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Metformin linked to higher risk of Alzheimer's and Parkinson's

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Study: Metformin Linked to Higher Risk of Alzheimer’s and Parkinson’s

The longer the intake of metformin, and the higher the dose, the higher the risk. And it seems to start at a pretty low dose of 240mg (in the article they made a mistake and put g instad of mg) - and 300 days and over.

In many trials it's been shown that exercise+metformin is not additive wrt. blood sugar and diabetes prevention - perhaps not surprising given the effects of metformin on mitochondria and the blunting of the benefits of exercise for those who take metformin. With all these negative effects of metformin, I'm growing increasingly nervous about the potential of metformin (at least alone) for life extension in humans. Possibly there might be a differential impact with pulsing dosages rather than continuous, but what we need more than anything else is high quality studies in non-diabetics with controls and so on. 

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Tom,

Over here you said:

Quote

I know Dean finds my what he calls "ultraconservative" stance of "primum non nocere" rather excessive if not even annoying, but then, my caution regularly pays off even for Dean (as when I questioned him about this lecithin supplementation on 07/23/04 - think of all that TMOA!). 

Given your philosophy of "first do no harm", I'm curious what has made you jump on the metformin bandwagon, given previous evidence metformin may interfere with the benefits of exercise and given this new evidence that it may also mess with your brain?

As you point out, there isn't any of the high quality evidence of the long term impact of metformin in healthy people that you usually look for. So why are you now inclined to risk taking it given your ultraconservative perspective on supplements, which would seem to extend doubly to outright drugs like metformin?

--Dean

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Sibirak has it. For context however, I'll say this: it all comes down to risk and time frame. I am getting old - moving out of middle age, even late middle age. For any intervention that slows down aging, the more time you have left from your natural lifespan, the more time a successful intervention to slow aging will gain you. Therefore the earlier you stage the intervention, the greater potential gain. Now, since there are no proven interventions to slow aging in humans (CR at best in animals, possibly rapa in mice), until recently I have elected to wait for something to come up. BUT. I have waited as long as I possibly could. Sadly, nothing proven has come up. Waiting any further, means in effect giving up on gaining anything appreciable from slowing down aging given how little time I have left. Therefore, I can give up on that path or gamble on risky, unproven and speculative treatments. I have elected to gamble. 

The risks are considerable - as I keep outlining, including in this thread wrt. metformin - but I am willing to take those risks for a fairly small chance of a gain. Simply resigning myself to doing nothing goes against my nature. It is psychologically easier  - for me - to exert a degree of control, even if it's down to not very good odds; at least I can say "I elected to gamble". Compare it to being condemned to death in prison with a certain execution sometime within the next 3 years, and given a chance of digging out in an escape attempt that has only a 10% chance of success, and will result in immediate death otherwise. In the worst case, you lose 3 years. I am old. That's not much time to lose in the grand scheme of things. I'd rather run for it. 

Obviously I try to do the best possible job of "digging out my escape", but I am also cognizant that the odds are against me. My personality however, compells me to try. YMM - VERY MUCH - VARY.

P.S. Obviously, if the day before I were naturally scheduled to die, medical science comes up with a way to reverse aging or powerfully prolong life even in the very old, I'm screwed if through my gambling I have cut my life short and so missed this amazing development. However, given the rate of progress I've seen so far, I think the odds of that happening are pretty low... there's a lot of hype and not much - if any - in the way of real breakthroughs that are applicable in practice. So the heck with it, I'm going for it. Again, YMMV.

PPS. Obviously, if your date of execution were to be sometime in the next 40 years, I'd NOT try to escape with such low odds of success - that's the context to my ordinarily being super conservative wrt. potentially shortening lifespan treatments. That means I'm very careful for the 37 years of time in prison I get to live, but the last 3 years, I pivot on a dime, and gamble wildly - because not much to lose.

Edited by TomBAvoider

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Fascinating Tom,

Thanks for sharing your thinking on this. I can certainly see the rational for eventually throwing caution to the wind and gambling on a "risky, unproven and speculative treatment" when you've got nothing left to lose.

But given your ultraconservative nature and your past vociferous arguments against trusting any results short of personalized medicine, e.g. when you said:

Quote

I was supremely correct to be deeply sceptical about the applicability of any population based study for any individual application.

I had assumed you'd be one of last to take such a gamble, particularly when the only real evidence for metformin's effectiveness for life extension is in rodents, the applicability of which you've (rightly) long been skeptical about.  

Was that all talk about high standards of evidence just bluster, to be thrown out when you perceive your prospects as getting desperate? If so, that's good to know.

I liked your prison escape analogy, but at the same time it seems pretty facile and self-serving. Given how deliberate and cautious you are, I presume you did a more realistic cost/benefit analysis before starting to take metformin. Would you mind sharing it with us, or reconstructing it? I think it would be a valuable exercise to discuss, since many of us have or will be facing the same sort of decision about whether to gamble on an unproven intervention or continue waiting for more evidence.

To illustrate what I have in mind, let me take a stab at it. These are rough, back-of-the-envelope calculations. If you have better numbers or a better approach to a cost benefit analysis, I'd love to hear it.

