48 replies to this topic

[Michael]

All:

Just in case you were convinced not to drop your huge supplement stack by supposedly sophisticated supplement hawkers' standard line that, "of course," those antioxidant trials were failing because they missed critical phytonutrients and obscure subclasses of supplement, without which the entire stack's otherwise-miraculous value was rendered null and void (even though they had been hawking those very combinations just a few years previously):

* * * *
Present data suggest that the consumption of individual dietary supplements does not enhance the health or longevity of healthy rodents or humans. It might be argued that more complex combinations of such agents might extend lifespan or health-span by more closely mimicking the complexity of micronutrients in fruits and vegetables, which appear to extend health-span and longevity. To test this hypothesis we treated long-lived, male, F1 mice with published and commercial combinations of dietary supplements and natural product extracts, and determined their effects on lifespan and health-span.

Nutraceutical, vitamin or mineral combinations reported to extend the lifespan or health-span of healthy or enfeebled rodents were tested, as were combinations of botanicals and nutraceuticals implicated in enhanced longevity by a longitudinal study of human aging. A cross-section of commercial nutraceutical combinations sold as potential health enhancers also were tested, including Bone Restore®, Juvenon®, Life Extension Mix®, Ortho Core®, Ortho Mind®, Super K w[ith] k2®, and Ultra K2®. A more complex mixture of vitamins, minerals, botanical extracts and other nutraceuticals was compounded and tested.

No significant increase in murine lifespan was found for any supplement mixture.

Our diverse supplement mixture significantly decreased lifespan. [The "diverse supplement mixture" looks suspiciously like LEF's "Daily Dozen"].

They also tested (using controls that lived a proper lifespan to begin with instead of being so poorly-husbanded as to need a supplement just to live a normal mousey life) McMaster's famous "Complex dietary supplement."(2) No benefit.]

Thus, our results do not support the hypothesis that simple or complex combinations of nutraceuticals, including antioxidants, are effective in delaying the onset or progress of the major causes of death in mice. The results are consistent with epidemiological studies suggesting that dietary supplements are not beneficial and even may be harmful for otherwise healthy individuals.

References

1. Lifespan effects of simple and complex nutraceutical combinations fed
isocalorically to mice. <http://www.ncbi.nlm....ubmed/24370781>
Spindler SR, Mote PL, Flegal JM.
Age (Dordr). 2013 Dec 28. [Epub ahead of print]
PMID: 24370781 [PubMed - as supplied by publisher]

2: Lemon JA, Boreham DR, Rollo CD. A complex dietary supplement extends longevity
of mice. J Gerontol A Biol Sci Med Sci. 2005 Mar;60(3):275-9. PubMed PMID:
15860460.

[Dorian Grey]

Bone Restore®?, Juvenon®? Yuck!

Still, if I don't take vitamin-C, my gums bleed and my breath putrefies. Vitamin-C prevents this.
If I don't take B-Complex, I get an energy crash after consuming carbs or alcohol. B-Complex fixes this.
If I don't take IP6, my iron creeps up to unhealthy levels due to all the universally iron fortified food I eat. IP6 prevents this.
If I go off my SAM-e, by back and bones ache as I stand all day at work. SAM-e works wonders for this.
Vitamin-E & Zinc intake strongly affects how often I am interested in sex. And I like sex!

If my girlfriend doesn't take PPC with her NSAID's she needs for her headaches, she gets dreadful and crippling GI inflammation. PPC fixes this.

Quality of life matters as much (if not more) than longevity, and this is what my supplements do for me and those I love.

Edited by synesthesia, 30 December 2013 - 02:12 AM.

[joelcairo]

(a) This result applies to life extension only.

(b) I'd want to see the full text before passing judgment. Spindler comes across as debunker in this and some previous publications, so these tests of a mishmash of supplements may have been designed to fail.

[Jeoshua]

Multivitamin Supplements are not meant for increasing lifespan, they are used to prevent vitamin defficiencies like scurvy, beri-beri, and other more obscure things. Quoting that study to say that vitamins are bad for you is like saying that standing in the sun for 2 hours per day does not prevent tooth decay. It's true, but it's also misleading and totally missing the point.

[Michael]

Bone Restore®?, Juvenon®? Yuck!

Juvenon (ie, ALCAR and lipoic acid) looked extremely promising a decade or so ago, when Hagen and Ames were apparently showing mice rejuvenated from the mitochondria up by these nutrients. [Edit: an off-Forum exchange has pointed out to me that my phrasing here, in the absence of further elaboration, might suggest that I still think these are promising supplements for such purposes. To be clear, I was not endorsing, and do not endorse, Juvenon/ALCAR+lipoid as a supplement: I stopped taking lipoic acid in the summer of 2011, and  stopped taking acetyl-L-carnitine in the spring of 2013. This study adds to the rack of evidence that these are not beneficial in healthy mammals (see my followup post on lipoic acid later in this thread for some of the evidence). Rather, I was simply explaining why it was rational for Spindler et al to test them in the first place. I also-MR, 2015-07-08]
 

Still, if I don't take vitamin-C, my gums bleed and my breath putrefies. Vitamin-C prevents this.
If I don't take B-Complex, I get an energy crash after consuming carbs or alcohol. B-Complex fixes this.
If I don't take IP6, my iron creeps up to unhealthy levels due to all the universally iron fortified food I eat. IP6 prevents this.
If I go off my SAM-e, by back and bones ache as I stand all day at work. SAM-e works wonders for this.

I don't mean to sound like a diet nag, but it sounds like you have a problem with your diet that whould be better addressed in terms of your overall long-term health by eating better. Eg, unless you're sick, you have to consume too much carbs or alcohol to get an energy crash; the solution is not to consume so much of these. Similarly, if you're eating iron-fortified food in any quantity, you would seem to be consuming too much processed food; you would be better served by eating less of it than eating it and then correcting it with IP6. Etc.

 

(a) This result applies to life extension only.

 

Yes --"only" .

