1079 replies to this topic

[Dstein]

 

Any chance, at least in theory, that this formulated "bio-fisetin" would work well? LE from their site quote "But during digestion, much of fisetin is rapidly converted into other compounds by a process called conjugation. That’s why we protected fisetin by combining it with galactomannans, a type of fiber derived from fenugreek seed. Doing so makes it up to 25 times more readily available than standard fisetin."

Furthermore, I found this from another website:

 

"LE's Bio-Fisetin page references their Curcumin Elite page (which uses the same bio-boost trick), which in turn gives journal references.  Chasing these references down two levels in the Journal of Functional Foods  yields the following description of how they combined Curcumin with Fenugreek Powder to boost bioavailability:

 

'Various percentage CGM were prepared by ultrasound mediated gel-phase dispersion of curcuminoids in fibre matrix. 

 

I would be wary of this product. The "ultrasound mediated gel-phase dispersion" step is probably the key step that makes this process work.  I suspect that if you liquefy your fisetin, and then put it into a high speed blender just before you drink it you'll achieve a similar effect.

If I'm not mistaken this is the person behind Bio-Fisetin:  https://en.wikipedia.../William_Faloon.  He sounds like a snake oil salesmen.

If you are trying to improve bioavailability, you may find these articles interesting;
Self-nanoemulsifying drug delivery system of fisetin: Formulation,optimization, characterization and cytotoxicity assessment
Strategies to Formulate Lipid-based Drug Delivery Systems.

The key takeaway is that you first dissolve the fisetin in oil and then add a solvent.  Two different solvents are preferable to one.

[cjacek]

I would be wary of this product. The "ultrasound mediated gel-phase dispersion" step is probably the key step that makes this process work.  I suspect that if you liquefy your fisetin, and then put it into a high speed blender just before you drink it you'll achieve a similar effect.

If I'm not mistaken this is the person behind Bio-Fisetin:  https://en.wikipedia.../William_Faloon.  He sounds like a snake oil salesmen.

If you are trying to improve bioavailability, you may find these articles interesting;
Self-nanoemulsifying drug delivery system of fisetin: Formulation,optimization, characterization and cytotoxicity assessment
Strategies to Formulate Lipid-based Drug Delivery Systems.

The key takeaway is that you first dissolve the fisetin in oil and then add a solvent.  Two different solvents are preferable to one.

 

Wow, great info, thanks but it's a little beyond me, to tell you the truth. I do usually mix the fisetin in a little bit of oil before consuming. Would it make even more sense then, as you suggest, to also add some lecithin (as an additional solvent), then perhaps add the oily mixture (oil + lecithin + fisetin) to a cup of milk and mix it on high in my blender, would it then yield better results? The "dispersion" idea you noted above.     

Edited by cjacek, 15 September 2021 - 08:41 AM.

[Dstein]

 Would it make even more sense then, as you suggest, to also add some lecithin (as an additional solvent), then perhaps add the oily mixture (oil + lecithin + fisetin) to a cup of milk and mix it on high in my blender, would it then yield better results? The "dispersion" idea you noted above.     

 

The mixture that I've been using is similar: oil + lecithin + alcohol (solvent) mixed in a blender.  I think the next time that I try fisetin, I'll replace the lecithin with Phosphatidylcholines (the active component of lecithin), and add some polysorbate 80 as an additional solvent.

[cjacek]

The mixture that I've been using is similar: oil + lecithin + alcohol (solvent) mixed in a blender.  I think the next time that I try fisetin, I'll replace the lecithin with Phosphatidylcholines (the active component of lecithin), and add some polysorbate 80 as an additional solvent.

 

Fascinating. Would you mind telling me the exact amounts that you're currently using of the mixture (oil, lecithin, alcohol)? 

[Dstein]

Fascinating. Would you mind telling me the exact amounts that you're currently using of the mixture (oil, lecithin, alcohol)? 

 

In the last batch that I made, I used MCT oil.  I picked MCT oil because I came across a study that looked at how various oils improve the absorption of fat soluble compounds.  MCT oil was the clear winner in this study.

I used just enough MCT oil to dissolve the fisetin.  I then let it soak for several hours to let the fisetin fully dissolve.  Afterwards, I poured in just enough alcohol (Everclear 190 proof) to dissolve the oil, and then poured everything into a blender with water and lots of liquid lecithin.  The only thing that actually got measured was the fisetin (I took 4 grams/day for 5 days).

 

[cjacek]

 

In the last batch that I made, I used MCT oil.  I picked MCT oil because I came across a study that looked at how various oils improve the absorption of fat soluble compounds.  MCT oil was the clear winner in this study.

I used just enough MCT oil to dissolve the fisetin.  I then let it soak for several hours to let the fisetin fully dissolve.  Afterwards, I poured in just enough alcohol (Everclear 190 proof) to dissolve the oil, and then poured everything into a blender with water and lots of liquid lecithin.  The only thing that actually got measured was the fisetin (I took 4 grams/day for 5 days).

 

 

 

Thanks!  

[cjacek]

Does anyone know whether or not the Mayo Clinic studies used unformulated Fisetin or some kind of delivery "vehicle" (liposomal perhaps?).

[DJSwarm]

Isn't it true that fisetin like quercetin is metabolized quickly by the human liver but not the mouse liver?

 

Human subjects can absorb significant amounts of quercetin from food or supplements, and elimination is quite slow, with a reported half-life ranging from 11 to 28 h [38]. The average terminal half-life of quercetin is 3.5 h [39].

from: :text=Human%20subjects%20can%20absorb%20significant,is%203.5%20h%20%5B39%5D.' class='bbc_url' title='External link' rel='nofollow external'>Quercetin, Inflammation and Immunity 

 

It has been reported that the maximum fisetin concentration reached 2.5 μg/ml at 15 min, and the plasma concentration declined biphasically with a rapid half-life of 0.09 h and a terminal half-life of 3.1 h after administration of fisetin at a dose of 223 mg/kg intraperitoneally in mice (68). https://www.aging-us...cle/101202/text

 

As a result of these findings J. L. Kirkland's team at the Mayo Clinic has recently designed and begun a clinical trial aimed at the “Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults” (AFFIRM-LITE) with fisetin administered orally in doses up to 20 mg per kilogram of patient body weight¹. In view of poor solubility (10.45 μg/mL), relatively low oral bioavailability (44%) and rapid metabolism, such a development warrants interest in the prospective fisetin sources for suitable pharmaceutical formulations. https://www.frontier...2019.00697/full

 

Haven't found a specific elimination article for fisetin but I've heard it is similar, about 3 hours.

