1079 replies to this topic

[Nate-2004]

There is no "THE" answer to aging. Obviously there are multiple hallmarks to address. Senescent cells is one of those.

[OP2040]

JR7,

Although I didn't do this due to circumstance, I absolutely think it's worth ramping up autophagy while using Fisetin.  It's all speculation, but this seems very obvious to me.  I don't think 5 day fasts are necessary given that intermittent fasting of 1-3 days does a good enough job, but that is your choice.

[Nate-2004]

JR7,

Although I didn't do this due to circumstance, I absolutely think it's worth ramping up autophagy while using Fisetin.  It's all speculation, but this seems very obvious to me.  I don't think 5 day fasts are necessary given that intermittent fasting of 1-3 days does a good enough job, but that is your choice.

 

I'm on a 5 day fast right now, the 4th iteration of my 6 month go at it. How do you know that 3 days is enough in humans?

 

I'm basing 5 days on the FMD in Valter Longo's studies, but I am not mimicking, I'm just water fasting.

 

Also, how well is fisetin absorbed or how bioavailable is it while in a fasted state? Some flavonoids take fat and other mechanisms to become more bioavailable.

 

It's weird that in that comparison study, quercetin actually appears to perform the worst.

Edited by Nate-2004, 24 October 2018 - 05:35 PM.

[sthira]

Do you folks feel there would be some auophagy synergy with combining fisetin and extended (5 day) fasts?

Right?! How hard would this be to test? Not hard at all. We could throw together some citizen science and see what happens. But the question will still remain how to know that what we did did anything at all? Fasting is powerful on all its own. Throwing senolytics into the equation just seems like a no-brainer to me. What do I know...

[ryukenden]

The second most effective senolytic in the paper was curcumin, and there are already bio-available formulations of curcumin available. Perhaps we should give curcumin a try.

How about combination of Fisetin and Curcumin?

[sthira]

Right?! How hard would this be to test? Not hard at all. We could throw together some citizen science and see what happens. But the question will still remain how to know that what we did did anything at all? Fasting is powerful on all its own. Throwing senolytics into the equation just seems like a no-brainer to me. What do I know...

Looking back over my notes, I tried fasting in conjunction with fisetin and EMIQ (the purportedly more bioavailable quercitin) back in March, 2017. I didn't report here just because I thought the experiment was useless.

FWIW, here's what I did:

Sun 3/19/17
Started eating @11am
Stopped@830pm
1pm: EMIQ (quercetin): 5,000 mg
Fisetin: 1,000 mg (senescent cell experiment)

Mon 3/20/17
Fisetin: 1,000 mg (am)
EMIQ: 1,000 mg (am)
Started eating@1230
Stopped@230pm
Quercetin: 5,000 mg (27)
Fisetin: 1,000 mg

Tues 3/21/17
150.4lbs
Fast Day 1 (24hrs)
1pm: EMIQ: 3,500 mg (28)
Fisetin: 3,000 mg

Weds 3/22/17
149.0lbs
Fast Day 2 (48hrs)
1pm: EMIQ: 3,500 mg
Fisetin: 3,000 mg

Thurs 3/23/17
147.8lbs
Fast Day 3 (72hrs)
1pm: EMIQ: 3,500 mg
Fisetin: 3,000 mg

I noticed nothing either positive or negative. My blood tests remained the same -- all values within their annoying ranges. Nothing changed; I'm aging on schedule just like you and everyone else on this planet. I considered the self-experiment pointless. I mean, without more advanced ways to test what we want tested, we can't know very much. I did a same self-trial fasting with curcumin, too, also noticed zilch.

For what it's worth, the EMIQ I swallowed was Natural Factors: https://naturalfacto...-quercetin-emiq

And Doctor's Best fisetin: https://www.iherb.co...ggie-caps/43592

[OP2040]

How about combination of Fisetin and Curcumin?

 

I'm doing that too, so obviously I think it's a good idea.  Seems like it would help with synergy, or with creating an opportunity for more Fisetin to get past the liver.

 

These are educated guesses, but IMO they are very good educated guesses.  Science being what it is, common sense doesn't always work and it could be completely the opposite.  But I doubt it...

[Turnbuckle]

I noticed nothing either positive or negative. My blood tests remained the same -- all values within their annoying ranges. Nothing changed; I'm aging on schedule just like you and everyone else on this planet. I considered the self-experiment pointless. I mean, without more advanced ways to test what we want tested, we can't know very much. I did a same self-trial fasting with curcumin, too, also noticed zilch.
 