 

(b) I'd want to see the full text before passing judgment. Spindler comes across as debunker in this and some previous publications, so these tests of a mishmash of supplements may have been designed to fail.

The doses are calculated from human doses by standard methods, with the exception of the McMaster nonsense, where he just fed healthy, normal mice the same amount of the same supplements by weight.

 

Multivitamin Supplements are not meant for increasing lifespan, they are used to prevent vitamin defficiencies like scurvy, beri-beri, and other more obscure things.

If you look at the formulation or marketing of Life Extension Mix or OrthoCore, it is very clear that they are not designed to or claimed narrowly to avert deficiency, which could easily be done with a generic drug store multivitamin. These formulas are explicitly (or as explicitly as the Chinese wall of DSHEA and LEF's aggressive lawyers will allow them to be) claimed to be ... well, a "Life Extension Mix." Similarly, LEF is clearly claiming that you will live longer if you take their "Daily Dozen." And in the face of clear evidence that it doesn't, they have been insisting for years that megadoses of various essential vitamins will prevent chronic disease rather than just deficiency diseases -- that selenium prevents cancer, etc.

Edited by Michael, 08 July 2015 - 06:36 PM.
Clarifying views on lipoic acid & ALCAR

[Jeoshua]

Multivitamin Supplements are not meant for increasing lifespan, they are used to prevent vitamin defficiencies like scurvy, beri-beri, and other more obscure things.

If you look at the formulation or marketing of Life Extension Mix or OrthoCore, it is very clear that they are not designed to or claimed narrowly to avert deficiency, which could easily be done with a generic drug store multivitamin. These formulas are explicitly (or as explicitly as the Chinese wall of DSHEA and LEF's aggressive lawyers will allow them to be) claimed to be ... well, a "Life Extension Mix." Similarly, LEF is clearly claiming that you will live longer if you take their "Daily Dozen." And in the face of clear evidence that it doesn't, they have been insisting for years thatmegadoses of various essential vitamins will prevent chronic disease rather than just deficiency diseases -- that selenium prevents cancer, etc.

And that, along with the price of most of their supplements, is a good reason to stay away from LEF. I mean, honestly, one simply cannot read through one of their catalogs and not come away with the sense that you've just been fed a line of bull from a very experienced snake oil salesman.

[joelcairo]

(a) This result applies to life extension only.

Yes --"only" .

Point taken. However I think it's strange that the abstract mentions that "health-span" was also measured, but there is no mention of what this means for mice or what the results were.

Anyway, despite the fact that the title of this forum is "Longecity", there are other reasons for taking supplements. In fact it's already widely acknowledged here that only a handful of drugs and probably no supplements have been demonstrated to significantly extend lifespan in mice.

And in my personal opinion, health-promoting supplements that hypothetically increase metabolism, wound healing and immune function, anabolism, and so on are every bit as likely to reduce lifespan (very slightly) by speeding up certain aging processes as to extend it.

(b) I'd want to see the full text before passing judgment. Spindler comes across as debunker in this and some previous publications, so these tests of a mishmash of supplements may have been designed to fail.

The doses are calculated from human doses by standard methods, with the exception of the McMaster nonsense, where he just fed healthy, normal mice the same amount of the same supplements by weight.

Fair enough, but there are plenty of more subtle ways to set up a test so that it produces no measurable result. The easiest is probably using a test sample small enough that the 95% confidence interval is ridiculously wide, and "no effect" is the almost inevitable result.

I also worry about the effect of having so many test groups (it looks like around 10 in this case) on the interpretation of what is "statistically significant". It seems like a false result, either in the direction of being beneficial or harmful, is not that unlikely.

But that's just two hypothetical concerns.

[Michael]

(a) This result applies to life extension only.

Yes --"only" .

Point taken. However I think it's strange that the abstract mentions that "health-span" was also measured, but there is no mention of what this means for mice or what the results were.

They only did limited assays of healthspan, at necropsy rather than eg. by having them run mazes or do rotarod tests. There were no apparent effects on a wide range of tumors, fatty liver, hemangioma, necrosed/inflamed penis (eew), enlarged seminal vesicles, distended bladder, skin/abdominal cavity fibroma, body cavity haemorrhage, etc.

Anyway, despite the fact that the title of this forum is "Longecity", there are other reasons for taking supplements. In fact it's already widely acknowledged here that only a handful of drugs and probably no supplements have been demonstrated to significantly extend lifespan in mice.

I don't actually think that's widely acknowledged, based on the pushback every negative finding on supplements receives, and the record is worse even than you state it: one drug (rapamycin) and no supplements have been thus demonstrated.

And in my personal opinion, health-promoting supplements that hypothetically increase metabolism, wound healing and immune function, anabolism, and so on are every bit as likely to reduce lifespan (very slightly) by speeding up certain aging processes as to extend it.

That's certainly plausible, though on the flip side nearly all of the means to extend lifespan in mice that do exist now (CR, rapamycin, various IGF-1 pathway mutations) also extend multiple aspects of healthspan.

(b) I'd want to see the full text before passing judgment. Spindler comes across as debunker in this and some previous publications, so these tests of a mishmash of supplements may have been designed to fail.

The doses are calculated from human doses by standard methods, with the exception of the McMaster nonsense, where he just fed healthy, normal mice the same amount of the same supplements by weight.

Fair enough, but there are plenty of more subtle ways to set up a test so that it produces no measurable result. The easiest is probably using a test sample small enough that the 95% confidence interval is ridiculously wide, and "no effect" is the almost inevitable result.

Similar sample sizes routinely successfully demonstrate life extension by CR (as indeed occurred in this study).

I also worry about the effect of having so many test groups (it looks like around 10 in this case) on the interpretation of what is "statistically significant". It seems like a false result, either in the direction of being beneficial or harmful, is not that unlikely.

Having multiple groups shouldn't really have any effect on the false negative rate: each intervention group is individually compared to the controls (and, separately, to the CR positive controls). IAC, even the nominal numbers don't suggest any increase in LS, and in the case of the LEF-Dirty-Dozen-Like cocktail the decrease was clear enough.

