957 replies to this topic

[Jaris]

One of the downsides of rapamycin is that it can activate myrostatin. What I find interesting is that sulforaphane inhibits myrostatin, at least in pigs.

 

https://www.ncbi.nlm...pubmed/23092945

 

However, sulforaphane still activates AMPK and NRF2. This would provide some of the same autophagy, mitochondrial, and antioxidant benefits.

 

So these questions come to mind.

 

1) Which is the most potent substance at inducing AMPK, sulforaphane or rapamycin?

 

2) If rapamycin is the most potent substance at inducing AMPK, is there a drawback to blocking myrostatin at the same time?

 

3) Other than supplementing sulforaphane at the same time, are there any other strategies to block the increase in myrostatin from rapamycin?

Sorry it took so long to answer. First, be aware that, with drugs like Rapamycin, the side effects at high, chronic doses are sometimes the opposite of their effects at low and intermittent doses. I don't know if that's the case for myostatin, but I can't seem to find any study result that says either way.

 

This might be unrelated, but to deal with inflammation being caused by microglia mistakenly and fruitlessly attacking misfolded proteins, a MD who has been mentioned several times by several people, has suggested that taking Cardesartan might be a good choice, It's a high blood pressure drug that's been around awhile. A new study is here: https://www.dddmag.c...kinson’s-effect and here: http://stke.sciencemag.org/content/8/376/ra45.full.pdf+html

 

At least that's my interpretation of what the study is saying.

 

Just found this study which, at first glance, might be useful in a discussion about myostatin: https://www.ncbi.nlm...pubmed/23868687

"Nonfunctional overreaching" sounds familiar. Not sure about any of this. Can you quote a study?

Edited by Jaris, 24 January 2017 - 02:29 AM.

[Jaris]

Maybe you've all seen this, but in case you haven't, it's' an interview about the dog study. For me though, the interesting part was towards the end (36 min) when they start saying that people - and the FDA - should decide what the acceptable risk should be when looking at ways to extend life in humans. Not any new technical info, but still interesting to get different viewpoints. BTW, I hear that there are quite a few self experimenters in the Silicone Valley, and that Rapa is big here. Interesting if true.

Edited by Jaris, 24 January 2017 - 03:58 AM.

[Valijon]

I'm not the least bit surprised about the S. Valley people. Everyone's looking for long liefespan, healthspan, and an edge over the competition. It won't be long before everyone is talking about Rapamycin. Look at other drugs like clenbuterol and adderral.

I agree that we need to decide what constitutes acceptable risk concerning these medications.

[tintinet]

Any thoughts on dose timing- AM, with or without meals, QHS, combination with Metformin and/or berberine?

[Jaris]

I guess now would be a good time to update my experiences so far. I won't get into each detail, but you're welcome to ask.

I've just taken the fourth dose of sirolimus, each dose 1 week apart. I drink 8-10 oz of grapefruit juice for 3 days, beginning with each dose. The subjects in a study that tested the effect drank juice every day, so this is a departure from that.

Week 1:  1.5 mg x 3.5 = 5.25 mg

Week 2:  1.5 mg

Week 3:  2 mg x 3.5 = 7 mg

Week 4:  1.5 mg

 

The reason that I've gone back to 1.5 mg is that when I went to 2 mg, I experienced small mouth sores; a known side effect. They began healing 2 days before it was time for another dose. I may go back to 2 mg.

 

Results: I'm starting to see small improvements, but nothing that can't be explained as a placebo effect. My mood is better (as seen in at least one mouse study). Endurance is improved. For many months  I've walked the same path nearly every day and there's a big hill towards the end. Today was the first day in all that time that I was able to walk it without losing my breath and having to stop for rest. I've lost 3 pounds in 3 weeks without trying or changing my diet.

 

But, again, nothing that can't be explained by placebo effect.

Edited by Jaris, 04 February 2017 - 08:40 PM.