 

A number of these bioflavonoids might be better in liposomal form to increase bioavailability. Anecdotally, fenugreek may potential and skullcap aka wogonin could synergize. Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca-dependent endonuclease  

[DJSwarm]

Say, can anybody find the actual article to Effect of Combined Dasatinib and Fisetin Treatment on Senescent Cell Clearance in Monkeys? doi: 10.1093/geroni/igaa057.432

All I can find is the abstract. It does have the dosing which I'm wondering if it might be a typo on the Dasatinib: 

 

"After baseline measurements, six older (mean age=21 years) female rhesus monkeys (Macaca mulatta) were given a combined oral dose of Dasatinib (5 mg/kg) and Fisetin (100 mg/kg) on two consecutive days. Animals were additionally assessed at 1- and 7-weeks following dosing. At 7 weeks post dosing, there were fewer (p<0.05) p16+ cells in the epidermis compared to baseline. Similarly, there was a reduction (p<0.05) in p21+ cells in the epidermis at 1- and 7-weeks post dosing compared to baseline. There were no negative outcomes associated with treatment."

 

Dasatinib 5 mg/kg for an 83 kg person would be 425mg. Human studies have all been in the 50-100mg total dose. You could probably subject them to that level dose but 42.5 or 0.5 mg/kg seems way more reasonable for senolytic effect and their claim of no "negative outcomes." 60 mg total dose had me feeling like a flu shot at its worst.

 

Fisetin (100 mg/kg) is 8,300 mg for 83 kg person. High but luckily, at least in humans, fisetin is non toxic to healthy cells. I don't know the upper limit is for humans, but in mice they tried 2,000 mg/kg without any signs of toxicity. The Mayo clinic is testing 20 mg/kg which is 1,660 mg for 83 kg person. I've tried 3,000 mg total dose for 83 kg (liposomal so actual bio-availability may have been higher) x 2 day run and did not notice any physiological side effects. (Unlike D 60 mg + Q 1000 mg which felt like a bad flu shot.)

 

Hoping I see improved fur density and vigor like brother mouse.

[DJSwarm]

 

Senescent cells are clearly one of the cellular and molecular lesions driving biological aging. However, you can't expect targeting just one of the seven categories of aging damage to increase maximum lifespan, because of the "weakest link in the chain" effect: you have to hit all seven, including all specific lesions within each category.

 

What would be the seven categories of aging damage to increase maximum lifespan?

 

Senescent cells - inflammation, cancer, autoimmune disease

 

Failure of protein synthesis from failure of ISR to reset. ISRIB looks promising here, I've seen it posited that quercetin may also do this as well as certain amino acids if in abundance. one of the things that sets ISR is "famine" and this study seems to suggest reversal Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model

 

Increasing mitochondrial loss and disfunction (NAD+ boosters, NACarnitine, PQQ but could be mainly an exercise issue)

 

Increasing sugar intolerance (metformin, berberine but could be mainly a diet issue, since fasting seems to reverse before it become serious; and senescent cell issue since fisetin seems to also help relieve it.

 

Shortening telomers (TA86 aka astrogalus and Epitalon, exercise, meditation, good diet)

 

mTOR1 inhibition and / or what ever the F rapamycin does. (Berberine tested as a mTOR1 inhibitor as well recently, potentiates R and has waaay fewer side effects.)

 

Both the ROS based theories and vitamins seem to be discredited. Some ROS is essential and its only when there is chronic over load (like from chronic stress) that there are issues. The body handles acute ROS spikes just fine. Vitamins really only help up to not being deficient.

 

Are there some I'm missing?

[DJSwarm]

The article I quoted is specifically ABOUT fisetin:

https://www.ncbi.nlm...les/PMC3689181/

 

And implying that I have some agenda because I might be working for some evil company is both aggressive and dumb, particularly if you were to look at my post history.

 

I may be "paranoid" but if something is known to cause chromosome loss and double strand breakage, I will err on the side of caution rather than to just jump in and assume that this damage is maybe somehow confined to cancer cells and therefore beneficial.

 

Again, go and do what you like, but if something causes this sort of damage in high doses, jumping into high doses seems reckless. And I say that as someone wo takes rapamycin

 

You may or may not have read that article, but your sure didn't understand a word they said: "In this review article, we describe the multiple effects of fisetin with special emphasis on its anticancer activity as investigated in cell culture and animal models."

 

They found it killed or stopped proliferation in a wide variety of cancers, and was a mouse antidepressant, but reported no harm to normal cells - in keeping with every other study. Fisetin is surprisingly safe to normal tissue at doses far above what is being used in phase 2 trials at the Mayo clinic for frail people 70+ (20mg/kg or 1,660 mg for me).

 

And if you take rapamycin, this is like the pot calling the chalk black. Fisetin is long proven non acutely toxic in even really stupid doses, but rapamycin inhibits mTOR2, resulting in various kinds of sores and other issues if you aren't careful. Berberine is also a mTOR1 inhibitor but it is way more selective and has none of the rapamycin side effects.

[DJSwarm]

I worry a lot about kidney stuff, so this is kind of a red flag for me. It pops into my head as well. I start thinking.... all of this mess is being excreted somehow and all at once, logically it could damage your kidneys.  But I try to go by the studies because I don't want my fears to guide my decision.  Lucky for us, as you hinted at, all the senolytic studies show better kidney health to the extent that they measure it at all.

 

I do plan to take NAC beforehand to protect my liver, and I think it works the same for kidney.  It's probably not necessary, but I have some I'm not using, so why not. 

 

NAC can inhibit a number of things, i'd double check to make sure you are negating the wanted effects. D+Q has already been tested in adv kidney patients and F seems about as non toxic as things get and still do something.

[DJSwarm]

Rapamycin when not taken very intermittently has a horrible safety profile. This is why I take very small doses on an 8-9 day frequency. The study you posted is not germane to that dosing regimen. I don't want to contaminate this thread with rapamycin info, but the intermittent dosing studies are referenced in the rapamycin threads. And people here who take it often get it from India, not from expensive US pharma companies.

 

 

Your characterization of 20mg/Kg as not a high dose has to be compared to the quantity one would get from dietary sources.

 

- The highest source of fisetin seems to be strawberries, at 160mcg/g. (see: https://www.ncbi.nlm...es/PMC3689181/)

- For a 150lb person, 20mg/Kg is 1367mg of fisetin

- To obtain 1367 mg of fisetin one would have to eat 8.5Kg of strawberries, which is probably 90x a normal quantity for a person to eat.

 

So the 20mg/Kg dosage is quite a bit higher than one would encounter in a normal diet.

