A Conservative View on Osteoarthritis, Failing to Mention Senescent Cells

This open access paper provides a conservative view on the state of research and development of osteoarthritis treatments. Some time is spent on the puzzling nature of inflammation in osteoarthritis, and the failure of immunosuppressive therapies used for other conditions to produce meaningful benefits in this case. Yet senescent cells - and their inflammatory signaling, shown in a number of animal studies to contribute to and even directly cause osteoarthritis - are not mentioned at all. This gives some idea of the mindset in evidence here: lines of research arising in the past five to ten years, and that have not yet progressed to later stage clinical trials, are not worthy of note. The clinical community progresses slowly indeed.

Despite an increasing burden of osteoarthritis in developed societies, target discovery has been slow and there are currently no approved disease-modifying osteoarthritis drugs. This lack of progress is due in part to a series of misconceptions over the years: that osteoarthritis is an inevitable consequence of ageing, that damaged articular cartilage cannot heal itself, and that osteoarthritis is driven by synovial inflammation similar to that seen in rheumatoid arthritis. Recent randomised controlled trials, using treatments repurposed from rheumatoid arthritis, have largely been unsuccessful. Genome-wide studies point to defects in repair pathways, which accords well with recent promise using growth factor therapies or Wnt pathway antagonism.

There are many reasons to be optimistic about new therapeutic developments in osteoarthritis. Although it is true that much of what has been learned in the past few years from clinical studies is what not to use in disease, these negative studies have been highly informative in reminding the medical community that osteoarthritis is distinct from inflammatory arthritidies, such as rheumatoid arthritis. Research has shown that inflammation in osteoarthritis is nuanced and that classical immunomodulatory pathways are not good targets, but that there are several other inflammatory pathways awaiting clinical exploration, including those driven by direct mechanical injury of the cartilage (so-called mechanoflammation), complement, and mast cells.

The nature and role of inflammation in osteoarthritis pathogenesis thus remains unclear. Clarification is crucially important, not only so that we can develop appropriate targeted therapies for patients, but also to decide whether patients require stratification before treatment. There has been a popular move to try to phenotype patients, with a view to personalising their treatment to improve the efficacy of a given drug. However, these phenotypes currently lack cohesion, and here is little or no evidence that stratification by any of these features changes the response to treatment.

Clinical successes point towards a focus on regenerative or anabolic pathways rather than inflammatory ones. This suggestion fits well with preclinical studies, although the reciprocal relationship between repair and inflammation in the chondrocyte suggests that targeting one will probably affect the other. Recent large genome-wide association studies in osteoarthritis also support the concept that osteoarthritis is a failure of repair. Several at-risk loci have been attributed to genes in the TGFβ and FGF pathways, and there is a notable absence of loci that predict the regulation of classical inflammatory genes. Newer targets identified by genome studies, including the retinoic acid pathway, also look promising.

Link: https://doi.org/10.1016/S2665-9913(20)30279-4

Comments

Senescent cells (ScC) seem to be everywhere in the aging body. Indeed any research on inflammation and degenerative conditions should at least consider the effects of ScC.

But still the the ScC findings are rather new and the clinical significance concepts have not penetrated mainstream medical science yet

Posted by: cuberat at October 14th, 2020 9:14 AM

Please...UBX0101 couldn't even beat a placebo

Targeting senescent cells in OA is fools errand and has little to do with disease progression or modification in the joint

Posted by: devon mcradle at October 14th, 2020 12:25 PM

Speaking of UBX, they have announced another human trial. https://www.lifespan.io/news/a-new-senolytic-enters-human-trials/

The choice of molecule and tissue target seems dubious but I do hope they know better despite of all the bad rumors about the UBX bad science and harassment .

Posted by: Cuberat at October 14th, 2020 12:45 PM

Senolytics.... the anti-oxidants of the 2020s... ;p

Anecdotal note: I did the 'Mayo Protocol' (2g Fisetin + 1g Quercitin for 2 days, again after 4 weeks)
3 times now (6 months pause between) + a single 3 days of 3g Fisetin + 1g Quercetin.

Result: Nothing. If anything... my eyesight got noticeably worse in the last 2 years, my beard is a lot 'whiter', my skin looks older, my joints still inflamed, hormone levels still declining, i'm still feeling old & tired all the time.

I stopped caring about 'significant' improvements shown in test tubes or mice or faked studies.

