1079 replies to this topic

[stefan_001]

Back to the fighting senescent cells. I am wondering whether we should try to figure out a comibnation:

 

- selective BCL-2 inhibitors such as Fisetin, EGCG

- selective ROS generators such as honokiol that does this in various cancer cells

 

In that way we would boost cell death.

 

[Kevnzworld]

Back to senolytics.
I’m trying to settle on a regimen
I’m already employing a mild intermittent fasting schedule, and moderate exercise 5 days a week. Both have been shown to upregulate autophagy.
I’ve decided to take 300mg of fisetin three times a day for two days during a 36 hour fast. I’m also looking into dosing Azithromycin during this period.
Until I read more about Azithromycin I’m holding off.
https://www.ncbi.nlm...pubmed/30428454
I’m maintaining my regular intake of NR and Metformin
Thoughts?

Edited by Kevnzworld, 08 December 2018 - 07:54 PM.

[stefan_001]

Back to senolytics.
I’m trying to settle on a regimen
I’m already employing a mild intermittent fasting schedule, and moderate exercise 5 days a week. Both have been shown to upregulate autophagy.
I’ve decided to take 300mg of fisetin three times a day for two days during a 36 hour fast. I’m also looking into dosing Azithromycin during this period.
Until I read more about Azithromycin I’m holding off.
https://www.ncbi.nlm...pubmed/30428454
I’m maintaining my regular intake of NR and Metformin
Thoughts?

 

Like I wrote earlier a compound that selectively generates ROS in senescent cells may be very usefull. Its one of the cancer killing properties of Honokiol and various other polyphenols. Which one would however do that with senescent cells?

[Oakman]

Back to senolytics.
I’m trying to settle on a regimen
I’m already employing a mild intermittent fasting schedule, and moderate exercise 5 days a week. Both have been shown to upregulate autophagy.
I’ve decided to take 300mg of fisetin three times a day for two days during a 36 hour fast. I’m also looking into dosing Azithromycin during this period.
Until I read more about Azithromycin I’m holding off.
https://www.ncbi.nlm...pubmed/30428454
I’m maintaining my regular intake of NR and Metformin
Thoughts?

 

Something like that. I was thinking, based on the discussion here, of taking one bottle of Swanson Fistein (30 x 100 mg), dividing it in two, then take that 1500 mg spaced over three doses for two days. That's based on 22 mg/kg for myself @ 68kgs.

 

Anyone have any add'l components that might be useful at the same time?

[Michael]

The stuff on whether aging is programmed or not has been moved here.

[Oakman]

Something like that. I was thinking, based on the discussion here, of taking one bottle of Swanson Fistein (30 x 100 mg), dividing it in two, then take that 1500 mg spaced over three doses for two days. That's based on 22 mg/kg for myself @ 68kgs.

 

Anyone have any add'l components that might be useful at the same time?

 

To expand on my own question and suggested dosing, based on the article below, perhaps a 5 day regimen would be better (safer, more effective) than a higher dose 2 day one, and also combined with quercetin and piperlongumine, both of which are readily available. I'm still gauging what I will eventually try, but this is all good information.

 

"Given that, results from the recent animal study of fisetin noted here greatly exceed expectations, surprisingly so. Fisetin appears about as effective in mice as any of the current top senolytics, such as the chemotherapeutics dasatinib and navitoclax. Per the data in the open access paper below, dosing with fisetin destroys 25-50% of senescent cells depending on organ and method of measurement. The dose level is large in absolute terms, as one might expect for a flavonoid. For aged mice and a one-time treatment, the researchers used 100 mg/kg daily for five days. The usual approach to scale up estimated doses from mouse studies to initial human trials leads to 500 mg per day for five days for a 60 kg human.

 

Given the wealth of new results emerging these days, it seems to me that people focused on self-experimentation, open human trials, and investigative mouse studies in this field should be moving to focus on combination therapies. Consider a combination of fisetin, dasatinib, quercetin, piperlongumine, and FOXO4-DRI- multiple different mechanisms to provoke apoptosis that are all hitting senescent cells at the same time. The goal would be to see if it is possible to engineer a significantly higher level of clearance of senescent cells than any of these senolytics can achieve on their own. This seems like a plausible goal, and may turn out to present meaningful competition to efforts such as those of Oisin Biotechnologies and other groups developing more sophisticated senolytic therapies that should have high rates of clearance."