 

Again, it may be completely safe. I just start getting paranoid when I read about double strand DNA breaks and chromosome loss.

 

Which is not to say that your level dose has no side effects - as reported in the R thread - mouth sores, eye sores, deep acne, and depressed sexual function. Rapamycin is no stroll through the park. Fisetin has no negative acute issues reported at a wide variety of large doses.

[DJSwarm]

All I know is that most, if not all of the studies have shown intermittent clearance.  If you are taking large doses every couple weeks that is way too much and it's no longer truly intermittent. especially for a human time scale.  We don't have any evidence for what would happen with such a protocol.  At best nothing since the intermittent dose is already really striking, and at worst tissue dysfunction based on losing the valuable signals for regeneration and/or cancer prevention that senescent cells are known to cause.

 

Agreed that long term replicative senescence and stem cell loss will require some sort of replacement strategy.

 

The Mayo clinic is doing 20 mg / kg x 2 days every week in frail elderly adults as a phase 2 trial (i.e. already passed phase 1).

[DJSwarm]

I noticed nothing either positive or negative. My blood tests remained the same -- all values within their annoying ranges. ...

 

How long did you wait? I find that I don't really notice much for about a month after a senolytic run.

 

I'll have to dig out my old blood tests but my hair is noticeably darker after 1 3/4 years of about quarterly senolytic tests, my son just told me my bald spot is filling in, I've had a minor sexual improvement ("morning wood" more often). I feel more vigorous, back to taking stairs two at a time. No negative side effects. So far I'm not constantly dosing anything. I do a two to three day run and then give it a break for a month minimum, usually a quarter, once as long as 6 months - so far results seem durable. The exception is fisetin has such a sweet safety profile I ran a test early, 2 weeks after testing D(60mg) + Q(1200mg) + F (1500). I did a 3000 mg x 2 days + 1 quercetin 500mg + 200mg bromalin + 1000 mg berberine. No side effects, too soon to say if there are any changes. 

 

A number of the human trials so far are D (50-100mg) + Q (1000ishmg) with short runs and lasting effects and reasonable safety profiles (D is a bit rough). The Mayo clinic is doing a fisetin 20mg/kg (~1500mg) x 2 days once a week run with frail 70+ aged people phase 2 trial so I think that should be about a minimum to see any effect. A number of studies seem to point to a dose dependent effect curve and since it has an excellent acute safety profile, I doubled it. It does seem to brighten mood while you are doing it, at least for me.

 

Also, NACist may interfere by helping the liver clear it faster. I'd save the NAC for after the run.

[Woody42]

Life extention sells what they label a Senolytic Activator  using a  a mix of Quercetin, theaflavin and  apigenin-bio-fisetin.  My question is  there any evidence that theaflavin has any senolytic activity. I have done some searches about this and can't find anything about this other  than the clams by Life Extention.    

[DJSwarm]

So I've seem this paper used as a warning the fisetin could be shortening your telomers Accelerated Aging during Chronic Oxidative Stress: A Role for PARP-1 However simply reading the paper shows:

"Chronic fisetin treatment of HF at physiological concentrations resulted in shorter telomeres compared to control cells [but not stressed cells - DJS], indicating reduced telomere stability and enhanced biological aging of these cells."

 

Once more chronic administration is not required or advised. All the actual human trials are intermittent dosing. 2-3 days on then at least the rest of the week off.

[DJSwarm]

An update:

 

Two days ago I entered in to my third dose of Fisetin, a couple of months or so since the last dose. Previous doses were of 3 and 4 grams, mixed in with olive oil. I upped the dose once more to 5 grams again in oil mixed with a sprinkling of black pepper. A minute prior I took a couple of lecithin gel capsules, I can't confirm the dose at this moment, but they were probably around a gram each, with 8 turmeric + black pepper capsules which were either 500mg or 600mg each. I undertook this a few hours before bed, which happened to be late am. (I don't have evidence anecdotal or otherwise that these extras improve the bioavailability of fisetin, though I appear to have experienced more than others have reported at these doses.)

 

Within an hour or so I experienced a mild headache and subsequently a restless night. I awoke to a sore throat, with my glands hinting at their presence, I also experienced an intermittent cough during the day. I would describe the experience as feeling a little run down as we do a the beginning or tail end of a sickness, but nothing that would cause the cancelling of plans - you'd just prefer to rest. Today I felt a little off when I awoke, but nothing significant.

 

This was certainly different to the previous experiences, with brief mild hints of flu-like symptoms: this was far more significant. Naturally, one can only speculate that the effect would have been more severe if this had been my first dose, without any prior senescent cell clearance. One observation I noted yesterday, as I had on the previous occurrences, was increased pain in my arthritic knee, which initially weakened and then strengthened on the previous two occasions. Also, I'm just reminded of something of an intermittent eye-socket pain which started yesterday, which I've experienced before but can't recall the context, possibly fasting.

 

Also, one of the notable first dose experience of fisetin was an overnight 90% cessation of an allergic/asthmatic cough I'd been struggling with towards the end of last year. I have passed through the pollen season with no problems thus far, I'm hesitant to attribute the long lasting effect on fisetin as I believe the problem was due to zinc deficiency which I subsequently addressed, a couple of weeks after the dose. Also red wine always seemed to trigger a cough, but has not done so that first dose.

 

So the question is what next? The dose related flu-like symptoms of fisetin I've experienced and the known effect of Dasatinib on senescent cell clearance (in people) with coupled with severe flu-like symptoms, leads one to ponder whether the fisetin dose needs to be ramped up significantly to attain similar effects. It is crude conjecture a Dasatinib is a drug and fisetin a flavonoid, but if the flu-like effects are purely down to senescent cell clearance then it seems a reasonable hypotheses.   

 

 

edit I should add this was the first time I used lecithin, black pepper and only may have taken a capsule or two of turmeric on the previous occasion. The primary difference between my experience and others, apart from dose, was the use of olive oil.

    

Also, I should add for those who don't recall the update, I experienced delayed blood clotting a few days after the first dose when I nicked a small mole while shaving - which is a known risk /effect of eliminating senescent cells (linked earlier in the thread) 

 

So "feeling something" when you dose is feeling side effects. Actual clearing of senescent cells doesn't feel like anything, which is why actual testing is needed to know what is actually happening; and, it takes time as the senescent cells die, are cleared and possibly replaced. Too fast and you start to burn through your stem cells and can trigger antinuclear antibodies from the immune system reacting to the spilled cell contents from the apoptosis. Normally you recover from this but it can trigger nascent autoimmune issues in some. 