Metformin is believed to be a CR mimetic. As such, it's unlikely to be as effective as the real thing. So I'm going to suppose that if it works, lifelong metformin treatment can extend a rodent's lifespan by 20% (compared with ~40% for lifelong severe CR) relative to ad lib fed rodents. I presume that there is actual data on this, so please feel free to correct me if I'm being pessimistic about metformin's potential for lifespan extension.

The evidence suggests that any longevity intervention that targets aspects of metabolism (like CR and metformin) is likely to work significantly less well in long-lived mammals relative to rodents, which are naturally programmed to live fast and die young by default. So metformin in humans is likely to be less effective that in rodents, cutting the 20% lifespan extension down to something closer to 10%. 

Given you are starting metformin treatment ~2/3rds of the way through your adult lifespan, you're not going to get the full benefit of lifelong metformin, but only ~1/3rd the benefit, cutting the 10% extension down to ~3%. 

Given you are already practicing mild CR, you are likely already enjoying some of the CR mimetic benefits of metformin. So for you (as opposed to an ad lib eater) the 3% probably gets cut still further, say to ~1-2%. 

Finally, since you are pulsing metformin in hopes of avoiding potential negative side effects, you likely won't enjoy the full benefits that continuous metformin dosing can potentially offer, further cutting you lifespan benefits to something less than 1%.

Human male lifespan is around 80 years. Less than 1% of 80 years is in the neighborhood of six months of extra lifespan.

Is this the kind of benefit you are hoping to gain from metformin? If you are hoping for more, can you suggest revisions to my assumptions to justify greater optimism? Do you think such a modest lifespan benefit outweighs the potential risks associated with metformin treatment (including potentially increased dementia risk) in a healthy older person such as yourself? 

--Dean

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14 hours ago, TomBAvoider said:

Compare it to being condemned to death in prison with a certain execution sometime within the next 3 years, and given a chance of digging out in an escape attempt ...

For me,  that comparison is rather misleading in that the prisoner has at least some chance, however small,  of permanently  escaping  imprisonment and execution, while you, no matter what you do,   have absolutely zero chance --zero! -- of escaping aging and death.

The best you could hope for  with your experimental met-stat-rapa drug cocktail would be some slight  slowing of aging and some slight extension of life expectancy  (assuming you don't have some specific disease apart from being just "old" on which  that drug cocktail might  reasonably be expected to have a more dramatic effect.)

So I too would be interested in knowing the details of  your "more realistic cost/benefit analysis",  as Dean put it,   and would ask the same critical questions that he did.

 

Edited by Sibiriak

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As an addendum to my previous post, the best available rodent evidence [1] suggests lifelong metformin doesn't extend lifespan at all in mice relative to ad lib fed controls. If you get the doses right, lifelong metformin + rapamycin appeared to extend median lifespan by 23% compared to controls, although the combination was only borderline statistically significantly different from the life extending effects of rapamycin alone.

Interestingly, the original research on metformin and longevity [2] from 2013 found a very modest (~5%) increase in mean lifespan for the right dose in one strain of mice, but no statistically significant increase in another. Plus, they found too high a dose of metformin decreased mean lifespan by ~15%.

So the assumption in my calculation of a 20% boost in rodent longevity from metformin was generous, to put it mildly.  But 20% improvement from the combination of metformin and rapamycin (which it sounds like you are considering Tom), may be in the right ballpark, assuming you start taking them at the human equivalent of age 35, get the dosages right, aren't already getting the same benefits from practicing CR, and happen to be a mouse :-).

--Dean

------------

[1] Aging Cell. 2016 Oct;15(5):872-84. doi: 10.1111/acel.12496. Epub 2016 Jun 16.

Longer lifespan in male mice treated with a weakly estrogenic agonist, an
antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer.

The National Institute on Aging Interventions Testing Program (ITP) evaluates

agents hypothesized to increase healthy lifespan in genetically heterogeneous
mice. Each compound is tested in parallel at three sites, and all results are
published. We report the effects of lifelong treatment of mice with four agents
not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and
metformin - the latter with and without rapamycin, and two drugs previously
examined: 17-α-estradiol and nordihydroguaiaretic acid (NDGA), at doses greater
and less than used previously. 17-α-estradiol at a threefold higher dose robustly
extended both median and maximal lifespan, but still only in males. The
male-specific extension of median lifespan by NDGA was replicated at the original
dose, and using doses threefold lower and higher. The effects of NDGA were dose
dependent and male specific but without an effect on maximal lifespan. Protandim,
a mixture of botanical extracts that activate Nrf2, extended median lifespan in
males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly
extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly
extended lifespan, suggestive of an added benefit, based on historical comparison
with earlier studies of rapamycin given alone.
The α-glucosidase inhibitor,
acarbose, at a concentration previously tested (1000 ppm), significantly
increased median longevity in males and 90th percentile lifespan in both sexes,
even when treatment was started at 16 months. Neither fish oil nor UDCA extended 
lifespan. These results underscore the reproducibility of ITP longevity studies
and illustrate the importance of identifying optimal doses in lifespan studies.

DOI: 10.1111/acel.12496 

PMCID: PMC5013015
PMID: 27312235  [Indexed for MEDLINE]
 

---------

[2] Nat Commun. 2013;4:2192. doi: 10.1038/ncomms3192.

Metformin improves healthspan and lifespan in mice.

Martin-Montalvo A(1), Mercken EM, Mitchell SJ, Palacios HH, Mote PL,
Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M,
Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, 
Bernier M, de Cabo R.