[joelcairo]

I'm just saying that, to simplify the math enormously, if you have 20 test groups then one of them is very probably going to return a p<.05 result that is due to random chance. The main value of screening large numbers of test groups is if you get an extremely significant result or if a result can be reliably reproduced. Anyway you have me at a disadvantage because I can't see any of the numbers, just very high-level conclusions.

P.S. I was thinking Metformin also extended lifespan, but I don't know how strong the science is behind that.

[kismet]

(b) I'd want to see the full text before passing judgment. Spindler comes across as debunker in this and some previous publications, so these tests of a mishmash of supplements may have been designed to fail.

There's a difference between being a skeptic and de facto fraud. All scientists should be skeptical towards (other) studies. However, you seem to be implying that Spindler may be guilty of gross scientific misconduct or fraud. Perhaps your statements were worded poorly?

Normally, his studies are of the highest quality. Almost always of higher quality than the papers he is refuting. A simple test of this is to check survival data: sick mice die early, bad labs publish data with sick mice that die early, but Spindler does not.

Do you have specific methodological concerns that were not addressed by Michael? Regarding mere "debunking", Spindler's studies produced some unexpected positive results as well, which you can read about when you follow the above link. It's not like his lab exists to publish negative data.

Edited by kismet, 30 December 2013 - 11:12 PM.

[joelcairo]

(b) I'd want to see the full text before passing judgment. Spindler comes across as debunker in this and some previous publications, so these tests of a mishmash of supplements may have been designed to fail.
There's a difference between being a skeptic and de facto fraud. All scientists should be skeptical towards other studies. However, you seem to be implying that Spindler may be guilty of gross scientific misconduct or fraud. Perhaps your statements were worded poorly?

Oh please. Anyone who has an agenda should have their work double- and triple-checked. Researchers deceive themselves far more often than they set out to deceive others.

Do you have specific methodological concerns that were not addressed by Michael?

How could I? I can't see even one number or any specific details of how Spindler conducted his research. Normally abstracts contain a reasonable summary of the experimental setup and statistical results, so this is disappointing. And Michael, although helpful and respectful, can't really address any concerns fully without posting essentially the entire text of the study.

[kismet]

Oh please. Anyone who has an agenda should have their work double- and triple-checked. Researchers deceive themselves far more often than they set out to deceive others.

What agenda does Spindler have? If anyone has an agenda here, it would obviously be someone seeking positive results. Your posts implied that he deliberately stacks the deck to debunk supplements (not unknowingly fools himself). If he did so, please contact retraction watch or his university. It is very possible that he could lose his job over such gross scientific misconduct.

Thinking there may be issues with a study is one thing, but implying some secret agenda without any evidence is just wrong. Even if there was a problem, it does not have to be deliberate or "an agenda". Do you see the difference in wording?

Do you have specific methodological concerns that were not addressed by Michael?

How could I? I can't see even one number or any specific details of how Spindler conducted his research. Normally abstracts contain a reasonable summary of the experimental setup and statistical results, so this is disappointing. And Michael, although helpful and respectful, can't really address any concerns fully without posting essentially the entire text of the study.

It's unfortunate that not all papers are made available for free. There are several ways to access a paper, that usually involve some leg work. Contact the authors, get access via a university (libraries!), become longecity member and gain access to our "resource sharing" forum, etc. Posting full text studies in public is generally considered to border on the illegal, though. A personal message might be a better idea. And once you read the paper you can criticize the methods in more detail (and without implying a big pharma cabal, I hope).

Note: some abstracts are better than others, but they never contain all relevant data

Edited by kismet, 31 December 2013 - 12:20 AM.

[niner]

The ImmInst/LongeCity community has been having this argument for eons... A couple comments: First, I don't think that these tests were "designed to fail". However, there may be a reason why they don't seem to "work". Spindler is a genius at mouse husbandry, and knows how to make mice live longer than most everyone else seems to be able to accomplish. In many of the published studies (by others), the life extension, if not due to crypto-CR, is apparently compensating for poor husbandry. So... Assuming these results have any bearing whatsoever on human lifespan (very large assumption), and knowing how poorly husbanded most humans are, why shouldn't the poor husbandry-compensation results be interesting (if not applicable) to us?

"Death", or longevity alone, is kind of a dumb endpoint. It's not really what I care about. I don't want the final ten years of my life to be spent confused, drooling, and incontinent. I'm extremely interested in healthspan. It does of course seem likely that these two endpoints will correlate, but they aren't the same. I'd like to see more attention paid to healthspan, but of course it is a more difficult thing to measure.

"Supplements" is a rather broad term. Are we putting "Bone Restore" in the same category as C60? Speaking of C60, why exactly does the published literature showing desirable biological activity in multiple species, not to mention radical life extension in a mammal, seem to not exist as far as this discussion is concerned? Why can we find the resources to test every compound that's ever been suggested to extend life, but not C60? Just curious. I mean, for godsake, the world got into a tizzy over resveratrol based on an alluring (though wrong) story and some yeast results. With C60-oo we have highly significant life extension in a mammal, in a controlled experiment from the lab of a respected toxicologist. Maybe the people who decide what gets tested in the ITP are convinced that "supplements" don't extend life, so testing anything else is pointless? I don't get it. To be fair, I did hear a rumor about them considering it, but only if they could deliver it in CORN oil instead of olive oil (which is part of the active species, not just a solvent), which starts to make "designed to fail" sound less like a paranoid conspiracy theory and more like a plausible explanation, but I suppose I'm digressing.

Finally, there's the multibillion dollar supplement industry, with no shortage of hucksters who are willing to let people believe anything, including actively encouraging them to believe things that aren't true. In some circles, this is known as "lying". If Spindler's goal is to shoot those guys down, that's ok with me.

Edited by niner, 31 December 2013 - 01:47 AM.

[Hebbeh]

I have the same goal and agree 100% with niner.

