Senolytic Treatment Improves Neurogenesis in Aged Killifish
Killifish exhibit proficient regeneration, but lose regenerative capacity with advancing age. Some of this loss is due to the growing presence of lingering senescent cells, as the balance between the pace of creation of senescent cells and timely immune-mediated clearance of senescent cells is disrupted by the mechanisms of aging. Senolytic drugs that can force senescent cells into apoptosis represent a way to greatly reduce the impact of senescent cells on tissue function in later life. Researchers here show that the production of new neurons is inhibited by senescent cells in aged killifish, and is improved following senolytic treatment, leading to greater regeneration after brain injury.
The young African turquoise killifish has a high regenerative capacity, but loses it with advancing age, adopting several aspects of the limited form of mammalian regeneration. We deployed a proteomic strategy to identify pathways that underpin the loss of regenerative power caused by aging. Cellular senescence stood out as a potential brake on successful neurorepair.
We applied the senolytic cocktail Dasatinib and Quercetin (D + Q) to test clearance of chronic senescent cells from the aged killifish central nervous system (CNS) as well as rebooting the neurogenic output. Our results show that the entire aged killifish telencephalon holds a very high senescent cell burden, including the parenchyma and the neurogenic niches, which could be diminished by a short-term, late-onset D + Q treatment. Reactive proliferation of non-glial progenitors increased substantially and lead to restorative neurogenesis after traumatic brain injury.
Our results provide a cellular mechanism for age-related regeneration resilience and a proof-of-concept of a potential therapy to revive the neurogenic potential in an already aged or diseased CNS.
Hey there! Just a 2 cents. TL DR: Another one, this one about killifish, they have the name for it.
Killifish have the most (in)appropriate name, i.e. they fit their name, and their name fits them like a glove. Because, Kill -ifish...(of is that 'kill the fish') do exactly just that ---kill themselves.
Killifish are the Shortest living animal, basically, fish. Of all fishes, it's the shortest lived one.
So, yes, Kill...(self) is apt-put (name).
I think studies done on killifish are slightly bit of self-defeating (like a selfkilling killifish);
I'm not saying there is nothing to learn from them, whether they live 3 days or 3 months...
I'm just saying, it's not very 'inspiring' in confidence...if we use such 'short-lived' animal models...
as surrogate for humans.
Now, I know, the reason why, is to have a 'FAST-aging' 'animal model'...since we can'T wait for humans...or use primates...or dogs...or pigs...any animal that is close to a human (in terms of aging/length/lifespan).
We do study c.elegans nematodes, bacterias, mice and other animals that live barely 4 months...
So, Killifish are just as good (as aging model)....'and some; but yeah, don't expect -Too Much out of such animal model.
It's Very like mice, they can get big effect of intervening therapy, but (translated) to/in humans, it's more minimal/redundant in effect/potency (yet again), or no effect.
When a Killifish lives such short of life....you think to yourself...why would anything from it...be really gainful....and not be a waste of time/money...it's like studying c.elegans worms or house flies'...and thinking it will translate into Huge Gains..in humans. It probably won't.
There is Only 1 Study that I know that was The Biggest Gain...ever....and it has never been reproduced in humans; it was a c.elegans nematode worm that lived nearly a Full Year (250+ days)...instead of 'regular life' of 30 days/a month...that was an extension of lifespan by 10 TIMES....1000% longevity extension.
No study has reproduced this in any other animal...yet. In humans, that would be like living
a 1000 years.
The mechanistic pathways that led to these worms living so long vs regular ones...
is impossible or be deleterious in humans (in humans, the PIPK3 pathway that these long lived nematode use -- cause Marfan Syndrome in humans; so I mean we would have this syndrome if this therapy was done on humans); I mean, that it causes 'ultra-slowed growth'..and
just, basically, 'metabolistically dead'; it's like, suddenly your heart pumps 1 beat per 1 minute.
You would die...impossible. It's the same thing with Icelandic Quahog Clams that their heart beats once per one minute....they are metabolistically dead -- and they live 4 centuries and more.
