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Fisetin Study

fisetin opencures

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#1 Mind

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Posted 24 February 2022 - 12:05 AM


I am planning an n=1 study with fisetin to evaluate its senolytic and rejuvenation potential.

 

I will use the OpenCures platform to conduct and record results of the study. I was hoping a few other LongeCity members would participate. A member perk of LongeCity is free access to all of the features of the OpenCures platform to organize and analyze biomarker data.

 

I was wondering if anyone could provide some critique of this potential study.

 

1. What fisetin dose do you think is required to produce a noticeable effect.

2. For what time frame should the fisetin be taken

3. What biomarker test (before and after) would definitively show whether or not there was removal of senescent cells

4. How long after the treatment should the test be taken

 

Initial design:

 

1. 2 LEF Bio-Fisetin per day. Both taken at the same time.

2. Taken for 5 days in a row

3. Not Sure? Maybe DNA methylation. Maybe the OpenCures prodrome scan which is very comprehensive.

4. Maybe 1 week after the treatment

 

No other new supplements or therapies would be initiated from 2 weeks before the trial through the final test.

 

Special note: If we can get 40 people to engage in the trial we can get a radically reduced price one the prodrome scan.

 

 


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#2 bobolander

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Posted 24 February 2022 - 01:00 AM

I'm anxious to learn the results.  I already take two LEF Fisetin tablets three times weekly with D+Q on the middle day as my weekly senolytic cocktail.  No before and after, but I still have the Epimorphy MyDNAge test every Spring.  It consistently shows minus 10 and minus 13 years for the blood and urine tests.  My Pheno Age also tracked the 10 year age reduction for the past two years.  I would recommend the MyDNAge test because of its tight range, and I think you already have a base-line with them.  Bob


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#3 Brian Valerie

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Posted 24 February 2022 - 04:13 AM

Good for you, Justin!  Here's my best effort at "wanna be" informative critique:

 

1. Dose:  Our friends at the Life Extension Foundation are suggesting three caps of their LEF Senolytic Activator, which contains 312 mg of their Bio-Fisetin Proprietary Blend (18% fisetin [56 mg]), but taken chronically once per week, regardless                  of body weight.  Yeah, sure!  I bet they chose once weekly because it's easier for people to keep track!  At least it does give us another rough (very rough, I'd say) dosing guideline.                        

 

2. Time Frame:  While the initial murine studies were of five days duration, one could argue for a longer duration in a longer lived species like ours.  The Mayo Clinic was no doubt being cautious in opting for two days.

 

3. Biomarker Test:  What do you think of the Senescense-Associated-beta-galactosidase (SA-b-gal) test by Jinfiniti?

 

4. Timing of Testing: One week after treatment seems reasonable, but since were barely on the frontiers of the relevant research, we must admit that most of all this is guesswork!   :unsure:  Best wishes!    



#4 Zarathrustra

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Posted 24 February 2022 - 12:14 PM

Thanks for the invite. I would be interested to read the outcome.

 

However, for me, having used fisetin 100mg over 70 times in various dosages, I found it correlated badly for my PNN50 and microhaematuria. So I'll pass being a participant. It seemed good for my total cholesterol though.


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#5 Oakman

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Posted 24 February 2022 - 04:26 PM

Some of this may be useful to you, not sure. I did this protocol a couple years ago, but it did not just include Fisetin, and so is quite different that what you have planned. Anyway, I've included the references / notes I saved from that time. 
 
The end result of taking this protocol was afterwards I felt odd/weak/weird (best I can describe and remember) for some number of days (which I did not like much), after which things went back to relative normal. But I did no testing/blood work. I have not repeated it.
 
Good luck with your trial and will be interested in the results!
======
 
"I was wondering if anyone could provide some critique of this potential study."
 
1. What fisetin dose do you think is required to produce a noticeable effect.
 
As a precursor to my Fisetin protocol, I started with a 3 day 'Senescence Activate" regimen divided into 9 doses (~1g) / 3 per day (~3g).
 
Total mixed and encapsulated:
Vitamin C 0.400mg
Watercress 0.400mg
Purple Fruit/Veg Complex 0.800mg
Betaine HCL / Pepsin 650/25 1.350mg
Ashwagandha 1.750mg
Reishi 2.000mg
Ginger 1.750mg
Zinc 0.022mg
Trans-Resveratrol - powder 0.500mg
Curcumin - powder 0.600mg
 
This was followed by a 2 day protocol - 1.25G/day Fisetin Combo (divided into three doses/day) for 2 days. The Fisetin was compounded together with Piper Longum and Quercetin as below. 
 
