44 replies to this topic

[Decimus]

mTor, JNK, AMPK, IGF-1/Calorie Restriction seem to be the four major routes that most supplements and drugs that have been shown to extend lifespan work through.  A few months ago it was shown that Rapa, Rifa and Allantoin could consistenlty double the lifespan of flies and c.elegans.  (Here is the full study: https://www.biorxiv....3205.full.pdf) 

 

Most of us that have been watching longevity animal studies over the years have noticed that when researchers add two or more drugs that are known to extend lifespan independently, the end result is often a decrease in lifespan.  The authors above noted that this phenomenon is likely caused by adding supplements with mechanical overlap/working through the same pathway which ends up negating each other's activity.  Therefore, they identified these three supplements to work on all four of these pathways with minimal overlap.  

 

So I am running Rapamycin at 1-2mg a week, Rifampicin at 150mg once every three days, and Allantoin through comfrey root with the harmful chemicals extracted.  I have dropped Metformin, which has unimpressive results with Rapa in multiple studies.  The only other supplements I will be taking are spermidine (which has been shown to have up to a 20% increase in mouse lifespan) and resveratrol (which works synergistically with spermidine on different pathways to promote autophagy).  I rotate these into the regime after the Rapa is out of my system, because Rapa also promotes autophagy.  I also rotate in Sulforphane Glucosinolate (Brocco Max) with NR to increase AMPK twice a week.  I try to add in some glycine from time to time, which was shown to increase rodent lifespan up to 40% but, it may overlap with the other CR mimetics (Allantoin and Rapa) so I use it when those two are not in my system.    

 

Thus far the only thing I have noticed is a surprising boost of energy about an hour after taking the Rifampicin and lasting several hours onward.  I am going to be taking periodic liver functions tests to make sure the Rifa isn't causing any hepatotoxic problems.  I will let you all know if anything comes of this, but I believe this regime is probably just about the best one available given the information we have thus far on longevity.  

[Razor444]

The link is broken (it works when the parenthesis & additional space is removed). Working link: https://www.biorxiv....153205.full.pdf

 

Does anyone know of JNK inhibitors, other than Rifampicin? It looks gnarly.

 

Side note: Looks like Rifampicin is an activator of CYP3A4. That should speed up the metabolism of the Sirolimus.

[ekaitz]

What is rifampicin for on is own? I mean, aside antibiotic function, what is its secondary mechanism we're looking for?

Edited by ekaitz, 12 February 2018 - 02:15 PM.

[poonja]

I have a question regarding the allantoin.  I purchased a quantity of powder but have idea how to dose it.  How did you determine the dosing schedule for the rifampcin.  I am contemplating experimenting with this combination as I am already using Blogskenny (sic) protocol plus NR and other supplements. I am 71 years old with CAD and leaky heart valve(s) but no damage as of yet and feel pretty well.  

[Decimus]

The link is broken (it works when the parenthesis & additional space is removed). Working link: https://www.biorxiv....153205.full.pdf

Does anyone know of JNK inhibitors, other than Rifampicin? It looks gnarly.

Side note: Looks like Rifampicin is an activator of CYP3A4. That should speed up the metabolism of the Sirolimus.

Thanks for fixing the link. I looked into JNK inhibitors awhile ago and only found a few that were in clinical trials. Rifa does appear to have some potentially heavy side effects, but keep in mind it is usually used for TB for several months at a time and at higher doses than I am using. I don’t believe intermittent use will be a problem.

[Decimus]

I have a question regarding the allantoin. I purchased a quantity of powder but have idea how to dose it. How did you determine the dosing schedule for the rifampcin. I am contemplating experimenting with this combination as I am already using Blogskenny (sic) protocol plus NR and other supplements. I am 71 years old with CAD and leaky heart valve(s) but no damage as of yet and feel pretty well.

I am using Comfree, which is a product by Solaray. It’s benign comfrey root, which contains an unknown amount of an evidently “safe” dose or Allantoin. I am in contact with the company and they are trying to find out how much Allantoin is in the product. Not sure if they will succeed. I came up with the dose and schedule for Rifampcin with Dr. Alan Green, whom I’m sure you are familar with if you know Blogskenny.

[poonja]

Thank you for your response.

[Razor444]

 

 

 I came up with the dose and schedule for Rifampcin with Dr. Alan Green, whom I’m sure you are familar with if you know Blogskenny.

 

Did Dr Green say anything else with regards to Rifampicin?

