Metformin and growth hormone reverse aging in humans

[Todd Allen]

6 hours ago, Saul said:

(Happily, I've never heard of anyone trying to supplement IGF1.)

You might want to speak with Novartis which spent a lot of money developing and testing their patentable version of IGF-1 modified to dramatically increase serum half life.  Worked great on mice with SBMA but unfortunately not so well in people with SBMA.

https://www.sciencedirect.com/science/article/abs/pii/S147444221830320X

Curiously all the researchers believe that low IGF-1 is somehow intrinsic to SBMA and yet I've managed to raise mine from well below the reference range to above the reference range without pharmaceuticals through fasting, exercise, therapeutic heat stress and switching my diet from high carb low fat plant based to a very high fat moderate to high protein animal based diet.

[Sthira]

Dean, I’m not real interested in arguing for the sake of it, as it appears you may be doing. The gist here is Fahy tried this protocol on himself, with the aim of regrowing his thymus. Evidently his success led him (during the course of many years and working within the confines of a severely limited budget) to try the protocol on some older males with atrophied thymuses.

Here in this published work he’s showing limited success at in that preliminary venture. Go ahead and throw your shade, argue all you want on this backwater site; but my point, as clearly expressed above and ignored, is that this is the type of experimentation that’s gonna be necessary to in order to advance longevity science. Advancement will occur through the efforts of those actually trying things. Even if Dean on the CR Forum doesn’t like it.

Since you appear so well-versed in regrowing involuted thymuses, perhaps you should send Fahy et al your advice and insights? I mean, they’ve devoted more than a decade to it, but maybe you know more.

[sirtuin]

I'm curious to hear more thoughts on the DHEA aspect of this study.

From what I've read, DHEA seems to increase estrogen in men. Is this not the case with lower dosages and different forms (7-Keto?)

I've also read that it can lower HDL and might be associated with prostate cancer risk. In other studies, I read "we found that DHEA increases this critical process of cholesterol accumulation in macrophages -- an event which may produce coronary disease." Anecdotal reports include increases in irritability and decreased libido.

Digging around on LifeExtension, I found this article:

https://www.lifeextension.com/magazine/2007/6/cover_dhea/page-01

I'm not quite sure what to make of this particular hormone available for OTC supplementation.

[Dean Pomerleau]

12 hours ago, Sthira said:

Here in this published work he’s showing limited success at in that preliminary venture [regrowing the thymus].

Sthira,

If the authors and the press had stuck to presenting their research the way you suggest (i.e. as a small, preliminary study showing promise towards regenerating the thymus), that would have been great. But the headlines covering the research gush about "the fountain of youth" and "reversing aging". For example:

Is This New 3-Drug Combo A Fountain Of Youth? (Forbes)

First hint that body’s ‘biological age’ can be reversed (Nature)

DRUG TRIAL REVERSES BIOLOGICAL AGING AS SUBJECTS REGAIN 2 YEARS OF YOUTH ON AVERAGE (Newsweek)

And it wasn't just a case of the popular press exaggerating the significance of the study. One of the authors (Horvath) added to the hype by saying:

"I'd expected to see slowing down of the clock, but not a reversal," Horvath told Nature. "That felt kind of futuristic."

12 hours ago, Sthira said:

but my point, as clearly expressed above and ignored, is that this is the type of experimentation that’s gonna be necessary to in order to advance longevity science. Advancement will occur through the efforts of those actually trying things.

It appears you may have missed the first three lines of my previous post where I said:

"I don't think anyone is suggesting they should have given up, or give up now. At  least I'm not. Small, exploratory studies and even self-experimentation (e.g. Liz Parrish or our own "small N" foray into human CR) have their place."

I'm all for more research (big and small). I just think everyone would be better off with less breathless hype.

--Dean

[Gordo]

I hope these guys continue their experiment and provide annual updates, I'd love to see 5, 10, 20 year followups.

HGH can play a medicinal role when it comes to healing, so I could see how it might be useful for reviving an organ in decline, but there are obviously trade offs as the science has shown.  With people taking a lot, their hearts actually keep growing larger, which leads to disfunction eventually, and then death.  But maybe lower doses are safer?  Maybe with better cancer detection/treatment in the future, one could cut the growth hormone as soon as cancer is detected and before it rapidly multiplies and kills you.

 

 

[Roger Evans]

On 9/14/2019 at 12:24 AM, Ron Put said:

"I'd say it's probably prudent to see this replicated and longer term studies showing the safety of such supplementation."

Metformin has been extensively used for decades for Type II Diabetes without, we're told, adverse indications.

[Roger Evans]

On 9/15/2019 at 11:22 PM, TomBAvoider said:

David Sinclair has a new book out, so he's hitting the marketing circuit, including podcasts such as Joe Rogan, and the above mentioned Peter Attia (the latest episode on the Peter Attia podcast). 