 

I've been doing this going on two years and only ever "felt" something from D, which is noted for being a rough ride from its undesirable side effects. It takes a minimum of about 2 weeks to a month for me to see the changes manifest. For example a wave of suddenly darker hair that freaked out my barber. From your description, you seem to be definitely stressing something you probably shouldn't with this combination. I would at least split out the fisetin and turmeric every other week like was posted earlier in the thread. So far my max dose of fisetin was 3g x 2 days in 2 doses. All I felt was "brighter" from the antidepressant side effect.

 

Rapamycin is another one that has undesirable side effects unrelated to the desired mTOR1 inhibition. Berberine, which also inhibits mTOR1 is more selective and does not have side effects from inhibiting mTOR2 like rapamycin does.

 

Side effects are not a good sign. I think you are either effecting other systems, immune, liver, ?; or, over suppressing something, PARK1 maybe, and interfering with normal cells. Its just like chronic dosing of fisetin seems to eventually cause problems from PARK1 inhibition.

 

It nice to know it hasn't killed you  but please be careful.

[DJSwarm]

Life extention sells what they label a Senolytic Activator  using a  a mix of Quercetin, theaflavin and  apigenin-bio-fisetin.  My question is  there any evidence that theaflavin has any senolytic activity. I have done some searches about this and can't find anything about this other  than the clams by Life Extention.    

 

I started with theaflavin because it seemed to have a good safety profile and looks like it should be effective. It was in a stack so it is hard to single it out but the stack did function.

 

LE's basis for thinking it works:

 

Scientists set out to identify a compound that would enhance quercetin’s senolytic effects by the same mechanisms as dasatinib, but without the side effects of a cancer drug. The most effective candidate they found was a group of compounds in black tea called theaflavins. In a similar way to dasatinib, theaflavins block an anti-apoptotic protein called BCL-2. If you wonder what BCL stands for, it is “B-cell lymphoma.” A compound that blocks BCL-2 might reduce risk of this common malignancy. In a mouse study, theaflavins demonstrated significant senolytic effects.

 

Noberini R, Koolpe M, Lamberto I, et al. Inhibition of Eph receptor-ephrin ligand interaction by tea polyphenols. Pharmacol Res. 2012 Oct;66(4):363-73.

Noberini R, Lamberto I, Pasquale EB. Targeting Eph receptors with peptides and small molecules: progress and challenges. Semin Cell Dev Biol. 2012 Feb;23(1):51-7.

Ting PY, Damoiseaux R, Titz B, et al. Identification of small molecules that disrupt signaling between ABL and its positive regulator RIN1. PLoS One. 2015;10(3):e0121833.

Leone M, Zhai D, Sareth S, et al. Cancer prevention by tea polyphenols is linked to their direct inhibition of antiapoptotic Bcl-2-family proteins. Cancer Res. 2003 Dec 1;63(23):8118-21

Han X, Zhang J, Xue X, et al. Theaflavin ameliorates ionizing radiation-induced hematopoietic injury via the NRF2 pathway. Free Radic Biol Med. 2017 Dec;113:59-70.

Cameron AR, Anton S, Melville L, et al. Black tea polyphenols mimic insulin/insulin-like growth factor-1 signalling to the longevity factor FOXO1a. Aging Cell. 2008;7(1):69-77.

Caruana M, Vassallo N. Tea Polyphenols in Parkinson’s Disease. Adv Exp Med Biol. 2015;863:117-37.

Chen SQ, Wang ZS, Ma YX, et al. Neuroprotective Effects and Mechanisms of Tea Bioactive Components in Neurodegenerative Diseases. Molecules. 2018;23(3).

Peng C, Chan HY, Li YM, et al. Black tea theaflavins extend the lifespan of fruit flies. Exp Gerontol. 2009;44(12):773-83.

Aizawa T, Yamamoto A, Ueno T. Effect of oral theaflavin administration on body weight, fat, and muscle in healthy subjects: a randomized pilot study. Biosci Biotechnol Biochem. 2017;81(2):311-5.

 

A Good review of a number of things The Review of Anti-aging Mechanism of Polyphenols on Caenorhabditis elegans

 

So if you can't or don't want to try D, T does seem to be an active senolytic and may be a good way to achieve BCL-2 inhibition so that Q becomes active, and it could potentiate F. Anecdotally, it seemed to work. 

[ambivalent]

"Actual clearing of senescent cells doesn't feel like anything, which is why actual testing is needed to know what is actually happening"

 

This is a little commanding, I am not sure how you know it doesn't feel like anything, based just on your experience? Side effects are often a good sign - it depends on what side-effects.

 

 

It's the downstream effect of clearing sensecent cells, that we experience rather than their in-the-moment-removal. I would expect to feel some detoxifyng symptoms, mirroring aspects of fasting, say. 

 

When my arthritic knee weakens the day following a large sensecent cell dose, a place I know those cells accrue, I consider that pain to be a very good and telling side-effect. 

 

The only side-effect that was bothersome obviously, was blood clotting but normal service was resumed within days. 

 

In short, if I'm not noticing much from high doses of fisetin than I can assume not too much clearance is going on, those effects are welcome. In that respect it is like fasting, the at times unpleasantness is oddly welcoming.

 

 

 

 

 

 

Edited by ambivalent, 16 January 2022 - 08:44 PM.

[DJSwarm]

"Actual clearing of senescent cells doesn't feel like anything, which is why actual testing is needed to know what is actually happening"

 

This is a little commanding, I am not sure how you know it doesn't feel like anything, based just on your experience? Side effects are often a good sign - it depends on what side-effects.

 

 

It's the downstream effect of clearing senescent cells, that we experience rather than their in-the-moment-removal. I would expect to feel some detoxifying symptoms, mirroring aspects of fasting, say. 

 

When my arthritic knee weakens the day following a large senescent cell dose, a place I know those cells accrue, I consider that pain to be a very good and telling side-effect. 

 

The only side-effect that was bothersome obviously, was blood clotting but normal service was resumed within days. 

 

In short, if I'm not noticing much from high doses of fisetin than I can assume not too much clearance is going on, those effects are welcome. In that respect it is like fasting, the at times unpleasantness is oddly welcoming.

 

Well there is the personal experience angle, have been using fisetin for a while and turmeric even longer; there is the reading of paper after paper looking if side effects or negative outcomes; and then there is the reporting of others, like say in these forums; but finally there is the fact that the Mayo clinic has switched from D+Q to just F for 70+ frail adults.