 

Wouldn't Rifampicin cause damage to your gut microbiome? It is an antibiotic after all.

[to age or not to age]

Decimus, I am very intrigued with what you are doing.  I read that study on worms and they look like only partially overlapping pathways, which may account for the additive effect.  I would add another interesting substance to your list though I'm not suggesting you do this, Betalapachone. It influences NQ01 which in effect influences the NAD/NADH ratio, possibly elevating NAD levels more appropriately than NR and NMN. I had some made but it was just too expensive to be practical. 

 

I mentioned the possibility of doing what you doing prior to reading your entry, and a scientist friend deeply into this research who's also not timid about self

experimentation said- referring to trying all 3 together - "I would wait until they try it in a mouse" 

 

Personally, a deep nod to you for your fearlessness/boldness.  I have a feeling it could work, though as usual, dosing is really an art because all these pathways wear white and black hats.  It's a dialing situation. Good luck.

[Decimus]

I came up with the dose and schedule for Rifampcin with Dr. Alan Green, whom I’m sure you are familar with if you know Blogskenny.

Did Dr Green say anything else with regards to Rifampicin?

Wouldn't Rifampicin cause damage to your gut microbiome? It is an antibiotic after all.

I take probiotics the day after I take the Rifa, but yes that is a concern.

[Decimus]

Decimus, I am very intrigued with what you are doing. I read that study on worms and they look like only partially overlapping pathways, which may account for the additive effect. I would add another interesting substance to your list though I'm not suggesting you do this, Betalapachone. It influences NQ01 which in effect influences the NAD/NADH ratio, possibly elevating NAD levels more appropriately than NR and NMN. I had some made but it was just too expensive to be practical.

I mentioned the possibility of doing what you doing prior to reading your entry, and a scientist friend deeply into this research who's also not timid about self
experimentation said- referring to trying all 3 together - "I would wait until they try it in a mouse"

Personally, a deep nod to you for your fearlessness/boldness. I have a feeling it could work, though as usual, dosing is really an art because all these pathways wear white and black hats. It's a dialing situation. Good luck.

Hello Age or not age. I would agree that a mouse study would be preferable before jumping on this regime, however, I’m certain that is years away. The researchers who ran this study say that tests in mice are coming but, we’ve all read those types of statements before only to never hear of a follow-up study. I believe that the low doses and the intermittent use will make side effects very unlikely and given that all of these pathways exist in mammals and it has been shown previously that mice lifespan can be increased on these pathways, it is probably a low risk high reward scenario.

I have looked at betalapachone. I was disappointed to see the mouse longevity studies on NM. It was essentially negligible. I understand betalapachone supposedly circumvents the issues with NM and NR, but for that, I am waiting for a mouse study

[ryukenden]

Decimus, I am very intrigued with what you are doing. I read that study on worms and they look like only partially overlapping pathways, which may account for the additive effect. I would add another interesting substance to your list though I'm not suggesting you do this, Betalapachone. It influences NQ01 which in effect influences the NAD/NADH ratio, possibly elevating NAD levels more appropriately than NR and NMN. I had some made but it was just too expensive to be practical.

I mentioned the possibility of doing what you doing prior to reading your entry, and a scientist friend deeply into this research who's also not timid about self
experimentation said- referring to trying all 3 together - "I would wait until they try it in a mouse"

Personally, a deep nod to you for your fearlessness/boldness. I have a feeling it could work, though as usual, dosing is really an art because all these pathways wear white and black hats. It's a dialing situation. Good luck.

Hello Age or not age. I would agree that a mouse study would be preferable before jumping on this regime, however, I’m certain that is years away. The researchers who ran this study say that tests in mice are coming but, we’ve all read those types of statements before only to never hear of a follow-up study. I believe that the low doses and the intermittent use will make side effects very unlikely and given that all of these pathways exist in mammals and it has been shown previously that mice lifespan can be increased on these pathways, it is probably a low risk high reward scenario.

I have looked at betalapachone. I was disappointed to see the mouse longevity studies on NM. It was essentially negligible. I understand betalapachone supposedly circumvents the issues with NM and NR, but for that, I am waiting for a mouse study

Where are the mouse longevity studies on NMN?

[Decimus]

Decimus, I am very intrigued with what you are doing. I read that study on worms and they look like only partially overlapping pathways, which may account for the additive effect. I would add another interesting substance to your list though I'm not suggesting you do this, Betalapachone. It influences NQ01 which in effect influences the NAD/NADH ratio, possibly elevating NAD levels more appropriately than NR and NMN. I had some made but it was just too expensive to be practical.