Total mixed and encapsulated:
Fistein pill 0.800mg
Piper Longum powder 2.000 mg
Quercetin - pill 0.500 mg
 

plus daily:

Vitamin D - pill 0.10mg

Black Seed Oil - 1 tsp

 
References: 
 
Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy > https://www.hindawi....i/2018/4159013/
 
Natural Compounds that Remove Aging Cells > https://www.lifeexte...g-Cells/Page-01
 
 
 
 
 
T = BSO Thymoquinone  > https://www.ncbi.nlm...ubmed/24579801/
 
Resveratrol activates p53 gene
Zinc protects p53 gene against caner causing mutations
Cruciferous (w/PEITC) esp. watercress support p53
P = Phenethyl Isothiocyanate Protects against mutated p53, restores normal p53 functions
 
Enzymes for Fat Digestion https://enzymedica.c...r-fat-digestion
 
As a major mediator of the DNA damage pathway, p53 has been shown to be critical for telomeric stress-induced cellular senescence >
 
The p53 tumor suppressor protein is a latent and inactive transcription factor in unstressed cells. Following genotoxic stress or oncogene activation, this protein becomes stabilized and activated as a transcription factor, capable of inducing a transient cell cycle arrest, senescence or apoptosis.
 
Anthocyanins suppress mutated p53 cells effects
Senescence Regulation p53 > https://link.springe...1-62703-239-1_3
 

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#6 Bike_to_120

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Posted 25 February 2022 - 12:51 AM

interesting to learn of OpenCures

 

I just purchased some higher dosage Fisetin - tried LEF but did not see any noticable effects

 

I'm thinking of 2 gms for two days as a dosage that may work


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#7 Mind

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Posted 25 February 2022 - 04:57 PM

interesting to learn of OpenCures

 

I just purchased some higher dosage Fisetin - tried LEF but did not see any noticable effects

 

I'm thinking of 2 gms for two days as a dosage that may work

 

Did you do any biomarker testing before and after?


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#8 Bike_to_120

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Posted 25 February 2022 - 09:52 PM

Did you do any biomarker testing before and after?

 

My blood tests before and after show no change at all on these low doses. I am interested in the larger dose as I have seen people report a change in PSA. Was just tested for that, so will reevaluate in June


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#9 Mind

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Posted 27 February 2022 - 07:17 PM

My blood tests before and after show no change at all on these low doses. I am interested in the larger dose as I have seen people report a change in PSA. Was just tested for that, so will reevaluate in June

 

Just standard blood tests? Like blood chemistry, CBC, triglycerides, etc.?


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#10 Bike_to_120

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Posted 27 February 2022 - 10:02 PM

Just standard blood tests? Like blood chemistry, CBC, triglycerides, etc.?

 

yes



#11 Mind

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Posted 28 February 2022 - 11:18 PM

3. Biomarker Test:  What do you think of the Senescense-Associated-beta-galactosidase (SA-b-gal) test by Jinfiniti?

 

 

I will look into the Jinfiniti test. What about the Buck Institute SASP biomarker test? Is it commercialized yet?

3. Biomarker Test:  What do you think of the Senescense-Associated-beta-galactosidase (SA-b-gal) test by Jinfiniti?


Edited by Mind, 28 February 2022 - 11:18 PM.

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#12 APBT

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Posted 01 March 2022 - 03:54 PM

Have a look at this short video.

 

[youtube][/youtube]


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#13 mike_nyc

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Posted 02 March 2022 - 10:14 PM

I have taken fisetin off and on over the years and one thing I would say is there is a vast difference in the effect depending on whether you just swallow a capsule (minimal effect) or open a capsule and take it sublingually (much more noticable).  Like I could see some moles on my skin becoming noticeably smaller over time.  I know one brand even has a lipo sublingual gel which may even absorb better.   



#14 osris

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Posted 24 January 2023 - 06:00 PM

I just saw this on YouTube:

 

"Quercetin & Fisetin – Why I’ve STOPPED Taking Them" by Dr Brad Stanfield
 
 
He says that testing by the Interventions Testing Programme, which he claims is an independent scientific body, came to the conclusion that fisetin wasn't a senolytic. Incidentally, he is looking for funding for a rapamycin trial he is organising, make of that what you will in the context of his video saying fisetin is useless.
 