 

I'm about a third of the way through Sinclair's new book and highly recommend it for its documentation of what lots of labs are doing.

[TomBAvoider]

1 hour ago, Roger Evans said:

I'm about a third of the way through Sinclair's new book and highly recommend it for its documentation of what lots of labs are doing.

Same here, I'm about a third way in. It's quite an engaging book, and a good writeup as to where we are today, but as I mentioned before, a note of caution - David Sinclair tends to let his enthusiasm carry him beyond where the evidence leads. So when it comes to his claims as to how close we are to conquering aging and how this one way is the sure to be the way, you should probably treat it the same way we treat all such big problems, energy from controlled fusion, real general AI, cure for cancer (despite his claim that solving aging is easier than curing cancer)... i.e. it's perpetually just around the corner (whatever the case may be 5, 10, 15, 20 years)... that time frame will continue to move as we approach it. Having said that, I'd be the last one to discourage anyone's efforts in that direction - if by some miracle we get there, I'll be the first to celebrate; I just sadly doubt we'll see any such thing within our lifespans, or the lifespan of anyone living today or over the next century and probably more. YMMV.

[Roger Evans]

5 hours ago, TomBAvoider said:

David Sinclair tends to let his enthusiasm carry him beyond where the evidence leads. 

Isn't that the most serious claim that can possibly be made against a scientist?

I'd think that  Harvard and his colleagues would have a great deal to say about it if they thought that.

[Sibiriak]

Quote

Isn't that the most serious claim that can possibly be made against a scientist?

No. Nothing wrong with enthusiasm.  In fact, it can be quite motivating.

Falsifying data and knowingly distorting facts would be a serious charge, though.

[Sibiriak]

Quote

Roger Evans:  Metformin has been extensively used for decades for Type II Diabetes without, we're told, adverse indications.

The question here is about long term intake of recombinant human growth hormone (rhGH)  + DHEA + metformin-- not  just metformin alone,  and not just as a treatment for a particular disease,  but as a means of reversing general human aging.

Edited September 23, 2019 by Sibiriak

[Ron Put]

On 9/22/2019 at 6:12 PM, Sibiriak said:

The question here is about long term intake of recombinant human growth hormone (rhGH)  + DHEA + metformin-- not  just metformin alone,  and not just as a treatment for a particular disease,  but as a means of reversing general human aging.

Yep. Sibiriak beat me to it.

[Ron Put]

While this thread is about a more complex concoction, let me throw this into the fray:

"Metformin is sometimes proposed to be an “anti-aging” drug, based on preclinical experiments with lower-order organisms and numerous retrospective data on beneficial health outcomes for type 2 diabetics. Large prospective, placebo-controlled trials are planned, in pilot stage or running, to find a new use (or indication) for an aging population. As one of the metformin trials has “frailty” as its endpoint, similar to a trial with a plant-derived senolytic, the latter class of novel anti-aging drugs is briefly discussed. Concerns exist not only for vitamin B12 and B6 deficiencies, but also about whether there are adverse effects of metformin on individuals who try to remain healthy by maintaining cardiovascular fitness via exercise.

...

In contrast to rapamycin, where data from all preclinical trials on mouse models and other lower-order organisms prove that the drug increases the lifespan (“longevity”), there is little such evidence for metformin (see below). Rapamycin also increases the health span or even reverses age-related diseases (“rejuvenation”) in worms, flies, mice, rats, and dogs. ..."

https://www.karger.com/Article/FullText/502257

Edited October 6, 2019 by Ron Put

[Sibiriak]

Quote

...adverse effects of metformin on individuals who try to remain healthy by maintaining cardiovascular fitness via exercise.

Thanks Ron for this recent article.  I haven't read the whole text yet,  but I jumped to the conclusion to see what the above statement was about.

Quote

Of greater concern are the results of small trials in which the effects of metformin on metabolic responses to exercise or on cardiorespiratory fitness were tested. In a placebo-controlled, double-blind, crossover trial with healthy young subjects, metformin caused a small but significant decline in maximal aerobic capacity [99]. A double-blind, placebo-controlled landmark trial with older adults with one risk factor for T2D investigated the effects of metformin and 12 weeks of aerobic exercise [100]. Contrary to expectations – namely, that the effects of exercise and the drug would be additive – “metformin attenuated the increase in whole-body insulin sensitivity and abrogated the exercise-mediated increase in skeletal muscle mitochondrial respiration.”

 

 

Edited October 7, 2019 by Sibiriak

[Clinton]

When I consider metformin and rapamycin, I come back to 2 truths.

1-We don’t have evidence that I am aware of that EVEN CR extends lifespan in humans.

2-I’m not aware of any supplement or combination of supplements has extended lifespan in mammals greater than CR (ref S.Spindlers studies).

