Fight Aging!

How will breaking glucosepane cross links extend life in animal models, given that mice and rats don't really seem to accumulate much of them before they die?

@Jim: That is exactly correct, and will be an interesting challenge. Production of models is a much more important part of the work here, and ideally they would probably bypass animal studies for anything other than safety. The thing to build would be a cross-linked vascular organoid, as the only other option would seem to be tissue samples from donors.

He looks truly haggard

If you don't mind for a moment that this could be seen as advertisement, here's a presentation how chemistry giant BASF tested their crosslink breaker (which is basically just niacin) on human skin tissue samples in vitro. Glucosepane crosslinked samples could be a bit harder to create than a-diketone ones, but apparently skin tissue sample are not that hard to get.

http://www.in-cosmetics.com/RXUK/RXUK_InCosmetics/2015-Website/Documents/in-cos15,%20IS,%20T2,D2,%20Collrepair%E2%84%A2%20DG%20The%20revolutionary%20active%20that%20reverses%20the%20glycation,Florence%20Trombini.pdf?v=635653965399198808

@Bill Demarco: If the technology existed to stop people from getting and looking old, then there would no need for people like de Grey to be out there trying to obtain the support needed to build the technology to stop people from getting and looking old.

It is just plain strange that people seem to think that someone involved in the development of a new technology should be somehow benefiting from it in advance of its existence. It is the worst of magical thinking.

Maybe monkeys have enough levels of glucosepane.

@Antonio - monkeys live a long time, so even if you begin with already aged monkeys, I'd guess that the experiments will take even more time than mice/rats and will cost more.

I think Glucosepane really is just a physical phenomenon. The longer an animal is alive with a certain level of blood sugar, the more cross links it has. Other types of damage such as cancer or senescent cells are influenced by biology. Mice have crap repair mechanisms compared to humans because evolution doesn't care what happens to mice after their reproductive age.

Maybe if there were strong hints of a cosmetic effect of glucosepane removal on skin samples, there might be a rush like that seen in senescent cells? Although to affect skin you'd probably need to remove multiple types of damage. Maybe glucosepane removal in combination with senescent cell remove would be enough to have a visible effect?

@Jim, it doesn't matter how long monkeys live because rejuvenation therapy remove damage very quickly. It takes many years for glucosepane to accumulate -- hovewer, it may take a few days for enzymes to remove them.

@Ariel - yes you are correct, but it will still take a long time for a lifespan effect to show up in a cohort of monkeys vs controls. And Reason's conjecture was that "as soon as the first studies are in hand to show significant results on animal aging, exactly the same will occur there as did for senescent cell clearance". Hopefully showing an actual lifespan effect is not necessary to get the field of glucosepane removal moving under its own steam.

@Jim: Lifespan is not the endpoint to aim at here; in many ways that will attract less interest than showing reversal of vascular stiffening, with consequent reduction in hypertension. The challenge is to produce a model that does that in a way that isn't up for debate. It would hinge on how artificial the model is. It might be better to move fairly rapidly to human pilot trials after safety is demonstrated in mice, but I think that groups will pretty much have to build some kind of tissue testing system along the way towards a viable candidate treatment.

Yeah, I agree with Ariel, you don't need to show life extension in monkeys, only glucosepane cleavage and the associated softening of blood vessel walls or skin.

And doing it in a living monkey instead of a skin sample is much more convincing and not prohibitively expensive.

Maybe even dogs could suffice.

Glucosepane is show to increase with age in mole-rats, and they are a readily available species for study, but I suspect that their negligible senescence will make them less helpful. Removing glucosepane in a 10 year old mole-rat may well do nothing easily detectable.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348492/

A quick search didn't turn up anything on primates and glucosepane, but I'd imagine that any but the longer-lived species are disqualified for the same reason as other short-lived mammals.

@Jim, the aim of individual therapy is not to increase lifespan and even not to increase healthspan but just remove the damage. SENS is a divide and conquer approach. That is the reason why I do not like lifespan experiments in SENS therapies. They do not supposed to extend lifespan alone. And in the case they do -- we are very lucky! But in general we shoud not expect life extension -- for that researchers need to combine all of them. When people say 'Your senescent cell clearance extends mice average lifespane by only 30%' -- they are just wrong! That is a whole 30% of only one therapy!