Author information: 
(1)Translational Gerontology Branch, National Institute on Aging, National
Institutes of Health, 251 Bayview Boulevard, Baltimore, Maryland 21224, USA.

Metformin is a drug commonly prescribed to treat patients with type 2 diabetes.
Here we show that long-term treatment with metformin (0.1% w/w in diet) starting 
at middle age extends healthspan and lifespan in male mice, while a higher dose
(1% w/w) was toxic.
Treatment with metformin mimics some of the benefits of
calorie restriction, such as improved physical performance, increased insulin
sensitivity, and reduced low-density lipoprotein and cholesterol levels without a
decrease in caloric intake. At a molecular level, metformin increases
AMP-activated protein kinase activity and increases antioxidant protection,
resulting in reductions in both oxidative damage accumulation and chronic
inflammation. Our results indicate that these actions may contribute to the
beneficial effects of metformin on healthspan and lifespan. These findings are in
agreement with current epidemiological data and raise the possibility of
metformin-based interventions to promote healthy aging.

DOI: 10.1038/ncomms3192 
PMCID: PMC3736576
PMID: 23900241  [Indexed for MEDLINE]
 

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"So the assumption in my calculation of a 20% boost in rodent longevity from metformin was generous, to put it mildly.  But 20% improvement from the combination of metformin and rapamycin (which it sounds like you are considering Tom), may be in the right ballpark, assuming you start taking them at the human equivalent of age 35, get the dosages right, aren't already getting the same benefits from practicing CR, and happen to be a mouse :-)."

"Finally, since you are pulsing metformin in hopes of avoiding potential negative side effects, you likely won't enjoy the full benefits that continuous metformin dosing can potentially offer, further cutting you lifespan benefits to something less than 1%."

This illustrates one of the problems in such extrapolations/speculations. Because rather than pulsing limiting health benefits as compared to continuous intake, I think the opposite. Pulsing, in my mind is superior to continuous intake of metformin. The reason is connected with what the poster "hamdog" alluded to: metformin is an inhibitor of mtor complex I. In this respect, it is really quite similar to rapa - and the protocol that's been speculatively developed for rapa absolutely assumes pulsing of rapa. Continuously inhibiting complex I has deleterious effects. Inhibiting it on an intermittent basis is however where you gain the advantages. This is really a very old idea, biologically speaking, employed for example by Longo in his FMD protocol - the idea being that fasting gets rid of old and damaged cells (and your organs shrink) - but then re-feeding populates the re-growth of organ tissues and immune function based off of newly activated (by the fast) stem cells, thus substituting fresh cells for senescent (and damaged) ones. As we know, getting rid of senescent cells is one way of slowing aging - this is where senolitics come in, but if it can be done through interventions such as fasting or perhaps through selective and temporary inhibition of complex I, then that works too.

If the pulsing of metformin/rapamycin can impact mitochondria through a hormetic mechanism, then it's obvious why continuous suppression is subpar.

But the reason I bring up this point is really quite simple: we have no proof, we don't know, it's all speculation. Ultimately, I don't know (and it's not knowable today), what the effect of pulsing metformin would be in humans. However, this is something that has much broader application. As I've repeatedly argued on these boards, there really is very little we can be certain about wrt. interventions - lifestyle, drugs, nutrition, exercise etc. in human beings when it comes to health/lifespan. As you yourself, Dean, have argued, even CR has not been proven as life-extending (certainly not in humans). Rapa, metformin, other drugs - same (at least for humans). Diet - again, what we know for sure is amazingly little. We can argue about very broad categories - f.ex. not overeating - but outside of such extremely broad categories, there is little actual proof. Throw in - as I've repeatedly argued - individual differences, and tailoring interventions the effect of which we can be certain about is going to be positive addition to health/lifespan is going to be well-nigh impossible. Yes, we can agree on some subtractive (as opposed to additive) interventions - such as not smoking or drinking to excess, but that's not very helpful - after all, nobody is going to prescribe "avoid cyanide in your diet, don't hit yourself in the head with a hammer, don't jump off tall buildings or airplanes without a parachute" as a life-prolonging nostrum.

Hopefully one day we may be in a position to confidently prescribe anti-aging regimens to specific individuals, but that day is not today - and I suspect is far off yet. That leaves us with this fact - we just don't know (outside of very broad caveats). 

It's similar to the problem of attempting to divine the position of a leaf being tossed about in a tornado and where it will ultimately end up. We might agree in very broad terms that given the speed and direction of the wind, it might end up in this rough geographical area (i.e. don't smoke, don't drink to excess), but trying to calculate whether the leaf will point its stem north vs south or lie one side vs the other once it rests, is absolutely hopeless. In physics we'd describe it as being able to tell where the wave is going, but not being able to tell what a specific one particle is doing positionally.

I as an individual don't have the information to determine the absolute best course of action to live as long and healthy life as possible. What do I do now? I do exactly what you do, Dean. There is no difference between you and me in this respect - you engage in behaviors you believe will benefit you healthwise, and so do I. The difference is that - perhaps, I'm speculating here, so forgive me - that you believe you have decent grounds for your behaviors, and I believe that such confidence is not possible to the degree of granularity we engage in. Both of us agree that smoking is bad - but once you get into smaller stuff I would claim that you have as good (or bad) a basis for your health behavior choices as do I, because I believe we're both trying to speculate as to which exact position the leaf will end up after the tornado. I think - speculatively! - that you have a degree of certitude that is unwarranted. And I'd be quite happy to argue with you - and for the position that we don't know. Pick almost anything you want - from your OMAD, to your exercise regimen, and I'd argue that you have no proof for any of it. 