I mentioned the possibility of doing what you doing prior to reading your entry, and a scientist friend deeply into this research who's also not timid about self
experimentation said- referring to trying all 3 together - "I would wait until they try it in a mouse"

Personally, a deep nod to you for your fearlessness/boldness. I have a feeling it could work, though as usual, dosing is really an art because all these pathways wear white and black hats. It's a dialing situation. Good luck.

Hello Age or not age. I would agree that a mouse study would be preferable before jumping on this regime, however, I’m certain that is years away. The researchers who ran this study say that tests in mice are coming but, we’ve all read those types of statements before only to never hear of a follow-up study. I believe that the low doses and the intermittent use will make side effects very unlikely and given that all of these pathways exist in mammals and it has been shown previously that mice lifespan can be increased on these pathways, it is probably a low risk high reward scenario.

I have looked at betalapachone. I was disappointed to see the mouse longevity studies on NM. It was essentially negligible. I understand betalapachone supposedly circumvents the issues with NM and NR, but for that, I am waiting for a mouse study

Where are the mouse longevity studies on NMN?

There was one floating around here a few months ago that showed an increase of 1-2% in lifespan. I actually forget the species, so I might be misremembering. Do a search.

[ryukenden]

Decimus, I am very intrigued with what you are doing. I read that study on worms and they look like only partially overlapping pathways, which may account for the additive effect. I would add another interesting substance to your list though I'm not suggesting you do this, Betalapachone. It influences NQ01 which in effect influences the NAD/NADH ratio, possibly elevating NAD levels more appropriately than NR and NMN. I had some made but it was just too expensive to be practical.

I mentioned the possibility of doing what you doing prior to reading your entry, and a scientist friend deeply into this research who's also not timid about self
experimentation said- referring to trying all 3 together - "I would wait until they try it in a mouse"

Personally, a deep nod to you for your fearlessness/boldness. I have a feeling it could work, though as usual, dosing is really an art because all these pathways wear white and black hats. It's a dialing situation. Good luck.

Hello Age or not age. I would agree that a mouse study would be preferable before jumping on this regime, however, I’m certain that is years away. The researchers who ran this study say that tests in mice are coming but, we’ve all read those types of statements before only to never hear of a follow-up study. I believe that the low doses and the intermittent use will make side effects very unlikely and given that all of these pathways exist in mammals and it has been shown previously that mice lifespan can be increased on these pathways, it is probably a low risk high reward scenario.

I have looked at betalapachone. I was disappointed to see the mouse longevity studies on NM. It was essentially negligible. I understand betalapachone supposedly circumvents the issues with NM and NR, but for that, I am waiting for a mouse study

Where are the mouse longevity studies on NMN?

There was one floating around here a few months ago that showed an increase of 1-2% in lifespan. I actually forget the species, so I might be misremembering. Do a search.

I already did the search before asking you. I couldn’t find any.

[Decimus]

 

Where are the mouse longevity studies on NMN?

There was one floating around here a few months ago that showed an increase of 1-2% in lifespan. I actually forget the species, so I might be misremembering. Do a search.

I already did the search before asking you. I couldn’t find any.

 

In case you missed it: http://www.cell.com/...4131(18)30112-8

 

Another study showing no increase in life span.  Granted this was with NAM not NR, but you can make a big bet the results would be pretty much on par with what you would expect if it were run with NR.  

[Sith]

I was under the impression that Allantoin was toxic when taken orally, can anyone shed some more light on this?

[joetsang]

Is Allantoin buy from ebay contains Pyrrolizidine Alkaloid?

[Decimus]

I was under the impression that Allantoin was toxic when taken orally, can anyone shed some more light on this?

There is not a lot information on the safety of allantoin. Large doses are probably toxic, like large doses of anything are toxic. However, comfrey supplements with the harmful aspects extracted have been studied and the doses that go into these are evidently safe.

I can you that I take Comfree and that I have had no issues other than if I take more than one a day my blood sugar seems to drop, which I find encouraging from a longevity perspective.

Edited by Decimus, 11 April 2018 - 06:34 PM.

[RWhigham]

So I am running Rapamycin at 1-2mg a week, Rifampicin at 150mg once every three days, and Allantoin through comfrey root with the harmful chemicals extracted.  I have dropped Metformin

 

From Doubling healthy lifespan using drug synergies 

Note that these drugs were given continuously unlike the once-weekly rap that avoids immune suppression. 

