Glucosamine instead of Metformin and Rapamycin?

I happened to read a very old blog by Vince Giuliano regarding Glucosamine 

http://www.anti-agingfirewalls.com/2014/06/09/glucosamine-for-longevity/

In it he gives sufficient evidence that  Glucosamine extends life in nematodes, mice, and humans, by activating AMPK, and modulating mTor.

There is one caveat: The life extension benefits are lost if antioxidants are also supplemented at the same time.

There are two questions that come to mind:

a) If this supplement is readily available, cheap, and gives the same benefits as Rapamycin and Metformin combined, without the side-effects, and since this information is available for a long time, why all the fuss about Metformin and Rapamycin? Why bother? It seems to me like a no-brainer. Am I missing something?

b) I currently supplement with antioxidants NAC and Glutathione. How can I continue to take them and still reap the benefits of Glucosamine? I would assume some intermittent schedule. But no sure about the intervas.

Any ideas will be greatly appreciated.

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  • I don’t think your #1 holds true. Efficacy of rapamycin for life extension is much higher and per dr Kaeberlein in reasonable doses rapamycin is no more dangerous than aspirin. Also per the research paper you have attached the average lifespan extension in mice is just 6%; basically, no better than Metformin or berberine. This is quite lower than rapamycin or calorie restriction in mice, which can achieve ~25% independently. Now human lifespan is much less pliable than mice, which means that 6% in mice may not extended human lifespan at all. Hence serious longevity researchers like Walter Longo don’t bother with such dubious therapies like Metformin and that’s why Glucosamine is not so exciting either. Now acarbose is much more interesting than Metformin and berberine or glucosamine as it extends an average lifespan in mice by 22%. Hence my suggestion would be to seriously consider acarbose , rapamycin and calorie restriction. These are heavy hitters and are very widely studied. Also I think your glutathione is actually a good and safe supplement although it doesn’t extend the lifespan.

    Like 1
    • Joe smith 

      Thank you for info.

      In fact, I currently take Berberine, and every now and then Rapamycin. But I am trying to figure out if I should change.  I am a bit scared of Rapamycin. Dr. Alan Green has mentioned that bacterial infections can be quite dangerous while on Rapamycin. In trying to extend healthspan/lifespan using Rapamycin, we risk dying very soon from bacterial infections.

      In the link that I provided, there is a reference to an epidemiological study on about 77000 persons (age 50-76) which concludes that " the probability of death for those consuming glucosamine per unit time is 83% of that of controls". For the same group, the risk for Colorectal Cancer was reduced by 45%.  It is true that epidemiological studies do not provide "proof" of causality. They do provide a strong indication. 

      In fact, I am more concerned that the benefits of glucosamine consumption disappear when at the same time antioxidants are consumed (I.e. NAC). Since I am also taking NAC, I would probably have to take both intermittently. I also wonder whether taking NAC while also taking Rapamycin, also negates the benefits of Rapamycin.

      Like
    • 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.  

      Like
  • The issue with Berberine is that it is just not as widely studied as Metformin and not fda controlled. It is probably ok and little bit beneficial for ldl-c and high blood sugar. If you take it do it just once a day 500 mg and cycle it on and off - 6 weeks on and 2 weeks off. With respect of nac and rapamycin I am not aware of any study investigating interactions between the two. That said nac being amino acid and rapamycin acting on mTOR, I suspect that they would counteract each other. I don’t see how staggering the treatments between the two be of any value. Now I think it makes for interesting lab experiment on mice but I wouldn’t try it on yourself. Idea is to minimize number of treatments and interactions as there are just too many unknowns. 
     

    With respect of rapamycin, I’m curious at what dosages the skin infections are observed? Can you find out from the doc who prescribed it to you?

    Anyway the idea behind combing cr and rapamycin and acarbose is that you can achieve combined effect without having to resort to extreme intervention. That is e.g. instead of doing 40% cr restriction you do 15% and instead of taking 10 mg rapamycin you take 3 mg and you still a have the same benefit without incurring a high risk like skin infections (and yes you should be concerned about it as you don’t live in sterile lab)  which comes with more extreme interventions. 

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    • Joe smith 

      Thank you for info.

      I take Rapamycin and others w/o prescription. So, no doctor to ask. But Allan Green usually prescribes 5mg / week or less. So I assume that at this dosage he observed the problems with bacterial infections. This is the reason why I am a bit scared of Rapamycin, and I would much rather use something benign like Glucosamine, even if the effect is smaller than Rapamycin.

      I agree with you that it might not be wise to take many supplements. Unfortunately, I end up doing the opposite. I find information about a supplement that presumable is useful. I add it to the stack. But do not remove something. 