[tintinet]

I've just taken the fourth dose of sirolimus, each dose 1 week apart. I drink 8-10 oz of grapefruit juice for 3 days, beginning with each dose. The subjects in a study that tested the effect drank juice every day, so this is a departure from that.
Week 1: 1.5 mg x 3.5 = 5.25 mg
Week 2: 1.5 mg
Week 3: 2 mg x 3.5 = 7 mg
Week 4: 1.5 mg

Taking 1.5 mg x 3.5 as one dose? AM, PM, QHS? Also taking Metformin, berberine, etc.?

Edited by Michael, 30 June 2017 - 10:29 PM.
trim quotes

[maxwatt]

Any thoughts on dose timing- AM, with or without meals, QHS, combination with Metformin and/or berberine?

 

As for AM or PM, good question and I wonder the same thing.

 

As for Metformin:  As a side effect rapamycin increases blood glucose, so self-experimenters often take metformin concurrently.  A blood glucose meter can be inexpensive and the test strips and lancets are not prohibitively costly when purchased online, so one can monitor and decide if metformin (or berberine, a non-prescription botanical extract with similar effect) is warranted. If one's glucose level on waking is greater than 100, and especially if it is greater than 125, the threshold marker for diabetes, one should then use metformin.

 

Increased blood glucose due to insulin resistance is a known side effect in those taking daily doses of rapamycin.  Other side effects, such as mouth sores (canker sores) have not been reported (yet) in those taking weekly doses of 3 mg of rapamycin, so I expect that insulin resistance is also not likely to be a side effect with intermittent dosing. Still, if one is gong to go this route, I recommend the use of a glucose meter to monitor possible side effects.  Also one should probably get a full blood and lipid panel before beginning, and again after say three months, and continue monitoring.

 

FWIW, a pre-diabetic known to me reports their fasting glucose has decreased to under 100, but it's only been a month, and confounding dietary and exercise changes may be involved.  I hope we can gather a bit more data here.  If you're experimenting with rapamycin, tell us what you experience.

[Jaris]

 

Any thoughts on dose timing- AM, with or without meals, QHS, combination with Metformin and/or berberine?

 

As for AM or PM, good question and I wonder the same thing.

 

As for Metformin:  As a side effect rapamycin increases blood glucose, so self-experimenters often take metformin concurrently.  A blood glucose meter can be inexpensive and the test strips and lancets are not prohibitively costly when purchased online, so one can monitor and decide if metformin (or berberine, a non-prescription botanical extract with similar effect) is warranted. If one's glucose level on waking is greater than 100, and especially if it is greater than 125, the threshold marker for diabetes, one should then use metformin.

 

Increased blood glucose due to insulin resistance is a known side effect in those taking daily doses of rapamycin.  Other side effects, such as mouth sores (canker sores) have not been reported (yet) in those taking weekly doses of 3 mg of rapamycin, so I expect that insulin resistance is also not likely to be a side effect with intermittent dosing. Still, if one is gong to go this route, I recommend the use of a glucose meter to monitor possible side effects.  Also one should probably get a full blood and lipid panel before beginning, and again after say three months, and continue monitoring.

 

FWIW, a pre-diabetic known to me reports their fasting glucose has decreased to under 100, but it's only been a month, and confounding dietary and exercise changes may be involved.  I hope we can gather a bit more data here.  If you're experimenting with rapamycin, tell us what you experience.

 

I'm taking my doses first thing in thee AM, then I don't eat for 2 hours.

I have Metformin ready to take, but wanted to see if it was needed first. I have access to glucose testing and I've been checking every 2-3 days. So far I've seen no trend up or down (I'm not pre-diabetic). I want to see what Rapa does without the Metformin first, and add it later depending on results.

I also take supplements as previously listed.

Edited by Jaris, 05 February 2017 - 05:32 AM.

[VP.]

Interesting story from yesterdays NYT. It's about Rapamycin, immune system and self experimentation. 