The immune suppression risks infection--a risk ameliorated by adding an antibiotic. 

Nevertheless, this study clearly shows how combining different biological pathways can be synergistic. 

 

We chose to target as primary longevity regulatory pathways 

1) AMP activated protein kinase (AMPK) 

2) Mammalian target of rapamycin (mTOR) 

3) Caloric restriction (CR) 

4) C-Jun N-terminal kinases (JNK) and 

5) Mitohormesis/mitochondrial metabolism

 

We found that only five compounds extended lifespan of C.Elegans reproducibly under conditions used in our laboratory 

1) Rapamycin   mTOR-1  antibiotic                  13.5% 

2) Rifampicin    JNK         antibiotic                   24.5% 

3) Allantoin       CR mimetic                              19.7% 

4) Psora-4        K-channel blocker, hormesis    23.5% 

5) Metformin    Mito-hormesis                           23.0% 

 

Combos 

1) Rap+Rif+Allantoin             76.3 % 

2) Rap+Psora+Allantoin        76.1 % 

3) Rap+Rif                             45, 46, 29 % 

4) Rap+Rif+Metformin           14.0 %    Met is toxic w Rif 

5) Rif                                      38.5 % 

6) Rif+Metformin                      9.5 %    Met is toxic w Rif 

 

Edited by RWhigham, 12 April 2018 - 04:25 PM.

[RWhigham]

Doubling healthy lifespan using drug synergies For all experiments Bristol N2 wild-type or mutant nematodes were grown and maintained on 6 Nematode Growth Medium (NGM) agar plates at 20°C using E. coli OP50 bacteria as food 7 source unless otherwise noted. After plates were poured and dried, they were sealed and 8 stored at 4°C. E. coli were spotted on plates on the previous evening and allowed to dry. For 9 compound treatments, all agar plates were prepared from the same batch of NGM agar and 10 treatment plates were supplemented with the respective compounds or vehicle as a control.

 

Figures 1 & 2 show the range of drug concentrations tried. The optimums are shown below: 

 

Optimum 1-drug concentrations (in the agar)

1) Rap     50 uM 

2) Rif     100 uM 

3) Met      25 uM 

4) Allan   250 uM 

5) Psora 100 uM 

 

Optimum 2-drug concentrations

1) Rap + Met    50 uM + 25 uM 

2) Rap + Rif    100 uM + 50 uM  *

3) Psora + Rif  100 uM + 50 uM

 

* When Rif was added, the optimum Rap doubled. Rif activates CYP3A4 to remove Rap faster.

 

Optimum 3-drug concentrations  

Not specifically shown--likely 250 uM of Allan added to optimum Rif + Rap or Rif + Psora 

1) Rif + Rap + Allan  50 uM + 100 uM + 250 uM 

2) Rif + Psora + Allan  50 uM + 100 uM + 250 uM 

 

I don't know how to translate these to human equivalent doses, but perhaps the important thing is relative amounts. This may show, for example, that only a very small dose of metformin is needed to synergize with a few mg of rapamycin.  Figure1 shows 25 mM of Met is about the same as the control, but 25 uM is much better than the control.

Edited by RWhigham, 12 April 2018 - 11:23 PM.

[to age or not to age]

There is not a lot information on the safety of allantoin. Large doses are probably toxic, like large doses of anything are toxic. However, comfrey supplements with the harmful aspects extracted have been studied and the doses that go into these are evidently safe.

I can you that I take Comfree and that I have had no issues other than if I take more than one a day my blood sugar seems to drop, which I find encouraging from a longevity perspective.

 

Decimus, are you still on this three drug combination? Do you have any anecdotal or biomarker info to report?

thanks.

Edited by to age or not to age, 30 April 2018 - 04:02 PM.

[joetsang]

There is not a lot information on the safety of allantoin. Large doses are probably toxic, like large doses of anything are toxic. However, comfrey supplements with the harmful aspects extracted have been studied and the doses that go into these are evidently safe.

I can you that I take Comfree and that I have had no issues other than if I take more than one a day my blood sugar seems to drop, which I find encouraging from a longevity perspective.

 

Is allantoin's toxicity from pyrrolizidine alkaloids related to the source of plant extraction?  Will the chemical synthesis of allantoin without such issue?