I'm not so concerned with living to 100 but am very concerned about staying healthy and enjoying life as long as I can. I live the lifestyle and at 56 I can look around and it isn't hard to believe that I am healthier and more able bodied than at least 90+% of my peers. It isn't hard to see at all. I have achieved that by living the lifestyle and walking the walk. And supplements are a part of that lifestyle. They may be a small part but they do play a role. A good supplement stack keeps me healthy so that I may continue to work at the important stuff. And although I take some supplements on blind faith, my n=1 has proven to me what has had a noticeable and positive effect (and a negative effect).

Coincidentally, I haven't had so much as a sniffle in at least 5 or 6 years. Had one mild cold in probably the last 10. It seems all my co-workers have been repeatedly sick with one nasty thing after another the past two winters and I'm the only one in the office that never gets sick...ever. So something is working. Think I'll just keep on keeping on.

BTW, did anybody ever ask those mice how they felt?

[Hebbeh]

http://www.scienceda...31230135106.htm

Most Clinical Studies On Vitamins Flawed by Poor Methodology

Dec. 30, 2013 — Most large, clinical trials of vitamin supplements, including some that have concluded they are of no value or even harmful, have a flawed methodology that renders them largely useless in determining the real value of these micronutrients, a new analysis suggests.

Many projects have tried to study nutrients that are naturally available in the human diet the same way they would a powerful prescription drug. This leads to conclusions that have little scientific meaning, even less accuracy and often defy a wealth of other evidence, said Balz Frei, professor and director of the Linus Pauling Institute at Oregon State University, in a new review published in the journal Nutrients.

These flawed findings will persist until the approach to studying micronutrients is changed, Frei said. Such changes are needed to provide better, more scientifically valid information to consumers around the world who often have poor diets, do not meet intake recommendations for many vitamins and minerals, and might greatly benefit from something as simple as a daily multivitamin/mineral supplement.

Needed are new methodologies that accurately measure baseline nutrient levels, provide supplements or dietary changes only to subjects who clearly are inadequate or deficient, and then study the resulting changes in their health. Tests must be done with blood plasma or other measurements to verify that the intervention improved the subjects' micronutrient status along with biomarkers of health. And other approaches are also needed that better reflect the different ways in which nutrients behave in cell cultures, lab animals and the human body.

The new analysis specifically looked at problems with the historic study of vitamin C, but scientists say many of the observations are more broadly relevant to a wide range of vitamins, micro nutrients and studies.

"One of the obvious problems is that most large, clinical studies of vitamins have been done with groups such as doctors and nurses who are educated, informed, able to afford healthy food and routinely have better dietary standards than the public as a whole," said Frei, an international expert on vitamin C and antioxidants.

Vitamin or mineral supplements, or an improved diet, will primarily benefit people who are inadequate or deficient to begin with, OSU researchers said. But most modern clinical studies do not do baseline analysis to identify nutritional inadequacies and do not assess whether supplements have remedied those inadequacies. As a result, any clinical conclusion made with such methodology is pretty much useless, they said.

"More than 90 percent of U.S. adults don't get the required amounts of vitamins D and E for basic health," Frei said. "More than 40 percent don't get enough vitamin C, and half aren't getting enough vitamin A, calcium and magnesium. Smokers, the elderly, people who are obese, ill or injured often have elevated needs for vitamins and minerals.

"It's fine to tell people to eat better, but it's foolish to suggest that a multivitamin which costs a nickel a day is a bad idea."

Beyond that, many scientists studying these topics are unaware of ways in which nutrients may behave differently in something like a cell culture or lab animal, compared to the human body. This raises special challenges with vitamin C research in particular.

"In cell culture experiments that are commonly done in a high oxygen environment, vitamin C is unstable and can actually appear harmful," said Alexander Michels, an LPI research associate and lead author on this report. "And almost every animal in the world, unlike humans, is able to synthesize its own vitamin C and doesn't need to obtain it in the diet. That makes it difficult to do any lab animal tests with this vitamin that are relevant to humans."

Even though such studies often significantly understate the value of vitamin supplements, the largest and longest clinical trial of multivitamin/mineral supplements found a total reduction of cancer and cataract incidence in male physicians over the age of 50. It suggested that if every adult in the U.S. took such supplements it could prevent up to 130,000 cases of cancer each year, Frei said.

"The cancer reduction would be in addition to providing good basic health by supporting normal function of the body, metabolism and growth," he said. "If there's any drug out there that can do all this, it would be considered unethical to withhold it from the general public. But that's basically the same as recommending against multivitamin/mineral supplements."

Story Source:

The above story is based on materials provided by Oregon State University.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

• Alexander Michels, Balz Frei. Myths, Artifacts, and Fatal Flaws: Identifying Limitations and Opportunities in Vitamin C Research. Nutrients, 2013; 5 (12): 5161 DOI: 10.3390/nu5125161

Edited by Hebbeh, 31 December 2013 - 01:17 PM.

[Gerrans]

I have the same goal and agree 100% with niner.

I'm not so concerned with living to 100 but am very concerned about staying healthy and enjoying life as long as I can. I live the lifestyle and at 56 I can look around and it isn't hard to believe that I am healthier and more able bodied than at least 90+% of my peers. It isn't hard to see at all. I have achieved that by living the lifestyle and walking the walk. And supplements are a part of that lifestyle. They may be a small part but they do play a role. A good supplement stack keeps me healthy so that I may continue to work at the important stuff. And although I take some supplements on blind faith, my n=1 has proven to me what has had a noticeable and positive effect (and a negative effect).

Coincidentally, I haven't had so much as a sniffle in at least 5 or 6 years. Had one mild cold in probably the last 10. It seems all my co-workers have been repeatedly sick with one nasty thing after another the past two winters and I'm the only one in the office that never gets sick...ever. So something is working. Think I'll just keep on keeping on.