His Doctors Were Stumped. Then He Took Over.

Last month, Dr. Fajgenbaum marked his three-year anniversary since starting on sirolimus, a period more than twice as long as any of his other remissions. “I feel 100 percent,” he said.

 

https://www.nytimes....nav=bottom-well

Edited by VP., 05 February 2017 - 02:37 PM.

[tintinet]

https://static1.squa...3/?format=1500w

Perhaps rapamycin and Metformin are synergistic?

http://www.longevity...testing-program

Edited by tintinet, 05 February 2017 - 04:05 PM.

[Jaris]

https://static1.squa...3/?format=1500w

Perhaps rapamycin and Metformin are synergistic?

http://www.longevity...testing-program

I believe that the tests they mention on Rapamycin were all conducted using large  chronic (daily) doses. There have been other studies that suggest that low, intermittent doses have far fewer side effects. As one example, the study using elderly human patients showed that it improved their immune response to a flu vaccine, and few other side effects showed up. This is the opposite of inhibiting immune responses in organ transplant patients; the result of large, chronic dosing.

 

Metformin could help keep Rapamycin's side effects in check, if they show up. But what if the low/intermittent dose approach largely avoids the side effects (or even has the opposite effect as with immunity)? I'd love to see more studies on that. The two drugs *might* be synergistic in other ways, but I don't think that the proper studies have been done to know.

Edited by Jaris, 05 February 2017 - 08:22 PM.

[Jaris]

Interesting story from yesterdays NYT. It's about Rapamycin, immune system and self experimentation. 

His Doctors Were Stumped. Then He Took Over.

Last month, Dr. Fajgenbaum marked his three-year anniversary since starting on sirolimus, a period more than twice as long as any of his other remissions. “I feel 100 percent,” he said.

 

https://www.nytimes....nav=bottom-well

Really fascinating article that brings up so many issues. While I understand the go-slow approach, if I had that disease, I'd try hard to find some way to get treated with rapamycin. Sure, one data point isn't enough to know much of anything, but if the alternative is chemotherapy, I think that I'd try a low dose of rapamycin first. Just my 2 cents.

[to age or not to age]

We have been taking 3 mg of rapamycin once a week for almost 4 weeks. No side effects. When I was at the SENS conference at the Buck Institute in August,

I heard people say they were combining rapamycin with metformin. We have not done this. So far, we can't put our finger on anything in terms of effects. 

[Jaris]

From this and other stories, it seems that there are a good number of people trying Rapamycin at low, weekly doses. Does anyone know if there's an organized effort to collect data from everyone, or are we it?

It wouldn't be a real study of course, but as the experiment continues, it would be a shame to lose any information that could be gathered. Maybe we could make a small database. If there's enough interest, I can look into it.

[tintinet]

We have been taking 3 mg of rapamycin once a week for almost 4 weeks. No side effects. When I was at the SENS conference at the Buck Institute in August,
I heard people say they were combining rapamycin with metformin. We have not done this. So far, we can't put our finger on anything in terms of effects.

3 mg once as one dose? AM, PM, with or without meals? Reasoning for this dose and timing?

Thanks

[to age or not to age]

We have been taking it in the AM.  I did a fair amount of research on possible dosing.  Spoke to a couple of MDs. 

As a general  comment, the more I speak with scientists researching various compounds which intervene in this or that 

pathway, the more I have realized that "dialing" is the key. Almost every molecular pathway - you name it - has a black and white

hat, on several levels, and dosing into the  sweet spot seems almost an art. So- there are a few compounds I am quite high on but

in experimenting on the edge (and filming it I might add) a conservative approach seems the way to go. For instance, I have had a number

of conversations with scientists about the possible interactions between a substance like rapamycin and things like beta lapchone and NR. 

 

[Jaris]

We have been taking it in the AM.  I did a fair amount of research on possible dosing.  Spoke to a couple of MDs. 