 

https://www.fightagi...tive-senolytic/

[Ducky-001]

An observation:

 

I did a trial a few weeks back with Mitochondrial fission (turnbuckle protocol + High dose fisetin (1.5g in olive oil). I did the fission like in day 1 or 2 here: https://www.longecit...-33#entry851034 , and took the 1.5 g fisetin in the evening (about 10 hours after the nicotinamide + ribose). This lead to a persistent headache and flu like symptoms for around 15 hours starting a few hours after taking in the fisetin. I don't know yet if this was good or bad for me.

 

Edited by Ducky-001, 11 December 2018 - 01:36 PM.

[QuestforLife]

Very interesting. Hopefully the double challenge on your mitochondria has caused a more severe senolytic action that will leave you better off on the long run.

 

Mito fission has given me headaches in the past, but no flu - have you experienced these symptoms before without the fisetin?

Edited by QuestforLife, 11 December 2018 - 01:39 PM.

[Ducky-001]

Mito fission has given me headaches in the past, but no flu - have you experienced these symptoms before without the fisetin?

 

Headache has happened with fission, but only after the first high dose fisetin (earlier in thread). This was much more severe though. So I suspect a connection.

[male_1978]

Btw isnt there a way to measure the number of senescent cells in the human body? So that we could directly see whether fisetin works or not?

[DJS]

I'm a 39.7 year old male. This is the first time I'm utilizing senolytics. I went with the protocol for two days at 1400mg fisetin, and I'll repeat that again in 30 days. I paused with the rest of my stack except for the cocaoVia and glucosamine sulfate. I'll report back if there's any noticeable effect.  

[DJS]

So there was definitely a noticeable effect. Approximately two hours after taking the 1400mg of fisetin I began to experience symptoms which I'd describe as similar to cold or flu. My face became flush and I felt overheated. I experienced some post nasal drip and a bit of a runny nose. At one point I began sweating profusely and could wipe the sweat off of my forehead with my hand. This only last for a few hours and then subsided. By later in the afternoon all of those symptoms went away but now I continue to feel unusually fatigued. I haven't experienced any positive effects but I wasn't expecting to, at least not in the short term. I will proceed with the second round tomorrow and see how it goes.

Edited by DJS, 16 December 2018 - 02:28 AM.

[DJS]

Alright, so this will be my last post for a while as I don't want to overwhelm this thread with just my posts. 

 

The second day went almost exactly the same as the first day (with flu like symptoms, and residual fatigue) but I do have a few interesting observations to report.

 

1. Sleep disturbance. I usually have no issues with my sleep patterns but on both nights after administering the senolytic dosage of fisetin I woke up after approximately five hours of sleep. I stayed up for about an hour before I was able to get back to sleep for about another 1.5 hours.

 

2. Cold sores. I use to get cold sores back in my 20's but I haven't had one in at least 7 or 8 years. This morning I woke up with two on my upper lip. That I find very unusual and obvious this would suggest that my immune system is being impacted in some way by this treatment.

 

And that about covers it. By midday today after two days of dosing at 1400mg fisetin I feel totally normal again. I feel great but I have no serious health issues so this isn't out of the norm.I haven't noticed any obvious improvements in my health but I will continue to monitor myself through out this month to see if there's anything that I could possibly attribute to the fisetin.

 

Best,

Don

[able]

Alright, so this will be my last post for a while as I don't want to overwhelm this thread with just my posts. 

 

The second day went almost exactly the same as the first day (with flu like symptoms, and residual fatigue) but I do have a few interesting observations to report.

 

1. Sleep disturbance. I usually have no issues with my sleep patterns but on both nights after administering the senolytic dosage of fisetin I woke up after approximately five hours of sleep. I stayed up for about an hour before I was able to get back to sleep for about another 1.5 hours.

 

2. Cold sores. I use to get cold sores back in my 20's but I haven't had one in at least 7 or 8 years. This morning I woke up with two on my upper lip. That I find very unusual and obvious this would suggest that my immune system is being impacted in some way by this treatment.