 

Actual side effects, particularly from things as non side effect-y as F and Cur, are almost never a good sign, seriously. Also, "detoxifying symptoms" makes no sense. Removing toxins and irritants should make you feel better, not worse. Also fasting doesn't always mix with things. It can trigger your ISR system which shuts down protein synthesis as a protective measure and may not work well with senolytics which also shutdown protein synthesis via AMPK.  "...[A]rthritic knee weakens the day following a large senescent cell dose, a place I know those cells accrue..." that isn't how it works for my arthritic thumb and that isn't how it works in the degenerative disk studies in rabbit and mice. Finally, the whole blood clotting thing should be a huge clue that you are causing harm. You do know a strong blow to the head could kill you while you "wait for service?"

 

You of course will do as you please, it's obvious you've already made up your mind. This is actually for the thread readers so they know you are not to be followed as an example and what you are doing is dangerous and self destructive.

[Woody42]

With the Mayo Clinic  trial with F  are they taking the daily dose once a day or divided into smaller doses throughout the day.

[DJSwarm]

With the Mayo Clinic  trial with F  are they taking the daily dose once a day or divided into smaller doses throughout the day.

 

I don't have direct access to their protocols, but so far F seems to be dose dependent (you have to get past the liver and limited bioavailability), i.e. you want to take it all at once. It clears fairly fast so I did my 2  doses 12 hours apart instead of 24 like they reported. I'm also not repeating every week like they are (trying to avoid chronic suppression of key cellular systems when I don't need it). (M, 60, 6'2" 180 good general health) 

 

They are using about 1500mg aka 20mg/kg (I don't know if they are using a tech to improve absorption and bioavailability, but there are several available). I did 3000mg (I'm younger and not frail) of liposomal F with some Lecithin/oil (in this case Belgian chocolate ) and bromalin to aid absorption. The run went without side effects or negative outcomes. (I also included 500 mg of quercetin and 1000 mg of berberine for mTOR1 inhibition (like rapamycin without the nasty side effects), next time I'll add in theaflavin (seems to act like Dasatinib without the nasty side effects) to activate the Q and boost the F)

 

That was just last week so I'm still waiting to see if there are noticeable emergent effects like improved pelt and vigor. Usually a successful run takes about a month to manifest for me as I can't really afford lab tests at the moment. So I'm mainly going by subjective measurements as reported by my family (to give it a bit of objectivity). So far my hair is reverting back to medium dark streaked with grey and it is reported my bald spot seems to be receding. I've been feeling like exercising more and have been back to taking steps two at a time. So subjective but steadily trending good.

[ambivalent]

Well there is the personal experience angle, have been using fisetin for a while and turmeric even longer; there is the reading of paper after paper looking if side effects or negative outcomes; and then there is the reporting of others, like say in these forums; but finally there is the fact that the Mayo clinic has switched from D+Q to just F for 70+ frail adults.

 

Actual side effects, particularly from things as non side effect-y as F and Cur, are almost never a good sign, seriously. Also, "detoxifying symptoms" makes no sense. Removing toxins and irritants should make you feel better, not worse. Also fasting doesn't always mix with things. It can trigger your ISR system which shuts down protein synthesis as a protective measure and may not work well with senolytics which also shutdown protein synthesis via AMPK.  "...[A]rthritic knee weakens the day following a large senescent cell dose, a place I know those cells accrue..." that isn't how it works for my arthritic thumb and that isn't how it works in the degenerative disk studies in rabbit and mice. Finally, the whole blood clotting thing should be a huge clue that you are causing harm. You do know a strong blow to the head could kill you while you "wait for service?"

 

You of course will do as you please, it's obvious you've already made up your mind. This is actually for the thread readers so they know you are not to be followed as an example and what you are doing is dangerous and self destructive.

 

 

As anyone knows who has experienced fasting detoxification comes with some unpleasant effects, it is the process of eilimination  that creates these detox symptoms - that's why it gets it easier with time. If you read forums on fasting you will see this is consistently observed. To suggest that it doesn't make sense to make for detoxing to feel bad is rather counter to our broad experiences of the benefits of stressing the body - such as intense exercising. Try fasting and see - eliminating toxins isn't a pleasant experience

 

Fisetin isn't well absorbed, as you will of course know. Again as you will know, blood clotting issues have been observed with senolytics, at least one other person here has noticed delayed wound healing at high doses. This has been reported as an important side-effect, and is consistent with the known mechanims of action of senescent cells. 

 

The very fact that said side-effect at high doses was reported, implicitly directs caution - why would you suggest otherwise? And no it isn't self-destructive because the effect was temporary, there may well be personal a window of risk of a few days.    

 

Honestly, you should really be less patronising - this is an experimental site and if you bothered to read this thread then you will see I have urged caution, why would you need to reaffirm?

 

If I am doing something different to you and observing different effects (such as impact on arthritis) why would you dismiss my claim because 'your doing something different' has different effects to 'my doing something different'? 

 

And it was entirely reasonable to expect there to be an arthritic benefit:

 

https://www.ncbi.nlm...les/PMC5785239/

 

 

UBX of course was a clinical fail for arthritus,  though there were claims of poor experimental design. 

 

In another thread you quoted dosing as per the Mayo Study, as if this were recommended. The study is incomplete, you're taking a risk. That's fine but don't lecture others.

 

And finally your regular dosing is comparable to my very intermittent dosing, and I am a 50-year old male. The primary difference was my attempt to augment bio-availability.

 

Intermittent dosing of senolytics is the way most are going. Regular dosing could be in fact be problematic without raising any alarms. I assume you are aware that sensecent cells can suppress tumours:

 

https://www.ncbi.nlm... of tumor cells.

 

The body doesn't always give us clues things are wrong until too late. Taking senolytics remains a risky game for everyone, but not without potential rewards, obviously - they are extremely damaging cells, so taking some risk to eliminate them is a matter of judgement. 

Edited by ambivalent, 17 January 2022 - 07:29 AM.

[PAMPAGUY]

As anyone knows who has experienced fasting detoxification comes with some unpleasant effects, it is the process of eilimination  that creates these detox symptoms - that's why it gets it easier with time. If you read forums on fasting you will see this is consistently observed. To suggest that it doesn't make sense to make for detoxing to feel bad is rather counter to our broad experiences of the benefits of stressing the body - such as intense exercising. Try fasting and see - eliminating toxins isn't a pleasant experience

 

Fisetin isn't well absorbed, as you will of course know. Again as you will know, blood clotting issues have been observed with senolytics, at least one other person here has noticed delayed wound healing at high doses. This has been reported as an important side-effect, and is consistent with the known mechanims of action of senescent cells. 

 

The very fact that said side-effect at high doses was reported, implicitly directs caution - why would you suggest otherwise? And no it isn't self-destructive because the effect was temporary, there may well be personal a window of risk of a few days.    