I am 59, and I am similar. Except that I did not really start taking care of myself and taking a range of supplements till three years ago. I had always been relatively healthy, but since then, touch wood, I have not had the usual colds, toothaches, etc., that I had before. A toenail that had been deformed since I split it playing football as a boy has become normal (this still staggers me). I no longer get blood in my spit after teeth cleaning (I am pretty sure this is from taking vitamin C pills). My arthritis hurts much less--I am hardly aware of it now. My libido is resurgent (not that it was gone, but it had gently reduced during my 50s). My blood pressure has gone from high to the low end of normal.

A lot of the above is to do with taking off weight and getting to a normal BMI; but some must be due to what I eat or supplement (or what I don't eat--namely junk). I do worry that supplements could be doing me harm, as the studies quoted suggest; but then I ask myself: what is a supplement? I mean, I eat dried fruits to help my bowels--does that not make them a supplement? I eat greens every day for my health, even though I do not like them much. Are they a supplement? Some of the supplements I take are really just a form of food: garlic, turmeric, green tea, kelp, cherry extract. Where is the line drawn?

Sure, some supplements might cause a little harm, but that is true of some of the food we eat too.

Edited by Gerrans, 31 December 2013 - 01:45 PM.

[Michael]

I'm just saying that, to simplify the math enormously, if you have 20 test groups then one of them is very probably going to return a p<.05 result that is due to random chance. [MR's added emphasis]

Right: that's a variation on the problem of multiple comparisons. But as you indicate, that is likely to generate false positives, not false negatives. As I said, "Having multiple groups shouldn't really have any effect on the false negative rate."

I was thinking Metformin also extended lifespan, but I don't know how strong the science is behind that.

Metformin "extends lifespan" in genetically cancer-prone and/or sick, ill-cared for mice. In normal, healthy mice, it increases life expectancy by 5%: that's not an extension of lifespan.

there may be a reason why they don't seem to "work". Spindler is a genius at mouse husbandry, and knows how to make mice live longer than most everyone else seems to be able to accomplish. In many of the published studies (by others), the life extension, if not due to crypto-CR, is apparently compensating for poor husbandry. So... Assuming these results have any bearing whatsoever on human lifespan (very large assumption), and knowing how poorly husbanded most humans are, why shouldn't the poor husbandry-compensation results be interesting (if not applicable) to us?

First, it only seems that Spindler is a genius at husbandry because (a) so few people do lifespan studies at all, (b) most people who do lifespan studies are sloppy, rank amateurs with no experience in lifespan studies and do things like let their animals eat themselves sick and fat, and ( c) many groups intentionally use disease-prone strains of mice (the McMaster nonsense, most of the nonsense coming out of Russia) and/or intentionally bugger up their otherwise-healthy mice (the original resveratrol mouse study, in mice fed a high-fat, high-sugar diet leading to diabesity). Then when their lifespan is mostly normalized by their intervention they speak as if (or the media or the supplement industry speaks as if) this tells you something about its potential in normal, healthy people. The media and less-than-rigorous researchers at least tend to include the caveats; supplement hawkers are even more breathless about the tantalizing potential, or omit the caveats altogether.

Plenty of people can raise normal, healthy mice: Spindler, Weindruch, Walford (when he was alive), the three groups running the NIA's ITP (though one of them is not as good as the other two), de Cabo, Bartke, etc. And note that "despite" their healthy mice, these groups have shown multiple interventions that extend LS: rapamycin, CR, IGF-1 pathway mutations.

Second: middle-class Americans taking any care of themselves at all are at least as well-cared-for as these mice.The US population includes a lot of smokers, people living in terrible working conditions, the poor, people who are murdered, people eating less than one vegetable a day, and people with no health insurance, and yet the survival curve for the USA as a whole still looks nearly as good as that Spindler's mice. If you don't smoke, don't have a BRAC1 mutation, aren't obese, eat a few vegetables, have and use health insurance, and get any exercise, you're at least as well-husbanded as Spindler's mice.

"Death", or longevity alone, is kind of a dumb endpoint. It's not really what I care about. I don't want the final ten years of my life to be spent confused, drooling, and incontinent. I'm extremely interested in healthspan. It does of course seem likely that these two endpoints will correlate, but they aren't the same. I'd like to see more attention paid to healthspan, but of course it is a more difficult thing to measure.

I agree -- but OTOH, robust, healthy mice don't just drop dead. Lifespan studies demonstrate that the animal is well enough to live, and maximum lifespan tells you something about the rate of aging. And again, multiple interventions that extend LS (rapamycin, CR, IGF-1 pathway mutations) do extend healthspan on multiple parameters. Slowing the rate of aging is required to extend maximum LS, and slowing the rate of aging (ceteris paribus) extends health.

"Supplements" is a rather broad term. Are we putting "Bone Restore" in the same category as C60?

Well, no -- C60 is not a supplement.

Speaking of C60, why exactly does the published literature showing desirable biological activity in multiple species, not to mention radical life extension in a mammal, seem to not exist as far as this discussion is concerned?

I'm only aware of one study claiming benefits in normal, healthy mammals.

Finally, there's the multibillion dollar supplement industry, with no shortage of hucksters who are willing to let people believe anything, including actively encouraging them to believe things that aren't true. In some circles, this is known as "lying". If Spindler's goal is to shoot those guys down, that's ok with me.

I honestly think he just wants to get to the truth -- and his sponsor, and the people who recommended things for him to try (myself included), all wanted to find things that work.

But yes: when he helps to catch people in lies (and also in just pushing things on flimsy evidence), it makes me happy. Just not as happy as discovering that metformin extends lifespan in normal, healthy mice by 40% would.

http://www.scienceda...31230135106.htm

Most Clinical Studies On Vitamins Flawed by Poor Methodology

Many projects have tried to study nutrients that are naturally available in the human diet the same way they would a powerful prescription drug [which is, in effect, what the supplement hawkers claim that they are -MR]. This leads to conclusions that have little scientific meaning, even less accuracy and often defy a wealth of other evidence ... Such changes are needed to provide better, more scientifically valid information to consumers around the world who often have poor diets, do not meet intake recommendations for many vitamins and minerals, and might greatly benefit from something as simple as a daily multivitamin/mineral supplement.

