Glucosamine instead of Metformin and Rapamycin?

Zisos Katsiapis 

Here is a link to research that show decreased all-cause mortality among those who took Glucosamine. " A population-based prospective cohort study included 495 077 women and men (mean (SD) age, 56.6 (8.1) years) from the UK Biobank study."

"Conclusions Regular glucosamine supplementation was associated with lower mortality due to all causes, cancer, CVD, respiratory and digestive diseases."

"Regular glucosamine use is associated with a lower risk for total mortality (15%), CVD mortality (18%), cancer mortality (6%), respiratory mortality (27%) and digestive mortality (26%)."

https://ard.bmj.com/content/79/6/829

My first thought was that users of glucosamine usually have painful joints and that they also take NSAID - aspirin etc. And that could explain some of the disease prevention. But they say "the associations between glucosamine use and all-cause and cause-specific mortality were not significantly modified by sex, age, ethnicity, obesity, current alcohol status, physical activity, diabetes, statin and aspirin use"

Yes Glucosamine is interesting.But does not have a long history of use in clinical settings like metformin. But according to the study I refer to it is not a shot in the dark.  

My main question is: Am I already using substances that give me the benefits the Glucosmine will provide? In that case will there be a risk that glucosamine only will  add the possibility of negative interactions.  

Zisos Katsiapis with rapamycin you need to have comprehensive lab work done before you start and then ongoing every six months. This needs to be reviewed by doc. To me the biggest concern with rapamycin is that it suppresses mtor effectively neutralizing the benefits of strength training. You need your muscles as you get older. Hence knowing a bit more about when and how much to take are big questions here. So rapamycin today as I see it is only useful as adjunct treatment to calorie restriction.

With respect to our question on antioxidants dosing. First of all I don’t recommend taking any antioxidant supplements (excepting some vitamins if you have low blood levels) as they shorten your lifespan perhaps excepting besides some vitamins and glutathione, which seem to be safe. The antioxidant precursors like sulforaphane make more sense to supplement and are more promising. These I would take either in low doses everyday or intermittently 6 weeks on and 2 weeks off. Now if we are talking about antioxidant vitamins then I would recommend obtaining rda doses everyday.  For example you need vitamin c, which happens to be antioxidant, before your weight training to synthesize collagen afterwards. As you know other fat solvable vitamins like vitamin d don’t have to be taken everyday. 

Joe smith 

I'm curious about your statement that antioxidant supplements shorten your lifespan. I hadn't heard that. Would you expand on it, with some sources?

http://www.digitaljournal.com/article/129836

Joe smith 

you stated. “me the biggest concern with rapamycin is that it suppresses mtor effectively neutralizing the benefits of strength training. ”

I have been taking rapamycin for 6 weeks on a weekly basis and have found that my workouts are more beneficial than before I started. My increased gains in muscle mass and have strength are noticeable so I don’t think your statement can be true. The only thing that has changed otherwise is I seem to have more energy to do workouts and so have been able to increase my number of workouts. 

Stevan Lieberman Thanks so much for the n=1 post on Rapamycin and resistance exercise! I've been hesitant to add Rapamycin to my longevity intervention stack, due to concerns about exercise blunting. Metformin has been readily shown to blunt exercise.

I gained some comfort through some personal communications with THE Rapamycin guru himself, Blagosklonny.

He wrote "Amino acids do not make muscle stronger, exercise does. And Rapamycin potentiates strength"

https://www.mikhailblagosklonny.com/how-rapamycin-prevents-muscle-loss-and-sarcopenia-first-draft/

It has been shown that there are MTOR INDEPENDENT pathways to MUSCLE hypertrophy in humans.

So I decided to take the plunge, waiting for my first Rapamcyin order to arrive.

May I ask what triggered your taking Rapamycin, and what is your dosing regiment?

MAC Dr. Nir Barzilai is a MD who is a medical researcher and expert concerning metformin. From the podcast notes, here is a summary what he said during a podcast interview by Dr. Peter Attis, MD.