When you think about #1 and #2 -logically you've got to come to the conclusion that if you want to slow aging at the moment supplements are hopeless.

Edited October 7, 2019 by Clinton

[Saul]

Well said Clinton.

  --  Saul

[Saul]

(Although several researchers -- including Matt Kaeberlein and Luigi Fontana -- believe it possible that rapamycin MAY extend maximal lifespan.

Kaeberlein is testing rapa supplemtation of pet dogs -- a large study.

I asked him how he thought CR and rapa might work together.  He answered that the effects of both have some overlap -- but that no researcher could hope to get funding for a study of both CR and rapa.

  --  Saul 

[Gordo]

On 10/6/2019 at 5:58 PM, Ron Put said:

Concerns exist not only for vitamin B12 and B6 deficiencies, but also about whether there are adverse effects of metformin on individuals who try to remain healthy by maintaining cardiovascular fitness via exercise.

Regarding metformin and exercise - in D. Sinclair's latest interviews, he has been saying the he pulses metformin and exercise on different days.  I don't know his exact schedule, but I think he said something like metformin every day during the week, but not taken on weekends, where he then hits the gym hard for like 4 hours or more.  I don't know, sounds a little goofy to me but there may be something to be said for not taking ANY medication every day...

[TomBAvoider]

Yes, Peter Attia also suggested that pulsing metformin - not taking on days you exercise - might be the way to go. And like Gordo says, not taking meds every day might be a good idea in general. Certainly Sinclair thinks so - in that interview with Attia, he explicitly says that we should probably pulse most medication, which he claims to do for all supplements except I think resveratrol. 

Btw. I have finally broken down and I've gone on metformin. I did so, because I'm also on atorvatstatin (and statins in general can elevate your chances of getting DMT2). But based on this, for the past month or so, I've been pulsing my metformin, taking it on non-exercise days. Unfortunately, in my case, I exercise 4 times a week, so I only take metformin 3 times a week. Who knows the utility of that. It could all be goofy as Gordo says, and honestly we just don't know, because there are no human studies that tell us any of this. It's all 100% pure speculation and a gamble. 

So far I'm on a statin and metformin and I'll be adding rapa soon (which I'll pulse for sure!). It might not do anything, it might be deleterious, or it might give me a small boost. I'm rolling the dice. We'll see!

[mccoy]

59 minutes ago, TomBAvoider said:

So far I'm on a statin and metformin and I'll be adding rapa soon (which I'll pulse for sure!). It might not do anything, it might be deleterious, or it might give me a small boost. I'm rolling the dice. We'll see!

Good luck! At least, you are already on metformin+statins, which seem to be almost mandatory when taking rapa.

[Saul]

According to Matt Kaeberlein, healthy adults should have no problem with rapa.  Matt believes that rapa is probably a true antiaging drug.  And that it has been shown to be beneficial in improving the lot of rodents that suffer from a model of human Alzheimer's disease.  Matt thinks that it's absurd that so far human clinical testing of Rapa for severe Alzheimer's patients hasn't been started.

Luigi also has shown an interest in the potential benefits of rapa.

  --  Saul

[Sibiriak]

13 hours ago, TomBAvoider said:

So far I'm on a statin and metformin and I'll be adding rapa soon (which I'll pulse for sure!). It might not do anything, it might be deleterious, or it might give me a small boost. I'm rolling the dice. We'll see!

That will be an adventure of sorts.  Good luck!

I'm curious,  what kind of  effects /endpoints will you evaluating?  What's the time frame?

 

 

 

[TomBAvoider]

That's a fair, but very complicated question. I have a bunch of baseline tests, full blood panel, urin analysis and a record of blood pressure, oximeter readings, blood sugar, weight, and so on gathered over many months or years. That was before any statin or metformin (and obviously rapa). I also have a very detailed health diary listing every symptom, dietary tweak, exercise protocol, supplement regimen, doctor visit, sleep length, even bowel movement, and crucially how I felt subjectively - a record of close to 20 years.

Following the taking of a statin, I had very frequent (every 3 months) blood and urine tests with special focus on the liver and kidneys. This was to establish the effect of the statin - it appears to have had no real effect on those biomarkers that were measured, except for blood lipids, where the LDL and triglycerides were lowered. I have now been on the statin - lowest dose of 10 mg atorvastatin (Lipitor) for some 18 months. 

I have been on metformin for 13 months - for 12 months daily, and the last month pulsed. I go to a diabetes specialist every three months for tests (liver, kidneys, blood sugar) - I have never been diagnosed with diabetes, but my fasting blood sugar has always been somewhat high 90-95 (although it was between 80-85 for a few years), however my post meal blood sugar levels have always been very good. It's just the first thing in the morning where it's in the 90's. In all the tests so far, metformin appears to have had no effect whatsoever on the markers being observed. I have not as yet had any tests with the pulsed metformin protocol. My next visit is scheduled for early December. Btw. the statin doesn't seem to have effected my blood sugar levels so far.