 

Try getting your epigenetic age checked by Osiris Green, before and after. Since OG uses buccal cells from the mouth and such cells take some 20 days from generation to shedding, you should wait a month after treatment to take the second sample. 

[sthira]

Try getting your epigenetic age checked by Osiris Green, before and after. Since OG uses buccal cells from the mouth and such cells take some 20 days from generation to shedding, you should wait a month after treatment to take the second sample.

Good idea. Here's a link to the OG test: https://www.osirisgr...com/product.php

[OP2040]

Good idea. Here's a link to the OG test: https://www.osirisgr...com/product.php

 

It's not clear from the phrasing in your other post whether your parameters were in or out of range to begin with.  If they were in range, I'm not sure what you were expecting.  After all, in range is good, so nothing to see there.

 

The test I would like to see more than anything is a senescent cell before and after test.  That would satisfy my curiosity since this can be considered preventative maintenance.

[Michael]

Good idea. Here's a link to the OG test: https://www.osirisgr...com/product.php

 

Not so much. This has only been very informally linked to chronological age (see here): we have zero evidence it's of any value whatsoever as a measure of biological age: as in, no one has even attempted to test it for this. I don't see the point of running the original Horvath clock (see my post earlier in this here), but at least it's been clearly demonstrated as closely correlated to chronological age; OG may be no better than a blindfolded dartboard toss for all we know at this point.

[sthira]

So summarizing, we're now awaiting a new Horvath test that's not commercially available, but developed by machine learning from mostly common blood tests -- https://www.aging-us...cle/101414/text -- in order to note personal effects of a promising, yet untested in humans senolytic substance easily available retail (fisetin).

Or you can just buy bottles and bottles of the stuff (prices have now risen, I see) and see if does something you notice.

[Audioque]

I've been taking this everyday short from two weeks now at 240-300mg a day. I'm a 34 year old 52kg woman who is healthy despite of very stressful schedule and is surviving on not enough sleep for the past 4 years (I know, I know.). The only thing I notice is I'm very slightly less fatigued. I also started more resistant exercises and planning to up that to every other day for the whole body once I have more time come December. 

Edited by Audioque, 26 October 2018 - 04:44 AM.

[Turnbuckle]

Not so much. This has only been very informally linked to chronological age (see here): we have zero evidence it's of any value whatsoever as a measure of biological age: as in, no one has even attempted to test it for this. I don't see the point of running the original Horvath clock (see my post earlier in this here), but at least it's been clearly demonstrated as closely correlated to chronological age; OG may be no better than a blindfolded dartboard toss for all we know at this point.

 

 

If there is value in it, it's in tracking changes in epigenetic age due to some treatment, not in the age itself. 

 

And once again, if tracking changes due to a treatment, keep in mind that there is a lag of 3 to 4 weeks before changes will be detectable as cells migrate from the basal layer and are ultimately shed. Buccal cells don't even live for a month, so their age represents the age of their source cells--the transit amplifying cells in the layer directly above the stem cell layer. If a senolytic treatment is to be effective in reducing epigenetic age, it would have to kill off some of those amplifying cells and replace them with stem cells. This would appear to be where chemo drugs can shine--by killing off still dividing cells that are epigenetically old.

 

Some tissues in the adult body, such as the epidermis of the skin, the lining of the small intestine, and bone marrow, undergo continuous cellular turnover. They contain stem cells, which persist indefinitely, and a much larger number of “transit amplifying cells,” which arise from the stem cells and divide a finite number of times until they become differentiated. 

--Britannica

 

[Michael]

 

Not so much. This has only been very informally linked to chronological age (see here): we have zero evidence it's of any value whatsoever as a measure of biological age: as in, no one has even attempted to test it for this. I don't see the point of running the original Horvath clock (see my post earlier in this here), but at least it's been clearly demonstrated as closely correlated to chronological age; OG may be no better than a blindfolded dartboard toss for all we know at this point.

If there is value in it, it's in tracking changes in epigenetic age due to some treatment, not in the age itself.

 

Sure — of course. That's the only reason it's being brought up in this thread. But of course, the thing that would change with an effective anti-aging intervention is your biological age, not your chronological age.
 