• He points out that while the metformin group had less muscle mass growth, the function was actually the same
• Nir’s main points:
  • In this elderly population, metformin kept the young profile of the muscle 
  • At the end, maybe you had less muscle, but you had the same function, and you gained by metformin protecting 500 transcripts that are aging transcripts

David H Not swayed. I am 55 yo, very lean and fit, following a strict ketogenic diet, OMAD (one meal a day) time restricted feeding. Glucose and insulin signalling are not any metabolic concerns; some days I am hypoglycemic. I am already doing some AMPK heavy lifting. I exercise daily 60-90 minutes, combined cardio (125 bpm/30 minutes) and whole body resistance training. 

Peter Attia has mentioned several times on various podcasts his concerns about metformin and exercise, and most especially for anyone who is very fit and far away from metabolic syndrome.

Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double‐blind, placebo‐controlled, multicenter trial: The MASTERS trial

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826125/pdf/ACEL-18-e13039.pdf

" In men and women aged 65 and older, 14 weeks of PRT induced the expected increases in muscle mass and strength. However, metformin administered along with PRT inhibited these gains. DXA showed that metformin gained significantly less total lean mass and less thigh muscle mass than placebo. Likewise, CT analysis indicated that normal density thigh muscle area increased following PRT, but metformin blunted this gain."

Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351883/pdf/ACEL-18-e12880.pdf

"Our findings in older adults at risk for T2DM demonstrate that compared to placebo, metformin blunted the improvement in CRF by ~50% after 12 weeks of AET. Since CRF and insulin sensitivity are primary predictors of age‐related morbidity and mortality, these data raise concerns about broad recommendations for the use of metformin as a treatment to target aging"

Since CRF is the only proven longevity enhancement lifestyle intervention (DR and fasting have not been proven in human RCT, although in many other animal models) in humans, I wouldn't do ANYTHING that would blunt that intervention.

MAC My parents started talking about taking anti-oxidants when I was in my mid 30's and convinced me I should take them too.  Then the focus was on Vitamin C and the discussion mostly surrounded how ones body could not use vitamins as easily so one needed to supplement with higher amounts.  It got me reading and I started adding on different supplements.  I am now in my mid 50's an I have been able to tell that I didn't have the same energy or ability to heal for a while and ran across Dr. Green's website.  After reading it I googled sirolimus and this site came up.  I showed both sites to my primary care who then had a chat with Dr. Green and based on that both agreed to prescribe for me and has started taking the same dosage she has prescribed for me which is 4 mg once a week.

Stevan Lieberman  I’m glad that rapamycin is working for you. How much and how often are you taking? Also what brand and where are you getting it from? Also do you plan on doing before and after bloodwork? My personal experience is with the sirolimus 2 mg taken once a week obtained from Walmart. From my tests all I saw is that sirolimus succeeded in lowering my urine ph ;hence, putting me in the starvation mode. During 48 hrs after taking it, I could barely exercise.

Joe smith I am taking 4mg once a week.  It is prescribed so just getting it from cvs. I had a blood test before and then 3 months later. I have always worked out pretty regularly which I assume is why there was no difference between before and after. I will do another test in 6 months. All of my numbers are within norms. I felt like I had more energy the first couple of weeks taking it but since then not a significant difference. I am 55, not overweight and also take a number of supplements and have been doing so since my 30’s. 

Stevan Lieberman Also, I had no issues exercising after taking it, and in fact I found that I was able to work harder and since starting I am finding it easier to do more weight on weight lifting day  

Stevan Lieberman  I’m 6 foot tall and about 160 pounds, thin and muscular. I exercise 5 times a week. I can do a single leg sit to stand. I’m about 5 years older than you are.  I do take sirolimus with lithium, 500 mg berberine and 500 Metformin per day. As b and m are mtor suppressing together with lithium, they augment the effects of the sirolimus. This combined with my calorie restriction diet most likely suppress mtor to the point that I have to push myself to exercise within 48 hours of taking it. I also may be more sensitive to sirolimus than others. 
 