Not only that, the worms were 'amorph' and 'slow moving'...it goes to show...humans move and do stuff....even become 'Athletes'...all this is great to keep the 'shape/fitness'...humans Need to keep fit...or else we get struck with disease (we just are 'made' to 'walk/stand up' and not be sedentary sitting on our Behind...in ancient past, humans were 'hunter-gatherers' that 'fetched/hunted' for food...there were no convenient 'grocery stores' 'around the corner'...you had to 'find the food/hunt for it...Go get it/hustle'...and that meant 'survival'...this caused humans' legs to lenghten for 'running/marathon/hunts/moving/nomadic life'...all this is because the body must preserve the 'fitness/shape' that we lose with age...but those Ultra-Long Lived worms...don't show that - at all - they are like a 'Paresseux' / A Lazy, this animal, is called, a 'Sloth'....well, its name fits it well...because it's 'slothy'...slowmo/lazy...amorph and does not move, does nothing and just (lazy)...)And that's the telling thing, it does not Need to Move, it does not need to do Anything...so long as it can breathe, eat and drink...that'S it. For hours on end...it does nothing but 'sit on its (sloth/lazy) *ss'. Athletes...don't do that...they 'move'...exercise.
Well, it seems that the ultra-long live fixed* worms, 500years old quahog clams and the Sloth are animals 'that get it'...they expend the LEAST possible energy and burn as little as is possible.
They Conserve theirselves, their energy, their resources. They SLOW the aging down to nothing.
Metabolistically dead.
Humans -> Fast Metabolism -> Fast Aging/death.
Certain animals have fast metabolism, and like humans, they are anomalies...they should be dying Earlier...but they live Very Long Lives..like humans -- FOR their 'Speed of Metabolism'.
Normally, humans are suppose to live only 30 years old...but because of their excellent repair mechanims - they circumvent their fast metabolism/fast aging problem...to make it less consequential and thus, they live long lifespans - Despite - they have fast metabolism.
But, for pretty much every other animal --- Being Athlete, Being Fast, Being 'Moving'....all this,
Bad. For Lifespan longevity...because you Expend/Expense(s)....and that is the Cost of the resources/energy...that you expend to 'move fast/live fast...' (''Living life in the fast lane.../
''Live Fast - Die Young''). ''Burning the Candle by Both Ends.'' is what is happening.
Then why do Athletes living long lifespans....because Fitness is important to maintain shape and muscularity/skeletal muscles - which are needed to 'move/walk/run...exercise'.
Frailty/sarcopenia/muscle loss/muscle wastage....alll happens at elderly age, and 'grip strength loss' is a good indicator of death/losing your hand grip strenght means you willl die; because experiencing frailty/sarcopenia. And muscles are also important for reducing insulin/diabetes/WBGD (Whole Body Glucose Disposal). So, you need (your/some) muscles...becuase they directly impact your capability to live; for, they participate in the blood glucose control - beyond just your pancreas. In these 'slow/amorph' animals...they may not have much muscles...but they 'keep them'...and as such they don't experience 'muscle sarcopenia'...
even if they are amorph; in humans, it's not possible, being sedentary and never doing exercise..is a recipe for sarcopenia/frailty/muscle loss with age.
This demonstrates -- taht humans were 'Born to Run', 'born to walk'...liek a baby...taking his/her first step and 'standiinng up' for the first time on his/her two legs; humans 'Grew UP' tall...instead of staying 'on all fours'...and it is why we 'became nomadic/hunters/runners/athletes', so that we could go 'get the food/hunt it'...and then we could 'travel' to 'new tribes' 'far away' and 'move aroud on the planet/travel -- by foot/walking/running...''. But the 'standing' of humans, is a telling sign, that humans, unlike primates/apes...did not 'hang in trees' anymore...they left trees...and went down..on the ground..to walk it...on all 4 limbs..and then' grew up(wards) into a
BIPED 'standing ape'.
Killifish don'T live long...but sloths do. Humans do too. We are the exception, because by sloth standard, we should be dead/gone, as we 'expend' too much energy...we 'burn' a lot of 'calories'.
Calories -> Metabolism (fast(er)) to burn them -- or else, we become obese/fat and can't burn'em as we don't 'expend them'...via exercise/moving...
Senolytics, are great, to a certain extent, but are redundant; we get some in food (already).
Strawberries, raspeberries, quercentin...you name it...it's there already, in the food.
Of course, not as 'potent' as senolutic therapy..but, still, it ends up same/same same.