 

Honestly, you should really be less patronising - this is an experimental site and if you bothered to read this thread then you will see I have urged caution, why would you need to reaffirm?

 

If I am doing something different to you and observing different effects (such as impact on arthritis) why would you dismiss my claim because 'your doing something different' has different effects to 'my doing something different'? 

 

And it was entirely reasonable to expect there to be an arthritic benefit:

 

https://www.ncbi.nlm...les/PMC5785239/

 

 

UBX of course was a clinical fail for arthritus,  though there were claims of poor experimental design. 

 

In another thread you quoted dosing as per the Mayo Study, as if this were recommended. The study is incomplete, you're taking a risk. That's fine but don't lecture others.

 

And finally your regular dosing is comparable to my very intermittent dosing, and I am a 50-year old male. The primary difference was my attempt to augment bio-availability.

 

Intermittent dosing of senolytics is the way most are going. Regular dosing could be in fact be problematic without raising any alarms. I assume you are aware that sensecent cells can suppress tumours:

 

https://www.ncbi.nlm... of tumor cells.

 

The body doesn't always give us clues things are wrong until too late. Taking senolytics remains a risky game for everyone, but not without potential rewards, obviously - they are extremely damaging cells, so taking some risk to eliminate them is a matter of judgement. 

 

Dr. Green, switched from D+Q over six months ago to D+F.  Saying Fistein was much better than Q(quoting Mayo Clinic) Schedule and dose is:  Once a month, 2 consecutive days of 100 mg D and 2,000 mg F.  Twice a month which is what he uses is 100 mg D and 2,000 mg F one day only. 

 

 

[Moondancer]

Last year I read the entire thread, so it has been a while and sorry if these things have been discussed before.

But admittedly I still keep wondering about some issues. This was reason that after one round of Fisetin in a hit-and-run fashion (3 days x 1500mg), I decided to wait until I'm better informed. Sorry if my questions may sound a bit ignorant.

 

- I remember there were some studies indicating senolytic agents (I believe it was D&Q in this rodent study, but correct me if I'm wrong), could cause fibrosis. If I remember it well liver fibrosis was noted in a rodent study, and I believe it was hypothesized that a potential cause would be the 'speed' at which tissue had to be regenerated as a result of SC-removal (and/or the fact that the older rodents had less tissue stem cells?). Has this been discussed, could this be a concern for those of us wanting to use senolytics? Any new thoughts about this? Edit to add: this interesting review discusses these aspects: https://www.linkedin...gs-blirando-phd

- On some forums a suggestion of potential stem cell depletion as a result of senolytic treatments was mentioned. Could this be a potential concern indeed?

- Dasatinib was additionally said to be not selective enough in only targeting SC's. I believe I had read an article with a scientist in senescence biology that expressed concern about that. Any thoughts about this?

 

(NB: I understand I should list the sources. But these were mostly suggestions I read on public forums).

Thanks in advance for any response!

Edited by Moondancer, 17 January 2022 - 11:55 AM.

[DJSwarm]

As anyone knows who has experienced fasting detoxification comes with some unpleasant effects, it is the process of eilimination  that creates these detox symptoms - that's why it gets it easier with time. If you read forums on fasting you will see this is consistently observed. To suggest that it doesn't make sense to make for detoxing to feel bad is rather counter to our broad experiences of the benefits of stressing the body - such as intense exercising. Try fasting and see - eliminating toxins isn't a pleasant experience

 

Fisetin isn't well absorbed, as you will of course know. Again as you will know, blood clotting issues have been observed with senolytics, at least one other person here has noticed delayed wound healing at high doses. This has been reported as an important side-effect, and is consistent with the known mechanims of action of senescent cells. 

 

The very fact that said side-effect at high doses was reported, implicitly directs caution - why would you suggest otherwise? And no it isn't self-destructive because the effect was temporary, there may well be personal a window of risk of a few days.    

 

Honestly, you should really be less patronising - this is an experimental site and if you bothered to read this thread then you will see I have urged caution, why would you need to reaffirm?

 

If I am doing something different to you and observing different effects (such as impact on arthritis) why would you dismiss my claim because 'your doing something different' has different effects to 'my doing something different'? 

 

And it was entirely reasonable to expect there to be an arthritic benefit:

 

https://www.ncbi.nlm...les/PMC5785239/

 

 

UBX of course was a clinical fail for arthritus,  though there were claims of poor experimental design. 

 

In another thread you quoted dosing as per the Mayo Study, as if this were recommended. The study is incomplete, you're taking a risk. That's fine but don't lecture others.

 

And finally your regular dosing is comparable to my very intermittent dosing, and I am a 50-year old male. The primary difference was my attempt to augment bio-availability.

 

Intermittent dosing of senolytics is the way most are going. Regular dosing could be in fact be problematic without raising any alarms. I assume you are aware that sensecent cells can suppress tumours:

 

https://www.ncbi.nlm... of tumor cells.

 

The body doesn't always give us clues things are wrong until too late. Taking senolytics remains a risky game for everyone, but not without potential rewards, obviously - they are extremely damaging cells, so taking some risk to eliminate them is a matter of judgement. 

 

Reviewing the research I see nothing to support extended fasting for senolytic purposes over calorie restriction for sirt1 activation. For the purpose of autophagy, Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans shows it doesn't seem to be needed. This is why time restricted diet is a thing. Also, amino acid starvation definitely does trigger ISR. 

 

Quercetin Regulates the Integrated Stress Response to Improve Memory The initiation of protein synthesis is suppressed under several stress conditions, inducing phosphorylation of the -subunit of the eukaryotic initiation factor 2 (eIF2), thereby inactivating the GTP-GDP recycling protein eIF2B. By contrast, the mammalian activating transcription factor 4 (ATF4, also known as cAMP response element binding protein 2 (CREB2)) is still translated under stress conditions. Four protein kinases (general control nonderepressible-2 (GCN2) kinase, double-stranded RNA-activated protein kinase (PKR), PKR-endoplasmic reticulum (ER)-related kinase (PERK), and heme-regulated inhibitor kinase (HRI)) phosphorylate eIF2 in the presence of stressors such as amino acid starvation, viral infection, ER stress, and heme deficiency. This signaling reaction is known as the integrated stress response (ISR).

 

Activation of ISR is not what we are looking for when using senolytic agents. Fasting hurts because you are starving your self, not because of "detoxifying." Exercise hurts because of microtears and build up of lactic acid. But if you really want to increase autophagy, intense exercise is superior to fasting: Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation. AMPK is a known senolytic target.