And once again, if tracking changes due to a treatment, keep in mind that there is a lag of 3 to 4 weeks before changes will be detectable as cells migrate from the basal layer and are ultimately shed. Buccal cells don't even live for a month, so their age represents the age of their source cells--the transit amplifying cells in the layer directly above the stem cell layer. If a senolytic treatment is to be effective in reducing epigenetic age, it would have to kill off some of those amplifying cells and replace them with stem cells. This would appear to be where chemo drugs can shine--by killing off still dividing cells that are epigenetically old.

I don't think that follows. We don't really understand what exactly causally connects epigenetic clocks to either chronological or biological age, but since it's reflected in circulating cells and is correlated with both subclinical disease and a composite score of multiple functional and biochemical tests that aren't obviously connected to the quality of those cells, it may well largely reflect the signaling environment, which you'd expect to change rapidly with senescent cell ablation. And in this case it's by definition not  killing off still-dividing cells that are epigenetically old, since growth arrest is the core characteristic of senescent cells.

 

Still, it may be wise to curb one's impatience and wait a while before being tested: if the rodent data translate, the delta should be pretty durable.

[Turnbuckle]

 And in this case it's by definition not  killing off still-dividing cells that are epigenetically old, since growth arrest is the core characteristic of senescent cells.

 

 

I should have used the phrase "age-reversing" rather than "senolytic." Ideally you would go after epigenetically old cells of any chronological age or any level of functioning as they are detuned to their purpose. Senescence simply makes them an easy target. Transit amplifying cells pose a problem, as they do most of the dividing in tissues like the skin, and they also produce telomerase. If they have more methylation than stem cells, then they can age epigenetically. Thus they would seem an interesting target for a telomerase inhibitor--dasatinib, for instance. Render them senescent with dasatinib and then kill them with a flavonoid.

Edited by Turnbuckle, 27 October 2018 - 10:44 AM.

[Turnbuckle]

Many natural hTert and telomerase  inhibitors can be found in Table 3 of this paper--https://www.ncbi.nlm...les/PMC5795965/

 

According to that table (a gold mine of possibilities), a number of flavonoids are inhibitors, and that likely adds to their senolytic activity. They are not just going after senescent cells, they are making them senescent.

 

Another potential down regulator of telomerase is calcium--

 

 We further show for human epidermal cells that differentiation-dependent downregulation of telomerase correlates with Ca++-induced cell differentiation and that increasing the amount of Ca++ but not Mg++ or Zn++ reduced telomerase activity in a dose-dependent manner in a cell-free system (differentiation-independent). Furthermore, addition of ethyleneglycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid completely reversed this Ca++-induced inhibition. These data indicate that Ca++ is not only an important regulator of epidermal differentiation but also a key regulator of telomerase.

https://www.jidonlin...0316-1/fulltext

 

 

Edited by Turnbuckle, 27 October 2018 - 11:39 AM.

[QuestforLife]

They are not just going after senescent cells, they are making them senescent.

This makes me question whether we really want to be doing this.

I mean I understood the logic of removing senescent cells in the way you'd need to reopen a wound to clean an infection before it will heal, or rebreak a wonkily healed broken bone, but actually pushing cells into senescence - this will obviously (in the long run) move all remaining cells in the tissue closer to senescence (as they divide to make up the numbers) and at some point make things worse rather than better.

We also need to take account of the fact that mice are not men - mice cells have much higher ROS, so will suffer a greater rate of attrition via this mechanism,but because of their much longer telomeres are more likely to have ready replacements for those lost via ROS. So in the case of mice senescent cell removal is a win-win. For humans I have my doubts it will be as beneficial.

[Turnbuckle]

This makes me question whether we really want to be doing this.

I mean I understood the logic of removing senescent cells in the way you'd need to reopen a wound to clean an infection before it will heal, or rebreak a wonkily healed broken bone, but actually pushing cells into senescence - this will obviously (in the long run) move all remaining cells in the tissue closer to senescence...

 

 

This should work on rapidly dividing cells that express telomerase. Obviously you will not use this treatment all the time, and certainly not when you are sick or injured. In the skin example with transit amplifying cells, let's say you wipe out half those cells that are then replaced by stem cells. In that hypothetical case, the average epigenetic age of those cells would be cut in half.

Edited by Turnbuckle, 27 October 2018 - 04:08 PM.

