Glucosamine instead of Metformin and Rapamycin?

Peter H. Howe a brilliant personal attack!

Joe smith https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594297/

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?

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. 

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?

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.

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?  

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. 

Paul Beauchemin Response in kind.

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! 

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.

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.   

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.

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.

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. 

Joe smith https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765582/

MAC See attached. Contains brief section on rapa and call by AgeXX for volunteers.

https://www.longevity.technology/a-year-in-longevity-progress-perspectives/?utm_source=ZohoCampaigns&utm_campaign=Longevity.Technology+News&utm_medium=email.

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