      You seem to know much more than me, so maybe you can answer a question for me: For antioxidants, is it better to take them all the time, or intermittently? If intermittently, what would be the most appropriate on-off interval?

       Thanks

      Like
      • Joe smith
      • Joe_smith
      • 9 mths ago
      • Reported - view

      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. 

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      • Don
      • Don
      • 8 mths ago
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      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?

      Like
    • 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. 

      Like 2
      • MAC
      • MAC
      • 1 mth ago
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      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?

      Like 1
      • David H
      • David_Hanson
      • 1 mth ago
      • 1
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      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
      Like 1
      • MAC
      • MAC
      • 4 wk ago
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      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.

      Like 1
    • 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.

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      • Joe smith
      • Joe_smith
      • 4 wk ago
      • Reported - view

      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.

      Like
    • 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. 

      Like
    • 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  

      Like
      • Joe smith
      • Joe_smith
      • 4 wk ago
      • Reported - view

      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. 
       

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    • 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?

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      • Joe smith
      • Joe_smith
      • 4 wk ago
      • Reported - view

      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. 
       

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    • 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?

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      • MAC
      • MAC
      • 4 wk ago
      • Reported - view

      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. 

      Like
    • 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

      Like
      • Joe smith
      • Joe_smith
      • 4 wk ago
      • Reported - view

      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.

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      • Joe smith
      • Joe_smith
      • 4 wk ago
      • Reported - view

      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.

      Like
    • 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. 

      Like 1
    • Peter H. Howe a brilliant personal attack!

      Like 1
      • MAC
      • MAC
      • 4 wk ago
      • Reported - view

      Peter H. Howe This is a really interesting debate. As it relates to aging and sarcopenia, it's now contested that it's actually OVER-ACTIVE mTOR which contributes to sarcopenia, and Rapamycin can reduce mTOR and geroconversion/senescence and actually REDUCE sarcopenia.

      I've already posted before on communication from Blagosklonny:

      “Amino acids do not make muscle stronger, exercise does. And rapamycin potentiates strength” The link explains the theory.

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

      A recent review paper from Cambridge University UK.

      Dietary protein, exercise, ageing and physical inactivity: interactive influences on skeletal muscle proteostasis

      https://sci-hub.se/https://doi.org/10.1017/S0029665120007879

      I wrote to the author asking about the mTOR over-activation causing senescence and sarcopenia theory, and Rapamycin possibly ameliorating. He replied. "I have an on-going project grant also testing this hypothesis."

      I am intrigued on my n=1 response when I start taking Rapa. I am currently 55 yo male, in super cardio and skeletal muscular shape, daily exerciser, who also takes testosterone. What will rapa do to my daily bouts of exercise and cardio and muscular response with once weekly rapa?? The half life is 3-4 days in blood, but what is CELLULAR level?

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      • Joe smith
      • Joe_smith
      • 4 wk ago
      • Reported - view

      Paul Beauchemin I will review the article, I know it mentions 42 female mice of particular strain. At best this is enough to form a preliminary null hypothesis.  I’m also familiar with newer research published in the same magazine, which draws different conclusions. Again until we have human data and larger sample size with longer duration, we just don’t know. 

      Like
      • MAC
      • MAC
      • 4 wk ago
      • Reported - view

      Joe smith The fact that Rapamcyin, being a macrolide, is not specifically mentioned in the article hardly gives me scientific comfort. Surely they would not have listed every macrolide in existence, but common ones. But I think your heeding the safety of long term Berberine supplementation by limiting intake to 500mg/day is prudent measure of concern.

      Is the metformin and Rapamycin doctor scripted, or are you flying solo? And the berberine, although not needing a script, your own intervention or doctor approved?

      Like
      • Joe smith
      • Joe_smith
      • 4 wk ago
      • Reported - view

      MAC Metformin and rapamycin is doctor prescribed. Berberine is really on my own that said  I fully disclose to my doc what I’m doing and hasn’t heard any objections or concerns yet. I guess being conservative with the berberine helps. My doc wanted exhaustive blood and other tests before I started on rapamycin. As I mentioned, rapamycin has decreased my urine ph from an optimal range of about 6.2 down to 4.5. After I stopped taking rapamycin,  it went backup to 6.2. hence word of caution you can get kidney stones at such low urine ph. I think that the explanation for the low ph is that  rapamycin really induces  “starvation” like state.