It'd be nice if gerontology moves away from lifespan studies but that's just wishful thinking

Hey there ! I think that glucosepane, crosslinks and other ECM AGEs clearance would have a sizeable effect health Wise; just like senescent cell clearance (p16 senescence cell removal), it would improve inflammation markers and improve collagen/ECM markers too. It is akin to what happens with metformin or other CR mimetics in diabetes. They reduce AGEs accumulation (pentosidine, CML (carboxymethylysine), furosine, Amadori products, methylglyoxals, HbA1c glycated hemoglobin, the whole Spectrum of diabetes features...), and also slow down glucosepane/crosslinks formation. As some have said, glucosepane is more of a problem in short-lived animals than long-lived animals because of lack of repair in them; they succomb to them unlike in long-lived animals whom simply accumulate them over a very long life (thus demonstrating they are more inconsequential than in short-lived ones, or rather just as consequential but rendered Inconsequential by repair mechanisms/ECM turnover (formation vs degradation)/MMPs degrading enzymes). Do you see metformin, CR mimetics or CR being that strong in Long-lived animals (not in short-lived ones whom benefit far more); studies in apes, monkeys or rhesys macaques show that these reducers of diabetes markers don't stop 'aging'; they simply improve health and allow you a longer lifespan (where you could live much longer, healthier because it slows the disease (which itself is accelerated aging as it drives spontaneous senescence; glycation/glycoxidation/IGF activation/insulin/groeth hormone production by glucose exposure accerelates this whole thing (seen in HbA1c))).
I wager, in humans, glucosepan breaking will be visible as somewhat skin rejuvenation equalling roughly the effect of senescent cell clearance or CR - which both rejuvenate the skin somewhat (as said, CR can make someone lose about 10 years of 'age' in the face/skin..it's subtle but's it's there/visible. In fact, your body is continuously 'changing' in a single day. I've noticed this after/before a large 'sugary' meal full of glucose. Glucose can alter your skin dynamics in a 2 hour window, and your skin shows it with before/after photos of your own face (the subsurface scattering reduces immediately after glucose load, and then comes back Later on as your boday disposes of the glucose. This means there ROS production after glucose load and this activâtes insulin/IGF cascade which, by ROS, activate nucleus translocation of ARE/NRF2 to responsd in a 'hormesis' way (NRF2 behind this). This is why ROS (by glycoxdation) are important - in small doses - as they 'signal' the ARE/NRF2 response)). While the Epigenetic age will be slowed down (since diabates shows accelerated epigenetic aging) but won't simply 'revert back' because you remoevd glucosepane....unless there is telomere changes - then all bets are off sincee the epigenetic clock and the telomeres are in constant talk (dependent and independent at the same time). Thus glucosepane breaking will be a cosmetic effect, mainly, subtle mostly or almost not visible - but it will increase the health of that person to be back to homeostasis - for their age (we might see more people 'looking somewhat 'younger' by this just like you see with skin cosmetic products for women (some not doing anything some doing Something somewhat)... Which means, they could live longer, healthier and thus reach, over 90-100 years old; possibly if they are genetically gifted with the right SNPs/genes.

Just a 2 cent.

@Ariel: If "only one therapy" extended life in humans by "only 30%" it would be revolutionary. It's probably way too optimistic to believe that it will, but then the results in mice surprised everyone including deGrey, who had this to say in his latest AMA:

"[When we will se the first evidence of rejuvenation] mostly depends on the extent to which humans reproduce what has been seen in rodents, where the benefits of removing sen cells were a lot broader than I or anyone, I think, would have anticipated".

This community seems to have a quasi-religious fear to question his doctrine - in this case that all seven categories of damage need to be removed to generate sizeable life extension - even though SENS was formulated over 15 years ago, when nobody knew that removing senescent cells would impact areas targeted by other SENS therapies (e.g. OncoSENS) by way of reducing the incidence of diseases previously not associated to cellular senescence.

The fact that 15 years later SENS has been proved to be largely correct does not mean that every single hypothesis that was ever formulated around it will be so too.

We have to become more urgent in developing and applying the aging solutions than what has happened in the last 15-20 years since de Grey formulated them. If we do not, guys like de Grey will be gone from the scene in a short 30 years without rejuvenation. Perhaps Liz Parish is a shining example of taking the Bull by the horns and more fully dealing with the aging situation. It is not time to sit back and speculate as what to do about aging but act with every fiber and brain cell in your body to take action and do something about it day by day, hour by hour.

PS: Just a 2 cent.

Sometimes I think that the effects of the combination of the 7 therapies will actually turn out of be Quite More similar to CR than anything else - and I'm not talking about just 1 therapy but all of them (which I know is not great but still....).