Some people in the video's comments stream quite rightly criticised him for not mentioning that the Interventions Testing Programme had not used fisetin mixed with an oil substance to make it bioavailable. 
 
 

Edited by osris, 24 January 2023 - 06:02 PM.


#15 Zarathrustra

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Posted 24 January 2023 - 10:38 PM

Alas, I have a problem with the whole theory of senolytics as I understand it. As APBT's video states "senescent cells are one of the hall marks of ageing". But I cannot find any research that has a whole-body metric for a human's total senescent cell burden. Without this, how does anyone know (a) whether there is an increase with age; (b) whether any such purported burden causes any measurable effect?

 

I grant the theory seems plausable, but if one cannot measure how much total senescent cells there are, the rest is just conjecture. 

 

It is said that the effecti of increasing senescent cell burden it increased inflammation. If that is so, then why not just concentrate on inflammation? And if, say, inflammation falls, does that mean there's less senescent cells; or that they aren't such aburden?



#16 osris

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Posted 25 January 2023 - 01:00 AM

Good questions. My guess is that treating inflammation itself would be treating but the symptom of the senescent cell build-up. My understanding is that it is the toxins released in these cells that cause the inflammation.

 

 



#17 Zarathrustra

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Posted 26 January 2023 - 08:11 AM

Inflammation is caused by many things, infection being the usual one - with the subsequent fever being part of the process of dealing with the infection.

 

Is there any proof that senescent cells cause inflammation? Is there even any proof that the whole-body senescent cell burden is a problem? Do older people have more of it? As we seemingly cannot measure whole-body senescent cell burden, how can we ever know?

 

Inflammation is itself, unless directly the result of infection, a problem. Hence attending to levels of this and reduction is a good thing in of itself.



#18 osris

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Posted 26 January 2023 - 04:28 PM

I can't answer your questions, unfortunately.



#19 Zarathrustra

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Posted 26 January 2023 - 05:18 PM

That's OK. I was being rhetorical.



#20 ambivalent

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Posted 26 January 2023 - 06:07 PM

Alas, I have a problem with the whole theory of senolytics as I understand it. As APBT's video states "senescent cells are one of the hall marks of ageing". But I cannot find any research that has a whole-body metric for a human's total senescent cell burden. Without this, how does anyone know (a) whether there is an increase with age; (b) whether any such purported burden causes any measurable effect?

 

I grant the theory seems plausable, but if one cannot measure how much total senescent cells there are, the rest is just conjecture. 

 

It is said that the effecti of increasing senescent cell burden it increased inflammation. If that is so, then why not just concentrate on inflammation? And if, say, inflammation falls, does that mean there's less senescent cells; or that they aren't such aburden?

 

 

Well, they're a hallmark of aging becase their numbers increase with age, stop dividing and are damaging to other cells. We can make plenty of assumptions without knowing the entire cell burden, as you phrased it - though I am sure it can be estimated. 

 

I agree with fisetin it would be tough to assume that the senescent cell clearance is the reason for longevity benefits, especially it ramps up sirtuin expression. 

 

But if we can specifically target senescent cells, note their removal and observe benefits then it doesn't seem too much to pursue them - but there are likely risk factors in doing so.  

 

I believe Aubrey de Grey mentioned a few years back that senolytics appeared to demonstrate considerable cross over benefit to other aging targets.  


Alas, I have a problem with the whole theory of senolytics as I understand it. As APBT's video states "senescent cells are one of the hall marks of ageing". But I cannot find any research that has a whole-body metric for a human's total senescent cell burden. Without this, how does anyone know (a) whether there is an increase with age; (b) whether any such purported burden causes any measurable effect?

 

I grant the theory seems plausable, but if one cannot measure how much total senescent cells there are, the rest is just conjecture. 

 

It is said that the effecti of increasing senescent cell burden it increased inflammation. If that is so, then why not just concentrate on inflammation? And if, say, inflammation falls, does that mean there's less senescent cells; or that they aren't such aburden?

 

 

Well, they're a hallmark of aging becase their numbers increase with age, stop dividing and are damaging to other cells. We can make plenty of assumptions without knowing the entire cell burden, as you phrased it - though I am sure it can be estimated. 