 

And that about covers it. By midday today after two days of dosing at 1400mg fisetin I feel totally normal again. I feel great but I have no serious health issues so this isn't out of the norm.I haven't noticed any obvious improvements in my health but I will continue to monitor myself through out this month to see if there's anything that I could possibly attribute to the fisetin.

 

Best,

Don

 

 

Thanks for updates Don. I find it encouraging that you had the same symptoms 2 days in a row.  Makes it less likely to be a coincidence.

[male_1978]

I would like to hear your oppinion on one counter-argument which came to my mind. 

 

According to this source here, strawberries contain 160 μg/g fisetin, but also apples contain a high concentration of it (26.9 μg/g). Eating one kg of strawberries (which is a reasonable amount in spring time) should already give you 160 mg fisetin. This is even more than most supplements contain (here in europe "Nature Power" sells capsules with 50 mg per capsule).

 

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

 

 

In the mice study, normal and progeroid mice were given a high amount of fisetin for only a few days, rejuvenating them for many months. To translate this to humans, shouldnt we consider, that we already take higher amounts of fisetin occasionally? If we talk about senolytics in general (including curcumin and maybe others, which are not even researched), an average human will occasionally get a higher dose of senolytics just by normal food.

 

I dont want to be too pessimistic here, but can it be, that the conclusion of all this is that eating healthy contributes to a longer life?

[Ducky-001]

Don: I also experienced cold sores after high dose fisetin. At first only small, almost invisible ones, but later also two larger ones. Cold sores are a common occurrence for me so I did not think so much of it. It was the first since summer and sun though.

 

male_1978: But you would have to eat 8-10 kg of strawberries in one go to get to the doses tried here.

[OP2040]

male_1978: But you would have to eat 8-10 kg of strawberries in one go to get to the doses tried here.

 

Exactly, it's very impractical.  People have a bias toward natural products, or getting this type of thing through food only.  But we have to remember, food is often borderline poisonous too, or at least it was before we domesticated the hell out of everything.   At the very least, many foods have anti-nutrients that decrease the availability of whatever target nutrient you are trying to deliver. 

 

I'm sure male_1978 might be more interested in the cost savings though, which makes perfect sense. Strawberry extract might be a good option to decrease cost and it was even used in a few studies I've seen.

[mikeinnaples]

So there was definitely a noticeable effect. Approximately two hours after taking the 1400mg of fisetin I began to experience symptoms which I'd describe as similar to cold or flu. My face became flush and I felt overheated. I experienced some post nasal drip and a bit of a runny nose. At one point I began sweating profusely and could wipe the sweat off of my forehead with my hand. This only last for a few hours and then subsided. By later in the afternoon all of those symptoms went away but now I continue to feel unusually fatigued. I haven't experienced any positive effects but I wasn't expecting to, at least not in the short term. I will proceed with the second round tomorrow and see how it goes.

 

"Perhaps" there is something to this or it is just coincidence. I had similar but slightly longer lasting symptoms using 2400mg Q that I followed an hour later with 8 Ultracur pills (curcumin supposedly with more bioavailability) on the first two days of a 5 day cycle.

 

I also had more mild symptoms when I tried 600mg of fisetin a month ago (also an hour or so after 2400mg Q). Of course the common denominator for me is the Q and I haven't tried either without it. Maybe coincidence, maybe not.

[Krell]

Alright, so this will be my last post for a while as I don't want to overwhelm this thread with just my posts. 

 

The second day went almost exactly the same as the first day (with flu like symptoms, and residual fatigue) but I do have a few interesting observations to report.

 

1. Sleep disturbance. I usually have no issues with my sleep patterns but on both nights after administering the senolytic dosage of fisetin I woke up after approximately five hours of sleep. I stayed up for about an hour before I was able to get back to sleep for about another 1.5 hours.

 

2. Cold sores. I use to get cold sores back in my 20's but I haven't had one in at least 7 or 8 years. This morning I woke up with two on my upper lip. That I find very unusual and obvious this would suggest that my immune system is being impacted in some way by this treatment.