Posted by: Jones at October 15th, 2020 2:56 AM

Lots of naysayers here who seem to forget that the road to success in science is littered with failures. Senolytics have great potential but they need to be used on the correct tissue type using the right pathway. Heterogeneity of senescent cell populations is critically important and senolytics are unlikely to work as intended until we understand that heterogeneity properly.

Posted by: Steve Hill at October 15th, 2020 4:37 AM

@Steve Hill: Leaving aside that the fate of van Deursen could cast doubt on what had been really achieved in the lab, there is the simple fact that mice and men are different creatures, especially with regard to the way their telomeres work.
Even assuming that senolytics could produce results once targeted and perfectly dosed, the following stands:
1. It will take decades before we can develop enough tissue-specific drugs and then figure how to dose them appropriately. Unity has just announced Phase 1 for a very specific eye disease, but even assuming that the drug works, if tissue and system heterogeneity is truly a problem then senolytics will get us nowhere. Just think about cancer: nobody believes that it will be cured in the next 200 years if the approach consists of targeting each and every disease variation.
The only way to achieve significant results is to look for a common switch behind all these variations.
2. It took decades for the scientific community to figure that clearing amyloid from the brain has no impact on alzheimer's disease, so it would be wise here to consider the possibility that senolytics could go down the same path, especially given that their brute mechanics (removal of a toxic element) are similar.
This is not being a naysayer, rather taking stock and looking elsewhere while dutifully finishing the experiments that we have started.
What worries me is the hype surrounding senolytics. If we have a few more failures they WILL become the anti-oxydants of the 2020s, as Jones said.
The blow to the field's credibility will be un-recoverable for decades.

Posted by: Barbara T. at October 15th, 2020 5:31 AM

@Barbara
Ironically most of the Senolytics happen to be anti oxidants too.

@Jones
Some of the studies might have been faked. The mice are not humans and they are a lousy model for human aging. All this is true.

My personal effects from quercetin and fisetin are consistent and as a good placebo. Again my experiments are far from a high quality science.
Regardless all this, this is the very first treatment which can not only slow down but even reverse some aspects. At least there's a good theoretical explanation

Posted by: Cuberat at October 15th, 2020 6:11 AM

A few bumps in the road does not write the approach off and van Deursen being effectively fired does not invalidate the work others are doing which target pathways other than P16. Dasatinib I do not have much faith in quite honestly and recent information from an experiment we are running does not improve that, I won't say more until the final lifespan results are in though.

That said it is my view that senolytics are likely not neccesary if the immune system is rejuvenated and the inflammatory environment can be managed. I am far more enthusiastic about partial cellular reprogramming and the work Conboys are doing with blood factor calibration which ties in with that.

Posted by: Steve Hill at October 15th, 2020 6:26 AM

The move of Unity from an easy to dose target like the knee, to an opthalamic indication which have a range of other PK vagaries, demonstrates that this company in going off the tracks and burning their investors money - although I guess Bezos doesn't miss a few million

And please explain why Bcl-xL, which is an also important "occu-protective", makes for the smartest target here??

Posted by: James Burnbrae at October 15th, 2020 6:31 AM

I'm optimistic on senolytics, not for any reasons due to the appropriateness or not of mouse models, but because there now appears to be quite enough money around to support several senolytic start up companies.

Invention (the creation or demonstration of an initial scientific possibility) and innovation (turning that discovery into a useful saleable product) are two different processes. The innovation process is really a team sport and depends on enough people having the financial and regulatory freedom to experiment with approaches (and copying from each other) until a saleable product is achieved.

Senolytic drugs are in a far stronger postion to succeed currently than drugs that remove damaged cholesterol, which only really have two finanically backed companies pursuing this approach at present (Repair and Underdog).

I also think that the failure of amyloid removing antibodies is perhaps not a good model for what might happen with the development of senescent cell removing treatments. There is no good animal model of alzhiemers disease at present, whereas lab mice do currently seem to be good models of the decline produced by senesecent cells. In that sense the basic scientific infrastructure for developing a senescent cell removing treatment does (at present) seem to be much more solid.