But what is the function of all those tests - they can't really tell me anything about whether my aging has been affected. All they can do is record the biomarkers tested. What do those markers mean for health is not clear, although if something went suddenly wrong (say, elevated liver enzymes), presumably that would point to problems.

I have not had my Horvath clock measured. 

I am left with purely subjective observed effects - how I feel, energy levels, sleep duration, skin appearance, hair quality, friend's spontaneous observations etc. This naturally is subject to all the biases and potential inaccuracies, placebo/nocebo effects etc.

I attempt to be as objective as I can be, but I can't prove anything. I have my health diary for comparison to before/after. Still subjective and prone to placebo/nocebo effects. 

That said, I try my best. So far, I have not observed any effects of the statin on exercise capacity, energy levels, muscle/tendons, cramps, mental confusion etc. - commonly listed side effects. Same for metformin, no subjective effects, no gastric issues, not even extra gas which is commonly reported - however ONE possible metformin effect - loss of about 2-3 lbs of weight. However, I cannot vouch that this is due to metformin - it just coincided with the time of my metformin taking. 

Time frame - indefinite. I will simply monitor my health, objective marker measurements, and subjective evaluations of how I feel (compared to my diary records). This will not tell me whether the drugs are having any effect other than subjective. It is my understanding that you can use certain proxies for the aging process - the state of your skin and hair (obviously extremely rough) - there is the skin pinch test for example. Same for reflex tests (f.ex. the ruler test), balance tests etc. But even if you do record a change (so far none), how would you know it was the drug that was responsible? You won't. 

Unless there are pretty immediate deleterious effects that come up on blood/urine tests, or subjective evaluations, you really won't know anything. In effect, it's a negative test - "we'll see" whether the combo met/stat/rapa results in something immediately negative. What else will it do? No way to know. Taking such drugs is a gamble that they are having a good effect - but you can't verify that, you can only tell if immediate disaster results.  

[Sibiriak]

Thanks Tom,  should be interesting.   I doubt there will be any immediate disaster. 

[kpfleger]

There is a lot to like about Fahy's trial and a lot to dislike. The main 2 points made in this thread so far are both right: (1) It's nice to have this data in humans despite the obvious negatives of small n and uncontrolled and (2) the press regrettably but predictably over-hyped its coverage. Let's move on from those points and let me add a few other points that haven't been brought up in this thread:

I'm disappointed that Fahy thought that the right order in which to do this science was human n=1 trial followed by uncontrolled human n~=10 trial without any work in mice or any other mammal. The thymus involutes in mice too. A controlled mouse trial with much larger n could have been could have been done for less than (I presume) the cost of the n~=10 human trial, and it could have included followup for a long fraction of mouse lifespan to watch for long-term negative effects (or even been a lifespan study with similar total real-time study duration, eg, start with 2-year-old naturally aged mice like the Oisin trial and follow until death roughly a year later).

A big question in this work is how long will the regenerated thymus remain more effective before re-shrinking. It's possible the negative effects of GH/DHEA are not so bad if only pulsed every 5 or 10 years, but if the thymus recovery is very short-lived then that is much more worrying. Followup with scans multiple years later will be very important. (And a mouse study would have been because this could have been tested on timescales relevant to how quickly the thymus shrinks in that model organism.)

Fahy is attempting to commercialize this protocol to make it available as widely as possible as quickly as possible through the company Intervene Immune. Good luck to him and his team!

They observed that FOXN1 was up-regulated as one of the consequences. FOXN1 is known from other work to stimulate thymus growth. Repair Biotechnologies (disclaimer: I am an investor) is working on thymus regeneration more directly via FOXN1 upregulation (via gene therapy). If all the benefit observed in the TRIIM trial is through the intermediate of FOXN1 increase,. then other direct interventions through that can avoid the HGH/DHEA/etc. Clearly an important space to watch in coming years.

A lot was made about the Horvath age-clock reversal.  Morgan Levine (former Horvath lab member now Yale professor doing great work on pushing methylation clocks forward) has said that she believes that though DNA methylation clocks are useful on a population level, she thinks they are too noisy on an individual level for changes in the age they report for an individual across a time interval to be reliable. She thus believes it's not useful to have one's methylation clock age tested and then retested after an intervention. If this is right (and she's clearly an authority), then it's not clear for n~=10 how much change you would expect to get due to random chance. Presumably Horvath himself could characterize this math but I haven't seen that done and presented for comparison to these results. I didn't read the paper directly. Did it present error bars on its Horvath clock averages (and cite the data and methodology by which they were computed)?

Karl