48 replies to this topic

[Ovidus]

As you all know,  the Dasatanib + Quercetin combo has been widely discussed as a senolytic.

 

Recently, Azithromycin has been brought up as well... see below

https://www.longecit...o-be-senolytic/

 

Now, all three substances above appear sufficiently well-studied and safe on their own. So, let us talk about combinations:

1- Can we combine all three in a  Azitromycin  + Dasatanib + Quercetin stack? 
We can talk all day about dosages, so perhaps best not to go on for 18 pages about what exact combo we should use. Rather, I am wondering if some adverse drug reaction is to be feared from this combo and if there is so much overlap between the  Azitromycin  and the (Dasatanib + Quercetin) in terms of pathways involved to make this combo unproductive -I really doubt that would be the case.

2- Where do we stand in terms of combining such senolytic agents with fasting? 

Would you recommend to combine this stack with fasting? How many days after the start of the fast should one start such a combo?

 

3- What should the rest of the plan look like? 

Is it really best to stop any and all anti-inflammatory anti-oxidant supplements beforehand? 
How about pro-inflammatory pro-oxidant items and actions? Shall we try to create inflammation right before we take this combo?
Where does exercise fit in? Shall we do extra heavy and hard exercise or refrain from even light exercise during this period?

 

And other suggestions please....

 

I am ready to do it after just a little more research really , so chime in please....
 

[Mind]

If one senolytic therapy is enough to clear out the majority of your senescent cells, then you only need it once. Then maybe do the treatment a few years later.

 

At this point in senolytic research, it would be unwise (IMO) to "stack" various substances which have not even been through human trials. You are more likely to do serious damage than help yourself.

[Daniel Cooper]

I agree with the above, with the only caveat that it appears that these senolytics seem to be somewhat specific to clearing out specific senescent cell types.  Some seem better at clearing senescent endothelial cells.  Others at clearing senescent muscle cells.  etc. etc.  Therefore some sort of cocktail to ensure that you had good clearance of as many cell types as possible might be warranted.  However, you aren't going to get that by just combining willy nilly whatever senolytics you might think of.  You would need to do the research and have an overall plan.

 

The only exception to this seems to be FOX04-DRI which would seem to be a non-specific senolytic.  It's just not well studied in humans at this point and we don't know if any home experimenters have managed to get a good sample of this compound yet.

 

 

 

 

 

 

[Turnbuckle]

If one senolytic therapy is enough to clear out the majority of your senescent cells, then you only need it once. Then maybe do the treatment a few years later.

 

At this point in senolytic research, it would be unwise (IMO) to "stack" various substances which have not even been through human trials. You are more likely to do serious damage than help yourself.

 

Tumors that aren't immortal can experience a Hayflick crisis where they all die nearly at once. The body is much the same, except that the crisis occurs over years with different rates for different organs -- so it's a period rather than a point. Once in it you need to clear senescent cells out far more frequently. In my experience, once every 2-4 weeks when you reach your middle sixties. And once you are past that crisis period -- if you've managed to replace your senescent cells -- then it ought to be smooth sailing for decades more.

 

As for stacking, one could try different combinations at different times, with the supposition that not every cell type will have the same response to particular senolytics.

Edited by Turnbuckle, 15 February 2019 - 08:53 PM.

[Ovidus]

 

 

As for stacking, one could try different combinations at different times, with the supposition that not every cell type will have the same response to particular senolytics.

 

why at different times?
so one can see the specific impact of each and make this a more easily analyzed experiment?

not disagreeing, just asking

 

If the above is the reason behind your suggestion, is there any other problem you see with the originally suggested stack?

[Turnbuckle]

why at different times?
so one can see the specific impact of each and make this a more easily analyzed experiment?

not disagreeing, just asking

 

If the above is the reason behind your suggestion, is there any other problem you see with the originally suggested stack?

 

If you take them all at once you'll have no idea if something is necessary or superfluous. Not that it is easy to tell if you break them out as the effects are so subjective. I've tried taking the senolytics that I believe work, then adding in another after a couple of hours. Doing this with Azithromycin, I didn't get much extra, subjectively. (See this post.) Whereas sodium butyrate had a substantial effect. Butyrate has a very short half life, and the subjective effects increased each time I took it.

 

Both Azithromycin and sodium butyrate are supposed to be p38 activators.