As a general  comment, the more I speak with scientists researching various compounds which intervene in this or that 

pathway, the more I have realized that "dialing" is the key. Almost every molecular pathway - you name it - has a black and white

hat, on several levels, and dosing into the  sweet spot seems almost an art. So- there are a few compounds I am quite high on but

in experimenting on the edge (and filming it I might add) a conservative approach seems the way to go. For instance, I have had a number

of conversations with scientists about the possible interactions between a substance like rapamycin and things like beta lapchone and NR. 

Could you share a little about what you've learned about beta lapchone and NR?

[tintinet]

We have been taking it in the AM. I did a fair amount of research on possible dosing. Spoke to a couple of MDs.
As a general comment, the more I speak with scientists researching various compounds which intervene in this or that
pathway, the more I have realized that "dialing" is the key. Almost every molecular pathway - you name it - has a black and white
hat, on several levels, and dosing into the sweet spot seems almost an art. So- there are a few compounds I am quite high on but
in experimenting on the edge (and filming it I might add) a conservative approach seems the way to go. For instance, I have had a number
of conversations with scientists about the possible interactions between a substance like rapamycin and things like beta lapchone and NR.

Thanks- so how does taking 3 mg in the AM once a week optimize the beneficial effects of rapamycin and minimize the possible adverse effects? Did you try other doses and schedules? Are there studies that support your dosing schedule? Have you tested biomarkers to compare the effects of various doses and schedules?

[Jaris]

Even though  the questions weren't asked of me, I'll try to answer some of them. I believe those who are taking small doses once a week, usually along with Metformin, are basing it on the results of the few relevant studies that have been published. I've listed them before, but here they are again:

 

https://www.ncbi.nlm...ubmed/26463117 Alternative rapamycin treatment regimens mitigate... side effects

http://www.kurzweila...isking-diabetes    Studied the use of Metformin taken along with rapamycin

https://www.research..._in_the_elderly   Studied several dosing regimens in elderly humans

 

The decision to take a certain amount once a week with Metformin might be consistent with these studies, but we can all hope that more studies will give everyone more and better data. For example, of the studies above, they all looked at different approaches to mitigate side effects, and 3 approaches seem to emerge: Metformin, Everolimus (a rapalog), and intermittent small dosing. But the Metformin study didn't use this dosing approach, so is combining them better or worse? Most are assuming that combining these 2 approaches is the way to go. I'm not so certain. And what small dose is best? Again, although there is some guidance from these studies, they looked at only a few possible dosing regimens. Would 10 mg taken 2 weeks apart be better than 5 mg taken 1 week apart? etc. etc. etc.

 

Most who try to decide what will work best based on these limited studies apply logic to extract more information. For example, the time period of a week might come from tests that show the level of Rapamycin dropping to almost 0 (in humans) in 6 days. But it's still guess work until studies have been done to see if other dosing regimens are better. Maybe you want to have a period of several days of cell autophagy (clean up/recycle/repair) followed by several days of cell growth, so 10-12 days might be a better period? Constant autophagy may have its own set of problems. Maybe there are other important factors that haven't even been discovered yet? You get my point.

 

Once again: I have my reasons for not waiting for more data, but for those who can wait, more studies and data might be worth it.

Edited by Jaris, 09 February 2017 - 08:40 PM.

[PAMPAGUY]

Have been reading this blog for the last couple of months because I’m aging and feeling the effects. (loss of energy, fatigue, weight gain, etc.)  I’m 70 yo, in good health, but have pre-diabetes because of being overweight.  I’m 5‘11“, 195 lbs., work out everyday, but have really slowed down.  CR is very good, but hard to stick with. (decided to go with rapa)  Ageing makes us all vulnerable to all the diseases that come with it.  After educating myself about the different drugs, and strategies used to delay ageing, have decided to start taking low dose Rapamycin + Metformin.  If one does not intervene, we all know what the outcome is at my age.  Upfront, I would like to say that this is a personal decision and would not recommend it to anyone else.   I have spent most of my life in the medical and biotech industry, but am not a trained medical professional (MD, RN, PHD).   Any drug that has the potential to compromise one’s immune system can be dangerous.  The limited human trials have not established the long term safety of Rapa for human aging.  One also has to be aware of any possible drug interactions with your medications.  I take a statin, and low dose aspirin daily.