 

"In summary, the most effective strategy to activate autophagy in human skeletal muscle seems to rely on exercise intensity more than diet."

 

Senescent cells go senescence to prevent that cell from becoming malignant, but that cell then pollutes the surrounding cells with cancer promoting SASP toxins. This is why cancer is more prevalent in older people.

 

Senescence is a double-edged sword that can function in opposite directions. It is a potential mechanism for a cell to avoid malignant transformation. However, senescence can also promote cancer development by altering the cellular microenvironment through a senescence-associated secretory phenotype (SASP) :text=Senescence%20is%20a%20double-edged,associated%20secretory%20phenotype%20(SASP).' class='bbc_url' title='External link' rel='nofollow external'>Senescence and Cancer - NCBI

 

Taking senolytics correctly is not a risky game. The most commonly available ones are all GRAS without acute side effects under normal circumstances (quercetin, fisetin, theaflavin, berberine, apigenin, curcumin). (Dasatinib and Rapamycin are the notable exceptions but Theaflavin and Berberine effect the same beneficial pathways - BLC-2 and mTOR1 respectively - without side effects.) So far they all show potent anticancer and antiproliferation activity as well as reducing SASP by removing the senescent cells instead of keeping them. Also, they are extremely not damaging to healthy cells, which is the whole point of senolytics - remove senescent cells without damage to healthy ones. This is why the Mayo clinic is working with frail 70+ adults. Your "pile it on it until it hurts" approach is both dangerous and unnecessary. I'd bet your knee complains because of a raise in antinuclear antibodies causing an increase in inflammation. You might want to get an ANA test to check. Uncontrolled bleeding is serious. Even if you never bled out from it, you aren't stopping the micro tears that happen throughout the day which lets blood leak into areas where it should not be. Strangely, blood is toxic to many cells and in particular it is toxic to neurons. 

 

Finally, for your knee: Researchers find method to regrow cartilage in the joints

[DJSwarm]

Last year I read the entire thread, so it has been a while and sorry if these things have been discussed before.

But admittedly I still keep wondering about some issues. This was reason that after one round of Fisetin in a hit-and-run fashion (3 days x 1500mg), I decided to wait until I'm better informed. Sorry if my questions may sound a bit ignorant.

 

- I remember there were some studies indicating senolytic agents (I believe it was D&Q in this rodent study, but correct me if I'm wrong), could cause fibrosis. If I remember it well liver fibrosis was noted in a rodent study, and I believe it was hypothesized that a potential cause would be the 'speed' at which tissue had to be regenerated as a result of SC-removal (and/or the fact that the older rodents had less tissue stem cells?). Has this been discussed, could this be a concern for those of us wanting to use senolytics? Any new thoughts about this? Edit to add: this interesting review discusses these aspects: https://www.linkedin...gs-blirando-phd

- On some forums a suggestion of potential stem cell depletion as a result of senolytic treatments was mentioned. Could this be a potential concern indeed?

- Dasatinib was additionally said to be not selective enough in only targeting SC's. I believe I had read an article with a scientist in senescence biology that expressed concern about that. Any thoughts about this?

 

(NB: I understand I should list the sources. But these were mostly suggestions I read on public forums).

Thanks in advance for any response!

 

Actually it was used to treat humans with senescent triggered lung disease: Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study "Our first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases." (one of the first studies that peaked my interest. )

 

D in the senolytic range of 50-100 mg doesn't seem to be problematic and has had a number of human trials like:

Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease

 

Also, why SASP is bad: Cellular senescence and the senescent secretory phenotype in age-related chronic diseases "Aging is a complex biological process accompanied by a state of chronic, low-grade, 'sterile' inflammation, which is a major contributor to the development of many age-related chronic disorders including atherosclerosis, osteoarthritis, Alzheimer's disease, type 2 diabetes, cancers, and others. It appears that cellular senescence plays a role in causing inflammation through the SASP."

 

One the stem cell question, studies do show that when senescent cells are killed in a tissue, the progenitor cells begin to multiply and/or to function better as stem cells. This benefit is not due to the progenitor cells automatically replicating themselves and taking the place of the senescent cell, but because the baleful secretions spewed out of senescent cells inhibit the progenitor cells’ regenerative function, such that destroying senescent cells allows the progenitor cells to begin working properly again. This is observed in blood-cell-forming cells,3 cardiac progenitor cells,6 bone-forming cells,8 and the cells that form new fat cells — in both mice21 and now (in a small, short-term clinical trial) even in humans!22

https://www.sens.org...enescent-cells/

 

Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice; Senolytics improve bone forming potential of bone marrow mesenchymal stem cells from aged mice

 

Rapamycin (and probably berberine) seem tohave more direct beneficial effect of stem cells but lowering SASP does seem to perk them up. 

 

All that said, D is hard to get and its side effects make you feel washed out while you take it (my experience was 3 days at 60mg once a day with 1000 mg Q and 1500 mg F). Rapamycin is even worse with reports of mouth sores, eye sores, deep acne and mild sexual dysfunction in the R thread.

 

Now the good news. Theaflavin also targets the BCL-2 path way like D and Berberine targets mTOR1 like R, both without side effects. Fisetin is an effective senolytic agent in 20mg/kg (1500mg-ish) all by itself and synergizes with D and T. 

 

I've been slowly adjusting my stack and am planning my next run to be 3000 mg liposomal F, 1000mg Q, still looking for dosing guidance on T but probably in the 1000-2000mg range, 1000mg berberine with chocolate (adds emulsified oil and lecithin - and taste),10mg bioperine and 400mg bromalin to aid absorption. (60, M, 6'2", 180lbs, good general health, good diet and exercise) I recommend not doing other things while doing these and I do a run for 2-3 days and then take off a minimum of two weeks, though many (like the Mayo clinic trial) run every week - 2 on 5 off, but just fisetin. My research has shown that chronic administration eventually seems to start causing undesirable side effects which might be tolerable if one was treating a specific disease, but not for what I need as the acute dosing seems to lead to durable effects without side effects. 

 

Hope this was useful.

Edited by DJSwarm, 18 January 2022 - 05:15 AM.

[ambivalent]

"Reviewing the research I see nothing to support extended fasting for senolytic purposes over calorie restriction for sirt1 activation."

 

That wasn't a claim. Nor was there any comparative statement made; however, there are benefits to fasting beyond CR. In autophagy for example. I brought up fasting, as was indicated, to demostrate that detoxification can be an unpleasant experience but highly beneficial - you seem to operate under the generalised assumption that if it is hurting its harming - which is quite obviously untrue: "Also, "detoxifying symptoms" makes no sense. Removing toxins and irritants should make you feel better, not worse." The toxins have to be removed. Once the fast is over, you feel great.