Posted by: jimofoz at October 15th, 2020 6:42 AM

@Steve Hill: "I am far more enthusiastic about partial cellular reprogramming and the work Conboys are doing with blood factor calibration which ties in with that."
I am all with you there. And immune system regeneration etc. In other words, approaches that target a whole system rather than a narrow component in that system.
The repair approach makes sense, but evidently there's a black box where things go awry in the space between assumptions and outcomes. I am trained in programme evaluation and public health, not life sciences, so I have absolutely no idea why one particular molecule may fail vs another.
BUT I am looking at the bigger picture and the evidence points to the following:
1. Precision senolytics are as much of a waste of time and money as precision cancer treatments. Actually worse, since at least precision cancer treatments do cure some people and result in added years per person, whereas precision senolytics may at best ameliorate some specific non-fatal disease that has little or no impact on life expectancy.
Will we ever have 20+ different drugs that target all disfunction in all tissues? Sure. Will we have them within the next 20 years in the lab? Sure. Will they be available within the next 20 years at your doctor's office? Absolutely no way.
-
2. While repair strategies may have a place in rejuvenation, it is becoming glaringly obvious that repairing one issue on its own won't work. And I don't mean in the original sense (as explained by SENS circa 2004), meaning that even if I cure Alzheimer's I will only live a couple of years longer unless I also cure cardiovascular disease and so on and so forth. What I mean is that most repair approaches on their own (e.g. amyloid removal) are one leg of a chair, so they won't even solve the specific issue they were designed for. Perhaps a universal senolytic drug + stem cell replenishing will have huge effects... but how long will it take before we get there?
Decades.
And how long before we get there with reprogramming approaches?
From the way it *looks like* it may take less.
The repair approach looks good on paper, but when you try to make it work in people it turns out that you don't have one target to shoot at, but hundreds. And yet the irresponsible popular press (flamed by irresponsible press releases) talks about senolytics as a silver bullet that will "slow down" or "reverse" all ills and make people live to 110. Yeah, dream on.
The way I see it, we are being slowed down by dogma and, alas, the good old sunk cost fallacy.

Posted by: Barbara T. at October 15th, 2020 7:22 AM

@jimofoz: "There is no good animal model of alzhiemers disease at present, whereas lab mice do currently seem to be good models of the decline produced by senesecent cells."
True (if you discount the telomeres problem), but it seems that there may be deeper issues with the repair approach itself. While I am in no way saying that it should be ditched lock stock and barrel, I cannot see how in practice, as opposed to on paper, it will yield meaningful results.
It is too piecemeal and it has too many targets = it will take an unthinkable amount of money and time to put all the pieces together.

Posted by: Barbara T. at October 15th, 2020 7:36 AM

@Barbara T - you seem to have become super pesemisitic quite suddenly! I almost supsect a troll of simply posing with your name in order to get a reaction.

Is there actually any way to stop someone using a name such as Barbara T or Steve Hill to stir up trouble? (Other than the fightaging comments community being too small to bother with at the moment).

I do agree that senolytics are all promise and no pudding until that first in human trial with an objective measure produces a result. We can all disagree on the likelyhood of this happening until that day.

Posted by: jimofoz at October 15th, 2020 8:46 AM

@jimofoz: Oh come on man! So everyone who doesn't ignore failed trials and the emergence of unforeseen difficulties is now a troll? My points are valid, if obviously nobody knows whether they are true since nobody knows how the future will unfold.
Have I become pessimistic about repair therapies? Given the evidence, yes.
Have I become optimistic about the reprogramming approach? Ditto.
Calling me a troll for changing my views as new evidence piles in validates my comment about spreading dogmatism.
Questioning theories (especially in the face of failure) is the bedrock of science.

Posted by: Barbara T. at October 15th, 2020 9:06 AM

@jimofoz how was I stirring up trouble? I also dont agree with the suggestion that disagreeing with someone = trolling. I am also on record saying there are possibly better ways to clear senescent cells, see here:

https://www.lifespan.io/news/long-term-solutions-to-senescent-cells/

PS- if you don't believe this is me, you are welcome to drop me and email or message on FB and I will confirm.

Posted by: Steve Hill at October 15th, 2020 9:06 AM

@Barbara T also, reprogramming is a form of repair if you agree that the proposed model of aging presented in the publication Hallmarks of aging (aka SENS 2.0) is close to the mark. Certainly the majority of researchers I encounter seem to think so. That in no way implies that aging is programmed ofc, which is a different matter entirely.

