Some Supplements - More harm than good?

[KarlT]

Interesting, how did you determine which ones to use and which ones worked?

[John_Hemming]

I cannot say whether any of the four are unnecessary or the balance between them is ideal. In a way i started with HDAC inhibitors that also have a good reputation and evidence base. There has not been enough testing to distinguish between them.

[RapamycinCurious]

@Olafurpall

The effect of metformin on muscle growth through mTOR inhibition is likely to be insignificant. Notice that metformin has been used by millions of people for decades, yet nobody has noticed any effect of metformin on muscle mass gains. The chances of its mTOR inhibitory effects having any significant effects on muscle mass gains is even smaller when you consider that people taking rapamycin generally don’t notice any negative effects on muscle gains even though rapamycin is a far stronger mTOR inhibitor than metformin.

Leaving mTOR aside, an argument that metformin is unlikely to meaningfully inhibit strength and muscle gains in response to resistance training on the basis that people would have noticed it if such an effect existed is very weak. Very few people do resistance training in the first place for MET to affect it — and even fewer diabetics, who are the vast majority of MET users: “only 12.4% (11.9–13.0) [of diabetics] met ADA resistance exercise guidelines, compared with 21.0% (20.8–21.3) in the general population (OR 0.51; 95% CI 0.48–0.53; P < 0.001).”

And people are all doing this on an n of 1 basis. How would one know that one would have gained more strength or muscle if one were not using MET? It’s not like MET causes people to go from making Schwartzenegger-on-roids gains to making no progress at all. People stall out on their progress or just make progress slowly at different points in their strength training careers, and it’s generally completely mysterious why, and people will attribute their lack of gains to any number of random and even superstitious connections.

The only way you’re going to reliably see an effect of MET on muscle and strength gains is with a clinical trial — and the clinical trial we have says it impairs strength and lean mass gains, consistent with impairments in other exercise training effects in other trials.

[Olafurpall]

@RapamycinCurious

Leaving mTOR aside, an argument that metformin is unlikely to meaningfully inhibit strength and muscle gains in response to resistance training on the basis that people would have noticed it if such an effect existed is very weak. Very few people do resistance training in the first place for MET to affect it — and even fewer diabetics, who are the vast majority of MET users: “only 12.4% (11.9–13.0) [of diabetics] met ADA resistance exercise guidelines, compared with 21.0% (20.8–21.3) in the general population (OR 0.51; 95% CI 0.48–0.53; P < 0.001).”

While you make some valid points, I don’t agree with you fully. Even if a lot less than 10% of people do resistance training, that’s still a massive number. We’re talking about one of the most used diabetic drug in the last several decades. Millions of people have used it for long. A small but significant portion are interested enough in resistance training and gaining muscle that they try different exercise programs and things and monitor their effects on muscle gain and fat loss. The biggest problem I see with looking at past experience is not the number of people that have used it while doing resistance training (the number is large enough) it’s more the fact that very few of the people that have historically used metformin are healthy. Most of them of course were diabetic and there is a chance that the effect in healthy humans is not the same. But even so, its use has been popular in the longevity society for several years now and we’re not seeing any significant number of anecdotes about it effecting muscle mass gains. That doesn’t mean it can’t, just that the effect is at best relatively small.

@RapamycinCurious

And people are all doing this on an n of 1 basis. How would one know that one would have gained more strength or muscle if one were not using MET? It’s not like MET causes people to go from making Schwartzenegger-on-roids gains to making no progress at all.

True, but it’s not like changing your protein intake from moderate to high takes you from gaining nothing to making roid gains either. Yet bodybuilders found out long ago that higher protein helps with gaining muscles even though the difference isn’t obvious on an n=1 basis. Most of what is known about what helps and hinders muscle gains in humans has been found out by experience long before any studies found out about it because it’s easily observable and measurable by individuals.

@RapamycinCurious

People stall out on their progress or just make progress slowly at different points in their strength training careers, and it’s generally completely mysterious why, and people will attribute their lack of gains to any number of random and even superstitious connections.