 

Fasting is good, ice baths are good, HIIT is good. So that assumption is false and should not be used to blindly support an argument. Creating stresses has regenerative effects.

 

The very fact that I have reported pain where sensecent cells are likely to be most accumulated, immediately post a fisetin dose that the knee weakens and then subsequently strengthens considerably in the following days would lead me to bet you're wrong. Once again experienced fasters are well used to old injuries flaring up, not noticed in years, then healing and strengthening.

 

The most likely explanation is of course, removal of senescent cells from the knee - weakening - infusion of replacement stem cells - strengthening. The higher the dose, the greater the number removed. 

 

You cited that the reduced blood clotting was a huge clue that I was doing harm - it was a huge clue that I was removing sensecent cells, I otherwise wouldn't have at lower doses. I pointed this out as a risk. However, as one would hope and expect the clotting returned to normal when I bled a few days later. The bleeding was not uncontrolled, it was less controlled. 

 

You seem to operate under the assumption that you will just get there safely at lower doses that A + A + A = 3A. This is not how biology typically works. 

 

To state that something harmful must have been done when a known effect of senescent cell removal was demonstrated is simply an untrue, because it is unproven. No blood clotting issues remained.  You are talking about risk, not harm. When fasting or exercising for example, you have to be careful, a person might feel light headed and so risk fainting, which can be obviously bad in the wrong circumstances. Your body though is better for the fast, in a subsequently less 'risky' state.  

 

You quote a paper highlighting the potential cancer risk yet say that there is no risk if done 'properly'. The paper makes no such claim, but you do and provide no evidence to support it, because there isn't any.

 

I sense that you just want to tell people to take this stuff and hang on it perfectly safe tag. No that label cannot be applied but we sure know senescent cells are long term unsafe. Senolytics have not been comprehensively researched. We don't have ten year follow up studies on thousands of 70 plus year olds taking several grams per week. My approach could well be safer, because my body unlike yours will have long breaks from senolytics. Most people on the site here, prefer the once every few months approach to senolytics. 

 

Aubrey de Grey was asked a couple of years why he doesn't undertake any age-reversing therapies, he replied because of the risk of cancer. Senolytics, NAD therapy will have many biological benefits, but they do carry theoretical tumour risk. I am sure if cancer was curable, then he would take do more but he believes he can wait it out.  The rest of us mostly have a different risk profile, that's why we are here. Everyone is different, some take greater risks than others, partly down to profile and partly because the do-nothing risk is obviously individual. From time to time, there is respectful caution urged - we want to learn but don't want people taking too big a risk. But lecturing people about personal risk, no - not unless they are encouraging others. Likewise, telling people what has beern not proven to be safe, is safe, is not being responsible. Absence of evidence and all that.

 

Re the article on cartliage regrowth, that was interesting, thanks.  

 

 

 

 

 

 

 

 

 

 

 

 

 

[Moondancer]

 

 

One the stem cell question, studies do show that when senescent cells are killed in a tissue, the progenitor cells begin to multiply and/or to function better as stem cells. This benefit is not due to the progenitor cells automatically replicating themselves and taking the place of the senescent cell, but because the baleful secretions spewed out of senescent cells inhibit the progenitor cells’ regenerative function, such that destroying senescent cells allows the progenitor cells to begin working properly again. This is observed in blood-cell-forming cells,3 cardiac progenitor cells,6 bone-forming cells,8 and the cells that form new fat cells — in both mice21 and now (in a small, short-term clinical trial) even in humans!22

https://www.sens.org...enescent-cells/

 

Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice; Senolytics improve bone forming potential of bone marrow mesenchymal stem cells from aged mice

 

Thanks so much for your response DJSwarm. Very helpful. 

Indeed I had seen some of the studies in which an improvement was noted in the progression of fibrotic diseases as a result of senolytic agents. Having said that, I also saw a rodent study indicating senolytic agents had resulted in liver fibrosis. I wish I could find the study, but I can't. However, I believe the suggestion of the researcher was that given the diseased state of the elderly rodents they did not have sufficient stem cells to quickly regenerate tissues after SC-removal. 

And, from the article I posted of Blirando: "Thus, on paper, senescent cells depletion, could halt chronic inflammation and boost tissues regenerative potential. However, in most ageing-associated chronic inflammatory diseases such as IPF, the pro-inflammatory factors are multiple (e.g., cigarette smoking, dust exposure, viral infections, genetic mutations) and the lung exposure to those factors sometimes span several decades. By the time patients are symptomatic, this long-term exposure has caused extensive pathological remodelling, which in itself contributes to the perpetuation of a dysfunctional and pro-inflammatory environment that could favour primary senescence. Moreover, this pathological remodelling has also likely contributed to the exhaustion of the stem cell compartment. In this context, removing senescent cells is unlikely to boost the tissue regenerative potential and reverse the damages, although it could slow-down progression.  In some cases, where senescent cells are numerous, a senolytic approach could even be detrimental by generating even more pro-inflammatory signals and a loss of tissue structures which in the absence of mobilisable stem cells would be compensated by further fibrosis. In this case, treatments by senomorphic might be more appropriate. Considering those elements, senolytic drugs use should be complemented by anti-inflammatory treatment to prevent the recurrence of primary senescence, and by a pro-regenerative approach (e.g., stem cells stimulation or injection) to improve tissue functionality."  https://www.linkedin...gs-blirando-phd

 

This statement of yours, is fascinating with that regard. "One the stem cell question, studies do show that when senescent cells are killed in a tissue, the progenitor cells begin to multiply and/or to function better as stem cells. This benefit is not due to the progenitor cells automatically replicating themselves and taking the place of the senescent cell, but because the baleful secretions spewed out of senescent cells inhibit the progenitor cells’ regenerative function, such that destroying senescent cells allows the progenitor cells to begin working properly again. This is observed in blood-cell-forming cells,3 cardiac progenitor cells,6 bone-forming cells,8 and the cells that form new fat cells — in both mice21 and now (in a small, short-term clinical trial) even in humans!22

https://www.sens.org...enescent-cells/"

 

Thank you. I had not seen that information before. Interesting for sure!

I have been pondering a bit about the suggestion of Dmitry Dhzagarov to combine SC-removal with ROCK-inhibitors and 5-LOX inhibitors, the rationale of which he explains here: https://www.longecit...on/#entry893523

Any thoughts about that? 

Edited by Moondancer, 18 January 2022 - 02:51 PM.