[sthira]

I don't think the technology is anywhere near well enough known in humans to be so specific as to knowing which cells shall die and which cells shall live because of taking unregulated consumer vitamin fisetin pills.

It may be wise to await development, as noted above, but some folks just don't have that option, and are trying to do whatever possible NOW to attempt removal of aging damages.

The human results of the fisetin study in 70-90 year old women may inch us closer to understanding what fisetin actually does to people, but that work may be years and years away (they're still recruiting). What are people supposed to do this moment? Keep experimenting, ye pioneers...

[OP2040]

I don't think it's realistic to expect an intervention to be more than probabalistic.  We will cure aging long before we need to micromanage every cell or cellular component in the body.  This misunderstanding and fearmongering results from a "damage" TOA, and an extreme reductionist view of biology.  But biology is a process.  And as such, senescent cells can be considered as a part of a homeostatic process that also exists on youth but goes awry in aging.  Consequently, it should be enough to merely push this process back toward the homeostasis we see in youth by clearing mostly senescent cells.  If one goes looking for "damages" everywhere, that is exactly what one will find. But so far this has in no way translated to heathspan or lifespan.  and as hormesis shows, they are not really relevant to the overall process of aging.

 

The fact that senolytics, including Fisetin, may have some off-target effects doesn't bother me in the least. 

 

 

[NoodleHead]

Hi no one seems to have said anything about bromelain.
Quercetin supplements often come combined with doses of bromelain, apparently to increase absorption. Could the same be true of fisetin?
I plan to take 600mg fisetin + 1600mg quercetin+. 500mg bromelain for 5 days and report back here.
I'm a 37 year old man with IBS pain issues, otherwise healthy.
* I'll probably mix this with a small quantity of olive oil for good measure.

Completed my 5 day course of this mixture. No side effects to speak of. It didn't even irritate my inflamed gut. This is a problem I have when taking a lot of supplements and medications. I can't tolerate alcohol or caffeine either.

 

Anyway, that's this experiment over for 6 months. I'll try again in March 2019. If I notice any anti-aging effects in the meantime (unlikely at my age I know) I will post here. Im happy to continue to take Fisetin every 6 months as an aging preventative as it's low cost and fairly low risk IMO. 

[OP2040]

Just completed my 5 day course as well.  It looks like NoodleHead and I have pretty much the same game plan (6 month intervals), until something even better comes along.

My experience:

 

~ 5 days, 1g first two days, 1.5g last three days.  Stacked with NAC, Curcumin (w/Piperine) and olive oil, but none of my other usual supplements.

~ Absolutely no negative side effects

~ Nothing significant to report.  Lots of subjective possibilities like improved mood, sleep and other ambiguous indicators that really shouldn't be objectively used.

 

[Harkijn]

Howmuch NAC and Curcumin did you take per day?

 

[OP2040]

Curcumin 1500mg

NAC          600mg

 

~Reasoning for NAC was to protect liver.  I don't think it was needed at all, but I have it and don't use it so I figured why not.

~Reasoning for Curcumin was to frontload liver metabolism hoping that maybe more Fisetin would then get through.  Also, in the study Curcumin performed second best

  as a senolytic which was surprising, so was also hoping for some synergy.

 

[QuestforLife]

Curcumin 1500mg

NAC          600mg

 

~Reasoning for NAC was to protect liver.  I don't think it was needed at all, but I have it and don't use it so I figured why not.

~Reasoning for Curcumin was to frontload liver metabolism hoping that maybe more Fisetin would then get through.  Also, in the study Curcumin performed second best

  as a senolytic which was surprising, so was also hoping for some synergy.

 

Curcumin - good, but NAC? Why would you want an antioxidant, which is likely to protect mitochondria from fission (and therefore apoptosis)?

[OP2040]

In the FOX04-dri thread, everyone was saying the same thing.  Basically, the idea was to stop taking supplements that help promote cellular repair or defense so more senescent cells will be available to massacre. 

 

I'm not sure I buy into that argument.  It could easily be spun the other way to say that we need to protect as many cells as possible to keep a senolytic from going too far.  

 

I took it specifically to protect my liver from possible effects of mega-dosing.  But I agree it's not really necessary since, Fisetin hasn't shown any liver damaging properties even at high doses.  Probably won't take it next time.

[ambivalent]

Around ten days ago I decided to experiment with Fisetin in a characteristically excessive manner: 3 grams of Fisetin dissolved in olive oil not long before bed. Perhaps mistakenly I also took around a gram of NMN (cell rescue?) and a few grams of taurine.