 

I agree with fisetin it would be tough to assume that the senescent cell clearance is the reason for longevity benefits, especially it ramps up sirtuin expression. 

 

But if we can specifically target senescent cells, note their removal and observe benefits then it doesn't seem too much to pursue them - but there are likely risk factors in doing so.  

 

I believe Aubrey de Grey mentioned a few years back that senolytics appeared to demonstrate considerable cross over benefit to other axis of aging.  


Edited by ambivalent, 26 January 2023 - 06:08 PM.


#21 Zarathrustra

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Posted 26 January 2023 - 06:29 PM

Thank you for those thoughts.

 

Can you give a research paper reference that reports that the whole-body senescent cell numbers increase with age please, as I couldn't find any? Similarly, that senescent cells damage other cells - at the moment, I cannot see how they would do so, given that they are by definition senescent.

 

I agree the theory is interesting, even plausable. But without research evidence for each step (a measure of the total number of senescent cells in a human; that these increase with age; that they interfere with the non-senescent cells to their operational detriment; etc), then the theory is without foundation.

 

As to senolytics, without any of the aforementioned emprical evidence of the aforementioned posited theories of senescent cells, their role seems to rest on sand.



#22 Mind

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Posted 26 January 2023 - 06:36 PM

Thank you for those thoughts.

 

Can you give a research paper reference that reports that the whole-body senescent cell numbers increase with age please, as I couldn't find any? Similarly, that senescent cells damage other cells - at the moment, I cannot see how they would do so, given that they are by definition senescent.

 

I agree the theory is interesting, even plausable. But without research evidence for each step (a measure of the total number of senescent cells in a human; that these increase with age; that they interfere with the non-senescent cells to their operational detriment; etc), then the theory is without foundation.

 

As to senolytics, without any of the aforementioned emprical evidence of the aforementioned posited theories of senescent cells, their role seems to rest on sand.

 

There are dozens of animal studies showing health and life extension benefits with the administration of senolytics. Maybe the cells are not being destroyed. Maybe something odd is going on in these studies that has nothing to do with senescent cells.

 

However, it is certainly worth further investigation - especially in humans. These senolytics are low risk and low cost. It is low-hanging fruit that needs to "be picked".


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#23 ambivalent

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Posted 26 January 2023 - 08:04 PM

Thank you for those thoughts.

 

Can you give a research paper reference that reports that the whole-body senescent cell numbers increase with age please, as I couldn't find any? Similarly, that senescent cells damage other cells - at the moment, I cannot see how they would do so, given that they are by definition senescent.

 

I agree the theory is interesting, even plausable. But without research evidence for each step (a measure of the total number of senescent cells in a human; that these increase with age; that they interfere with the non-senescent cells to their operational detriment; etc), then the theory is without foundation.

 

As to senolytics, without any of the aforementioned emprical evidence of the aforementioned posited theories of senescent cells, their role seems to rest on sand.

 

Senescence is an end-state of a cell, apoptosis another, and senescent cells are known to be resistant to apoptosis. So that is a growing biological problem.

 

A senescent cell may have stopped dividing, but it is not inactive - it is emitting cytokines which induce senescence in neighbouring cells

 

They accumulate with age because they are cells that stop dividing and they do not submit or submit easily to autophagy. Senescence is triggered through critical telomere length, which results from division, which correlates with age - at least those cells that are not induced into that state.

 

There isn't an alternative that they increase with age by virtue of the fact that it is an end state of a cell.

 


Edited by ambivalent, 26 January 2023 - 08:53 PM.


#24 Zarathrustra

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Posted 28 January 2023 - 07:17 PM

You make assertions, as do others, without aa reference. You may be correct, but I’ve been around anti-ageing enough (50+ years) to have become cautions about such. Even with research papers, one-offs are to be treated with circumspection.

 

Assuming, as seems reasonable, that senescent cells are resistant to apoptosis, we then have to show several other things – which would depend on being able to assay the quantity of such cells in the human body, as we would, say, body fat, water, etc. As far as I know, this is not yet possible.

 

So without this metric, we do not know (a) whether older people have more senescent cells (tho’ that seems reasonable); (b) that they are a problem (it is possible that tho’ there is more of them, they may sufficiently degrade with time that they cease to be a problem); © whether lifestyle effects their quantity or quality (maybe exercise/nutrition changes this, as they do inflammation).