The reason I'm saying this is CR is so multi-faceted and might be weaker in effect that the combination of all therapies but there is Something:

OncoSENS : WILT/removal telomerase in cancer cells vs CR. CR does not do that but it does one thing, it reduces inflammation which is the largest cause of cancer formation by immunity loss; oxidative stress is behind this and CR reduces oxidative stress which means selective reduction of p53/p21/p16, which themselves are needed to counter cancer cells; along with TNF-a; which is double-edged sword (just like p16/p53), it destroys cancer cells with the cost of killing the other surrounding healthy cells; this is 'inflammation response'. CR is capable of selectively altering p53 to destroy tumor in tandem with immune system - or inhibit it and it works mostly that way. Since, p53/TNF/IL-6 are Inflammatory (mostly, albeit sometimes p53 is actually anti-inflammatory in certain instances) and CR is mostly anti-inflammatory (it increases IL-10 over the long term because it is an hormetic response, CR increases ROS production by the reduced nutrient intake (it is step fashion where CR will reduce EXcess ROS but will not stop ROS and will increase ROS gradually to be able to gain back the hormetic response/this will manifest at the mitochondrial membrane potential mV), this in turn signals NRF2/ARE and activâtes the proteasome to 'dispose' of the garbage/aggregated Junk proteins, oxidized DNA and faulty mitos. CR does all of this. This has strong impact on the cancer cells because now the immune system can Work for the oxidative stress is reduced; and once the immune system is 'back online' well those cancer cells can count their days..or minutes; because now the NK/T-cell/macrophages will be seeking/phaging them anytime soon and better (in concert with p53 that should be reduced because p53 is a last ditch response to kill cancers...it kills you at the same time because of excessive ROS production by p53/p53 creatse DDR at telomeres and can create cell cycle arrest (thus it is 'oxidative stress by cancer inflammation signal to counter these cancer cells by producing More ROS than the Inflammatory level that cancer cells produce in order to - exterminate them' (fight fire with fire). In other words, it's a concerted effort of ROS and phaging to destroy the cancer cells - but all of this is not without cost on you).
CR is thus helping just as much in terms what OncoSENS would do, of course not as good because telomerase WILT would stop the cancer dead in their tracks; but it would be ressembling.

LysoSENS : removal of lysosome crap vs CR. CR is actually not too bad on that.. it does not remove anything but it slows the accumulation of lipofuscin (that has been shown already in c.elegans cells that are CR'ed/like long-lived DAF2/DAF-16 dauer larv e stage types).
In my book, lipofuscin is causal or least Very important to our maximal lifespan specie; and contributes to Proteasome/lysosome blockage (and proteasome/lysosome blockage studies showed that wen lipofuscin is put in these areas..it creates accelerated aging that is equal to the amount of lipofuscin put in/how quick and how much, because the cell Junk disposal mechanism is gone). Thus of course LysoSENS is a lot better than CR because you are removing to the contributor to aging (lipofuscin pigment) since it cloggs the proteasome/makes it become faulty with age as 'fills it like a dump'. Removing it will have VERY sizeable effect, it's impossible to be with little effect because it drives aging by making a dysfunction proteasome.
With that said it may not be that visible - but Inside, the effect will be tremedous, you cuold gain great longevity gains with this - for you would keep a proteasome clean Far longer.
And the proteasome is Causal to lifespan/maximal lifespan too (I use to think it was only a backgrouf element, it turns out it is a KEY element because it degrades so much Junk and some of this Junk; is the protein aggregates (and studies demonstrated that they are very consequential to the failure of the protaesome (since they fill it) and to the instability (you proteins must be kept intact/undamaged/refolded not be unfolded, for they control so many things). CR works with the proteasome, in fact, the major reason that CR works is because it activâtes the proteasome. It might not stop lipofuscin but it does slow it and also slows protein aggreates - most all types of damages it slows them. This means CR is somewhat comparable to LysoSENS but nowhere as powerful of course, because it works on tsame pathway.

MitoSENS : allotopic 13 proteins expression vs CR. CR affects mitopathy a little bit but not that much. STill, it does alter mitochondrias towards a less harmfull and less oxidative stress in them. It increases ATP (over the long term) or rather reduces ROS at the membrane over the long term (not in the short term where it increases ROS for hormesis/proteasome activation). It does that at Complex I and III, and also IV; thus more electron flow backflow less electron loss means healthier mitos. It also influences the mitophagy process (since it activates proteasome/autophagy) and also alters to mitofusion/mitofission dynamics.It may increases mitofusion where bad mitos are salvaged through fusing together in a large mass (just at it happens in centenarians' mitos).

ApoptoSENS : ablation of senescent cells vs CR. CR reduces senescent cell accumulation and helps Strongly in the removal of them by allowing the body more Tools to dispose of them.
In fact, I would think that this therapy could underwhelm and be less powerful than CR or immune syustm boost by CR; normally speaking if we remove p16 senescent cells we see 20% lifespan extension/healthspan improvement in mice (in humans it would 5-10%). CR does that, very easily, but only if done over the Long Term. not the short term 2 months CR. I'm talking CR for a life time.