Posted by: Steve Hill at October 15th, 2020 9:12 AM

@Steve Hill: I agree with your definition, but I think that whether aging is truly programmed or not is an academic question to anyone who isn't looking for a master code to rewrite the epigenome. That may work too in the far away future, but we are looking at "our lifetime" here, which general consensus puts in the ballpark of 2-3 decades.
My point is that the original SENS proposition - attacking each class of damage individually will yield a handful of years - doesn't seem to bear out in the clinic, and that a comprehensive approach that considers signalling and solves different problems in one tissue at the same time (partial reprogramming, if you like) is more likely to give faster, cheaper, and more effective results.
So, Hallmarks or any future development along the same lines. The important thing is to not crystallise on one approach just because we sunk money and / or got emotionally attached to the original idea.

Posted by: Barbara T. at October 15th, 2020 9:43 AM

Yeah sorry guys, I could definitely have worded that better. Barbara's sudden (to me) pesmisim just set off my paranoia.

I hope senolytics are not at the start of a multi decade voyage from promise to product like other biotechnologies such as gene therapy and RNAi, and I don't think they are due to good animal models and the decades of cancer research that have gone into finding ways to kill particular cells. I do think the real cause for optimism is that there is enough money flowing to allow inovation and experiments with multiple approaches to take place.

Posted by: jimofoz at October 15th, 2020 9:50 AM

@jimofoz no worries matey

Posted by: Steve Hill at October 15th, 2020 9:52 AM

One can become suddenly pessimistic . It happens to me too. But if you compare to what Audrey and Reason were enduring over the last 15 years without much tangible proof, our pessimism it is nothing, . With Senolytics at least we have a proof of concept unlike
CR which only slows down the degradation. I am optimistic that it is possible. I am pessimistic that I will love long enough to reap the benefits

Posted by: Cuberat at October 15th, 2020 2:09 PM

Hi there! Just a 2 cents. TL DR: Antioxidant are still good, just won't live to 300 with them. We need more mitochondrial repair/action/ROS quenching and telomere shortening must be stopped (by ROS control).

After reading the comment of the user of senolytics not doing much or anything, it is worrying; but, we kind of knew all along (we already get sneolytics from food) so the surprise (is surprising...nothing surprising/you knew, so no need be surprised). We like to surprise ourselves, because it's fun to be surprise (in the good way that is, not when it's an awful/bad surprise). In this case, no surprise. IN mouse, p16 senescent cell alblation give 20-30% lifespan extension; which is pretty much the max (except calorie restriction) that any study has given for pretty much any type of intervention to slow aging. In humans, mouse translation to human = much less; so I would say 5 years lifespan extension possibly by senlytics (maybe we could see 10 years, maybe 20, but the chances of that are small because most studies in mice have strong effect and low effect when in human, or no effect; but I think that senolytics were greatly help on the health issue/overall health). People thinking will reach 100+ years doing senolytics is optimistic thinking but wishful; too (wishful). The user's comment above shows it, like been doing senolytics and ..still aging.

Now I read something even more demoralizing, that tall telomeres mean longevity/health/genomic stability - but it also means accelerated attrition rate; it's truly 2-faced; when telomeres are shortened the body attemps to 'decelerate' the telomere shortening rate (to counter the small telomeres/from uncapping), while when the telomeres are tall the body 'has to stop lenghtening telomerse/they too tall' and the tall telomeres accelerate proliferation of cells/stem cells to rebuild tissue; but in doing so this accelerates 'growth' and accelerates the telomere shortening rate - at tall size. So what this means, is that as your telomeres lenghten/are tall(er) the faster the telomeres shrink...while when they are smaller, they will accelerate in telomere shortening rate but the body will 'block that' (since we know that small telomerse are unstable/uncap and trigger replicative senescence (p21) by the DDR (DNA Damage Response) signal at telomeres when y-H2aX telomere foci accumulates on telomeres)...