 

Ordered Rapamycin (Sirolimus) 1mg tablets and have started taking Rapa a few days ago.  Intermediate dosing of 7mg. once weekly along with 500 mg Metformin daily. There is a strong likelihood that the 2 drugs work in synergy.  Am fully aware of all the side effects, as outlined in the Novartis trial of 2014 for elderly people and will keep close tabs on my health.  Blood test for glucose, liver, kidney function, ulcers, etc.

 

Any questions or comments would be appreciated.

 

[Jaris]

It seems that you are at least as well informed and prepared as i am, so I have no advice to give. I would like to hear your reasoning behind your decision to take 7 mg. I'm not saying that I disagree; just curious.

[PAMPAGUY]

I decided on the 7 mg weekly dose by reading all the other studies and/or trials on intermediate dosing.  I'm treating ageing so these comments may not apply to any other diseases.  There is a MD, Alan Green who has been taking rapa for a year and his comments are posted here http://joshmitteldor...apamycin-redux/.  He started out with 6 mg and weighing 170 lbs., I weigh 195 so I started with 7 mg.  He has had no side effects.   Also in the 2014 elderly study by Novartis one of the doses was 5 mg once per week without any major side effects.  It was stated that the 5 mg dose blocked the TORQ1 signal by over 50%.  The 20 mg weekly dose almost completely blocked the signal, but with more side effects. The purpose of taking rapa is to block the signal so cells can go from growth mode to repair mode.  You must take sufficient rapa to block as much of the signal as possible while not too much to avoid side effects of TORQ2.  I felt that taking 7 mg weekly should block around 70% of the signal.  Also rapa has a half-life of 72 hours for men, meaning most of the rapa will be out of your system before the next dose thus minimizing the chance of side effects.  The following clinical trial from University of Texas on elderly individuals is scheduled to be published in June 2017.  All of the patients are taking 1 mg. rapa daily or 7mg weekly.  https://clinicaltrials.gov/ct2/show/NCT02874924?term=rapamycin%2Fageing&rank=3.  I personally feel that much higher doses can be tolerated without side effects, but will wait.  There is no big hurry for me.  I can stay at this dose until new studies come out in the coming years.

[Jaris]

I agree with everything you wrote. I wasn't aware of the U of T study, which is welcome news! Do you know if they are combining Metformin with Sirolimus in this study? I don't see it mentioned.

I'm sure you know that you should not drink grapefruit juice while taking a statin (or several other drugs), but I mention it just in case. I drink it to increase the amount of Sirolimus I absorb, and it has other benefits: http://www.diabetesi...lin-resistance/.  But again, avoid it if you take statins.

I might begin taking Metformin, depending on what my on-going glucose testing.reveals.

[PAMPAGUY]

I would not recommend using grapefruit juice.  I have read that different brands, and varieties of grapefruit contain different amounts of the chemical that enhances drug absorption.  It could be 400% increase or 50%, you don't know without an analysis.  I read this in a trial where they wanted to keep a low dose of rapa or one of the rapalogs.  They actually contacted the grapefruit growers association to get the % contained in there grapefruit juice.  This is not telling you what to do, but be careful.  I buy my rapa from India. ($2 mg)  without a Rx.   Blister packs of 10.   You could take 5 mg a week for $40 month.  It is made by Bicon, the largest pharm manuf in India.  There are real FDA inspectors paid by the company, but report to the FDA to make sure all there drugs meet that criteria.  They sell billions of dollars of drugs yearly to the US, Europe, all over the world.