GlycoSENS : CR wins that one, glucosepane removal wins, but on the diabetes part as a whole; CR has dramatic effect on diabetes - not always best though. CR is very precise and most done dilligently for you may increase or reduce a disease progression/depending on health state. My father was told to not do overt CR when having diabetes; it's Dangerous when you play yo-yo with your glucose levels (hyperglycemia/hypoglycemia; insulin/IGF activation or deactivaiton).
GlycoSENS would equal the CR or senescence cell removal; not much more though, it would remain cosmetic effect mostly.

RepleniSENS : new stem cells/replenishment. Very long-lived Dwarf mice (AMES/Snell) have shown that they live this long because they have more v-Cells (very small like stem cells), that rejuvenate their body/repair better than regular house mice. CR by reducing oxidative stress ameliorates bone marrow output of stem cells and different niches in the body. By reducing oxidative stress the stem cells lose their telomeres slower on CR and can remain quiescent; only activated when an injury or Something; they won'T divide/differentiate madly in a very speedy turnover and their doom because they are self-exhausting as the balance is tipped towards differentiation rather then quiescence, would only self-divide/regenerate once a blue moon as such remain quiescent niche and non-dividing. Again, replenishing stem cells will greatly improve health over the long term - and tecnically could allow extreme lifespan - only if we can have All Types Cells (from stem cell differentiation) and Replace All tYpes of Organs in the body (A to Z). As is it CR is not doing the same at all, but it is improving your stem cell markers, substantially. RepleniSENS wins this one of course.

AmyloSENS : CR, again, slows amyloid accumulation ebcause amyloids, taus and others are aggregates/aggregates proteins that accumulate Because of oxidative stress (alzheimer's is called diabetes type III), and CR helps you keep a sharper mind, longer, less 'clumping' of proteins in the brain by CR. CR is no magic bullet - my uncle died of Alzheimer's and he practically did CR for all life - and still died (Young, 74 years old). If CR can't even keep you from dying from disease it means that the disease are truly 'too powerful' and overtaking; and you must be VERY careful with what you do/eat/exercice/etc...or else, they will win over your body. IT is a a struggle. Oxidatiev stress is the largest/most major cause of why we age because oxidation problem (oxygen/rusting/oxidation ROS..which damage DNA...mitos, etc. If you stop breathing you die, you need ATP in mitos from O2. But not only that, it is a every-second 'phenomenon' that O2 rusts you from Inside by the ROS at complex I in mito membranes).
Studies of CR in patients with dementia or other dengerescence of the brain, did show slight improvements (only if Before/at very start of the diseaes..not later/late stages); and helped to 'ease' the pain as long as it was not Overt CR/Starvation which created frailty andcan kill you even faster (for you need some 'weight on you/adipocytes improve insulin/IGF/glucose disposal and when PGC-1a/UCPs are activated it helps to burn white/Brown adipose tissue by thermogenesis (UCPs increase HSF-1/HSPs'). CR already does that and can alter body temperature towards slow temperature/slowed metabolism (in general it does that) or rather, increase body temperature/increase metabolism to improve thermogenesis/fat burning. CR is not good like amyloSENS therapy but it does slow amyloid accumulation thus is quite substantial.

All in all this demonstrates that the effect of SENS combination, we could see is very Akin to what we get when do long-term CR. Rejuvenation is far more powerful that's sure, but the effects may more subtle than we thought -and quite likely, similar 'externally' at least, in erms of what CR does. Because CR ACTS ON ALL of these therapies pathways TOO. Mechanism redundance. All this is conjecture and

Just 2 cent.

In my opinion, we can test glucosepane breakers in a more pirated way - right on humans. There are enough biohakers and self-experimentators who wants to test powerful drugs on themselve.

Forget the FDA and other progress decelerators. We meed a more agile, a more flexible, a more pirated paradigm. For example - sell anti aging drugs on silk road like sites in the darknet.

@FDA hater
I think at the current state of affairs your idea will slow down further development quite a lot. Do some toxicity studies on cell cultures and if they die throw them into the bin. This is as quick as it gets.
Doing the same right on humans (lets say on small patches of the skin) just slows things down even in the best case, because that needs a lot of paperwork. Doing it without the paperwork might get the scientists into jail which doesn't help to speed things up either.

@CANanonymity you always are so negative

Hi Scott !