this is Really Catch 22, when you think about it, it's like...we can't lengthen the darn telomeres because they shrink fastEr as they get Taller...talk about nature doing a catch22 on us.
So,...the whole 'telomere lengthening' is greatly exaggerated, I mean it's important to keep taller telomeres; but taller telomeres will not make you live That much longer; it's why I understood.
A short telomere could lose 35bp (base pairs DNA repeat)/division/year, while a long telomere could lose 70bp/div/y, so it makes no difference, you still end up dying same point because no net Positive Gain; you lose telomere twice faster (by telomere attrition speed/rate) with tall telomeres than when they are short. As such, it's why you only see like 10 PDs (Population Doublings) extra by telomerase boost...telomerase will keep on adding the telomeres...but it will not be a 'standstill'; the telomeres will still shrink Because telomeres are High Size - shrink faster. so it means 'no loss no gain' kind of kind. It is balanced that way. So it is Very 'balanced in-out' (things 'balances themselves out/in'), so that you can'T 'gain' telomeres. In other words, telomeres are coded if you will or do this to themselves: when tall (growth/division ...etc) they shorten quicker; when small (soon senescence), they retard shortening to post-pone senescence soon since they become unstable. So iti s compensation (once more)/auto balancing of rate/speed of shortening depending on size/tallness/amount of telomeric DNA repeats/bps.
Now animals that lve 500 years maintain tall telomeres that is the paradox, you need tall telomeres to live long (because you lose telomeres each year); it means that to Counter Telomere Loss, you need Moer than just telomerase...you need to Stop the Telomere shortening rate/to reduce it. Because, telomere shortening rate will accelerate as Telomere Length Increases In Size.So I mean, that means double-triple-quadruple 'piling' of telomeres to counter the accelerated telomere loss - as you lengthen them-. A futile attempt.

But I think that is exactly why animals can live centuries, because they have telomerase in permanence; but it's only a small part of the equation..because taller telomeres mean faster shrining rate - so Need Something Else to slow shortening rate at High Tallness.

Like several studies showed that it is not the Length of the telomeresthat matters but the speed of/shortening rate and the number of 'short telomeres' accumulating. So, now I think that the telomerase therapy is great but will not stop the aging process because you still lose telomeres and it was demonstrated that Even If You Increase their Size...telomeres can make entry into senescence; it is why we see Rather Tall Telomeres in elderly people - and they Still senesce anyway...it is very paradoxical... it means this: the length is not so important, what is important is the Integrity of the Telomere Itself; a taller telomere means more integrity (because more DNA repeats) but it's more complicated then that. A tall telomere could have dna damage/foci on it and SAHF (Senescen Associated Heterochromatic Foci), which could 'Force' the telomere into a sort of premature senescence (not the same as replicative senesnce) but ends up the same; just earlier then 'spending entire telomere'...it's why old people can have human cells that
senescence at like 8kb Tall...size...a supercentenarian woman's leukocyte went down to 2-3kb...so she had 'spent them' in nearly full...but cells can senescenc with TAller telomeres Too. So an old person with cells with 6-8kb size they can still senescence, I think that is due to 3 main things: Telomere integrity (as this late point), Age/epigenetic age...of that person, an old person will have more epigenetic mutation/load which can cause epimutation/telomere fusion/problems..., cells are 'telomere shortening rate' dependent for their replicative lifespan...so a mouse with 50kb tall telomeres (much higher than ours...) will lose telomerse extremely fast (because remember Tall Telomeres Shrink Faster), and indeed it is the case, a mouse loses 2000-5000/div/year...(vs 50 for a human), thus they live 2-3 years. They might have telomeres 3 times longer than humans (mouse 50kb vs human 18kb), but makes no differenec, they lose telomeres 50-100x much faster/so it negates the 'tall advantage'/making it 'null/nill', and their Tallness Contributes to that. Having tall telomeres is clearly a 'negatively controled' element, meant to protect the chromosomes (for having 'more telomeres size') but it is a signal to accelerate the telomere shortening rate (when taller). In fact, one telomere shelterin protein controls tahat 'hPOT', hPOT negatively controls telomere size and impedes telomerase access on telomeres. In doing so it preserves the 'correct length' of telomeres - not too tall, because if it did not, telomerase could add processively an 'infinite' amount of telomeres repeats...and we could end up with telomerest that 250kpb tall...it does not work/incompatible for chromosomal function. So telomeres msut be in a 'certain size/window/range' for that specie...for it to work/make life. Mouse can have hyper long telomeres, and still die much quicker than us (because lose them so fast). While humans much smaller telomeres..but we keep them longer by slow attrition rate.