 

The paper you reference is an in vitro based one. Not to decry this, but it fails to address my points. Whether adjacent cells are impacted, in-vivo may ameliorate this through many different methods (immune cells, ageing itself, etc).

 

You say “They accumulate with age because they are cells that stop dividing and they do not submit or submit easily to autophagy.” But how do we know? It is not unreasonable to think they do, but empirical evidence trumps assumptions. It could be that they plateau, or reduce with exercise, etc.

 

Again, you asset “There isn't an alternative that they increase with age by virtue of the fact that it is an end state of a cell.” Not an unreasonable assumption, but it may be incorrect. We know that lifestyle effects ageing. Maybe one of the ways it does so is by getting rid of senescent cells. Again, without a whole-body assay, it is all conjecture.

 

As to Senolytics, as Hickson, L. J. et al note (in “Whole-body senescent cell clearance alleviates age” “.no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans.”

 



#25 ambivalent

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Posted 28 January 2023 - 08:46 PM

It is not conjecture that senescent cells increase with age. Why, because all that is needed is to compare the tissues of old mice with those that are younger - senescent cells are known entites - and there will be more of them in the old over the young. There is evidence to support this, otherwise there would be no basis to support the theory. 

 

Conjecture is an opinion based without evidence - in vitro isn't non-evidential, and an if in vitro observation points to an expected and realised in vivo outcome, then is amounts to a strong indication.  

 

If there is in vitro evidence for induced senescent and we see in tissue cell culture senescent cells group together, then we have some pretty compelling evidence. If too for example, senescent cells are injected into organism then sacrificed some time later and find as a result there are considerably more senescent cells in some tissue than would be expected, through comparing to controls were the injected number were just added on, then we have evidence for senescent cells causing more senescent cells.

 

"Injecting senescent cells into young mice results in a loss of health and function but treating the mice with a combination of two existing drugs cleared the senescent cells from tissues and restored physical function. The drugs also extended both life span and health span in naturally aging mice, according to a new study in Nature Medicine, published online on July 9, 2018. The research was supported primarily by the National Institute on Aging (NIA), part of the National Institutes of Health."

 

We have seen the damaging effects increasing senescent cell numbers - of directly injecting senescent cells - and the rejuvenating effects of removing senecent cells. We know too they accumulate in diseased tissues, in arthrtitis for example

 

With respect, these are not theories based on sand, nor conjecture. 

 

   



#26 Zarathrustra

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Posted 28 January 2023 - 10:24 PM

I think yoyu misunderstood my point. I understand that there are senescent cells. I further understand that there are more of them in some older organs than younger ones. It does not follow that the overall numb er of senescent cells increase in older people. This contradicts what we know agout the effect of lifestyle on ageing - that it can reverse inflammation, musscle-loss, etc. If one of the effects of senescent cells (and often the proxy for their existence) is inflammation, then reducing this implies it might be reducing the amount of senescent cells. My point is that we just do not know.

 

I disagree that conjecture is an opinion without evidence. Much of science is based on an initial conjecture on odd empirical data. Nothing wrong with that.

 

I also disagree that in-vitro evidence is ever compelling - for example, there are many things that kill cancer cells in-vitro but have no effect in-vivo. However, it is a good starting point for theories and testing further. Again, a good scientific approach.

 

Your point from young mice is good, but it is in mice. It may not happend in humans (but I agree probably does). Again, you miss my point: lifestyle too may have a similar effect. Without a metric for senescence burden in humans and then checing with lifestyle, we'll never know.



#27 ambivalent

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Posted 29 January 2023 - 03:36 PM

I am sure lifestyle may have an effect in determining less or more but not whether they increase as we age nor their association with age related pathologies. I agree that we can't say that almost anything in biology is certain, but in language conjecture does imply a lack of sufficient evidence to draw conclusions - and we aren't there with senescent cells: we can conlcude plenty.

 

Reducing inflammation doesn't mean a reduction of senescent cells - there may be many mechanism to reduce inflammation without touching the senescent cells. I don't need to know the biological burden of senescent cells to know they are burdensome.

 

To suggest that someone old might have a lot less sensecent cells than an average young person is real conjecture which should be supported with evidence - it seems to me that you're saying 'I might not have any given the lifestyle I lead, so why should I take supplements to remove them?'  