Removing senescent (p16) cells...is a good thing and improves health (as said multiple times).
But, killifish...still (self) 'kill-ed....at the end of the study...this animal dies...whether senolytic or not. And it dies VERY FAST...in a couple days. no matter how much senolytic.
In humans, senolytics help to relieve teh senescent cells burden and thus alleviate SAF/SASP by senescent cells --reduce inflammation; a very good thing. But, I say, it's an EXTRA layer..that you get wtih age nto the Principal layer. Senolytics remove the 'extra stuff' we don't want with age; namely - Extra burden of 'diseases'...but ..what if you don't have that and are Healthy...
How much/How little will senolyics help - or not. The way I see it, they will help little, because redundance. Replicative Senescence -- will come anyway. And, it is Quite different than
'Spontaneous/cell cycle exit' Senescence; which, is mainly, what senolytics attack at.
And, is not, the same as replicative senescence.
Replicative Senescence = / = Spontaneous Senescence.
Not really the regular/time passing/'aging cells'...these don'T get much from senolyics.
This means, that senolytics will improve health and, just like in mice or killifish, they will make them healthy-er, but will not change anything much of longevity. Perhaps, we might make it to 130 with senolytics, i have some dout. Hey, it's better than nothing when nothing else works; except CR/exercise.
So, this is why I said, ii is important to slow aging...if senolytics are not enough; CR slows it;
exercise improves health rather than slow aging; it does slow slightly things but overall not really.
It was demonstrated in humans that did more vigorous exercise, and they gained about 500bp in telomeres...so yeah they got about 5 years lifespan extension doing good exercise..
while CR, this one, slows telomere shortening; and you could add another 5 years, together
CR + exericse = 10 years roughly...in DNA (slowing) aging.
Which is great...but, yes, lackluster/so far from lev or any longevity; it'S the 'healthy aging'
no gain but 'average lifespan gain' by improving health.
But, like if you look at Athletes...they live long lifespans...only those that don't Overdo it--
burn the candle by both ends; they are fit and well...intol their old age.
Centenarians... could 'ride a bike'...at 105....when many people can'T even stand on their two legs when they reach 90...(they need a cane to walk).
But, exercise, is a 2-faced game/is 2-faced. We need it to remain healthy/fit...but exercise only 'slows a bit' the aging and improves health...
And, the reason why, is because of Oxygen; we need Oxygen to Breathe...but O2/Oxygen is a killer/2-faced.
You need oxygen for your cells/energy ATP and your organs...to live; you breathe.
But O2 = ROS (Reactive Oxygen* Species); RUSTING; we rust each day, as we breathe...
and Breating HEavily..is what you do when you exercise...
Quahod clams 'bury themselves' in 'hermetism' and No oxygen...they live centuries...
they live in Anoxia (no oxygen).
Oxygen - on top of rusting you - ADVANCES the epigenetic clock; literally; just 'exposing' yourself to O2...makes the clock 'tick' forward. O2 is negative epigenetic clock element.
It'S 'Role' is to give you 'Energy' to live...but the Cost of that is Oxidation/Rusting (ROS) and 'advancing' of the aging (epi)Clock. Also, O2 contributes to the 'maturing' of cells; differentiating and thus the 'Advacement' of the 'progression' of the epigenetic script/roll/program.
Literally, it 'MATURES' you...maturing cells...are cells that approach death.
O2 is INVERSE OF JUVENILE; re-JUVENATION; juvenation = juvenile = child/reverse aging.
So...this is why exercise, breathing -- is 2 faced. Because O2 is (O)2faced. You need Oxygen to Live...but Oxygen 'kills you - little by little'...as you age. - By It.
2 faced (game).
I'm not saying we have to 'stop breathing'...I'm saying, it is a demonstration that it's not because you like to 'Take Long Breaths'...taht you will live centuries..it's the very Contrary...you breathing ASSURES your demise...in the long run..it only 'makes you live' --for a certain while; and then you die. As the Oxygen...rusts/damages you..and makes your clock 'Run Down' until its countdown - sounds the Alarm (that's the end). We are 'code/program' (Genecode/epigenome) and Oxygen makes our epigenome 'follow its course' 'in due course'...it follows and 'fulfills itself' like a 'prophecy' (self-fulfilling prophecy); -- in our code/epigenetic code; it'S written - 'we age' and 'we break down, and we stop repairing ourselves' and that's ALL thank to oxygen we breathe daily...as we rust. Like the AdG 'car rusting/damage/repair the car' analogy. O2 makes us scrap yard used cars...over time. Because our DNA repair systems falter and are Stopped from continuning to repair.