Joe smith You're strong.  I've never been able to do a single leg to stand and only workout with 150 lb bench (I workout 3 days a week).  I'm five foot 7 give or take and 165 pounds a little stocky. I take the lithium as well, 5mg. I don't really do calorie restrictions intentionally, I just don't get particularly hungry (my work has me sitting most of the day) so have a small breakfast of toast with a lot of olive oil and some nuts and blueberries and a lunch which is a full meal around noon and don't eat anything else for the rest of the day other than a spoonful of peanut butter around 5 sometimes (200 calories?). I am averaging between 1000 and 1500 calories unless I have a beer which is 2-3 times a week which I figure adds around another 150 calories.  My weight hasn't changed by more than a couple of lbs in years. I also find I am not particularly sensitive to any drugs / supplements.

I thought b & m did essentially the same thing, so why do you take both?  I also understand they both give you loose stool. Do you have an issue there? I do not understand why suppressing mtor makes it harder to exercise. Can you or anyone else explain?

Stevan Lieberman both berberine and Metformin are organic compounds but derived from different plants. Hence different mechanism of action. Berberine also lowers ldl-c and triglycerides, which you need when you take rapamycin. Berberine also counteracts negative side effects of Metformin.

Mtor is basically growth regulator. You activate it more growth, bigger muscles, etc., you deactivate it then you stop/slow down the growth. Recovery from the strength training involves activating mtor in presence of amino acids and includes muscle hyperthropy and conversion of the stem cells into muscle fibers.  Now if you suppress mtor then you slow down recovery from the strength training. So in my case when I take rapamycin it impacts my recovery as I train 5 times a week. So when I exercise next time within 48 hrs of taking rapamycin my mtor is suppressed, I’m not properly  recovered and I can barely go through my routine. 
 

Joe smith Ok, that makes sense, but you say strength training.  Does that apply to cardio as well?  Yes, I know that also includes substantial muscles, but everything is a muscle, re heart, lungs, etc.  Thoughts?

Joe smith Just doing a bit of a deep dive on berberine. You say you take 500mg berberine with Rapamycin? I've read some papers and references that berberine and macrolides (of which Rapamycin is one), are contraindicated?

https://liftmode.com/blog/berberine-side-effects/#_ftnref6

The enhancement of cardiac toxicity by concomitant administration of Berberine and macrolides

https://sci-hub.se/10.1016/j.ejps.2015.05.009

"Collectively, these results demonstrated that concomitant use of Berberine with macrolides may require close monitoring because of potential drug toxicities, especially cardiac toxicity"

As well, find many articles indicating concern over long term effects of Berberine, much less well studied vs Metformin.

https://diabetesupdate.blogspot.com/2013/08/berberine-works-but-may-very-well-be.html

I assume you are under care of MD, since metformin and Rapa are typically needing prescription?

Do you take anything to help with bioavailability of berberine?

Since I am strict keto/OMAD, my glucose and insulin are typically very low, so I wasn't thinking I'd need berberine to help dampen down any potential elevated glucose that might present itself when I start taking Rapamycin. 

Joe smith very strange. I take 10 mg a week and am an avid hiker and mountain biker. Ramamycin has no effect at all on my workouts

MAC well yes rapamycin  is micro-glide but the paper focused on antibiotics and it doesn’t appear to mention rapamycin. I think it would be a stretch to think that it covers it too. Berberine actually appears to be heart protective.  and yes berberine is not as widely studied as Metformin; hence, I only take 500 mg and only do it once a day. Berberine half life is about 3 hrs so I don’t overload my system with constant berberine drug pressure. I also cycle it on and off. To increase absorption I take berberine and rapamycin with fish oil.

Paul Beauchemin well according to the research I reviewed it should impact resistance training in mice by 50 %. Anyway I wish Dr Green publish some studies to give us more insights here.

Paul Beauchemin Must be placebo. Clearly from the literature that I recently attached to posts on this topic, mTOR inhibition is a no-no  in terms of repairing muscle fibers after exercise. Use  will also contribute to sarcopenia and frailty in seniors.

In terms of Joe Smith's comment, fish oil stimulates mTOR in terms of muscle repair. It also inhibits mTOR in terms of preventing neurological diseases. Biology is complex.