 

Anyway, there are two big producer of allantoin for cosmetic add-on (not for medical usage), Sunpu Biochem (less than US$5 per KG for bulk purchase of 25KG up) and Clariant International Ltd (less than US$10 per KG for bulk purchase of 25KG up).

[Sith]

There is not a lot information on the safety of allantoin. Large doses are probably toxic, like large doses of anything are toxic. However, comfrey supplements with the harmful aspects extracted have been studied and the doses that go into these are evidently safe.

I can you that I take Comfree and that I have had no issues other than if I take more than one a day my blood sugar seems to drop, which I find encouraging from a longevity perspective.

 

That's very interesting, thank you! So what dosage do you use? Is it safe to use alongside metformin (2 x 500mg)?

[Decimus]

That's very interesting, thank you! So what dosage do you use? Is it safe to use alongside metformin (2 x 500mg)?

If you read the study linked in the original post Allan beats out Met. Who knows though? It might be species specific or dose specific or even an anomaly. However, if you buy into the premise of the paper, that supplements with mechanical overlap should be avoided as much as possible, then I wouldn’t mix Allan and Met, regardless of any safety concern. I would choose one or the other.

[Decimus]

Decimus, are you still on this three drug combination? Do you have any anecdotal or biomarker info to report?
thanks.

Hi age or not to age,

Yes. I am still running the regime. I would note two things. One, which I mentioned previously, if I take more than one Comfree my blood sugar drops. So I take one a day. I do look at the drop in blood sugar as a positive. On the negative side, I have cut down on the Rif. It is a very heavy drug. My pharmacist even warned me about it when I picked it up. I had two incidences when I took 150mg and I felt horrible for 24 hours or so. So I am doing 75mg once a week. I’m not sure if that is enough but, it’s the place where potential risk versus potential reward meets for me.

[Andey]

Hi age or not to age,

Yes. I am still running the regime. I would note two things. One, which I mentioned previously, if I take more than one Comfree my blood sugar drops. So I take one a day. I do look at the drop in blood sugar as a positive. On the negative side, I have cut down on the Rif. It is a very heavy drug. My pharmacist even warned me about it when I picked it up. I had two incidences when I took 150mg and I felt horrible for 24 hours or so. So I am doing 75mg once a week. I’m not sure if that is enough but, it’s the place where potential risk versus potential reward meets for me.

 

Its dangerous to take Rifampicin intermittently. Look at TB treatment studies, they've studied a lot of regimens. When taken intermittently it sensitizes immune system and causes an autoimmune flu-like reaction, usually transient but sometimes it ends with acute hepatitis. I am pretty sure its written in the drug manual too.

Counterintuitively small dosage every day is the safest approach. 

 

P.S. I dont sure if 75mg weekly is giving you a desirable effect, in my book it's just too low of a dose.

Edited by Andey, 04 May 2018 - 07:45 AM.

[ekaitz]

I am using Comfree, which is a product by Solaray. It’s benign comfrey root, which contains an unknown amount of an evidently “safe” dose or Allantoin. I am in contact with the company and they are trying to find out how much Allantoin is in the product. Not sure if they will succeed. I came up with the dose and schedule for Rifampcin with Dr. Alan Green, whom I’m sure you are familar with if you know Blogskenny.

 

I don't find any reference of this Dr. mention to rifampicin. Did you meant rapamycin?

[ekaitz]

Its dangerous to take Rifampicin intermittently. Look at TB treatment studies, they've studied a lot of regimens. When taken intermittently it sensitizes immune system and causes an autoimmune flu-like reaction, usually transient but sometimes it ends with acute hepatitis. I am pretty sure its written in the drug manual too.

Counterintuitively small dosage every day is the safest approach. 

 

P.S. I dont sure if 75mg weekly is giving you a desirable effect, in my book it's just too low of a dose.

 

Do you think 40mg ED would be a more convenient approach?
 

[Andey]

Do you think 40mg ED would be a more convenient approach?
 

 

  Rifampicin is a serious drug and, personally, I would not take it based on c.elegans research.) 

Usual RIF dosages as an abx treatment are 600mg QD (once a day) for a 75kg male, sometimes it goes up to 600 two times a day. What dosage would be appropriate here? - I don't know.

[roberth2309]

I've been trying the same thing. At the moment 8mg of Rapa once a week. About 150mg of rifa once a day but I sometimes skip. I also take about 1000mg of allantoin spread throughout the day. I made the mistake at first of taking 1000mg of metformin with about 500mg of synthetic allantoin... but I've now quit the metformin.