 

Also, Metformin is not only for glucose control, but it is a mTOR inhibitor.  It is an ageing drug all on its own.  Just not as strong as Rapa. https://www.fightagi...through-mtorc1/

[Jaris]

Yes, I know. I get mine from India too - same manufacturer - but mine costs $3 a pill. I guess the real reason I'm avoiding metformin is that I'm primarily taking rapamycin to help with my Parkinson's Disease. The main 2 studies that show it, in effect, curing PD in mice don't use metformin, and I know that drugs can have unexpected effects on each other. There are other things in the studies that I can't reproduce for myself (I'm not a mouse), so I feel that it's important to stick to what I can.

As for the juice, I appreciate the input, and I'm re-thinking it. After all, juice is not used in the PD studies either.

[longévité]

 

Also, Metformin is not only for glucose control, but it is a mTOR inhibitor.  It is an ageing drug all on its own.  Just not as strong as Rapa. https://www.fightagi...through-mtorc1/

 

As has been mentioned previously in this thread perhaps by Jaris, Sulforaphane is another mTOR inhibitor worth examining its relative potency in relation to Metformin and Rapamycin.

 

"Activation of autophagy by SFN (Sulforaphane) in normal human fibroblasts only marginally affected their viability and was accompanied by an inhibition of a major negative regulator of autophagy, mTORC1. Autophagy induction and mTORC1 inhibition was preceded by activation of AMPK kinase, a known inhibitor of mTORC1 and thus autophagy activator. The autophagy induction by SFN coincided with a block in protein synthesis which might be, together with the induction of autophagy, the molecular mechanism leading to reduction of the mutant huntingtin amount in cells by sulforaphane." http://jnnp.bmj.com/...7/Suppl_1/A94.1

 

Another study that mentions the impact of Rapamycin and SFN (Sulforaphane) on Autophagy: "In conclusion, co-treatment with rapamycin may enhance SFN-induced autophagy": https://www.ncbi.nlm...les/PMC4214451/

 

Along with inveterate contributor Mrkosh1 http://www.longecity...-the-sirtulins/ I am intrigued by the high bioavailablity of Sulforaphane (reportedly 80X higher than other AMPK activators like Curcumin): 

 

http://imgur.com/a/KqhtO

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736808/

Edited by longévité, 12 February 2017 - 04:29 AM.

[tintinet]

I've also started eating steamed broccoli sprouts with brown mustard seeds for sulforaphane.  I've been taking metformin for years already. So far, I've been taking 1 mg rapamycin QOD for about a week now. I've noticed no effects from any of these recently. When I first started metformin, I notice a marked reduction in appetite. 

[VP.]

I've also started eating steamed broccoli sprouts with brown mustard seeds for sulforaphane.  I've been taking metformin for years already. So far, I've been taking 1 mg rapamycin QOD for about a week now. I've noticed no effects from any of these recently. When I first started metformin, I notice a marked reduction in appetite. 

What dose of Metformin are you taking?

[tintinet]

I've also started eating steamed broccoli sprouts with brown mustard seeds for sulforaphane. I've been taking metformin for years already. So far, I've been taking 1 mg rapamycin QOD for about a week now. I've noticed no effects from any of these recently. When I first started metformin, I notice a marked reduction in appetite.

What dose of Metformin are you taking?

Started with 250 mg/day. Last couple years I've been taking 1,000 mg time release/day.

[Jaris]

I've also started eating steamed broccoli sprouts with brown mustard seeds for sulforaphane.  I've been taking metformin for years already. So far, I've been taking 1 mg rapamycin QOD for about a week now. I've noticed no effects from any of these recently. When I first started metformin, I notice a marked reduction in appetite. 

Interesting that you chose QOD. As I understand it, that means that you aren't waiting for the sirolimus to be out of your system (72 hours?) before taking another dose? I'm dabbling with the idea of cutting my dosing period from 7 to 6 or even 5 days. I'll be very interested in anything you experience.