True, but if you combine the experience of lots of people, patterns will start to be noticed. That’s how most of the things that influence muscle gain were discovered long before any studies were performed.

@RapamycinCurious

The only way you’re going to reliably see an effect of MET on muscle and strength gains is with a clinical trial

That is only true if the effect of metformin is very small. If you care so much about gaining maximum amount of muscles that you won’t take the chance of something that might possibly reduce muscle gain to a degree that you won’t notice, then sure, metformin is not for you. The important point is that, even if it were to have a small effect on muscle gain, that effect is insignificant relative to the effect of doing a well designed resistance training program. If muscle gains is your concern, the potential effect of metformin on it is one of the last things you should be thinking about.

@RapamycinCurious

the clinical trial we have says it impairs strength and lean mass gains, consistent with impairments in other exercise training effects in other trials.

AFAIK that’s not entirely true. Yes there are some studies showing that it reduced the adaption to endurance exercise in humans, but I don’t think there is any good evidence that it impairs muscle gains. Note that I asked Nir Barzilai in an online conference about the results of the TAME trial. I asked him specifically if they were monitoring effects on muscle mass. If i recall, he said that in one of the studies (I can’t remember which one) metformin was found to have a small effect on muscle mass, that is, it was reducing muscle gains slightly, but as he said, more importantly, it did not reduce muscle strength, and actually improved muscle quality!

I will say though that it’s been two years since I looked into metformin in much detail so I’m not really up to date on the newest studies. If you know about a study that showed reduced strength with metformin, please post it. Btw, personally I haven’t noticed any difference in my ability to gain muscle or strength after I started metformin many years ago (I’ve been lifting weights for 25 years). Of course that doesn’t mean it couldn’t be having a small unnoticeable effect. But if it did, why should I care, when I can easily gain muscles anyways by simply increasing my calorie intake while continuing the resistance training I’ve been doing for decades? If I was old and frail and for some reason could not do resistance training, then maybe I would care about potential tiny effects.

[lin]

One option is to dose metformin on off-days and avoid it on workout days. Given that the drug is a mitochondrial inhibitor and exerts hormetic effects, it may be better to dose it on a weekly schedule like rapamycin, rather than daily, for longevity applications.

[Olafurpall]

I agree on taking it on off days being a good idea for people that are particularly concerned about it interfering with their exercise benefits/performance. Of course they will have to weight that out against the potential negatives of missing out on blood glucose benefits on their on days.

[KarlT]

If you’re not diabetic, why not just stop taking Metformin and then you don’t have to worry about it.

[RapamycinCurious]

@Olafurpall

@RapamycinCurious

the clinical trial we have says it impairs strength and lean mass gains, consistent with impairments in other exercise training effects in other trials.

AFAIK that’s not entirely true. Yes there are some studies showing that it reduced the adaption to endurance exercise in humans, but I don’t think there is any good evidence that it impairs muscle gains.

It is entirely true .

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

we hypothesized that metformin would augment the muscle response to [progressive resistance exercise training (PRT) ] in healthy women and men aged 65 and older. In a randomized, double-blind trial, participants received 1,700 mg/day metformin (N = 46) or placebo (N = 48) throughout the study, and all subjects performed 14 weeks of supervised PRT.

Although responses to PRT varied, placebo gained more lean body mass (p = .003) and thigh muscle mass (p < .001) than metformin. CT scan showed that increases in thigh muscle area (p = .005) and density (p = .020) were greater in placebo versus metformin.

Knee extension 1 repetition maximum (RM) increased 23.1% (SD 18.9) in [PRT+] placebo and 15.3% (SD 18.5) in [PRT+] metformin (between groups p = .055); knee extension isometric strength increased 11.8% (SD 12.7) with placebo compared to 6.7% (SD 14.5) with metformin (between groups p = .082); and peak knee extension power increased 29.4% (SD 40.7) in placebo versus 14.3% (SD 35.7) in metformin (between groups p = .064).”