 

There are plenty of ways we can intervene biologically, to alter the rate of aging but not the biological destiny - not til now anyway. They correlate strongly with age and disease states and we have some good animal studies showing that removing them is rejuventating. Sure we may not know enough, to be certain, but we don't the time to wait without significant cost - senolytics seem a very good bet based on the accumulated evidence - there may be risks in clearing them but there is certainloy a biological cost in not doing so. They appear to be a vital part of nature's way of killing us off - and its quite unlikely exercise and good diet will keep them at youthful levels. 

 

As for in-vitro, I wasn't suggesting in vitro evidence is always strong, but rather if in-vitro evidence infers an effect which is in vivo realised (e.g. cancer remission) then we have a strong argument that the in-vitro based intervention is working as we guessed, without necessarily directly witnessing the in-vivo activity.  

 

The benefits of fisetin are wide and in no sense limited to senescent cell clearance. I would think it is worth giving a shot. 

 



#28 Zarathrustra

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Posted 30 January 2023 - 02:58 PM

I’m not sure I quite understand what you have written. But if you are saying that lifestyle cannot alter pathologies associated with biometrics, then that seems wrong. Many of my biometrics have improved with age.

 

As to knowing whether senescent cells are a burden – how do you know, if you cannot measure them? Without a measure, you cannot know if (a) they relate to anything, burden or not (b) whether they are affected by lifestyle factors.

 

To be clear: I think the theory that senescent cells might be a problem is reasonable. But to explore this, we first need to be able to measure them as a total, preferably simply like muscle-mass or inflammation. If we cannot do this first step, then the rest is moot. We just do not know whether older people have more; whether having more is even a problem; whether various lifestyle factors will alter the total; whether altering this total helps or hinders.

 

When you say (4th para) “They correlate strongly with age ..”, does the ‘They’ mean senescent cells? If so, then I’m not aware of any such metric by which this statement could be made. Again, a reference would help clear up my ignorance.

 

The mouse study you have mentioned is interesting. But injection is not the same as naturally occurring. Without a measure of total senescent-cell burden, we cannot know whether adding these injected senescent cells significantly increased this burden/overwhelmed it/were a trivial addition.

 

The non-injected mice treated with D+Q did show improvements, tho’ it is unclear whether that was due to reduced senescent-cell burden, as such was not, and seemingly cannot, be measured. Dasatinib is a drug with serious side-effect; quercetin, like fisetin is found in many foods and may explain why such foods improve age-related biometrics; tho’ fisetin itself has shown mixed benefits for me (correlated with raised resting HR but improved muscle- and bone-mass).

 

I agree that it is a conjecture that a specific older person may have less senescent cells than a youngster. It was a throw-away remark given that there is no measure of how many senescent cells anyone has. By the same argument, neither can you say otherwise.

 

I’m all for anti-ageing theories being tested – I follow many myself, but only those with a great deal more of long-standing scientific evidence – such as exercise, nutrition, oral hygiene, etc. The unproven theory of accumulating cellular senescence being a major determinant of ageing and thus the even less proven supposed reversal using dubious drugs I will let others dabble in them and hope I am around long enough to use them if and when they have a vastly more weight of evidence behind them.

 

You claim there is “certainly a biological cost in (clearing out senescent cells) not doing so”. But there is no such certainty – you are pre-empting the proving of the theory, yet to be done, given that (as I repeat) there is no measure of what, if any, a senescent burden is. I hope you are correct tho’, and will continue tracking events relating to this as I meanwhile put into practice already proven anti-ageing lifestyle factors and see my own biometrics generally improve with age.

 



#29 ambivalent

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Posted 30 January 2023 - 09:19 PM

"I agree that it is a conjecture that a specific older person may have less senescent cells than a youngster. It was a throw-away remark given that there is no measure of how many senescent cells anyone has. By the same argument, neither can you say otherwise."

 

Of course I can say otherwise when it is known senescent cells resist apoptosis, when senescence is triggered when telmomeres reach a critical length and so stop dividing - this is what happens when we age - cells stop dividing. So given that senescent cells result from aging and they resist apoptosis, then they will accumulate. Thus there is no alternative to them not accumulating and so correlating with age - sure we can do something with the rate, take on CR and reduce the rate of accumulation - now though we may have hacks to undo an aspect of aging in some areas. 