Thank your response. I agree with you, I'm not always positive, much more negative (but when you nearly died of a disease as I did (And can Still die of it), you get quite irritate quickly because time is life). The Truth is, it is not always rosy when we talk about aging; it's only normal to be more Realistic than Fanciful and Outlandish/Fantasy believing; I think charlatanism is worse; as such we are better to tell it like it is. Being optimistic is important, but not deluded and many are. That is why we have faith in it but be real too; it's a balance. I agree I might be on the negative quite often but don't let that make you think I don't belive in SENS (even if by the sounds of it it sounds like it) I really believe in it but like all, I have my doubts and will share no problem even if it may make me look more negative. Gerontologists, in general, are positive (they are Open to Something that would Indeed solve/slow aging), but they are very critical and negative to remain 'realistic' about it since they studied the mechanism; they ahve every right to suspect and critique Something that says : 'I will solve aging....here it is....'. It's only normal for them to talk about it and it may Sound negative; but that'S becaue they understand the mechanisms and can extrapolate (a little bit at least); that does not mean they are 100% true (I know myself, I am not...I ahve been wrong oftenly, and mind changes often since aging is so complex and one minute they say this; next minute they say that..so who do you believe anymore). You have to make your own judgment and it may not please everyone. Sorry if I sound 'deep' and negative; but it's not too complain it's too show it like it is (or like I think it is). I will try to be more positive but lately, I'll beh onest, I've lost a little bit of hope because it's like it'S a never ending battle; you're bound to get tired a little (we must no abandon); it truly is one-baby step at a time but in ultra-slow-mode, thus it discourages. We don't have enough funds, FDA bodies don't want anything, people don'T want anything either (they love death/fatalistic), you see what I mean...it's demoralizing all this; and th thérapies may not be so Wonderous as everyone would like it to be. Does that mean they are bad, no..just we need a dose/shot of realism to be put back 'on earth' Down to Eearth'. It May be harder that we thought. that's what I'm saying. Again I apologize if i sound very negative. Thank you for your input/opinion/saying.

@CANanonymity - if the senolytic drug trial results this year are underwhelming, than I will lose hope too, but until then I have a lot of hope...

@alt-transhumanism
Hope for what?
Senescent cell removal is not a true damage removal technique as I've tried to point out before. It takes some signaling burden away from your stem cell niches. That's about all it does.
So the older you are the less effective it will be - Why? Well because you still have your old ran down stem cells making up an exhausted pool. You've not solved the real damage part of the equation.

So when Unity gives senolytics to arthritic 80 year old ladies this year - don't except them to start dancing rumba and doing back flip splits on the dance floor.
I'm not sure what to expect in fibrotic tissue but I don't expect people who had lung fibrosis to become Olympic swimmers. Even if they were young.

It'd be nice if people could set their expectations to a rational level.

@CANanonimity I understand exactly what you mean but please don't lose hope. I don't think full Sens will be anything like CR. Remember that CR is an evolutionary "program" that has evolutionary limits in what it can achieve. It Might for example make a huge difference if a waste product is removed entirely like Sens or accumulates slowly like in CR because even that slow accumulation will eventually cross the tolerance threshold of the cell. I agree that Sens simplifies the aging process but it may still be the best approach. We must see, let's hope for the best. Kind regards, K.

Also note that SENS is beyond what we can do naturally - while CR is just enhancing what we can already do naturally.

@Anonymoose then do you actually have any idea what might happen if the senescent cells removed from body, will patient will feel anything cellular level,/look wise

@anonymoose I didn't say I expected 80 year olds to turn into Olympic swimmers, I just said I had some hope. I'm not an expert at all, but the author of this blog has written that senolytics 'will turn the clock back' in some sense, even if just a little. That's all I am hoping for.

@K.

Hi K. ! Thank you greatly for these words and do agree to keep hope, and I wish you the best too, (and happy new year too in good health).

: )

@salman it's preventative maintenance.
Senescent cells are to tissues what salt water is to iron - in the context of aging.
You can't remove the rust that has been created already if you remove the salt water, but at least you can prevent further rusting.
To refine the analogy further, you're not even removing the water as such, the iron - your tissues - are producing water at a constant rate, you're just removing the salt to slow down the reaction.

As far as feeling, in the cases where senescent cells are driving inflammation, there might be less pain. Maybe even significantly less pain. But there are always caveats, if for instance arthritis has progressed to the point where significant bone deformation has occurred, I expect there will still be quite a sizable amount of discomfort and loss of function.

I've not read anything that makes me believe loss of tissue integrity can be reversed by simply removing senescent cells. But even just halting serious conditions of old age and disease like fibrosis and arthritis is quite better than expected.

Thanks for your valuable answer, I have another query which I never find answer yet senescent/mito/lipofusin,amyloid are internals things
I know aging is the result of many processes running at a time but what specifically turn a yound guy into a old guy for instance what makes arnold look 70 years old vs arnold in his prime further explanation is, what process make my father vs me as he is 60 and I am 25 , is it only glycation, you just remove glycation and my father will look 21. Is it like this?