If I have no proof of metformin (or anything else) working - why do I do it? Because of reasons I alluded to in other posts. First, you have to do something anyway - even if that something is to elect to engage in zero health behaviors and just go with the flow. My something involves metformin. Yours may not. I'd argue we're both equally justified from the position of the information available to us. Now, that doesn't mean I am a nihilist - if a study comes out tomorrow showing convincingly (to me) that metformin (or anthing else) is deleterious, I will alter my behavior. All I'm saying is we're both gambling with incomplete info. 

I don't know what the impact of my behaviors (metformin etc.) will be - and I won't know, ever (unless science undergoes a revolution very soon). I'm placing bets the outcome of which I can't ever know - so why do X (metforin) and not Y (not-metformin)? Because it's psychogically beneficial - and I like to live a good QOL, so spending it being at peace with my health behavior is key. I like to feel that I'm doing the best I can given the info and resources at my disposal. That I think is key. As I always say to my wife when she asks me about some change or behavior (say, whole body vibration) - "I have no idea if it will help, hurt or do nothing, but at least my conscience is clear that I've done the best I possibly can". So if someone in 10 years, or 100 years were to say "that TomB was an utter fool to take metformin - it shortened his life considerably" - I'd be 100% at peace, because "I did the best I knew how to - my conscience is clear". 

I'm placing bets the outcome of which I will never know. But because I'm doing the best I can (doing my research, reading, speculating etc.) - I am at peace. And being at peace pushes up my QOL - I experience no worries or anxieties about my health behaviors, unlike so many folks out there.

So when you ask:

Is this the kind of benefit you are hoping to gain from metformin? If you are hoping for more, can you suggest revisions to my assumptions to justify greater optimism? Do you think such a modest lifespan benefit outweighs the potential risks associated with metformin treatment (including potentially increased dementia risk) in a healthy older person such as yourself? 

I answer: I know nothing for sure... I am speculating - I might be wrong, but I don't care, because it's the best I can do given info at my disposal... and I don't believe anyone knows any better anyway. I think there are a thousand other variables that might make metformin risky or beneficial including a particular individual in a particular situation - we don't know. Nobody knows. Here's something timely from Al Pater, posted just today:

Naive extrapolations, overhyped claims and empty promises in ageing research and interventions need avoidance.
Rattan SIS.
Biogerontology. 2019 Nov 27. doi: 10.1007/s10522-019-09851-0. [Epub ahead of print]
PMID: 31773357
https://sci-hub.tw/10.1007/s10522-019-09851-0
Abstract
Most proclamations about another wonder breakthrough and another imminent miracle treatment of ageing are usually overhyped claims and empty promises. It is not that the experimental science behind those claims is totally wrong or fake. But it is often a case of being ahistorical and ignoring the cumulated knowledge and understanding of the evolutionary and biological principles of ageing and longevity. Furthermore, remaining stuck to the body-as-a-machine viewpoint reduces ageing and its associated health challenges to a mere problem of engineering and design. However, highly dynamic nature of the living systems with properties of interaction, interdependence, tolerance, adaptation and constant remodelling requires wholistic and interactive modes of understanding and maintaining health. The physiological relevance and significance of progressively accumulating molecular damage remains to be fully understood. As for ageing interventions, the three pillars of health-food, physical activity, and social and mental engagement-which actually show health-promoting effect, cannot simply be reduced to a single or a limited number of molecular targets with hopes of creating an exercise pill, a fasting pill, a happiness pill and so on. If we want to increase the credibility and socio-political-economic support of ageing research and interventions, we need to resist the temptation to overhype the claims or to make far-fetched promises, which undermine the theoretical and practical significance of new discoveries in biogerontology.
KEYWORDS:
Ageing; Anti-ageing; Holistic; Homeodynamics; Homeostasis; Longevity; Stress

You do the best you can. Nobody has access to perfect information. I speculate that pulsing metformin around exercise and in careful concert with rapa and my other behaviors will benefit me. I have no idea - nor does anyone else - whether I'm right. Show me otherwise, and I modify my behavior. I have seen nothing dispositive so far. YMMV.

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Tom,

I think we agree more than we disagree. I agree that we have tenuous evidence that many of the interventions you and/or I practice will positively impact our long-term health or longevity, beyond the basics like eating a healthy, mostly plant-based diet in moderation, engaging in moderate exercise and avoiding things that are known to shorten life like smoking. In the "speculative interventions" category (as far as humans are concerned) I would include calorie restriction, "optimal" nutrition, cold exposure, fasting/time-restricted eating, and vibration therapy.

For the above listed speculative interventions, I think there are sufficient hints from the animal evidence and the limited human evidence that they may be beneficial, and most importantly that there is little evidence for downsides, at least in the doses and protocols that you and/or I have chosen to practice them. 