Edited by Turnbuckle, 16 February 2019 - 10:39 PM.

[Kimer Med]

Fasting for 14 hours induces autophagy. If we assume the claims / studies about the value of CR are valid, that suggests to me that reasonably frequent use of senolytics is probably reasonable as well. Maybe not daily, but something like for 2 to 7 days every 2 to 8 weeks, depending on your age.

 

That's just a guess, though -- a potential starting point. We'll need a lot more studies to optimize compound choice, dosing and frequency.

 

[bobolander]

Two months ago (1 Dec. 2019) I added Azithromycin to my monthly senolytics stack of Desatanib, Quercetin, Fisetin, and rifaximin.  No apparent immediate effects, and I'll test blood work, DNAm, and telomeres In June 2019.  As an 83 year old lab rat, I feel I have more to gain than lose. 

[xEva]

Fasting for 14 hours induces autophagy.

 

There is a thread dedicated to this subject (active before you joined the forum): https://www.longecit...ins-in-fasting/

 

What is this 14h number based on?  thnx

[Kimer Med]

What is this 14h number based on?  thnx

 

I don't know the original source of the 14 hour number, but it's widely quoted on the net. For example:

 

https://ancientandbr...ick-sugar-habit

 

I also heard it from my doc, who I have a lot of respect for, and who has considerable experience using fasting in her practice.

[Iporuru]

it's widely quoted on the net. For example:

 

 

It's widely quoted on the net that the Earth is flat.

Here we're trying to provide scientific evidence for any claims we make. Otherwise, you're just spreading misinformation
 

[Gern]

Sorry for not locaing the original source, but a I recall seeing a chart on time spent fasting and it’s effect on senescent cells. It’s not a brick wall. The effectiveness of fasting increases as you get beyond 12 hours or so and continues to increase for 2-3 days. I aimed for 16 hours and figured it was an optimal choice for me between effectiveness and trying to cram all your meals in a few hours. I’m not sure a 14 hour fast every day would be more effective than an occasional two day fast.

[xEva]

Sorry for not locaing the original source, but a I recall seeing a chart on time spent fasting and it’s effect on senescent cells.

 

I doubt this.  Who was fasting, human or mouse? Or was it an in vitro study -- how else they determined the effect on  the senescent cells?

Edited by xEva, 19 February 2019 - 03:11 AM.

[Kimer Med]

It's widely quoted on the net that the Earth is flat.

Here we're trying to provide scientific evidence for any claims we make. Otherwise, you're just spreading misinformation
 

 

Point taken.

 

I'll see if I can find some actual data / research on the subject.

[extendcel]

Those considering the use of azithromycin should consider the effects of antibiotics on gut flora. Negative alterations of gut flora may have the opposite desired effect when it comes to longevity.

[poonja]

What is the recommended dose of azithromycin.  As far as I can tell, it is very small.  How often should it be used.  At such a presumably small dose, depending on the frequency of use, some fermented foods and probiotics should be helpful in counteracting any disruption of the gut flora.  currently using fisetin (1.5 g for two successive days for two successive months with a break of four months).   At 72, I should have a good amount of  senescent cells to get rid of. 

[Ovidus]

Thanks a ton for all the answers Guys

3 Questions

 

- Despite the definitive positive effect of fasting on senolysis, how come so few people are combining fasting and senolytics? For some reason it appears that those who use senolytic compounds do not really try hard to fast before or during the use of the senolytic exogenous agents. Are people maybe thinking that fasting activates the same MOAs as the senolytics and is therefore redundant?

 

- Any verdict you guys have reached on hyperthermia's effect on senolysis? Anyone thinking of sitting in the sauna at some point during their senolytic cycle? If so, how often and at what point?

 

- Would taking azithromycin as an injectable eliminate all the gut-related issues or would some of the antibiotic still find its way into the gut to cause damage to the intestinal flora?

 

 

[OP2040]

I did the Azithromycin self-experiment about 1 month ago.  My goal was not just as a senolytic.  Rather I'm convinced microbial load and balance is also an important factor  in aging-related disease. 

 

Anyway, my experience was very interesting to say the least.  I am very used to seeing absolutely no movement in any of the things that I subjectively feel or objectively measure.  But the Z-pack certainly did affect two things for me.  My memory improved significantly.  I am absolutely convinced of this, and it has stayed at about 90% of the improvement that I noticed.  I did do some very unscientific tests of this, which are relatively easy to do for memory.  I won't catalog the other things I noticed, simply because they are much more speculative.  