@CANanonimity. Thank you and likewise. :)

@CANanonimity - forget about CR, from the ape experiments it obviously doesn't do much for them, and probably does even less in humans. The only thing it does is stop you dying early from eating too much; and only if you do it carefully and don't give yourself malnutrition. If you're overweight then use CR or intermittent fasting or rapamycin/metformin - but you're not going to push out max lifespan that way.

Whatever humans die of at the extremes of lifespan, it's not metabolic. More likely to be telomere exhaustion and/or stem cell epigenetic drift. I tend to agree with Anonymoose - removal of senescent cells alone is only likely to have large rejuvenation effects if the permanently elevated inflammation is locking stem cells that otherwise could proliferate. We'll find out soon if this is the case.

I think the larger point of this article is that the Globalist Masters of the Universe (in this case TPTB at Google/Alphabet) have realized they have lost control of the SENS meme, that despite there efforts to limit availability to the masses, it IS going to happen and they are resigned to that now.

We should look for more transparency at Calico and perhaps a shake-up in management as further signs of this. 2018, or maybe 2019 will likely see the mass popularization of SENS among the hipsters and chattering class, followed quickly by their followers. This is step number one to overturning the "Why would you want to live forever? I wouldn't." nihilistic and resigned attitude of still a majority. Expect multiple "Do you want to live forever?" articles in MSM by year's end. Then the research money really starts flowing. Watch Alexa on this site! I expect it to break into the top 1000. https://www.alexa.com/siteinfo/fightaging.org

Huh? Aubrey has been giving these talks at Google much before Calico's creation (there are several of them in Youtube), and Google's founders know about SENS since at least ten years ago.

The public has basically zero imagination. So people would say stupid things like why would I want to live longer anyway. So you have to run ads showing them people like them who are their same age taking your medicine, and now doing things like going on a cruise and appearing to have a great time in the ad. Then the public will be like, 'hey I could be that person having fun on the cruise.. maybe I will ask my doctor about this new drug'.

Basically you aren't telling them how it works or whether it is a good or bad thing philosophically, just showing the benefits of using your product.

@Mark @Anonymoose

Hi Mark ! Hi Anonymoose ! (long message)

What to make of this (on the point of stem cell division/differentiation exhaustion being the element causal (?)/behind why SASP-senescent cell removal would dependent on it (to have a visible effect on aging) in the first place) ?

''Chronic SASP and loss of tissue homeostasis: the "stem-lock" zone
From a non-cell autonomous perspective, if the loss of differentiation features following reprogramming is not accompanied by re-acquisition of the original or alternative differentiated cell fate, the resulting tissue plasticity might impair the repair or replacement of damaged cells. The ability of SASP-associated pro-inflammatory cytokines to regulate stemness and nuclear reprogramming raises the notion that a SASP-impaired local environment could interfere with tissue rejuvenation by imposing the so-called "stem-lock" state (de Keizer, 2017). Chronic inflammatory conditions via exposure to IL-1, which normally functions as a key "emergency" signal and a master regulator of SASP by inducing downstream effectors such as IL-6, has been shown to impair tissue homeostasis and to induce an aged appearance of the hematopoietic system by restricting stem cell differentiation (Pietras et al., 2016). Moreover, biological conditions linked to chronic senescence, such as tissue injury or aging, favor in vivo OSKM-driven reprogramming via enhanced production of IL-6 as shown by the appearance of Nanog-positive cells in the vicinity of senescence areas (Mosteiro et al., 2016).

While counterintuitive, the ability of SASP factors including IL-6 to transiently create a permissive environment for in vivo reprogramming capable of inducing cellular plasticity and tissue regeneration (Ritschka et al., 2017), a prolonged promotion of such progenerative response might reduce tissue rejuvenation and promote aging by self-enhancing futile cycles of SASP/IL-6-driven reparative cellular reprogramming. Compared with young tissues containing few senescent cells where transient SAIS might cause temporary reprogramming and differentiation/proliferation to replenish cells, the prolonged accumulation of senescent cells in tissues that are old or under high levels of stress (e.g., following medical procedures such as chemotherapy) might be accompanied by a defective clearance of damaged, senescent cells, which can promote further SASP accumulation. A situation of chronic SASP secretion might not only counter the continued regenerative stimuli by promoting cell-intrinsic senescence arrest in single damaged cells but also paradoxically impose a permanent, locked gain of stem cell-like cellular states with blocked differentiation capabilities in surrounding cells (Figure ​(Figure2).2). Such a scenario of prolonged survival of senescent cells and enhanced phenotypic plasticity of neighboring cells would drive a loss of tissue homeostasis by impeding the reparative replenishment of damaged cells. As mentioned earlier, core SASP factors such as IL-6 can mimic the effects of in vivo reprogramming (Mosteiro et al., 2016), thereby favoring the emergence of CSC-like cellular states in neighboring cancer cells (Cahu et al., 2012; Chang et al., 2015). Thus, chronic SASP-driven loss of tissue homeostasis might go hand-in-hand with an accelerated generation of trade-off forms of undifferentiated types of cells with CSC-like states. Accordingly, the protracted presence of senescent cells that can promote local and systemic SASP in stressed normal tissue has recently been shown to cause and exacerbate short- and long-term effects of genotoxic stresses ranging from weakness and fatigue in skeletal muscle to CSC-related cancer recurrence (Demaria et al., 2017).''