I think where we may disagree is over whether there is sufficient evidence to support the idea that the potential benefits outweigh the risks when considering adding pulsed metformin to one's regime starting relatively late in life when one is already quite healthy and practicing moderate calories restriction. As far as I can tell, there is no evidence that metformin benefits healthy people, to say nothing of healthy people already practicing CR (in whom presumeably mTOR activity is downregulated already), to say nothing of older healthy people already practicing CR. Similarly, as you suggest, pulsing metformin may be better, but then again it may be worse and we have no evidence (even in animals), one way or the other.

You once said "primum non nocere" or "first do no harm". It seems to me the potential risks associated with metformin that you've identified outweigh the potential benefits, even if one takes a very optimistic interpretation of the rodent data on metformin and given the lack of evidence that pulsing metformin will preserve any benefits while mitigating the risks. But as you say, YMMV.

Where I am in wholehearted agreement with you is that it's worth trying something different from the usual approach to aging and to life more generally.

This is speculative so correct me if I'm wrong, but I think the difference between you and me may be that you seem pretty focused on the personal benefits that may accrue if you chose your regime wisely. I, on the other hand, am wired to as I've said before "go out on a limb" with my very usual regime simply to explore a part of the space of human possibility that has seldom if ever been visited, whether it works out well in the end for me or not. In short, I see value in being different for the sake of being different, as long as I'm not hurting anyone else by doing so, and I think there is a reasonable chance I'm doing myself more good than harm, and as long as there is the potential for me or others to learn something from my non-conformity.

In fact, I think the ultimate purpose in life is to rationally explore the "adjacent possible" - things (or combinations of things) that nobody (or very few) has tried before. I'd rather push the envelop to see what's possible, and what works (or doesn't) in hopes that others will benefit from my exploration and experimentation. 

This has gotten pretty philosophical, so I'll stop there and return to the topic of the post. But for anyone new interested in the philosophical stuff, herehere, here, here and especially here and here are discussions about my philosophy of being inclined to "go out on a limb for a worthy cause."

Gambling that pulsed metformin started late in life in someone who is already healthy and practicing CR is an example of going out on a limb in a new or seldom explored, potentially fruitful direction that I generally approve of. So kudos for that.

The reason I personally wouldn't chose to start taking metformin now based on the available evidence is that I don't think it is likely to add more than a few months (at best) to the healthspan/lifespan of an older person who is already healthy and who has been practicing long-term moderate CR, like you and me. Such a small effect is unfortunate both because it confers little benefit on the person doing it, and because it will be so small as to be lost in the noise and therefore fail as a guide for anyone else. It's just going to be too little, too late, I'm afraid.

If there were absolutely no hints of negative side effects, I might think even a few months extra might be worth it, and start taking metformin (+ rapamycin) myself. But downregulating mTOR is not something to be triffled with, and both drugs have clear hints of potential downsides (for muscles and brain at least), as you yourself have pointed out.

If I thought it was time to throw caution to the wind and gamble on an unproven intervention with promising early results and modest potential for negative side effects, rather than metformin + rapamycin, I think I might gamble on the senolytic cocktail of dasatinib + quercetin which shows promise in rodents and older humans, particularly since I think I'm already getting most of the potential benefits of met + rapa from my practice of CR. 

That's why doing a more quantitative risk/benefit analysis like I was suggesting has merit, because it might allow you to rationally assess which interventions are likely to give you personally the most bang for your buck given your circumstances and existing practices.

--Dean

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As an addendum to my post from this morning, last week Reason from "Fight Aging" summarized a talk he recently gave on self-experimentation. He seems to agree with me that the risk/reward tradeoff for metformin makes it not worth taking and that the existing senolytic agents (dasatinib  + quercetin) are likely a better option. Here is a quote from that talk summary about the four types of self experimentation:

We might consider four classes of self-experimentation at increasing levels of sophistication. Class 1: the sort of thing that everyone does with dieting for weight loss or eating foods and supplements for benefits. Class 2: compounds that are easy to obtain, easy to use, have great human safety data, and that may have effects on aging, such as metformin (a poor idea, I think) or senolytics (a better prospect). Class 3: treatments that are logistically challenging, and that may need a personal lab. Few people would be able to safety inject themselves with myostatin antibodies, for example. Get that wrong, and you die. But it is technically plausible, and helpful in terms of spurring muscle growth, given the evidence. Class 4: treatments that require a company or other significant effort to create. Liz Parrish's efforts with Bioviva , in order to self-experiment with telomerase gene therapy, for example. Or cryonics, for that matter. In near all cases, from dieting to quite sophisticated efforts, people tend self-experiment poorly. They do not do the one fundamental thing, which is to measure the effects.

In the "a poor idea, I think" link, he says:

This review paper more or less leans towards my thoughts on metformin as a treatment to slow aging: the animal data is not great, the human data is a single study, the effect size on life span is far too small to care about, and the detrimental side effects are large in comparison to that effect size. 

