. So, it's normal that people 'reject' long life...because it NEVER happened in human history.

This is why they are stubborn and insult scientists trying to resolve aging. (Look, there are charlatans and 'quick buck' snake oil seller/guys...yeah...we know; not everyone is with ill intention). They think they are joke and just the 'joke'...out there.

But, they don'T realize something that if aging is defeated - the Joke will be - On Them.
(they...the joke now). Because, they will ask (now) to live longer...funnily. Have a 'change of hearth'....and 'pleading/begging' that they were wrong...
I don't force people to 'wish to live'...or 'wish to die'...I just accept their - wish - period.

Many people will 'suddenly' decide to 'alltogether'...tehy don't wish to die 'after all....'...
many will spit on that and just wish to die anyway; but, some, will have a change of heart and realize it's not some fantasy/sci-fi thing anymore and They Can live longer.

If we cannot repair all these things then no will not live much beyong 150.

I think, sometimes, that if we cannot do these things....that we should SLOW aging...which is not enough..generally speaking.

We tried to slow aging...but it is always never enough...we need to REVERSE aging....but if WE CAN'T.

Then, SLOWING aging is a 2nd option.

Now, slowing aging...has been a 'catch up' game and it' never enough; like, in mice, slowing aging gave like 15-20%...30-40% extension of lifespan...namely Caloried Restriction.

But, in humans, it's less in effect...but it DOES slow the aging.

So...what we need to do, in that case; is to slow MUCH MORE; but, so dice.

Right now, we can slow aging...about 20-30% pretty much the big max.

But that is not much. We need to be albe to slow aging - by 100%; and even that, is not that much.

In my POV, we must be able to slow aging by 1000% -- 10 TIMES slower aging, and Then we get Real longevity.

This is what I found with C.elegans worm....c.elegans worms live 20 days....after the PIK-3 therapy, these c. elegans are 'amorph' and 'slow growth' (near metabolistically dead) and they live 250 days. Thus, nearly a year, vs the regular ones. 10 Times longer lifespan.

In humans, this effect is much less pronounced and PIPK3 kinase therapy can have dire effects on slowing metabolism/no metabolism; which is impossible in humans, because our tissues/organs need some metabolistic speed to function/replace their cells/tissues.

But, it demonstrated, that if we cannot reverse aging, Slowing Aging or HALTING/Freezing our aging is anotehr solution (sort of); well...reversing aging...may end up - only - halting aging...or slowing it.

But, it we can't reverse aging; slowing aging could possible be another (sort of) solution which right now is not.
But, if we Improve it and make a MUCH SLOWER aging speed, than yes, that is tantamout to extreme longevity.

FOLDS/Several Times slower aging speed..

Currently, Humans age (normal ones) at 50 bp/per year (bp base pair nucleotide in DNA)...while people that have HGPS progeria age at 500 bp/year; they live 10 times less than regular people;
so, it means, that INDEED, SPEED of aging is Absolutely a decider of how long you live.

These people live 10 TIMES less long; 15 years vs 120 years. That's an Immense gap.

So, then, we would have to make 10 Timse Longer Lifespan - for regular people who live up to 120.

so 1200 YEARS.

Now, I know you are thinking, how could we ever slow aging, by 10 TIMES...and live to 1000 years.

We could, but that it entails Fixing the DNA damage/chromosomal problems with age. that dictacth the SPEED of aging/attrition of telomeric DNA and chromosomal depletion/methylomic depletion.

IT was found that mouse lose epimethylome content on 50-100 times faster than humans; it's why they live 2 years. So, it becomes a 'keeping your stuff longer'. If we can'T go back to a 100% 20 years old body...then we have to PRESERVE what we have 'freeze it' at the age we have attained so far. If we can't 100% FReeze it/halt it....well SLOW it/its attrition each year...

I mean seeing that we can make a mouse back to a '20 year old body'..but this mouse lives only 10-20% longer...that means there is more to the equation than just partial reprogramming of epigenome/epigenetics.

People have become resolved that slowing aging is hopless and not worth'S a catch up game we lose at. So we have to 'reverse aging'.

But, I think, it's not Total hopeless loss..but Only if we are able to make a MUCH stronger 'slowing'. Several Folds more slowing.
So far, no dice, as said.

But' it's something else to consider if all the efforts fail in 20 yaers or so;...then we have to focus on Slowing Aging ORDERS of magnitude. And then, yes, we could live 1200 yaers, 12000 years; If I looked in a Great Basin Bristlecone Pine (lives 5000 years) or Turritopsos Nutricula (live semi-immortal trrough self-rejuvenation by stem cell/dematuring back to immature state/a jelly fish);these animals show Dramatic Slowing of aging; folds folds more slower aging than us. We age Muchhh faster than them. Yes, even a tree taht can live thousands of years as much slower aging than us. SO, it is 100% Assured that slowing aging will allow us to reach that 1000 years; but only we Do make it happen and slow aging Folds/X-many Times more.
IT was even demonstrated in P. Leucopus (white-foot mouse) and M. Musculus (regular mouse); P.Leucopus lives 8 years...while regular mouse lives 2-4 years...there was EXACTLY 2 times slower aging in that mouse that lives twice the age of the short-lived one. SO, it is crucial that we slow aging, if we cannot reverse it in the future. In fact, it May end up that reversing very Lackluster...and gives like 30-40% extension lifespan...thus, WAYyyy far from '10-times lifespan extension' -- 1000% extension. Slowing aging - can - give 1000% extension; or even At Worse..Double life span; it may be even Stronger than reverseing aging; but, only as said, if we are capable of slowing it More/many times more (and that means, repairing DNA damage/ chromosomes.. and the rest').

Just a 2 cents.

Posted by: CANanonymity at March 27th, 2023 3:47 PM

Another wellness clinic owner trying to drum up business, and for a treatment that "will likely be priced at hundreds of thousands of dollars per person." These kind of articles are just so damaging.

Posted by: Barbara T. at March 27th, 2023 8:21 PM
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