I noticed that many animals seem to have a 5kbp (5 kilo base pairs/5000 base pairs) 'range/window' of telomeric DNA repeat...no matter how long they live (from 3 to 500 years). So we can lose aboutr that much in a life, whatever the animal is. If you have Taller telomeres and you lose 5kbp... you will lose them Faster...then if you had smaller size telomeres and lost that same 5kb. So, a 5kb range, will be lost faster or slower depending on the size of the telomeres (so a 50kbp telomere losing 5kbp...will go down to 45kbp...but the animal will lose it extremely fast; in that 'mouse rate' of 2000bp/y loss so that in 2.5 years you will have lost the entire 5kbp (2000bp (2kbp/2KiloBasePairs) x 2.5y = 5000bp).

It's really disheartening that cells can even senescence with taller telomeres and not necessarily 'prematurely'...they senescence of regular 'repliactive senescence' But at Taller Size, not just short size.

4th, senolytics will be of help on health...but as comment said above...he did not see that much change, and still 'Graying'/wrinkling...despite taking senolytics; Senolytics = Healthy Aging...promotion...not stopping aging. It reduces inflammation/SASP and will reduce a bit SAHF but this not enough; telomeres still shrink despite so; Telomeres are the real deal here, and so is mitochondrial ROS and epigenetic landscape...I hope that reprogrammation is able to reverse the entire DNA damage, make teloemres tall again (which it does), and cells to not commit 'sudden' senescence...because then it will be very hard to defeat aging. Cells must continue to divide once reprogrammation or else, we will never defeat aging. But, I am remainin cautiously otptimistic it's just that...when you look at studies on fibroblast that made them last longer/more replicative bouts they ALWAYS end up senescencing at some point (of replicative senescence)..now if we could do the 'looping' of DNA repair on and on..maybe they would never senscence, not so sure of that. Because, cells can spontaneously stop dividing...as shown for example in fibroblast after some 70 population doublings...and this is interesting because when DNA is repaired or antioxidant stave off the DNA damage...the cells continue replicating a bit more but stil Stop replicating Later some more replicative rounds later....so it's like, we can't get past the M1 Crisis point...(replicative senescence) and then Antoehr barrier awaits us M2 Crisis point where 'imm*rtalization' can happen should the cell continue dividing by 'overcoming replicative senescenec barrier/Haylflick Limit, as the p21/p53 oncogenes will again show up when replicative senescence happens). The cells seem to have clear 'replicative memory' in the sense they are limited by that No Matter if DNA repair or not...so they remember (by epigenetic print metthylation) that the amount of roudns they made...can't continue forever - or else transform (and possibly imm*rtalize) into rogue/cancer cells that evade replicative/hayflick limit.

I think only if we can erase this 'replicative memory' can we extend lifespan to infinite because cells would lose some that (not their entire identitty/signature) but just enough so that the replication tabs are erased so the cell does not commit senescence - Even after rejuvenation.
Because that is a real possibility, the cells could end up replicating Only just a little bit more after DNA repair/rejuvenation..but reprogramming could solve that if we lose the memory print of replications bouts.

Just a 2 cents.

PS: Currently telomere shortening rate is controlled by the mitochondrial ROS efflux (at complex I), I am amazed that it really is the largest contributor to the speed of telomere shortening rate. Thuis, we must target antioxidant to the mitochondria (such mitoQ, quinones/ubiquinol, ...but especially mitochondiral thiols which are the largest protectors such as cysteine and gsh; which without them the mitos commits apoptosis/or senesce since overproducition of ROS). Animals that live the longest have the lowest ROS and lowest ROS Eleveation With Age...at mitos. And not just any ROS but the SuperOxide Anion being the Biggest contributor to Telomere shortening rate. It is why when cells are culutured in low O2 they have quite a few more population doublings/divisions...because low O2 = Low ROS (by less oxygen to begin with). Oxygen is the cause of the Reactive Oxygen Species (ROS), cells culture in ambient O2 (20%) has less replicative bouts..and HyperOxia (40-100% hyperbaric oxygen) cause Rapid senescence of cells because so much accumulation of ROS in them.