--Dean

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Thanks, Dean - I think I've pretty much discussed most of the issues wrt. metformin identified by Reason in that link. However, I'd point out again that my metformin regimen is part of a complex of interventions, and therefore looking at that one compound in isolation is a mistake - again, that timely Al Pater post I mentioned above alludes to this. Metformin as tested in mice was a single drug intervention. But what happens if you combine metformin with other drugs (like rapa), or take metformin according to a different protocol (f.ex. pulsing)? We are all individuals in specific physiological situations, subject to a variety of interacting variables. After all, Reason himself mentions (and I've done so too) the fact that metformin is not additive when combined with exercise - so the idea that one intervention may impact another in non-obvious ways should not be a foreign concept. One of the undesirable side effects of rapa can be a tendency to DMT2 - and metformin counteracts this. Meformin by itself might be a net neutral or negative, but combined with something else, all of a sudden the sum is greater than the parts. Now, obviously, this gets out far into the sticks speculatively speaking. Ordinarily I stay far away from acting on biomechanistic speculations and much prefer outcome data, but in the absence of the latter and compelled to act, I have little choice but to venture along that path. So, my metformin adventure is in the context of looking at other aspects of how metformin acts, not simpy as an anti-aging agent. Metformin inhibits gluconeogenesis in the liver - in the last few years, my FBG has been edging up at the end of my longer non-feeding windows (currently approx. 18 hours out of every 24). Metformin might be useful here to me (but perhaps not to someone else - again, we're all in individual situations) - not as an anti-aging agent per se, but as a piece of the puzzle - you have to look at the whole picture, not just at individual pieces (i.e. every piece by itself is not the whole map of anti-aging, which is what people sometimes focus on). Perhaps no single drug in a given cocktail is anti-aging by itself, the effect happens only once all work in concert.

You are also correct that it's possible such interventions might not buy us much in lifespan. I was struck by another study Al posted, where they tracked 40 variables and over a dozen conditions in a large group of elderly people and found that if you did everything right the difference between the best and worst individuals in lifespan was as little as 6 months (this was in a setting of a retirement home). My response is that part of why I do this is purely intellectual/hobby - you have to do something anyway (as I said, even if that something is "nothing"), you have to eat anyway, so why not do as good a job as you know how to, regardless of whether it'll actually buy me anything; the resources don't matter, and I can't take it with me, so if I can afford it, why not (we have no kids)... hey, hobbies have a cost in time, effort and money - this is no different :)... I also continue to believe that there isn't a perfect alignment of healthspan with lifespan 1:1 - and so even if I gain nothing with lifespan, I am hoping that perhaps it might be good for some gains in healthspan, which is nothing to sneeze at.

On a completely different note, and perhaps it belongs in a different thread, but there's one psychological aspect to all of this that admittedly slightly troubles me, namely - what about the ethical implications of all this? Is it terribly self-indulgent? In a world of constrained resources, is such extravagant attention to ones own health and mortality not a wasteful and selfish pursuit? The health insurance my wife and I have allows for once-yearly general health exam. We very rarely go otherwise go to the doctor. Also, I believe research shows that such checkups are useless and should be only done about once every five years. Are we taking up time from our busy PCP, who has patients with actual problems - (this is what we think as we sit in the waiting room, surrounded by patients who are visibly struggling). Then we go in, and have to report no real problems - seems very wasteful and self indulgent to have this battery of tests for no real reason other than curiosity. When asked about what might trouble us, it's actually embarrasing to bring up niggling QOL issues such as "there's a persistent itching in my ears that wasn't there a year ago" - because other than cleaning them out (which resolves nothing), there's not much that he can do. Why even bring up such trivial stuff. My wife and I are gradually coming around to the idea that we won't go in for yearly checkups any more - it takes time away from other patients and the doctor. Instead, if we're so curious, we should pay for tests out of pocket in an external lab and not be a burden on a strained healthcare system. What's your view of this whole thing - are we all, life-extension hobbyists, being a bit self-indulgent, and shouldn't we all spend more of our time and resources helping out instead of focusing on ourselves? Or is this also self-indulgent overthinking? Inquiring minds want to know.

Edited by TomBAvoider

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Thanks Tom,

I totally understand your thinking - you might as well try something and who knows, a novel regime of pulsed metformin + rapamycin might turn out to have dramatic health and/or longevity benefits. 

But it leaves me wondering whether you considered senolytic therapy instead of or in addition to your met + rapa strategy. 

Regarding us healthy people using up scarce medical services better spent on people who are actually sick. I agree with you. I've skipped my last couple yearly checkups with my GP and instead buy lab tests myself whenever I want to get insights into my health status. I can often get much more comprehensive lab tests done paying out of pocket to a place like LEF or Direct Labs than paying my insurance co-pay on a doctor's visit plus the lame list of standard bloodwork he'll order.

Regarding your larger question:

Quote

What's your view of this whole thing - are we all, life-extension hobbyists, being a bit self-indulgent, and shouldn't we all spend more of our time and resources helping out instead of focusing on ourselves? Or is this also self-indulgent overthinking? Inquiring minds want to know.

My answer is yes, spending a lot of time on life-extension minutia is being self-indulgent and yes, I believe it is worth spending more time helping others. Personally, over the last several years I've redirected a lot of the inordinate amount of time I used to spend posting here into pursuits that I think more directly impact people's lives in a positive way. Tom, I'm curious, are you and your wife still actively involved in animal rescue efforts? That certainly seems like a worthwhile, other-centered pursuit.

--Dean

 

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6 hours ago, Dean Pomerleau said:

... I think I might gamble on the senolytic cocktail of dasatinib + quercetin which shows promise in rodents and older humans, particularly since I think I'm already getting most of the potential benefits of met + rapa from my practice of CR. ...