      Like
      • MAC
      • MAC
      • 4 wk ago
      • Reported - view

      Joe smith Thanks for sharing. I'm on strict keto, one meal day diet, and haven't had any issues, although to be honest, don't recall my doc asking for urine PH to be tested. My keto is plant fat based, not animal, and I don't overload oxalates (major cause of stones) and stay hydrated. My protein intake is max 20% macros of total calories, rest in plant fats. Been 4 yrs, no health issues so far. Duly Noted.

      So you're back on Rapamycin, and doing anything to address the urnine pH issue?

      Any significant change in your biomarkers baseline after Rapamycin?  

      Like
      • Joe smith
      • Joe_smith
      • 4 wk ago
      • Reported - view

      MAC no real change in my bio markers. A1c always around 5.2, hdl about 80, triglycerides 100 and ldl about 130. To address urine ph I take potassium citrate now foods supplement and eat lemons. 

      Like
    • Paul Beauchemin Response in kind.

      Like
      • MAC
      • MAC
      • 4 wk ago
      • Reported - view

      Joe smith The after lipids is with berberine and metformin correct, which would help blunt glucose and possibly lipids? Do you have results before/after with just Rapamycin? Sounds like you are hacking what comes your way! 

      Like
      • Joe smith
      • Joe_smith
      • 3 wk ago
      • Reported - view

      MAC without Metformin and berberine my a1c is 5.3 with Metformin and berberine after 6 months and longer, it is 5.1 - 5.2, Ldl without berberine is about 180 and after six month on berberine it is 122. Berberine doesn’t seem to affect my hdl and triglycerides much before and after hdl 80 and triglycerides about 100.  When I take statins 20 mg Lipitor no berberine after 6 months my triglycerides go down to 70 and my ldl to about 65. Hdl stays at about 80.

      Like
    • MAC The following is from an 80 yo who is trying to make it to a healthy 100 which has less than a 1 % probability.  It gives me something to do and science is ever changing along with the multiple type 1 and type 2 errors in any scientific undertaking that has a very wide 95 % confidence interval. What can help me may be detrimental for someone else. With that said:

      In my opinion rapamycin is dangerous for a senior.  Not considered so far is the potential adverse impact on a seniors immune system.  You can ask Mr. Google and find that rapamycin inhibits the innate immune system. I am taking many steps to insure my immune system is properly stimulated and functioning, The last thing I need is interference.

      I saw your earlier reference to the Blagosklonny draft manuscript.  I prefer to take a different path and it appears to be working for me. I am going to continue my 1 gm/kg protein/day with ~ 40 grams of that from whey protein which also stimulates my immune system. It also contains all the essential amino acids in the proper amounts. It is ( along with egg whites) natures best protein. As you probably found there a multiple peer reviewed papers on the need for seniors to get more protein in order to prevent sarcopenia, some suggest up to 2 gm/kg/day. . 

      Before attaching several papers on the issue, you should know that I  also consume ~ 5.5 grams/day of EPA/DHA (fish oil). I have been taking this for 25 years after I had an emergency bypass. It is a "miracle" drug that is critical in terms of me reaching the 100 mark. More on this latter. 

      The following papers should explain my rational as to why I am going to stimulate mTOR in the interest of preventing sarcopenia and why I referenced my consumption of fish oil.

      https://pubmed.ncbi.nlm.nih.gov/19188252/

      The second reference is to a "sales pitch" article but it contains references to fish oil ,and the  stimulation of mTOR in the interest of preventing sarcpenia.

      https://www.intelligentlabs.org/how-omega-3-supplementation-increases-muscle-mass-and-strength/

      Another on fish oil and sarcopenia that references mTOR.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936484/

      You should be aware that maintaining your testosterone,  estrogen and DHEA are also critical in preventing sarcopenia and also prevent osteoporosis, dementia and a host of other ailments. They blend in with fish oil,  proper diet and exercise along with the ability to change your mind.

      I note that your previous post on metformin failed to mention that it inhibits testosterone production by inhibiting leutenizing hormone.  I stopped its use about five years ago due to this problem. I also stopped a severe 5:2 diet with rigid 18:6 eating interval in May of this year after 2.5 years. It also severely limited my testosterone production.  You can verify that calorie restriction and metformin  impairs testosterone production with a simple google search. 

      MAC You are apparently where I was 25 years ago after my emergency bypass. After an extensive search, I got lucky and found a cardiologist who integrated a statin with fish oil to prevent a future heart attack. I can assure that over the years, I have encountered a number of cardiologists who claim that fish oil is worthless.