 

And that about covers it. By midday today after two days of dosing at 1400mg fisetin I feel totally normal again. I feel great but I have no serious health issues so this isn't out of the norm.I haven't noticed any obvious improvements in my health but I will continue to monitor myself through out this month to see if there's anything that I could possibly attribute to the fisetin.

 

Best,

Don

DJS, thanks for your report.

 

I have tried fisetin1000mg x 3 days with no discernible effects. 

Now I have a new bottle of Drs Best Fisetin 30x100mg capsules and would like to try to duplicate your dosage. 

Some questions:

 

1. What brand did you use?

2. How did you prepare your dose?  In olive oil?  Raw powder removed from capsules?  Swallowed or under tongue?

3. What time of day did you take it?  With food or on fast?  Other food that day?

4. Did you check your blood pressure or temperature?

 

TIA

[Rocket]

DJS, thanks for your report.

 

I have tried fisetin1000mg x 3 days with no discernible effects. 

Now I have a new bottle of Drs Best Fisetin 30x100mg capsules and would like to try to duplicate your dosage. 

Some questions:

 

1. What brand did you use?

2. How did you prepare your dose?  In olive oil?  Raw powder removed from capsules?  Swallowed or under tongue?

3. What time of day did you take it?  With food or on fast?  Other food that day?

4. Did you check your blood pressure or temperature?

 

TIA

 

Maybe people should post their ages when discussing lack of results from senolytics. It is not logical for someone 23 years old to get an effect from a senolytic as compared to a 45 or 55 year old.

[Krell]

Maybe people should post their ages when discussing lack of results from senolytics. It is not logical for someone 23 years old to get an effect from a senolytic as compared to a 45 or 55 year old.

 

Agree. I am 74yro, so I expected at least a double whammy from my previous 3dayx1000mg fisetin in OO trial.

But nada, as far as I can tell.

Maybe it's a quantum effect and 2dayx1500mg will kick me over the edge?
 

[extendcel]

What I'm noticing is the people noticing effects from fisetin are all taking more than 1000mg. As stated before, people may just be taking too small of a dosage. Fisetin is quickly metabolized by liver enzymes so there is likely a threshold. You'd have to overwhelm the enzymes with a large enough dose. We should take care though because there seems to be some senolytic side effects with large doses.

[Rocket]

What I'm noticing is the people noticing effects from fisetin are all taking more than 1000mg. As stated before, people may just be taking too small of a dosage. Fisetin is quickly metabolized by liver enzymes so there is likely a threshold. You'd have to overwhelm the enzymes with a large enough dose. We should take care though because there seems to be some senolytic side effects with large doses.

I have concluded about the same thing with dasatanib. People were taking far far too low of a dose. When I took 200 to 250mg i most definitely got results. Though they diminished over subsequent doses.

[male_1978]

I (40 years, 90 kg) now took 1,5 g fistein on two days (total of 3 g), and didnt feel or see any effects by now. I also went for excercise and measured blood pressure during that time and also saw no difference.

 

Maybe i am too young or the dose was too low, how knows. I still assume that humans, who occasionally eat curry and strawberries, already kill many of those senescent cells, which are vulnerable to fisetin or curcumin.

[QuestforLife]

I (40 years, 90 kg) now took 1,5 g fistein on two days (total of 3 g), and didnt feel or see any effects by now. I also went for excercise and measured blood pressure during that time and also saw no difference.

 

Maybe i am too young or the dose was too low, how knows. I still assume that humans, who occasionally eat curry and strawberries, already kill many of those senescent cells, which are vulnerable to fisetin or curcumin.

 

As far as I understand it, senolytics works by stressing cells in someway (often through mitochondria), and this is sufficient (depending on the tissue) to push senescent cells over the edge into apoptosis, whilst more metabolically flexible and resilient cells are unaffected. So there are several explanations for feeling nothing from a senolytics protocol:

 

• Dose may be insufficient in concentration or duration.
• Tissues type/s affected may not impact the body in a noticeable way
• Number of senescent cells may be too small to notice their removal

Humans will obviously accumulated senescent cells MUCH more slowly than mice, so even if dose is sufficient and the number of tissues affected is substantial, we might still not notice, unless we are very old.