Relative strength (knee extension kg/bilateral thigh muscle mass kg) gains following PRT were similar in both groups, with placebo improving 19.7% (SD 19.0) and metformin improving 14.5% (SD 17.9) (between groups p = .188).
https://doi.org/10.1111/acel.13039

The impaired strength gains in MET versus placebo in each of the individual exercise strength tests did not reach statistical significance, but the differences are consistent across nearly every single test, and also consistent with the statistically-significant reduction in muscle tissue gains. Additionally:

we show that intermuscular adipose tissue (IMAT) was not associated with baseline function or response to PRT, contrary to previous reports. On the other hand, thigh muscle density (TMD), as an indicator of intra- and extramyocellular lipid (IMCL and EMCL), remained strongly and independently positively associated with physical function and performance following adjustment. Baseline TMD was inversely associated with gains in strength, independent of muscle mass. Percent change in TMD was positively associated with improved chair stand and increased type II fiber frequency but was not associated with muscle hypertrophy or overall strength gain following PRT. For the first time, we show that metformin use during PRT blunted density and strength gains by inhibiting fiber type switching primarily in those with low baseline TMD.
Associations of muscle lipid content with physical function and resistance training outcomes in older adults: altered responses with metformin - GeroScience

In other words, those who need it the most will be most impaired by metformin. (On the other hand, this means that beasts like @Agetron may have less to lose ).

[Agetron]

At the gym right now. Needed a good laugh.

Now back to muscle resistance.

[Olafurpall]

Interesting study on metformin. Thanks for posting.

Note that the participants were over age 65. Note that metformin is a mild mitochondrial complex I inhibitor and as such can slightly inhibit ATP production in mitochondria. It’s possible that older people tolerate the mild inhibition less than young people since they will already have experienced reduced mitochondrial function due to their advanced age at which point the extra inhibition caused by metformin may do more harm than good. This study suggests that old cells don’t tolerate metformin as well as young cells. Late life metformin treatment limits cell survival and shortens lifespan by triggering an aging-associated failure of energy metabolism

[lin]

Thanks for the info and discussion, would like to ask for your thoughts on metformin vs acarbose vs SGLT2 inhibitors for promoting longevity.

From the longevity studies I’ve seen, metformin did not have promising results in the ITP or TAME trials for increasing lifespan. Meanwhile the ITP trials for acarbose and SGLT2i showed robust lifespan increases in mice.

On a mechanistic level, I’d be more concerned by the function of metformin to inhibit the electron transport chain, vs inhibiting glucose absorption in acarbose, or promoting excretion for SGLT2i. Other ETC inhibitors include some nasty compounds like antimycin and cyanide. I understand metformin performs this inhibition in a relatively safe way that promotes a robust AMPK response (in relatively healthy individuals), but it looks like there is a significant possibility of harm in weaker/older individuals from the paper you linked. Combined with the relatively long half life of metformin, I’d be wary of taking it daily at prevailing doses that would cause chronic mitochondrial inhibition.

At the same time, there are highly informed experts in the longevity field who continue to take metformin, so I am sure there exist compelling reasons in favor of metformin. To put it to a question, in what sorts of situations would it be better to take metformin over acarbose/SGLT2i?

[KarlT]

@lin Agree with what you’re saying.
You will get a wide variety of opinions on Metformin. The TAME trial has not been done yet so that could change opinions. Most longevity experts I follow do not take it. My opinion is that it’s a mitochondrial poison without proof of benefit.
Acarbose and SGLT2’s are proven to work in non humans, and are generally safe with some side effects. Of course you may not experience any benefit that is noticeable. I have tried both and didn’t really care for the side effects.

[desertshores]

As originally posted by RapAdmin and confirmed by my own experience, If you eliminate wheat products from your diet the side effects of acarbose disappear. I don’t know why that is so, but wheat products, especially in the form of wheat germ were the worst for me.

[Joseph_Lavelle]

Is acarbose better at blocking wheat or is wheat especially gas forming when it gets to the bacteria? If you aren’t farting, does that mean acarbose isn’t doing anything? Hmmmm. I don’t take it because my doctor said “no one prescribes that ancient drug anymore.” Whatever.