Needed are new methodologies that accurately measure baseline nutrient levels, provide supplements or dietary changes only to subjects who clearly are inadequate or deficient, and then study the resulting changes in their health. Tests must be done with blood plasma or other measurements to verify that the intervention improved the subjects' micronutrient status along with biomarkers of health. And other approaches are also needed that better reflect the y.different ways in which nutrients behave in cell cultures, lab animals and the human body.

All emphasis mine. Agreed! If supplement companies marketed on that basis, I would have no problems with them. I supplement this same way myself, along with some relatively modest, more experimental things (and these days, almost all within normal dietary intake).

I am 59, and I am similar. Except that I did not really start taking care of myself and taking a range of supplements till three years ago. [...] A lot of [my health improvement] is to do with taking off weight and getting to a normal BMI; but some must be due to what I eat or supplement (or what I don't eat--namely junk). I do worry that supplements could be doing me harm, as the studies quoted suggest; but then I ask myself: what is a supplement? I mean, I eat dried fruits to help my bowels--does that not make them a supplement? I eat greens every day for my health, even though I do not like them much. Are they a supplement? Some of the supplements I take are really just a form of food: garlic, turmeric, green tea, kelp, cherry extract. Where is the line drawn?

The line can certainly begin to be drawn by looking at the levels one could realistically get from a healthy diet. Ie, when evidence accumulated that high intakes of gamma-tocopherol FROM FOOD might prevent prostate cancer, it would have been non-crazy to start offering people who don't get much gamma-tocopherol in their diet (in particular, who consume no soy or soybean oil) supplements matching the intakes of high dietary consumers. But that would mean twenty milligrams (or less, since even low consumers don't get zero milligrams), not 325 mg plus other nutrients designed to elevate your blood levels!

Sure, some supplements might cause a little harm, but that is true of some of the food we eat too.

Yes, but you can get evidence on that question in the epidemiology. What supplement hawkers routinely do is say "people who get "a lot" of Nutrient X from foods (that also contain many other things) have lower risk of disease Y! Let me sell you an isolated pill that contains ten or twenty times that much Nutrient X, and you can take it blind for twenty years! Then, if a clinical trial or animal study refutes my optimistic sales job, I will deny, deny, deny, or (since the competition has been undercutting me for years on Nutrient X anyway) move you on to my newer, better Nutrient X⁺¹!"

To paraphrase the outgoing mayor of New York: "This is your life, people! Don't screw it up."

Edited by Michael, 31 December 2013 - 03:31 PM.

[joelcairo]

I'm just saying that, to simplify the math enormously, if you have 20 test groups then one of them is very probably going to return a p<.05 result that is due to random chance. [MR's added emphasis]

Right: that's a variation on the problem of multiple comparisons. But as you indicate, that is likely to generate false positives, not false negatives. As I said, "Having multiple groups shouldn't really have any effect on the false negative rate."

Just to clarify, I never said anything about false negatives. I was saying that having too many test groups could produce false positive results showing that supplementation either increased lifespan or DEcreased lifespan (which is what Spindler claims).

BTW, I was able to get hold of the full text. Overall I don't have any specific criticisms about the methodology. However the paper is perhaps too short to give a full accounting of the whole ambitious project. And I couldn't figure out this part: "The studies used male B6C3F1 mice... randomly assigned to 58 treatment groups and to a control group, at 12 months of age." That's a lotta different groups, but I couldn't account for nearly that many test conditions being reported.

Maybe it's because there are references to groups of mice being fed 20% and 40% calorie-restricted diets, and carbohydrate-restricted diets which may be referring to the same groups, but I don't see this data being reported anywhere. Is this data unpublished or merged into the other data or what?

[Michael]

I'm just saying that, to simplify the math enormously, if you have 20 test groups then one of them is very probably going to return a p<.05 result that is due to random chance. [MR's added emphasis]

Right: that's a variation on the problem of multiple comparisons. But as you indicate, that is likely to generate false positives, not false negatives. As I said, "Having multiple groups shouldn't really have any effect on the false negative rate."

Just to clarify, I never said anything about false negatives. I was saying that having too many test groups could produce false positive results showing that supplementation either increased lifespan or DEcreased lifespan (which is what Spindler claims).

Ah -- sorry, gotcha. Well, in some of these cases and a couple of others, he's linked this to signs of liver toxicity, which in several cases seems mechanistically very plausible.

BTW, I was able to get hold of the full text. Overall I don't have any specific criticisms about the methodology. However the paper is perhaps too short to give a full accounting of the whole ambitious project. And I couldn't figure out this part: "The studies used male B6C3F1 mice... randomly assigned to 58 treatment groups and to a control group, at 12 months of age." That's a lotta different groups, but I couldn't account for nearly that many test conditions being reported.

He has already published some of the results elsewhere,(1-3) and has one more in press((4) below, as cited in the MS of the recent report) and (I believe) others yet unpublished.

References
1: Martin-Montalvo A, 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. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192. doi: 10.1038/ncomms3192. PubMed PMID: 23900241; PubMed Central PMCID: PMC3736576.

2: Spindler SR, Mote PL, Flegal JM, Teter B. Influence on longevity of blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin, morin, pycnogenol, quercetin, and taxifolin fed iso-calorically to long-lived, F1 hybrid mice. Rejuvenation Res. 2013 Apr;16(2):143-51. doi: 10.1089/rej.2012.1386. PubMed PMID: 23432089.

3: Spindler SR, Mote PL, Li R, Dhahbi JM, Yamakawa A, Flegal JM, Jeske DR, Li R, Lublin AL. β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice. Age (Dordr). 2013 Dec;35(6):2099-109. doi: 10.1007/s11357-012-9498-3. Epub 2013 Jan 15. PubMed PMID: 23314750; PubMed Central PMCID: PMC3824994.