 

It might be instructive to get a LifeLength Telomere test which gives you the percentage of very short telomeres. Those with a high proportion of these should be more affected by senolytics.

Edited by QuestforLife, 19 December 2018 - 09:41 AM.

[DJS]

DJS, thanks for your report.

I have tried fisetin1000mg x 3 days with no discernible effects.
Now I have a new bottle of Drs Best Fisetin 30x100mg capsules and would like to try to duplicate your dosage.
Some questions:

1. What brand did you use?
2. How did you prepare your dose? In olive oil? Raw powder removed from capsules? Swallowed or under tongue?
3. What time of day did you take it? With food or on fast? Other food that day?
4. Did you check your blood pressure or temperature?

TIA

1. Rejuvenation Therapeutics. I purchased it on Amazon.
2. I did all 1400mg at the same time. I opened up the capsules and mixed the powder in about 1/3 of a cup sweet potato mash along with three table spoons of evoo.
3. On both days I dosed myself around 12ish. I wasn’t on an extensive fast but it was the beginning of my feeding window (12-7pm) so I hadn’t eaten since the night before. Just a large cup of coffee with a splash of almost milk around 930am. On both days I had a large meal at 6pm but by then I was already feeling the effects from the fisetin.
4. I did not. When I do the second round next month I’ll try to be more thorough in taking measurements.
I see a lot of different options for dosing being mentioned here. I went with the Mayo Clinic phase 2 protocol which is 20mg/kg body weight for two consecutive days. Repeat again 30 days later and then wait 6-12 months before doing another round. I’m 5’9.75” and weigh 67.6kg.

[DJS]

Also, I’m not sure if any of you watched the LEAF journal club yesterday on fisetin but it was mentioned that mice have been administered literally grams per kilogram of this stuff with no apparent toxicity. So the concern is really just about bioavailability. This is the reason that I pulled the trigger on fisetin but have not tried other senolytics such as foxo4-dri

Edited by DJS, 19 December 2018 - 03:13 PM.

[Nate-2004]

Also, I’m not sure if any of you watched the LEAF journal club yesterday on fisetin but it was mentioned that mice have been administered literally grams per kilogram of this stuff with no apparent toxicity. So the concern is really just about bioavailability. This is the reason that I pulled the trigger on fisetin but have not tried other senolytics such as foxo4-dri

 

They post their videos on FaceBook for some stupid reason. I can't listen with the phone locked to FB videos but I can with YouTube. 

 

I think bioavailability is definitely the biggest issue. I tried 1200mg yesterday, I'm on my final 5 day extended fast of my 6 month commitment of one fast per month. So I'm doing the same thing I did last time with fisetin, quercetin, apigenin and dasatinib. I might do this again next year but until then any other fasting will be less than 48 hours, maybe alternate day.

 

I think people are right about "noticing" things, I'm not sure what people are trying to notice without lab work and testing like pre/post BP and HRV and other factors. Also it may only be a significant impact over the long run. Like, if senescent cells are something that builds up over time then killing what few there are in one's 40's may stave off a buildup for a decade.

 

Also there's more at play than just senescent cells obviously. If people wanna look and feel younger they're going to need to deal with the increasing human neutrophil elastase dysfunction that contributes to the loss of elastin in skin and blood vessels. They're going to have to break AGE crosslinks, etc.

 

Also apparently senescent skin fibroblast cells can be killed with some kind of radio frequency needling.

Edited by Nate-2004, 19 December 2018 - 04:13 PM.

[Oakman]

So I'm doing the same thing I did last time with fisetin, quercetin, apigenin and dasatinib. 

 

Could you share your amounts of each used?

[Nate-2004]

Could you share your amounts of each used?

 

I posted these earlier but here's what I'm doing this time around based on recent posts.

 

For 3 days in a small shot glass:

80mg Dasatinib

1000mg Quercetin

150mg EMIQuercetin

1500mg Fisetin

100mg Apigenin

 

Drenched in 1 tsp of MCT oil

 

Today I'm feeling way worse than I usually do on the third day of fasting but gonna push through it.

 

The third day I won't have any fisetin left but I'll do the other stuff.

Edited by Nate-2004, 19 December 2018 - 05:17 PM.