 

I have also taken Fisetin and Quercetin on and off quite a lot without much affect.  As for Dasatinib, I would love to try it but it's not the cost that worries me.  It seems to have a lot of potentially extreme side effects and my risk profile just won't allow for that.  

 

I think it's a great idea to combine different senolytics, as long as they are things like F+Q, which should be relatively harmless.  At most, you are wasting your money.  We relly need to map out more thoroughly which senolytic works where.  While they all matter, it is much more important to get rid of certain senescent cells than others.

 

On the other hand, I recently read something about skin having the most senescent cells of any tissue, something like 8% at some arbitrary age, whereas lots of other tissues were more in the range of 2-3%.  Since the skin is so accessible and observable, this might be a great starting point.   There was another study that showed that applying a skin formulation had body-wide beneficial effects.  Although I am skeptical of the study, it would seem reasonable that it is possible.

 

With that in mind, I'm going to try my now useless FOXO4-dri on my skin.  I haven't ironed out the details, so any suggestions would be helpful, and I'll let you guys know and possibly see with pics, how if goes.  

[Heisok]

OP2040, Do you have a name for the study or a link to it? Was it targeting senescent cells or Autophagy or is the possible clearance of skin senescent cells due to Autophagy. I have been procrastinating about trying D+Q+F+?

 

On the other hand, I recently read something about skin having the most senescent cells of any tissue, something like 8% at some arbitrary age, whereas lots of other tissues were more in the range of 2-3%.  Since the skin is so accessible and observable, this might be a great starting point.   There was another study that showed that applying a skin formulation had body-wide beneficial effects.  Although I am skeptical of the study, it would seem reasonable that it is possible.

 

With that in mind, I'm going to try my now useless FOXO4-dri on my skin.  I haven't ironed out the details, so any suggestions would be helpful, and I'll let you guys know and possibly see with pics, how if goes.  

 

Reason recently posted about an skin aging Autophagy decrease connection: https://www.longecit...-in-skin-aging/

 

I have fragile skin on my forearms. Easy to rip, and under the skin bleeding with minor impacts. Very ugly, and a concern.  I have had some  luck with CeraVe maybe the Ceramides work. It is also possible that my 60 day trial of higher oral Glucosamine doses helped my skin.. Plan to add more Ceramides, Trehalose, Apigenin, Glucosamine Sulfate and caffeine. If you have success with FOX04 I might try adding that.

 

See post # 131 about topical Glucosamine : https://www.longecit...e-5#entry878704

Edited by Heisok, 06 September 2019 - 05:30 PM.

[OP2040]

Heisok,

 

I actually saw it in passing in this Stat article:

 

https://www.statnews...enescent-cells/

 

Yet because senescent cells are quite rare even in the elderly, reaching their highest proportion — about 8 percent — in the skin, eliminating them should not leave any organs with too few cells to function.

 

Unfortunately, it doesn't look like they reference their articles, although they seem like a highly trustworthy source.  I know there are people, including de keizer, who are trying to come up with a sort of "senescent cell atlas" which would be super-helpful.

 

I like using skin as a test, and I have done so a couple other times.  I remember I tried a mix of several supplements I already use alongside high molecular weight Hyalaruonic Acid once.  Not only did it do absolutely nothing, it may have damaged my skin a little.  Oh well, that is the benefit of skin.  Plenty more where that came from, and likely won't seriously hurt yourself.  I only being that up because I think mixing too many things, while very tempting, is the wrong way to go about testing.  But I understand why it's done.  I can't wait to try FOXO4-dri, but my mind is already drifting toward various combination approaches.  I want to avoid that mess, but I do want something that will help it absorb as deeply as possible.

Edited by OP2040, 06 September 2019 - 07:33 PM.

[Daniel Cooper]

OP2040, Do you have a name for the study or a link to it? Was it targeting senescent cells or Autophagy or is the possible clearance of skin senescent cells due to Autophagy. I have been procrastinating about trying D+Q+F+?