[lin]

I think its starchy foods in general that cause flatulence with acarbose, so if wheat is your main source of starch, then yes eliminating that should have the biggest effect.

Right the flatulence is a sign that acarbose is working, so if you avoid the foods that cause it, then arguably you don’t need acarbose to begin with. That said, the flatulence provides good feedback to guide your diet, and the flatulence decreases with continued use as your microbiome adapts to processing the large carbohydrates.

[KarlT]

I had side effects from Acarbose without eating any wheat. I associated it with fruit intake.

[desertshores]

Could be the fruit. I have been on a low carb diet for quite some time and don’t eat fruit. When I first started taking acarbose I was adding wheat germ to various things and had to stop taking acarbose because the side effects were not worth it. RapAdmin, who had been taking acarbose before me suggested that wheat products were the cause. Once I eliminated wheat from my diet, I was able to take acarbose again with little or no side effects.

I think acarbose may have other life extending effects than just stopping blood sugar spikes.

“Acarbose can extend the life span of mice through a process involving the gut microbiota. Several factors affect the life span, including mitochondrial function, cellular senescence, telomere length, immune function, and expression of longevity-related genes.Jan 17, 2022”

“Mechanistically, acarbose has been suggested to influence the human life span by modulating the gut microbiota”

Extension of the Life Span by Acarbose: Is It Mediated by the Gut Microbiota? - PMC.

[Kira_Miftari]

" Dr. Peter Attia, and as someone who prioritizes exercise and nutrition above other longevity-promoting interventions" - Except for statins which is his primary longevity-promoting intervention

[Olafurpall]

@lin

On a mechanistic level, I’d be more concerned by the function of metformin to inhibit the electron transport chain, vs inhibiting glucose absorption in acarbose, or promoting excretion for SGLT2i. Other ETC inhibitors include some nasty compounds like antimycin and cyanide. I understand metformin performs this inhibition in a relatively safe way that promotes a robust AMPK response (in relatively healthy individuals), but it looks like there is a significant possibility of harm in weaker/older individuals from the paper you linked. Combined with the relatively long half life of metformin, I’d be wary of taking it daily at prevailing doses that would cause chronic mitochondrial inhibition.

Your concerns are certainly warranted. Btw you mention nasty compounds like antimycin and cyanide as ECT inhibitors. Arsenite (a form of the well known toxic element aresnic) has been found to be toxic at high levels but to have hormetic effects in mitochondria at low levels. Mitochondrial hormesis links low-dose arsenite exposure to lifespan extension - PubMed Glucosamine also has been found to have mitohormetic effects, which may be a reason for its benefits. I think the benefits of metformin in some cases are partly caused by the mild inhibition of the electron transport chain resulting in hormetic effects. But of course, if someone already has slightly impaired mitochondrial function due to poor health or old age, then maybe the slight inhibition from metformin would just do more harm. In this sense, SGLT2 inhibitors and specially acarbose are safer.

@lin

To put it to a question, in what sorts of situations would it be better to take metformin over acarbose/SGLT2i?

I think acarbose is most likely the lowest risk of these three and would be the safest choice for most people. I can’t say much about SGLT2 inhibitors since I haven’t researched them much. Acarbose would be a good choice for someone that wants to lower postprandial blood glucose. However, acarbose won’t do much for fasting blood glucose. Metformin might improve the blood glucose more in someone that has a high fasting blood glucose but good postprandial glucose. I also think the risk/benefit ratio of metformin is best in people that are not very old and don’t exercise much since they are more likely to benefit from the hormetic effects of metformin. Note that metformin has also been found to lower blood glucose by influencing the gut microflora, not merely by increasing AMPK in cells, and that’s something you probably won’t get from acarbose/SGLT2 inhibitors. But it’s getting harder to predict whether the overall effect of metformin will be beneficial, when combined with things like regular exercise. I understand many people wanting to be careful until more is understood here. I’m hoping the results of the TAME trial will have analysis of groups depending on whether and how much they exercise so we can see better whether benefits differ depending on people’s physical activity.

[KarlT]

He’s at it again:

Popular Supplements You Should NEVER Take