4: Spindler SR, Mote PL, Flegal JM (2013a) Dietary supplementation with Lovaza and krill oil shortens the lifespan of long-lived F1 mice. Submitted.

[sthira]

Niner asks:

Why can we find the resources to test every compound that's ever been suggested to extend life, but not C60?  Just curious.

Michael has friends:

I honestly think he just wants to get to the truth -- and his sponsor, and the people who recommended things for him to try (myself included), all wanted to find things that work.

Is it inevitable that you will suggest to Dr. Spindler a test of this stuff (in olive not corn oil)?

To paraphrase the outgoing mayor of New York: "This is your life, people! Don't screw it up."

Maybe a longer life on C60, or maybe not.

[Hebbeh]

A recent study in humans rather than mice.

http://consumer.heal...r-s-683455.html

http://www.scienceda...31231163755.htm

Daily High-Dose Vitamin E Might Delay Alzheimer's

Although study showed a small effect, experts note the nutrient doesn't attack underlying cause

By Dennis Thompson
HealthDay Reporter

TUESDAY, Dec. 31, 2013 (HealthDay News) -- There might be some good news in the fight against Alzheimer's disease: A new study suggests that a large daily dose of vitamin E might help slow progression of the memory-robbing illness.

Alzheimer's patients given a "pharmacological" dose of vitamin E experienced slower declines in thinking and memory and required less caregiver time than those taking a placebo, said Dr. Maurice Dysken, lead author of a new study published Dec. 31 in the Journal of the American Medical Association.

"We found vitamin E significantly slowed the rate of progression versus placebo," said Dysken, who is with the Geriatric Research Education and Clinical Center of the Minneapolis VA Health Care System.

Experts stressed, however, that vitamin E does not seem to fight the underlying cause of Alzheimer's and is in no way a cure.

The study involved more than 600 patients at 14 VA medical centers with mild to moderate Alzheimer's. Researchers split the group into quarters, with each receiving a different therapy.

One-quarter received a daily dose of 2,000 international units (IU) of alpha tocopherol, a form of vitamin E. That's a relatively large dose; by comparison, a daily multivitamin contains only about 100 IUs of vitamin E, Dysken said.

The other sets of patients were given the Alzheimer's medication memantine, a combination of vitamin E and memantine, or a placebo.

People who took vitamin E alone experienced a 19 percent reduction in their annual rate of decline compared to a placebo during the study's average 2.3 years of follow-up, the researchers said.

In practical terms, this means the vitamin E group enjoyed a more than six-month delay in the progression of Alzheimer's, the researchers said.

This delay could mean a lot to patients, the researchers said, noting that the decline experienced by the placebo group could translate into the complete loss of the ability to dress or bathe independently.

The researchers also found that people in the vitamin E group needed about two fewer hours of care each day.

Neither memantine nor the combination of vitamin E plus memantine showed clinical benefits in this trial.

Therapy with vitamin E also appears to be safe, with no increased risk of illness or death, the researchers found. The annual death rate was 7.3 percent for people in the vitamin E group and 9.4 percent for those on placebo.

People should keep in mind, however, that vitamin E taken at such large doses can have an effect on other medications, said Heather Snyder, director of medical and scientific operations for the Alzheimer's Association.

"We know there might be some interactions with other medications that people might be taking, including blood thinners or cholesterol medications," Snyder said. That means that people who want to take vitamin E to treat Alzheimer's should do so under the supervision of their doctor, Dysken and Snyder said.

Snyder said the findings are "certainly positive enough to warrant further research," but she'd like to see the study replicated with another set of patients. The patients in this study were nearly all male, so were not wholly representative of the general public.

Research also needs to be done to figure out why vitamin E helps Alzheimer's patients, both Snyder and Dysken said.

At this point, no one is sure how it helps slow mental decline. The vitamin E used in the study is a fat-soluble antioxidant, but "we don't have a cogent theory why that property should be positive in patients with Alzheimer's disease," Dysken said.

However, such research into treating Alzheimer's might not be as potentially beneficial as studies that focus on preventing the disease altogether, Dr. Denis Evans, of Rush University Medical Center in Chicago, wrote in an editorial that accompanied the study.

"This is an excellent trial, and it points out the limitations of finding ways to treat the disease," Evans said. "It's a reasonable argument for putting more emphasis on prevention. If you look at all trials of Alzheimer's disease, of which this is an example of one of the best, the treatment effects are real but they are also relatively small and they focus [only] on the symptoms of the disease."


SOURCES: Maurice Dysken, M.D., Geriatric Research Education and Clinical Center, Minneapolis VA Health Care System; Heather Snyder, Ph.D., director, medical and scientific operations for the Alzheimer's Association; Denis Evans, M.D., Rush University Medical Center, Chicago; Dec. 31, 2013, Journal of the American Medical Association

Journal Reference:

• Maurice W. Dysken, Mary Sano, Sanjay Asthana, Julia E. Vertrees, Muralidhar Pallaki, Maria Llorente, Susan Love, Gerard D. Schellenberg, J. Riley McCarten, Julie Malphurs, Susana Prieto, Peijun Chen, David J. Loreck, George Trapp, Rajbir S. Bakshi, Jacobo E. Mintzer, Judith L. Heidebrink, Ana Vidal-Cardona, Lillian M. Arroyo, Angel R. Cruz, Sally Zachariah, Neil W. Kowall, Mohit P. Chopra, Suzanne Craft, Stephen Thielke, Carolyn L. Turvey, Catherine Woodman, Kimberly A. Monnell, Kimberly Gordon, Julie Tomaska, Yoav Segal, Peter N. Peduzzi, Peter D. Guarino. Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease. JAMA, 2014; 311 (1): 33 DOI: 10.1001/jama.2013.282834

Edited by Hebbeh, 01 January 2014 - 06:53 PM.

[platypus]

I think these results are somewhat disturbing. I did not think that vitamins or minerals extend lifespan but I was hoping that the many superfood-extracts within LEF Mix would make some kind of a difference. Are superfood-extracts useless??