--Dean

Quercetin appears to increase gastrointestinal barrier permeability, which may cause a host of issues, including increased inflammation.

Currently, there is really no rational reason to conduct such experiments on oneself with either of the concoctions discussed above. Reasonable CR and maintaining healthy habits (including eating a plant-based diet) are currently the main rational options, primarily because they are likely to extend "healthspan," if not necessarily lifespan. Perhaps in a decade or two we may see better options, but right now it just looks like grasping at straws, some of which may in fact be poisonous.

Edited by Ron Put

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30 minutes ago, Ron Put said:

Perhaps in a decade or two we may see better options, but right now it just looks like grasping at straws, some of which may in fact be poisonous.

Ron, 

For once we agree! 🙂 

But Tom is older than we are. If he feels he doesn't have time to wait and wants to play the lottery with one of the unproven and potentially deleterious treatments available today, I don't think it is an irrational choice.

Tom knows the chance of these treatments making a dramatic difference is pretty low, but you shouldn't discount the psychological and QoL benefits of knowing you've left no stone unturned. 

--Dean 

 

 

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Hi Dean and Tom!

About Rapa -- Matt Kaeberlein gave a talk here at the annual forum on anti-aging at UR.  He believes that the evidence is strong that just plain rapa is safe for healthy subjects, and really might have an anti-aging effect; he is engaged in trials of rapa on pet dogs now.

I asked him how he would compare the ant-aging effects of CR and rapa -- he answered that there were some common features, but some of the pathways are different.  I asked him if he thought whether CR and rapa would work together -- he answered that it would be impossible to test such things -- that such a trial would never be sanctioned.

About rapa:  Your discussion suggests that rapa is easy to get.

Is it?

(Not that I'd be likely to try it.)

  --  Saul 

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53 minutes ago, Dean Pomerleau said:

For once we agree! 🙂 

Dean, I actually agree with you quite often and have learned a bunch from you and a few others here :)

 

51 minutes ago, Saul said:

About rapa:  Your discussion suggests that rapa is easy to get.

Is it?

Saul, take a look at the last post here:

P.S.  I just read through this, which may be familiar to many here, but it was new to me. Interesting.

Edited by Ron Put

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Thanks, Dean. Yes, we're still involved in animal rescue, although given that we're more pressed for time, we've upped our financial contributions to rescue organizations as a means of contributing. However - even that has been questioned, given the humanitarian crisis we witness on a daily basis here in LA, namely homelessness. Can we really justify expending as much resources on animals when humans are in such dire need? Shouldn't our priorities be inverted from the current 90% animal 10% human (at least as far as charitable giving)? Maybe it's just another sign of old age that I'm increasingly fretting about making/leaving a lasting contribution behind, rather than just having lived a life focused mostly on selfish pursuits.

 

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Tom,

41 minutes ago, TomBAvoider said:

 Should our priorities be inverted from the current 90% animal 10% human (at least as far as charitable giving)?

That depends. If you were to choose to start helping people (e.g. homeless people) rather than animals, would you still feel morally obliged to carefully vet each one to make sure he/she is deserving of your assistance and not some kind of criminal?

That attitude would seem to preclude either charitable giving or direct volunteering, so it might be better to stick with helping animals.

--Dean

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Yes, there's the issue of moral hazard. But in this case, it's on a much larger scale. My problem with charity giving in this scenario is not so much the moral hazard in the case of individuals, but rather the moral hazard of the whole enterprise. What I mean is this: homelessness is a societally created problem; it didn't use to exist in such numbers, and in some countries didn't exist at all for many decades (Sweden, when I lived there in the 80's). But as a result of various policies, homelessness has been created. Now I'm - as in Joe Schmoe - supposed to step in and clear up the mess while those who profited from such policies go scott free? It's like cutting taxes and social services with resultant massive money transfer to those who are already super wealthy and then turning around and saying "let charity fix the mess". It's the same moral hazard reason why I absolutely refuse to donate to any "veteran" cause - if you engage in aggressive wars, you should also finance the help veterans need. It can't be that when the soldiers come back from war it's not the war-monger's problem to support the veterans. That leads to the long term costs of war being offloaded on charity and so encouraging endless wars. Pay for your wars, don't cry "charity". Providing charity under such circumstances results in less political push to hold accountable those responsible for such disasters, because "charity will fix it". Instead I'd like to see a Bonus Army, veterans organizing politically to demand services instead of having to rely on handouts and charity. Veterans deserve our support in taxes paid, not having to rely on chance and charity. So the question is how to help the individual while not encouraging further abusive policies that will only multiply the problem.

 

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4 hours ago, Dean Pomerleau said:

... That depends. If you were to choose to start helping people (e.g. homeless people) rather than animals, would you still feel morally obliged to carefully vet each one to make sure he/she is deserving of your assistance and not some kind of criminal?

That attitude would seem to preclude either charitable giving or direct volunteering, so it might be better to stick with helping animals....

I guess I agree with Dean, again....

3 hours ago, TomBAvoider said:

... It's like cutting taxes and social services with resultant massive money transfer to those who are already super wealthy and then turning around and saying "let charity fix the mess". It's the same moral hazard reason why I absolutely refuse to donate to any "veteran" cause - if you engage in aggressive wars, you should also finance the help veterans need. ...