      In this regard and in the interest of preventing dementia in your case, you might want to examine the attached review of fish oil benefits in preventing various forms of dementia by inhibiting mTOR ( 13 co-authors, 50 + pages ~250 references).  Its introduction contains  a extensive review of fish oil benefits. There are approximately  7,000 similar references on fish oil benefits. . 

      https://idus.us.es/bitstream/handle/11441/96286/mTOROmega3.pdf?sequence=1&isAllowed=y

      Keep on truckin, keep your triglyceride/HDL ratio at~1 and have a good new year. If those Brits publish that  paper, please let me know.   

      Like
      • MAC
      • MAC
      • 3 wk ago
      • Reported - view

      Peter H. Howe Healthy 80 yr old..you are way ahead of the game Peter! Less than 1% chance...depends, are you APOE 2/3, they are highly enriched for longevity vs. say APOE 4/4. I am APOE 3/4, so I have my work cut out...must work that much harder.

       ApoE e2 and aging-related outcomes in 379,000 UK Biobank participants

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343499/pdf/aging-12-103405.pdf

      Varying Effects of APOE Alleles on Extreme Longevity in European Ethnicities

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330482/pdf/glz179.pdf

      APOE2 is associated with longevity independent of Alzheimer’s disease

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588231/pdf/elife-62199.pdf

      Re Rapamycin and innate immunity...you missed that clinically, weekly intermittent dose ONLY impacts TOR1, and leaves TOR2 (innate immunity) unaffected. You are referencing chronic DAILY high dosing in transplant type scenarios. Many people taking intermittent Rapamycin are having their immune system checked, and in control. You can google this.

      I have been taking 3g/day DHA, and I eat wild sockeye 3x/week plus sardines. My last RBC Omega 3 blood test was 13%, very high. When I prick my finger for blood ketone measurement, the blood squirts out. I am aligned with you, I think DHA is super beneficial. DHA, keeping TG/HDL low, and very high cardio respiratory fitness are major interventions to prevent CVD.

      My philosophy at 55 yo is to PREVENT...and not wait for a chronic disease to manifest. Preventing a major mortality event is going to greatly increase my healthspan and mortality odds.

      I leave you with this 80yr old (at the time of the video) to consider what is truly the key metabolic lifestyle intervention to successful aging.

      https://www.youtube.com/watch?v=1IDbO8v0YOk

      His muscular physique didn't come from DHA or protein or pharmacology. It came from EXERCISE...that is THE key to skeletal muscle. That's what stimulates anabolic growth and is THE key to preventing sarcopenia. How many seniors are pounding the weights like he is? I've never seen a senior in the gym doing this type workout. I hope to continue this type resistance training as long as I can.

      Sarcopenia (barring some chronic disease that prevents exercise) in seniors is preventable. Seniors are not inactive because their bodies are falling apart, their bodies are falling apart because they are inactive.

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    • MAC Have differences of opinion on several issues--it is biology.

      I am well aware of the APOE issue and  I am APOE3 homozygous. Women in my family have tendency for alzheimers. Men, if they make it past cardiac arrest, it is ministrokes followed by the big one. We have very little incidence of cancer, probably due to low levels of IGF-1.

      It is my opinion that the most important thing one can do in preventing mental illnesses related to the APOE gene is to follow the Bredesen protocol.  

      http://www.aging-us.com/article/NjJf3fWGKw4e99CyC/text

      As documented in this  paper he reversed AZ in 9 of 10 patients and 6 of those returned to work. He has authored a book on the subject which goes into more detail. As I understand it, some enlightened neurologists are following it in terms of treating dementia. 

      There are 3 steps which in general are:

      1. No simple sugars, no eating between 6 pm and 6 am to give microglia time to clean up and some calorie restriction

      2.Return  hormones to youthful levels,  supplement with  fish oil and critical vitamins (D and B ) if they are low, and some additional supplements such as ashwagandha

      3. Remove toxins such as lead, mercury and pesticides.

      It is my opinion that the protocol is also an essential part of of an extended health span as it treats more than dementia. .

      Thank you for clarifying my issue with rapamycin and suppressing the immune system. I will however refrain from from it until I see a good risk assessment from some group like Forever Healthy. There are just too many unknowns. 

      I recognize the need for senescent cell removal, and have initiated use of fisetin based on comments of a number of persons on this form, risk assessment by Forever Healthy and  studies and current trials at Mayo.  It is also a mTOR1 inhibitor . I follow the Mayo protocol, with some exceptions, and the intermittent use may suffice in terms of mTOR.  Wish I had convenient way to measure effect levels as I have with blood test for statin and fish oil and cardio protection.

      In terms of fish oil my Omega Index is 9.16 %. Would like to get it somewhat higher, but if increase fish oil, I will start getting contusions. Had to stop baby aspirin due to the interaction of the two  and almost daily bruises. Getting old. Cardiologist told me to stop the fish oil, not the aspirin, due to my history. Told him thank you but no thank you.