 

 

Reason recently posted about an skin aging Autophagy decrease connection: https://www.longecit...-in-skin-aging/

 

I have fragile skin on my forearms. Easy to rip, and under the skin bleeding with minor impacts. Very ugly, and a concern.  I have had some  luck with CeraVe maybe the Ceramides work. It is also possible that my 60 day trial of higher oral Glucosamine doses helped my skin.. Plan to add more Ceramides, Trehalose, Apigenin, Glucosamine Sulfate and caffeine. If you have success with FOX04 I might try adding that.

 

See post # 131 about topical Glucosamine : https://www.longecit...e-5#entry878704

 

 

I'm curious about your adding trehalose.  I assume you're adding it to increase autophagy?  How are you planning on getting around it being broken down in the gut by trehalase?

Edited by Daniel Cooper, 06 September 2019 - 07:55 PM.

[Heisok]

Daniel, I do not have an answer. I have seen you post a lot about it, and you know more than I do, and perhaps most others here.

 

I am going to simply give it a shot topically. It might be a waste, non soluble or not absorbable even at the top layer of skin, but it is cheap. Nothing to lose, since I think my issue is mostly cosmetic, as none of the cuts have resulted in infections, and the under skin bleeding eventually goes away.

Edited by Heisok, 06 September 2019 - 08:32 PM.

[Daniel Cooper]

Topically you obviously aren't going to have an issue with trehalase breaking it apart.  You just need a vehicle to get it to penetrate.  H2O + DMSO?  Maybe one of these DMSO gels I've seen sold.  Trehalose is soluble in DMSO (0.5mg/ml) so that ought to work.

 

 

 

 

[Heisok]

Thanks Daniel. That is a great idea.

 

OP2040, thanks for the information, and warning about doing too much.

[OP2040]

There’s another thread somewhere that Daniel and I contributed heavily to. Trehalose has amazing potential and the thread is all about getting it into our vascular system to work it’s magic.

Here’s another study to bank up some of the evidence for that magic:

https://www.ncbi.nlm...ubmed/30506717/

The plaques just melt away..... as long as it gets to the veins.

[aribadabar]

I did the Azithromycin self-experiment about 1 month ago.  My goal was not just as a senolytic.  Rather I'm convinced microbial load and balance is also an important factor  in aging-related disease. 

 

Anyway, my experience was very interesting to say the least.  I am very used to seeing absolutely no movement in any of the things that I subjectively feel or objectively measure.  But the Z-pack certainly did affect two things for me.  My memory improved significantly.  I am absolutely convinced of this, and it has stayed at about 90% of the improvement that I noticed.  I did do some very unscientific tests of this, which are relatively easy to do for memory.  I won't catalog the other things I noticed, simply because they are much more speculative.  

 

Would you share more details about your experiment - age, dosage, duration, the memory effect onset etc?

 

What is the second thing that was affected that you were referring to in the bolded sentence above?

 

Thanks!

[OP2040]

Would you share more details about your experiment - age, dosage, duration, the memory effect onset etc?

 

What is the second thing that was affected that you were referring to in the bolded sentence above?

 

Thanks!

 

Oops, the second thing was inflammation.  Unfortunately, that one was not permanent, but was very noticeable at the time.  I measured inflammation by how stiff my legs felt, and other various aches and pains.

 

I am fairly young @ 45 but a perfect age for experimenting.  Sad to say, I seem to be aging pretty quickly despite the fact that I don't smoke, or any other unhealthy habits.  So when I say that my memory or inflammation improved, you just have to trust me that for whatever reason they are both pretty substantial and bad for my age.

 

I think my dose was 500MG first day, 250MG for day 2-10.  This is a pretty standard regimen when using a z-pack for an infection.

 

The reason I emphasized memory was because it was a very obvious and undeniable effect, while any and all other possible effects were much more ambiguous.  It was as many people describe, a fog lifted, greater mental clarity.  But most of all, I could recall names much more easily.  This has been a problem for me for a long time.  I have always been weak recalling peoples names, but in recent years it has spread to other things as well.  And when I say this, I am not being dramatic, I've had quite a few scary moments where someone I know is standing right in front of me and I can't remember their name, or have to actually think about it.  To add to my suspicions about this, I carry a copy of the APOE4 gene and I've read a recent report that people with this gene often have less than stellar cognitive ability even at younger ages. And combine that with the recent studies showing that there may be a microbial spark that lights the fire of Alzheimer's, notably Gingipains and HSV1 have been reported so far.  