And I guess I disagree with the logic of Tom's argument, again:

Budget cuts cannot be the main reason homelessness has become ubiquitous in major American cities today. The fact is, welfare spending as a percent of GDP has increased dramatically since the 1960s.

109135723_ScreenShot2019-12-01at16_40_49.png.e89494165a96fedc256cba04d0f064d0.png

What is far more likely to be the cause can be traced to Supreme Court decisions in the 1970s which declared most vagrancy and loitering laws unconstitutional, and to the ACLUs mid-1970s win which resulted in the closing of a large portion of state-run mental facilities over the next couple of decades.

Add to this the nonsensical drug policies of the latter half of the 20th century, which criminalize addiction. Add to it the screwy and expensive healthcare system in the US, which is still the main cause for personal bankruptcies. And yes, shifting the main tax burden to the middle class has not helped, either.

Government policies and charities have for decades worked to effectively encourage the robust procreation of those least capable of taking care of themselves or their children, mostly without a thought about effective family planning and without a plan for what to do with the resulting exploding population. Which is, in fact, the main cause of the environmental crisis we are all facing.

As the old adage goes, "the road to hell is paved with good intentions."

Edited by Ron Put

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Well that's encouraging, if Ron disagrees that's a sure sign I'm on the right track. But Ron, perhaps you should read more closely. I said "it's like", meaning I'm comparing the policies, not saying that just cutting taxes was was the (sole) reason - otherwise I'd have said "it's because". I'm well aware of other reasons why homelessness exists, amongst them the closing of mental hospitals and changes to laws governing when someone can be committed. The reasons are complex and posts on this board are not a good medium to explore them, so I just reference things glancingly. And no, I don't believe vagrancy/loitering laws are to blame in the least - I believe there are policies with far greater impact, as just one example - the way capital has been encourged to buy up vast amounts of properties and then not be taxed for leaving them unoccupied (effectively a way to park capital):

https://thehill.com/changing-america/respect/poverty/471675-in-los-angeles-vacant-homes-outnumber-the-homeless

 Meanwhile the old vagrancy/loitering laws were exploited to imprison folks based on racial grounds, often as a covert way to re-introduce forced labor, slavery in all but name:

https://en.wikipedia.org/wiki/Black_Codes_(United_States)

I'm glad these evil vicious laws were put under scrutiny - good riddance, too bad not more comprehensively as in fact they're still used to harrass people for purely discriminatory reasons feeding the industrial prison system. Vagrancy and loitering laws are hardly a factor in homelessness... people don't become homeless in the year 2019 or 2000, because someone in the 70's determined that you won't get arrested for loitering "hey, no loitering laws back since the 70's? Cool, I'm dropping my apartment today in 2019 immediately and going homeless! Whoowee! What a way to save on rent!"... and conversely, tougher loitering laws won't create housing, jobs and drug rehabilitation... if you want to understand why there's homelessness, follow the money... always a good rule... someone is getting rich and the rest are getting ripped off.

But again, it's too complex to discuss in detail here. Glad you disagree though.

Edited by TomBAvoider

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I totally agree with Ron.  (I often find Tom's ideas interesting -- but I totally disagree with his thoughts on this topic.)

  --  Saul

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18 hours ago, TomBAvoider said:

... Vagrancy and loitering laws are hardly a factor in homelessness... people don't become homeless in the year 2019 or 2000, because someone in the 70's determined that you won't get arrested for loitering .... if you want to understand why there's homelessness, follow the money... always a good rule... someone is getting rich and the rest are getting ripped off....

Another day, another Tom conspiracy theory: now the uber-rich are out to make America homeless.... I am somewhat familiar with some of the issues involved and often stay in Downtown LA. DTLA's homeless problem is worse than NY's ever was, and probably even worse than in SF. Unfortunately, the images here are commonplace.

But, the fact is that on an average night, LA shelters have between 50%-70% occupancy. VA shelters traditionally have 50%-60% or less occupancy. Which tells you that for many, homelessness has little to do with available housing or housing prices. It has more to do with mental illness, addiction and to some extent, a choice.  Shelters and city housing have policies governing behavior and alcohol and drug use, and many prefer to stay on the street, rather than abide by the rules. Many may not be able to make a rational choice, but in most jurisdictions they cannot be compelled into shelters or rehabilitation programs. In addition to those with mental health or addiction problems (60%-70%), there are former inmates and vagrants who travel around, engaging in mostly petty crime -- many of those you find begging at stop lights are there to sell drugs -- which is why you see the same relatively able-bodied men, often "working" in shifts. Most such corners, as well as most blocks on Skid Row, are run by gangs. And of course, we have a whole cottage industry of "non-profits," which relies on the ever increasing budgets allocated to homelessness ($2.5bn just in the City ofLA, if I recall).

Which brings me to loitering laws: Your accusation of "evil vicious laws... feeding the industrial prison system" can be applied to any law you don't like, and be just as meaningless. The point of such laws is so I should not be able to invite a few friends to get drunk or shoot up at the entrance to your store, and then defecate on the sidewalk in front of it. And then do it again tomorrow, and the day after.... My guess is, you don't live in an urban environment, so you never have to deal with it.

Anyway, I wasn't going to engage further, since it does no good in this case, but here I am.... And that's the last I'll write on the subject here. Cheers.

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