''Here we uncover timely new functions of the SASP in promoting a proregenerative response through the induction of cell plasticity and stemness.''

''The effects of Wnt signaling, however, have been shown to be highly tissue-specific and Wnt-specific. In the case of hair follicle stem cells in the skin, signaling through Wnt1 activated stem cell hyperproliferation via an mTOR-dependent mechanism, but long-term this activation of mTOR led to stem cell exhaustion and senescence [147]. This finding led the authors to conclude that while Wnt signaling can be a potent stimulus for stem cell proliferation, prolonged mTOR activation may serve as a protective mechanism to prevent tumor formation. The cost of this, of course, is exhaustion and depletion of that stem cell pool, ultimately resulting in impaired regeneration and aging of the tissue. In patients with acute myeloid leukemia, aberrant Wnt/β-catenin signaling, which controls self-renewal in the HSC pool, was higher in patients with unfavorable karyotypes and predicted a shortened survival [157].
In HGPS the tissue-specific patterns of accelerated aging point to a defect in MSC function. The defect in this adult stem cell compartment has been shown to be the result of both impaired self-renewal and dysregulated differentiation resulting from aberrant Notch and Wnt signaling [158]. Disruption of the nuclear lamina by progerin was shown to be directly responsible for downstream activation of Notch signaling effectors, spurring uncontrolled sporadic differentiation of MSCs along all three germ layers and enhanced osteogenesis at the expense of adipogenesis when differentiation was directed [159]. Wnt signaling was found to be severely disrupted in the progeroid Zmpste24-/- mouse model (deletion of this enzyme causes restrictive dermopathy in humans), where the absence of normal lamin A resulted in an absence of active nuclear β-catenin in follicular stem cells, leading to down-regulation of cyclin D1 and repression of Akt and mTOR activation [160].
Another mouse model of accelerated aging also points to aberrant Wnt signaling as a causative factor in degeneration due to stem cell defects, but from a different perspective. The Klotho mouse, which lacks klotho, a transmembrane and secreted β-glucuronidase involved in regulating insulin sensitivity among other functions, displays an accelerated aging phenotype, including short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis, and emphysema [162]. Analysis of tissue-resident stem cells from multiple organs in Klotho mice revealed that they were reduced in number and displayed abundant senescence-associated markers prematurely [163]. Klotho was found to be a secreted Wnt antagonist capable of binding Wnts1, 3, 4, and 5a, and over-activation of Wnt signaling in Klotho mice drove tissue-resident stem cells into an early senescent phenotype, resulting in lack of self-renewal and stem cell compartment exhaustion.
Taken together with findings regarding aberrant Wnt signaling in the Zmpste24-/- mouse, these studies reveal the exquisite sensitivity of adult stem cell pools to the fate-determining effects of Wnt signaling, too much or too little of which results in failed maintenance of quiescent progenitors in adulthood. Perturbation of this pathway one way or the other has been demonstrated to result in adult stem cell aging and exhaustion, along with impaired differentiation, in the muscle compartment [164], the hematopoietic compartment [165,166], the vasculature [161], and the skeletal system [161,167] in addition to the skin, the gut, and the kidney. It is suspected that these processes unfold in normal aging as well as accelerated aging phenotypes, especially given the accumulation of low levels of progerin over time in normal individuals and declining serum levels of klotho in human aging [168].
''

So from one side, SASP contributes to a 'stem cell lock' (at least in the healthy niches that are not rogue yet and that are meant for 'normal' tissue repair)
while from another side, SASP actually increases 'cancer ''stemcellnes'' '. And this not a surprise, SASP
is all about 'enabling cancer'. Klotho-KO mice that are prematurely aging (like HGPS syndrome in humans) have
reduced number of stem cells, impaired differentiation (the 'good one' that is (to repair tissue), not the differentiation towards 'cancer stemcell-ness/cancer cells hijacking of stem cells markers (SOX, OCT, NANOG) themselves to become 'stem-cell like and increase tumorigenesis', and have high SASP markers (p53/p16ink4a/p21/Wnt (either too much or too little)/B-catenin/IL-6 inflammatory cytokine/etc).