 

So with all that said, it was a no-brainer (pun intended) to give it a try.  My cognitive status now is still much better than baseline.  Naturally, I'm concerned that it was a temporary effect.  I am by no means sharp like some people, who seem to have no problem recalling any and all information immediately.  But at least I feel normal and functional now.  I work in a technical field so this is very important for me.  But that brings up one potential confounding factor, which is the fact that we google everything now.  I'm fairly convinced that this effects our recall memory because we are relying on it.  And I am particularly guilty of this.  I will often search for something right away rather than trying to recall. For example, an actors name that I can't quite remember.  I do think this is a factor for all of us. 

 

Anyway, outside of that quite welcome and dramatic effect, there's not much else to report from this experiment. 

[Andey]

 

The reason I emphasized memory was because it was a very obvious and undeniable effect, while any and all other possible effects were much more ambiguous.  It was as many people describe, a fog lifted, greater mental clarity.  But most of all, I could recall names much more easily.  This has been a problem for me for a long time.  I have always been weak recalling peoples names, but in recent years it has spread to other things as well.  And when I say this, I am not being dramatic, I've had quite a few scary moments where someone I know is standing right in front of me and I can't remember their name, or have to actually think about it.  To add to my suspicions about this, I carry a copy of the APOE4 gene and I've read a recent report that people with this gene often have less than stellar cognitive ability even at younger ages. And combine that with the recent studies showing that there may be a microbial spark that lights the fire of Alzheimer's, notably Gingipains and HSV1 have been reported so far.  

 

 

  Have you considered ketogenic diet or implementing some elements of Bredesen protocol?

[OP2040]

Andey,

Yes, I did the ketogenic diet for years, and quite religiously.  It was a miracle in terms of completely effortless weight maintenance.  However, it did little for memory or other health issues.  For the last couple years I've been on what can be described as a very moderate med diet alongside some I.F. once in a while.  I was quite surprised that I could just as easily maintain my weight with this diet as well, even when eating significant amounts.  I never tried it before because it requires planning and cooking, and it was not feasible before I met my lovely gf who has been a game changer in this department.

 

I don't think diet and metabolism interventions are all that important for humans.  We need to take the decades of evidence for all these calorie restriction diet interventions, implement what we can, and move on.  They will likely add .06 years to your life and possibly some healthspan, but that's about it for humans.  

 

I've become intrigued by microbial causes of disease which are little discussed on this forum.  They are a major source of dna or other damage, and the evidence has been mounting for years that eliminating specific microbes can result in an outright cure to a major class of disease.  HPV-cancer connection is the most recent obvious example of this.  The fact that a viral vaccine can virtually eliminate one cancer in a population, and majorly reduce several others, is an amazing fact.  

 

 

[Andey]

Andey,

Yes, I did the ketogenic diet for years, and quite religiously.  It was a miracle in terms of completely effortless weight maintenance.  However, it did little for memory or other health issues.  For the last couple years I've been on what can be described as a very moderate med diet alongside some I.F. once in a while.  I was quite surprised that I could just as easily maintain my weight with this diet as well, even when eating significant amounts.  I never tried it before because it requires planning and cooking, and it was not feasible before I met my lovely gf who has been a game changer in this department.

 

I don't think diet and metabolism interventions are all that important for humans.  We need to take the decades of evidence for all these calorie restriction diet interventions, implement what we can, and move on.  They will likely add .06 years to your life and possibly some healthspan, but that's about it for humans.  

 

I've become intrigued by microbial causes of disease which are little discussed on this forum.  They are a major source of dna or other damage, and the evidence has been mounting for years that eliminating specific microbes can result in an outright cure to a major class of disease.  HPV-cancer connection is the most recent obvious example of this.  The fact that a viral vaccine can virtually eliminate one cancer in a population, and majorly reduce several others, is an amazing fact.  

 

  Its hard for somebody to get infectious disease diagnosis and treatment starting just from a "something wrong with my memory" point, imagine what doctor would think about it)

  I think Bredesen protocol is the only thing that works for ALS know and it includes infection causes too. Basically its a few different protocols for different causes.

  If ketogenic diet haven't worked than probably its not a metabolic subtype.

 

  On a practical note, from my experience my cognitive capacity improves a bit when I take phosphatidylserine, when I deep into ketosis and when I am able to consistently day after day hang upside down for a few mins.