 

Now for the previous 6 weeks or so I was battling an apparent asthma/allergy chest problem triggered by an infection, which also I was beginning to wonder if it had entirely disappeared. Brief relief occurred with ante-histamines and inhalers, however, but not always, it was gradually improving but a struggle to shift: at times the coughing was very bad. Only fasting brought complete (but temporary) relief and I felt, but not conclusively, an ante-inflammatory diet. A few days prior I'd been out, following reduced symptoms, and had a few glasses of wine (both colours): this triggered persistent coughing.

 

Anyhow, upon awaking the morning after my chest felt pretty clear, coughing much reduced, but this could happen especially after the mini-fast that is sleep but also, as mentioned, if I was careful with what I was eating. Two days on I was good, but I fell shy of the acid test: alcohol. In the evening I decided to drink a couple of glasses of red wine. No coughing. Buoyed somewhat, unfortunately, I drank rather to excess, still no coughing but obviously a host of alcohol-related problems :-) Anyhow, the next day I was less than great and my chest was not fantastic either and some coughing returned, unsurprising for a clobbered immune system. There is still a trace of the problem but I would say quite confidently that Fisetin had a considerable effect, typically I have to wait til a change in season which admittedly is transitioning (with regular fasting over the years the previous persistent symptoms didn't arise).

 

During the Fisetin-dose night I slept shorter and experienced a vivid and disturbing dream (this might be NMN related)  I'd also noticed that day some increased clarity but strangely what appeared to be an increase in verbal errors. This is a weak effect though.

 

Over the next couple of days I noticed my likely arthritic knee worsened noticeably, my other largely problem free-knee also become painful, albeit considerably less. This flare of injuries can be quite common during fasting as healing occurs. The last few days has seen a stubborn post sleep neck-kink. Its not that common for me to get them these days, and they rarely hang around this length of time. Again, though, a fairly weak Fisetin-effect.

 

Finally the most interesting and worrying post-experimental observation. I remember last year reading (on a blog: ref?) that one unfortunate senolytic side-effect is delayed wound healing. A week after the Fisetin dose I nicked a small wart at the base of my nostril while shaving. It was one of those dreaded nicks that you know will bleed for a while, it wasn't a deep or sharp cut, but warts bleed. The blood-flow was slow and low in volume but persistent. Given I immediately wondered about the possible senolytic effect, I thought my perceived slowness of recovery might have been down to 'watching the pot' - an hour plus is normal for me for a bad razor cut. I dabbed with a bit of vitamin E oil to potentially help healing and stem the flow - a small blood-blob would surface after say 15 seconds. The rate of flow didn't seem to change over the ensuing hours, I kept dabbing until around 5.5 hours later it abated. (today I accidentally caused it to bleed and it bled very briefly and stopped). I can't ever recall this nick, which has happened a few times in the past ever taking anything like this long.

 

The three effects I would take with high confidence from my Fisetin experiment are overnight alleviation of my likely allergic-cough, increased knee pain and blood-clotting inhibition.

 

 

* additional effect: definite softening of the skin (strong effect but could be due to confounding factors).

 

** one other confounding factor the night of the razor was a brief a basic stearic acid/c60 stem cell protocol, which I hadn't undertaken for at least a couple of weeks.

 

 

 

[Turnbuckle]

 

 

** one other confounding factor the night of the razor was a brief a basic stearic acid/c60 stem cell protocol, which I hadn't undertaken for at least a couple of weeks.

 

Fisetin promotes mito fission and thus operates in the opposite direction of stearic acid, so I wouldn't mix them. It works with NAD+ to decrease mitochondrial content. 

 

Nicotinamide-induced mitophagy: event mediated by high NAD+/NADH ratio and SIRT1 protein activation.

[ambivalent]

Fisetin promotes mito fission and thus operates in the opposite direction of stearic acid, so I wouldn't mix them. It works with NAD+ to decrease mitochondrial content. 

 

Nicotinamide-induced mitophagy: event mediated by high NAD+/NADH ratio and SIRT1 protein activation.

 

Thanks, Turnbuckle. I didn't include the timeline of the cut, it was around 5 days after Fisetin - I seem to recall it has a short half life. If it isn't well known I'll see if I can dig around and find the reference to senolytics and healing.