So everyone here is experimenting with a drug that hasn’t been proven to work yet their all trashing Metformin. Metformin’s been around for a long time. What proof thus far is there to show that Rapa works? Show me a long term trial? Sinclair isn’t the only doctor that uses Metformin. I happened to mention him but there are many others less well known. Sinclair does mention Rapamycin as another potential longevity drug. Should we throw that in the trash bin after he mentions it. I say everyone here is an adult and we all have to do what we think is best for ourselves. I for one never got any covid shots and Im 75. I go for 90 min bike rides at least 4 or 5 days a week. Gave up red meat at least 40 years ago. Lost 10 lbs since going on longevity diet and feeling better then ever.
Interesting listen. Another Doctor that takes Metformin and also mentions both Metformin and Rapamysin.
No drug is proven. There are no long-term prospective trials proving any life extension in humans for any drug. So the first argument you make is not particularly applicable to the question of what drug to take if any.
From what I know so far, many people are happy and “healthy” while smoking at age 100. If I recall correctly a large cohort of centenarians are >50% smokers. If you like the logic of large retrospective studies (not even in healthy individuals) without looking at the negative evidence, then one can also claim smoking could work and argue that smoking potentially causes life extension. One could further build the claim that smoking could prevent ulcerative colitis and Parkinson’s disease that would pass peer review. I can’t even say with 100% certainty that nobody would actually benefit from smoking. Plenty of smokers claim they feel better than ever. I don’t mean one should start smoking but you feeling better with any drug doesn’t really necessarily translate for others.
I’d highly suggest avoiding a common human tendency that plenty of “smart” people can make if you didn’t look at the negative evidence here. That would be confirmation bias.
The harder part is going through the strongest arguments of both sides. I’ve gone through Nir’s claims - broken them down, metformin monotherapy is not particularly compelling when compared to known issues of metformin and “gold standard” ITP and human trials as opposed to other options.
If better quality evidence surfaces on metformin, then I’d change my mind. Simple as that.
I’m not out to trash any specific drug, but back to smoking as an example - if one develops basic research methods knowledge and then reads through all the quality evidence about say smoking dispassionately without any preconceived notions or hidden positive feelings, while completely ignoring what others are saying first before you compare notes and see it from different angles - it’s clear to me why I would be negative about say smoking as a life extension intervention. It might seem trivial for something like smoking, but it’s not.
I repeated the process for many different interventions, including metformin. Not going to bias myself to let taking anything based on what someone else says and feeling good about it shape my opinion on any intervention. I suggest anyone do the hard work first if they aren’t, don’t let anyone influence you with preconceived notions. But it’s clear most likely most people aren’t keen on it. It’s not much different than reading the terms and conditions before accepting.
It’s really quite straightforward. Metformin failed the ITP whilst Rapamycin has been successful in every single model organism and has generated the most significant life extension.
Not sure what your fitness and diet have to do with the discussion?
It’s all about the size and schedule of the dose, and interaction with exercise (since that’s where it seems to harm), correct?
I use berberine (since I don’t have metformin) occasionally, often before a rapamycin dose, both to improve rapamycin’s bioavailability, and to help slightly with the glucose intolerance that rapamycin may cause. And I’m usually fine with using it if I don’t see much exercise happening on that day and the following day (e.g. before flying, etc.).
And perhaps the lower doses like 250mg used intermittently are helpful without causing irreversible harm.
I need to read the link between metformin and Parkinson’s. Is this for real? Since the mitochondria is implicated in parkinson’s, perhaps the manner in which metformin comes in the way of exercise benefits, and the manner in which it (potentially) causes Parkinson’s, are similar? By its effects on the mitochondria?
um no, met + lower-dose rapa >> rapa by ITP
Erm no, metformin plus low dose rapa = high dose rapa
(Due to metformin’s effects on CYP3A4)
That’s true. Acarbose, 17 estradiol, and metformin all exhibit mTOR inhibition as part of their pathways. That’s not a true synergy and it’s very difficult to sort it out. In the treatment of hypertension we may use:
Hctz + inderal. The one is a diuretic and the other, a beta blocker. Totally different mechanisms resulting in a greater response. A true synergy.
Curcumin and EGCG both inhibit mTOR. If we combine them with rapamycin would we get a greater response? Probably.
I worked as a welder for 19 years at a plant where we make Steam boilers. the time I was there we had 7 people die. One was at least 60 and he was a heavy smoker and after only a year at the plant, they found a spot on his lungs. Two weeks later he was dead. Five of the other six that died had one thing in common. They all smoked and probably drank too much. The last one shot himself after becoming depressed when his girlfriend left him. Another welder younger then me was always coughing. I used to kid him about COPD. I bet by now he’s a lot worse off. Just my experience with smokers at work. There’s always the rare one that drinks and smokes and goes on forever. There must be a reason they have that warning on cigarette packs.
I’m not pro-smoking and I always recommend against smoking. However, while smoking is a major risk factor for COPD, only ~20% of smokers actually get COPD. I always seem to get some surprised looks when I mention this in the clinic.
This isn’t a justification for smoking - there are plenty of other disease processes where smoking is a large risk factor such that smoking is always a terrible gamble based on current knowledge, even in say ulcerative colitis where it may “help” with only the UC part. It’s just to illustrate that there is a huge luck factor and perhaps some small unidentified portion of those who are lucky may be genetic where one can have “terrible” lifestyle factors and still live to a healthy 100 years or much less likely, there may be a silver lining in smoking we don’t know about in very rare cases. It would be prudent to find out how that might work or what protective factors are involved, if any, despite it being seemingly trivial.