Oxygen is great to destroy cancer (hyperbaric O2 chamber); you get a huge Energy boost and it produces massive ROS that destroys the cancer....via p16/p53 tumor suppressors genes...
Hyperbaric oxygen is used as cancer therapy...cancer cells can't survive ROS BLAST/O2/peroxide blast from O2 surge.
But don't think this is a therapy that will slow aging; it will energy surge...in the short run.
In the long run, if you repeat that, you accelerate the aging/rusting - by O2, by ROS, by maturing', by your 'program/script' 'continuing' merry allong...
We are a 'Script'/Roll...that unrolls/unfurls...with time and 'plays itself' like (a prophecy);
and then one day, we die - whe nwe reach the 'end of the (script/code) roll';
A Papyrus...you read it...it is written down (alraedy) in your dna/epigenome...and you live it..as it 'reads itself'...and 'accomplishes itself' -- that's the dna gene cone/script....'playing itself'; until the end. Like scroll-ing down to the botoom of a web page...you reached the bottom - of the scroll. That's th end.
We would like --- to Extend 'the roll/papyrus script roll/scroll...' to last longer
And, the only way, is slowing aging (or as said, reversing the aging, repairing the damage).
And this will ALLOW US TO GO BACK in the SCROLL/SCRIPT/CODE/PAPYRUS...
same thing (analogously) to a film...you want to Go Back to the Start of the Film; you press Rewind on the remote;;and you go back to the start of the film; then, you do this Infinitely/Repeat button = LEV/Eternal life. We woudl never 'Age to the End'...there would never be an 'END/FIN.' to our film/movie...it would Only be the Start - the Middle...and no end/ever. We would always go back to the start (that's like going back to a 20 year old body...when you are 66 years old).
Then, it's 'rinse repeat' and we obtain forever life. It'S not some impossibilty anymore.
Anyways, to conclude this long ramble//shouting at clouds, in the void..., I think we need
re-prioritize, senolytics are great, I get em when I eat berries or what not...need more.
Killifish does not inspire confidence ---kill, self--ish..(don't expect them living long, with such name, or expect, much extension when translated to humans neither).
Thanks for reading,
Just a 2 cents.
As I've read more about it recently, it seems to me at least that senolytic therapy will rely on gene therapy advances. Sure dasatinib + quercetin can get rid of some of the senescent cells in an aging body, but to remove specific senescent cells in specific tissues will probably require more than inhibiting a few cellular pathways, and instead will require targeting of cell types or sub types for destruction.
Thanks for your 20 cents CAN. A lot of good points. While any life extension in Killifish is certainly meaningless to humans, I do find the results showing reduced SC burden after Senolytic treatment to be instructive.
Hi John! Thank you for that. 2c. Absolutely, there is lots of good to reducing the senescent cell burden, is a great thing. I just hope that researchers see that it's only the tip of the iceberg (there's 'everything' (else) below/under water; and that big chunk under, is that dna/damage/repair).
It's like temporary band-aids plasters or filler in a flat tire...it will allow you to run for a while; as you 'hold' the bleeding (band-aid), and you 'cover' the hole (flat); but, you do not stop the bleeding nor will your tire work forever; this is a 'patching' of the tire; the tire will let go at some point/another flat.
bleeding = cause (band-aid = temporary solution/'Bandaid solution', slows/holds the bleeding); losing air = cause (band-aid solutino of patching it with a patch/patch-job; fixes the flat...for now).
Going at the cause, is stopping the bleeding/hemorhaginh and changing the tire for a new one, no flat/patching. 'Band-aid/Patch-up' (half-solution) = Catch-Up game; we always lose at that. IT's why we must go at the source/cause of aging if we ever wish to not just be FightAging.org.
But, DefeatAging.org, or better, AgingDefeated.org ... (this site would be the most popular in entire human history/and internet history; I can't wait for it).