      Strongly suggest you incorporate EPA in your fish oil. It is the primary component that suppresses inflammation. Check your IL-6 and tumor necrosis factor alpha. It does not affect CRP according to the literature.  

      That guy in the video looks old. Check out his face. Too much stress from all that weight lifting. Charles Atlas only lived to 82 as I recall. The average life expectancy of a male in the vegetarian Seven Day Activist community in La Jolla Ca. is 95.

      There is no question that exercise isn't important, but it cannot get you to 100 on its own.  Most seniors simply do not have the ambition to do what you are doing, due in most part to a host of deficiencies. 

      Thanks for the post. It keeps me alive along  with the 110 deep knee bends with 2, 20 lb weights that I have to do next.

      Like 2
      • MAC
      • MAC
      • 3 wk ago
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      Peter H. Howe apoe3/3 well that’s a better starting point, but still 60% of AD is 3/3. But apoe is NOT singularly causative, it’s a complex polygenic risk disease. My mom had AD, and maternal AD increases APOE4 risk. Sigh. So for me, my journey is neurological avoidance based. CVD or cancer death is not a known early mortality pathway in my family tree. 

      Been on the Bredesen protocol for 4 yrs, started immediately after taking on a Functional Medicine Doctor. We push it to even farther ranges like overlaying keto/OMAD, DHEA/hormones, Vitamin D, toxins, iron dumping, much higher exercise (the protocol is lacking in exercise) 

      Sedentary lifestyle and insulin resistance is the bane of western disease. Too many excuses and people waiting for “sick care” medicine to help them live longer AFTER you become chronically ill. 

      But it did take discovering I was apoe 3/4 4 yrs ago to give me that “scare” self motivation to PREVENT disease while I still have window. 
       

      Exercise is my #1 lifestyle intervention for longevity. Will keep running and lifting weights as long as I can! 
       

      Will keep you posted on my n=1 Rapamycin experiment. I haven’t even told my doc yet I plan on adding this hack! I did ask him to explore it with me earlier this year, and he was open to it. 

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      • MAC
      • MAC
      • 7 days ago
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      Joe smith Started my first dose 4 mg weekly Rapamycin. No obvious effects. Most importantly, my exercise regiment and recovery seem unperturbed. 

      Like
  • I write this post because I have read that AMPK activation could possibly be detrimental in neurological some diseases. (not knowing if it is correlation or a possible causation).

     

     I am not bashing AMPK activation. Its has many benefits but it might be the right time for me to dig in deeper and be more specific in my AMPK activation. I consider the possibility that I AMPK can be overactivated.

     

    One paper stated that “results demonstrate that AMPK signaling plays a critical role in the age-related decline of hippocampal neurogenesis.”.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764723/

     

    “AMPK is a master energy sensor which was reported to be overactivated in the brain of patients affected by these neurodegenerative disorders. While the exact role played by AMPK in these diseases remains to be clearly established, several studies reported the implication of AMPK in various signaling pathways that are involved in these diseases’ progression.”

     

    https://link.springer.com/chapter/10.1007%2F978-3-319-43589-3_7

     

    “Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are neurodegenerative disorders that are characterized by a progressive degeneration of nerve cells eventually leading to dementia. While these diseases affect different neuronal populations and present distinct clinical features, they share in common several features and signaling pathways. In particular, energy metabolism defects, oxidative stress, and excitotoxicity are commonly described and might be correlated with AMP-activated protein kinase (AMPK) deregulation. AMPK is a master energy sensor which was reported to be overactivated in the brain of patients affected by these neurodegenerative disorders.”

     

    https://pubmed.ncbi.nlm.nih.gov/27812980/

     

    this leads me to the question: which are the best ways to activate AMPK in muscles, fat and liver etc without over activating it in hypothalamus. And maybe even in some situations the aim might be to inhibit hypothalamic AMPK in the brain .

     

    Some indications point towards Lipoic acid and quercetin as supplements that inhibit hypothalamic AMPK while activate AMPK in muscles, liver and fat cells.

    Green tea and Curcumin promote neurogenesis in hypothalamus. While activating AMPK outside the brain.

     

    I have not seen any research about metformin and the effect it might have on disorders in the brain. I find exercise and diet to be the safest ways to activate AMPK. But I look for the smartest combinations of drugs or supplements to activate AMPK in some cells in my body and possibly to inhibit it in the brain, or at least avoid over activating it in my brain.  I post these thoughts here and hope that some might reflect on these ideas and lead me on to a better understanding of AMPK activation.

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