Also, stem cell are called on (and exhaust if too much injury) when demanded for tissue injury repair.

This is all very confusing but clearly, the stem cells are Both contributor to cancer and also preventers
in highly renewing organ tissues (since they repair these tissues when they differentiate in the right cells for repair).
They contribute to cancer by making cancer cells become 'stemcell-like' (acquiring a 'stem-cell' like shape/features that make them 'highly proliferative/dividing' in order
to 'divide and conquer' (fig.) as tumors do when metastasizing). This is due to the fact that stem cells
entire metabolome/metabolic profile can turn from 'healthy' (dividing only in case of injury/remaining quiescent for pool maintenance) to 'SASP 'activated'' when exposed to SASP from senescent cellsl or rather 'stem-cell repair Locked',
as in the differentiation process is weakened and they don't repair damages (by cell differentiation replacement) anymore. Instead, they
exhaust proliferatively to try to repair the injuries and in doing so, they acquire SASP like features and become senescent too, thus
differentiation is lost and the stem cells die/or enter senescence themselves - while the SAPS senescing cells can turn malignant and make
the cancer cells acquire that ,stemcell-ness/very proliferating feature - that stemcells have. This, in turn, makes cancer cell highly proliferative
and 'Take over'. While your organ becomes inflammation stricken and damage accumulating; while cancer is enabled.

If SENS will remove senescent cells - and a study of p16 senescent cell removed did increase the lifespan
of mice by 20% - it means that SASP is causal to stem cell dysfunction and loss of differentiation/differetiation Lock/cancer highjacking of stem cells/acquiring stem cells features'.
I am sure the stem cell markers in these mice that ablated for p16-senescent cells have had Improvements in their
stem cells - it is nearly absolutely sure; because there is a loss of differentiation potential (or put another way, a loss of Tissue Repair By The Stem Cells) as SAPS rises/as the number of senescent cells rises/thus the env becauses SASP filled.
This changes the metabolic/epigenetic/phenotype of the Stem Cells themselves 'to behave' wrongly in a 'Lock' where they don't repair anymore/differentiate towards that;
they increase SASP capacity (since SASP perniciously allows that) and it becomes a 'cancer haven'.

My 2c take is this, Inflammation is behind all this, and of course keepnig low inflammation means a 'clean niche/non-rogue like' that behaves correctly
and repairs the tissues/maintains tissue homeostasis and allows a longer lifespan (such as is the case in the p16 removal mice; or in HGPS humans whom show accelerated stem cell depletion/dysfunction/Lock and age prematurely)).

As such, from these information we could say that stem cell are Being Locked by inflammation
- and this drives aging in part, since there is a loss of tissue homeostasis becuase of this lock. Thus, removing senescent cells (p16 ablation) and the SENS ApoptoSENS therapy of senescent cell clearance will definately improve healthspan, and lifespan, and also cancer.
But I agree with the point that it is just the tip of the iceberg; for other limits are more important in extreme age (telomere attrition/epigenetic aging/TTR/lipofuscin/proteasome clog/protein aggregation/chromosome laxing/nuclear defects/histone loss/epimuations/so forth...)

IT's much more complicated than we thought.

Just a 2 cent.

Senescence-Inflammatory Regulation of Reparative Cellular Reprogramming in Aging and Cancer
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418360/

The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration
2. genesdev.cshlp.org/content/early/2017/01/31/gad.290635.116

Unbiased analysis of senescence associated secretory phenotype (SASP) to identify common components following different genotoxic stresses
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993333/

Pharmacological mimicking of caloric restriction elicits epigenetic reprogramming of differentiated cells to stem-like self-renewal states
4. https://www.ncbi.nlm.nih.gov/pubmed/21047255/

Adult Stem Cells and Diseases of Aging
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992297/

Hi CANanonymity.

I am speculating here, but I am pretty convinced that senescent cells are used by the body to spur regeneration by the spurring of stem cells into action and perhaps even by the generation of new stem cells.

As we age stem cells epigenetically drift into normal somatic cells, so take more inflammation (IL-6) to de-differentiate back into useful stem cells. At the same time somatic cells are losing telomere length and therefore proliferative potential. So the body is trying to restore the stem cell pool, maybe even generating stem cells on demand from somatic cells. We know that p53 is downregulated as well, so the body is trying to make all your cells more plastic and able to regenerate, with less control over aberrant cells.

That is why I am saying loss of regenerative potential is the underlying cause of the rising inflammation that then causes so many issues.