“only ~20% of smokers actually get COPD.”
That’s a major alarm, not a minor one.
It is a major risk factor as mentioned - it’s just that asking peeps to guess - they’d believe it’d be closer to 80-90%
New research on rapamycin / metformin (in mice):
Sirolimus (SRL) is widely used as an immunosuppressant to prevent graft rejection, despite the risk of impairing glucose metabolism. Metformin (MET) can reduce the detrimental effects of SRL in many patients, including diabetes and renal transplant recipients. Limited in vivo studies have reported on SRL and MET therapy, particularly in relation to cellular bioenergetics, glucose metabolism, and insulin resistance. Herein, we investigated the efficacy of SRL and MET co-treatment in BALB/c mice over 4 weeks. Balb/c mice (4–6 weeks old) were divided into four groups and injected intraperitoneally (i.p.) with water (control, CTRL), MET (200 µg/g), SRL (5 µg/g), or MET (200 µg/g) +SRL (5 µg/g) over a period of one month. We evaluated the body weight, food consumption rate, random blood glucose (BG), insulin levels, serum biochemistry parameters (ALT, Albumin, BUN, Creatinine), and histomorphology in all groups using standardized techniques and assays. All drug-treated groups showed a statistically significant decrease in weight gain compared to the CTRL group, despite normal food intake. Treatment with SRL caused elevated BG and insulin levels, which were restored with SRL + MET combination. Serum biochemical parameters were within the normal range in all the studied groups. SRL+ MET co-treatment decreased liver cellular respiration and increased cellular ATP levels in the liver. In the pancreas, co-treatment resulted in increased cellular respiration and decreased cellular ATP levels. Liver and pancreatic histology were unchanged in all groups. This study showed that co-treatment of SRL with MET alleviates hyperglycemia induced by SRL without any deleterious effects. These results provide initial insights into the potential use of SRL + MET therapy in various settings.
That’s a pretty good confirmation of the synergistic benefits of taking Rapamycin (SRL) and MET together. However, it may be better to use SRL and Acarbose. You definitely need something to address the “Rapamycin Diabetes” issue.
Not necessarily - its still unclear. As I’ve mentioned - there are researchers I talk to in both camps… so its largely undecided.
Fasting and rapamycin: diabetes versus benevolent glucose intolerance
https://www.nature.com/articles/s41419-019-1822-8
But from a risk reduction standpoint, probably a good idea right now… plus the ITP studies point towards significant benefits of rapamycin + acarbose.
Not only rapamycin + acarbose, but also rapamycin + metformin. If we are going off of data, the ITP studies have shown that rapamycin + (metformin or acarbose) had a significant effect on longevity over Rapamycin alone. When you add in papers like the one above and others like it, you find that the combination prevents fatty liver and other diseases as well as other potential problems. Also, what’s the downside? The cost of acarbose or metformin? Based on the research I have seen, using the combination of Rapa + Acarbose or MET beats Rapamycin alone.
If it was a wager to see who would live longer, someone taking either Rapamycin or Rapamycin + (acarbose or MET), I know which side I would bet on! But then, I place a high importance on the ITP results.
Our main finding here is that a multi-drug approach utilizing metformin can alleviate common metabolic deficits associated with chronic rapamycin treatment as a pro-longevity therapeutic. Moreover our data are in line with recent studies suggesting the metabolic dysfunction of rapamycin can be dissociated from its molecular effects on inhibition of mTOR either pharmaceutically or through alternative pharmaceutical regimens [10,16]. This has been an ambiguous question since the initial report of the pro-longevity effect of rapamycin administration in mice by the ITP in 2009 [1]. One interpretation of this seemingly paradoxical outcome is that rapamycin promotes long life despite also developing glucose intolerance, insulin resistance and/or decline in insulin production and that preventing these metabolic defects may extend lifespan further still. While glucose impairments promote clear health deficits in humans, one potential confound of this interpretation for mouse studies is that their lifespan is typically thought to be due to the development of cancer rather glucose metabolic dysfunction. However, such metabolic impairments have been associated with the acceleration of cancer progression and even the development of certain types of cancer in mouse models suggesting that glucose metabolism could impact mouse mortality at least indirectly [35,36]. The ITP has recently reported the lifespan of eRapa+Met mice is at least as long, if not longer than historical data for mice treated with eRapa alone [32]. Together, our data provide modest evidence for this interpretation, but leave open questions regarding the next steps in research pursuit. While both young and old mice are susceptible to rapamycin-mediated glucose intolerance [34], it is unknown whether metformin would have the same benefit in aged mice. More testing will be required to address whether metformin can alleviate the greater degree of glucose intolerance caused by higher doses of rapamycin than the 14 ppm dose used here [37].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892694/
Towards natural mimetics of metformin and rapamycin | Aging.
Don’t forget all the other medical problems most smokers end up with later in life. Smoking is bad on your bones. Smoking means a higher risk of Cancer and other diseases. Thats why theres a warning on the packages.
I was a welder for 19 years. During the time I was working as a welder, we had 7 employees die. All had one thing in common. they all smoked. Thats a big percentage since the most ever working in the plant at any time was 26 employees and a manager and co manager.