This proves that mitochondrial ROS dictate animal lifespan/avg and maximal (at least a Large part of it/maybe not entirely but are very susbtantial contribution to the weigh/importance of why living this long). That theyt are the largest cause of the length of animal lifespan. They are Upstream of All the rest (telomere shortening rate, DNA damage accrual, epimutation/nuclear and mitocondiral DNA mutations/deleteions/lesions...etc). Radicals/ROS cause damage to DNA, and this accelerate sthe epigenetic clock advancement. Animals that live for centuries - do not have necessarily more telomerase or taller telomeres - in fact they have less, but what they Do have is Less Susceptible molecules/proteins...so that the damage is rendered futile in them/inconsequential/are resistant to it (unlike in short lived animals that are Highly Susceptible to the damages/it affects them and they unresistant to it). One studies showed that metabolic rate is 33-50% explanation to to longevity...a bowhead whale can live 211 to 268 years because its hears beats 10 beats per minute/very slowmo/very low metabolism = very little damage production from 'metabolsm'...while humans are faster metabolism/live 'fast' = shorter life = accumulation of damage quicker...mouse Even More ..fast/extremelt fast metabolism (5000bp/y loss; a heart beat of 300-700bp/minute...they 'spend it fast'), it's the old 'burning the candle by both ends', mouse burn the candle 'in a wick'...while humans burn only one side...and greenland shakrs (that live 450 years) just don'T burn the candle at all.

Humans have evolved better antioxidant production/protection to counter our 'relatively fast' metabolism...because if not we would liev only 20-30 years..but thanks to high consumption of mitochondrial ROS in our cell mitos (by thiols/redox system), we can live 120. The only way to live 400 years like that shark/whale...is to curb the increase of ROS with age to slow down telomere shortening rate (since it is dependent of ROS emission rate at mitos).

.

Posted by: CANanonymity at October 15th, 2020 9:57 PM

@CANanonymity Fisetin is as twice as strong as quercetin... which still makes it very weak senolytic. It do not even reverses build up of pre-cancer (called also senescent) cells (even taken twice a month) in most tissues, and probably not just even slowing their buildup in these tissues, even in late 40-ties of age. These tissues it does are worth of taking it alone, but globally it is still too little. Do not expect too much effect from it alone. It's still strong anti-SASP agent on itself (apart form it's senolytic properties), but SASP has too many molecules to fight it efficiently with one anti-SASP natural molecule only, and there are already stronger anti-SASP agents, even between flavonoids that do not exhibit antisenolytic properties. That's why doctors are exchanging Q+D into F+D. But we still do not have cheap tests to quickly evaluate other anti-cancer combinations in vivo, or measure how much and how long is enough.

Posted by: SilverSeeker at October 16th, 2020 6:45 AM

Hi SilverSeeker! Thank you for that. It goes to show that it will take a lot..that food flavonoids would be more efficient that a synthetic senolytic is worrying; but the old saying is : ''health cure/healing through food (natural one)'', it's why they often tout the keto/paleo/mediterranean/vegetarian diet because they contain a ton of polyphenol/flavonols that arrest cancer growth, stop SASP inflammation and reduce senescence. A lifestyle/diet change can slow a lot of disease problem (but not necessarily reverse it though, it's why it's not because you suddenly become vegetarian that you are 'saved' of whatever disease, it always takes time/healing and sometimes, it's too late stage advancement of the disease/even these diet do nothing anymore/or Contribute even to the disease progression despite their 'all touted benefits'. Something good/healing (when healthy) can turn bad/toxic (when unhealthy)). If It ends up being so, people will not be impressed by senolytics and it will not pick up 'big' or anything, but remain 'another supplement/antioxidant' in the list of things you can do; which means it will 'sit on the shelf' and wait 'one day' to picked...which could be very long. We so much choice now (because medical supplement/pharma industry) is a big business running (low) on cash, so 'what do you choose' when going to buy supplements?

Too much choice = k*lls choice....people don't know what to choose...so they choose whatever they heard is supposedly the right thing....and they try lots of stuff...to find out 99% of the supplements do jacksh...on their health. This is why it is both good and bad for senolytics, if indeed they really help, they could obtain a big boost in their use..but if not, it's 'just one more'...and because there are a zillion types of supplement...people are not 'at loss of choice'...they have pick of the litter...senolytics just one more in the litter. That is the problem, they may end up just another one because people don'T differentiate between the various supplements; and don'T care either; so that is to the disadvantage of senolytics; they must Stand Out from the rest of me-too products for people to Actually Notice. It takes A Lot for people to be convinced now (because nothing works, at least if it does work (later) than that gives it a serious leg (to stand on)/credibility over the rest). But, as you said, it will take quite a lot of 'effect' for them to be noticed (if they can't slow cancer or slow inflammation much (beyond a fruit containing flavonol that are senolytifcs), then, won't be. Here's hoping.

Just a 2 cents.

Posted by: CANanonymity at October 16th, 2020 10:51 AM

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