 

As for needing a reference as whether they correlate with age, as mentioned, the evidence will be in the tissues, and is:

 

"Senescent cells are present in premalignant lesions and sites of tissue damage and accumulate in tissues with age."

 

 

What else are they to do - given there is a conveyor belt of cells running out of telomere length which don't want to die?When we look at tissues of age related diseases, whether in the eye's of AMD sufferers or those with arthritis in the joints we find an abundance of senescent cells. 

 

We may not have lifespan studies on humans until we're all nearly dead - remove senescent cells from mice and they live longer - they are harmful but equally they too may prevent harm through signalling wound healing and suppressing tumours. 

 

Measurement is not the acquistion of certainty, but the reduction of uncertainty - not having perfect proof, doesn't make this a "who knows" 50:50. You are not going to have perfect evidence, anyone intervening with biohacking therapies is taking a risk. 

 

Reversing effects of aging are obviously not reversing its causes and could well provide false comfort. Hope is not so bad when it doesn't obstruct agency, it is hopeful to believe they have not accumlulated in the old when tissue samples and cell-biology suggest otherwise and still more hopeful to believe, if they are there, that they are harmless when they appear in the tissues of age related diseases and make mice sick when injected, healthy when removed and where rapid accumulation harm chemotherapy patients.

 

 



#30 Zarathrustra

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Posted 31 January 2023 - 05:58 PM

Thank you for another step in our quest for resolving this issue: whether we can measure the total senescent cell burden in a human, and from this determine whether this is a determinant in ageing. Whether it can be altered; and maybe how.

 

May I go a step at a time with you assertions?

 

it is known senescent cells resist apoptosis” – by defninition

 

“senescence is triggered when telomeres reach a critical length and so stop dividing” Yes, but for other reasons too.

 

“this is what happens when we age” No, it occurs throughout our llifespan

 

“So given that senescent cells result from aging” As above, this is not true; it happens because cells age, not the host.

 

“they resist apoptosis” – no; most (all?) do not.

 

“then they will accumulate” – this is to be proved, not asserted.

 

“there is no alternative to them not accumulating” Yes there is. Apoptosis clears some (all?). This is the nub of the problem.

 

I’ve now spent quite some time reviewing many of the referenced research papers, both from your reference and others. Most of the papers quoted are themselves only reviews, not empirical research. Those that are empirical are focused on niche areas (mouse organs; cancers; lungs). Non are whole body senescent cell assays. I have failed to find any – such may exist, but I haven’t found them, and nobody I’ve read has quoted any.

 

The conjecture is not an unreasonable one: that we carry an increased amount of senescent cells as we age. But so what? We then have to prove that this causes a problem. Any problem such may cause is thought to be due to inflammation and/or a weakening of the immune system due to the latter being worn out by dealing successively with them. Hence, by implication, if either or both the inflammation and/or the immune system is healthy, then presumably the senescent cells are causing a problem – could that be due to them being mopped up? Or really being quiescent?

 

If there is anything to the senolytic idea – that there are compounds that clear the senescent cells – then why may that not already be being done by various aspects of one’s lifestyle, as perhaps indicated by reversing ageing problems (muscle-mass loss, inflammation, hand-grip, glossiness of hair a la the mice?)?

 

So what we need – and seems to be lacking, which is a shame, but hopefully someone’s on it, as without it nothing else can be done – is a biometric of total senescent burden. Present indications are that this will be difficult (Then, and only then, we can check all the assumptions being made: as Anat Biran st al notes in Quantitative identification of senescent cells in aging and disease - Biran - 2017 - Aging Cell - Wiley Online Library “ In vivo identification, quantification and characterization of senescent cells are challenging tasks that limit our understanding of the role of senescent cells in diseases and aging.” Before going to do that, with difficulty, in mouse tumours, fibrotic cells,, and tissues).

 

With such a metric, let’s call it Whole Senectic Cell Burden – WSCB – we can then, and only then, do the following:

 

On average do younger people have less WSCB than older people.

Does the WSCB continually rise as a person ages?

Does any lifestyle factor change the rate of WSCB in any one person?

Can WSCB be reduced?

Does WSCB correlate with other ageing biometrics?

Does reduction in WSCB improve other ageing biomarkers?

Etc.

 

There’s a long way to go before we make any sense of proposed synthetic Senolytics – which may not even better than lifestyle effects.

 







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