[timar]

I don't think that they are useless, but they are not the fountain of youth either

Meanwhile, the LEF has published a comment on Spindler's study.

[kismet]

Meanwhile, the LEF has published a comment on Spindler's study.

It's surprisingly weak and factually incorrect. I would have expected a better piece of sophistry. In particular I would like to comment on this statement by LEF:

The number of animals used per study was small. Although exact numbers in the groups are not described in the full text, the authors do note 297 mice were used in 58 treatment groups and 1 control group. If the mice were divided equally between the groups there would only be 5 mice pertreatment group; a small number to provide meaningful data. Also, the number of mice per group was likely smaller than 5 because the authors describe the control group as “large."

Each treatment group had 36 mice! Someone who is following the literature would not get group size so absurdly wrong. It's absurd because a group size of 5 would be a complete farce and someone who is following the literature would know this. They should hire better people. The cynical interpretation is that LEF employees are lying for money.

Here the correct statistics:

An unbalanced statistical design was employed to minimize the number of mice utilized per test group while maintaining statistical power (Jeske et al. 2012). In this design, a large group of control mice and many smaller groups of “test” mice are used to maximize the number of test groups. When comparing multiple treatments to a common control, unbalanced designs have been shown to offer economic advantages (see for example, Jeske et al. 2012 for a discussion of this in the context of Weibull analyses). Specifically, we used 297 control mice and groups of 36 mice per treatment. The sample sizes in this study are similar to those required for a Weibull survival analyses set up to have an 75 % probability of detecting an 10 % increase in mean life span with a 1 % (α≤ 0.01) probability of a false positive across 58 test groups.

Jeske, D. R., Flegal, J., and Spindler, S. R. (2012) Minimum size survival analysis sampling plans for comparing multiple treatment groups t o a single control group. Communications in Statistics–Theory and Methods (in press)

[Mind]

Just wondering if it would be beneficial to future readers to merge this thread with this one; http://www.longecity...harm-than-good/

[Mind]

In regards to bias, it can work on a subconscious level, of course. Spindler has achieved a sort-of fame from "de-bunking' supplement claims, using mouse studies. Fame can induce bias. That being said, from what I have seen and read, I trust Spindler's work.

I also trust LEF's intentions. They are certainly biased, but I like what they do with their money (research into life extension and cryonics). I don't think they intentionally market/sell harmful products, just that within their echo-chamber of doctors, advisers, members, the potential positive aspects of supplements are touted more loudly. if their customers were getting ill and dropping dead (more than the general population), they would not be in business anymore. From the people I talk to, LEF customers are generally happy and healthy. Would I like to see more people supporting rejuvenation research instead of wasting so much money on supplements, sure, but I am not going to tear down LEF to get there.

Lastly, Spindler's work is in mice. After years of following research results, I now place little value in mouse studies, very little, no matter if they are deemed "positive" or "negative".

If you want to live longer and healthier, your best bet is to follow what healthy people do. Some diets seem to perform better than others (blue zone research), exercise is as close to a magic health pill as you can get, CR (or at a minimum, avoid accumulating extra white adipose tissue) could offer a small benefit as well. Do these things, save a little money on supps, and you will be able to support more significant(real) rejuvenation research.

[Michael]

Meanwhile, the LEF has published a comment on Spindler's study.

It's surprisingly weak and factually incorrect. I would have expected a better piece of sophistry. In particular I would like to comment on this statement by LEF

Indeed -- it's actually shocking how incorrect it is. There is, literally, nearly not a single sentence in the rebuttal that is factually accurate and non-misleading, when taken in context. I'm gearing up for travel, but may make a post with corrections on the site if someone (Kismet?) doesn't have time to do so first.

Just wondering if it would be beneficial to future readers to merge this thread with this one; http://www.longecity...harm-than-good/

That's really about an entirely different series of studies, of a quite different kind (human epidemiology) and on quite different supplements; I don't think there'd be any benefit to merging it, and it would probably lead to confusion as people started alternately referring to Spindler's lifespan study vs. the epidemiological study of that other thread.

[Darryl]

The major issue I see with massive supplement stacks is that many of the compounds are mild toxins (in vivo prooxidants, respiratory chain poisons, DNA intercalators etc.) that, in moderate doses, induce beneficial homeostatic responses to restore redox and energy balance (this is certainly true of most phytochemicals of interest, and I wouldn't be terribly surprised if C₆₀ functioned as a mitochondrial uncoupling agent). Which is fine, except I see regimens that hit the same biological pathways with 15 different herbs hoping for synergies: at some point the innate toxicity overwhelms any induced response.

Exogenous radical scavengers offer a different kind of impairment, by interfering with redox signalling and endogenous stress responses. Plus, they're mostly mopping up spilled water when the faucets (NADPH and xanthine oxidases, mitochondrial coupling) are more attractive targets.

I'm far more comfortable in looking at the plausible cellular mechanisms for anti-aging compounds (eg: AMPK, Sirt1, autophagy, telomerase, and xenobiotic response induction; inflammation (NF-κB, XO and selective Nox) inhibition; DNMT3,HDAC,HMT, and selected HAT modulation; carbonyl, peroxynitrate and ¹O₂ scavenging) and then working backwards identifying interventions. For most of these pathways, there are no bioavailable nanomolar EC₅₀ compounds without accompanying off-target effects. Ideally, a pharmaceutical/supplement anti-aging regimen would include no more than one potent inhibitor or allosteric modulator for each pathway (or preferably, pathway convergence), with few other strong interactions.

For now we're mostly playing the piano with our fists, and the larger the stack, the more fists are involved.

Edited by Darryl, 04 January 2014 - 07:49 PM.

[Dorian Grey]

Perhaps LifeExtension did a better job with there rebuttal here?
http://www.lef.org/f...Supplements.htm

Any study on longevity related to "general supplement use" generally is going to include: (1) Old people, and (2) use of popular multi's and tonics, most of which include iron.

With old people (women in particular), the love of iron goes back a long way, and I believe any conversation about supplement use in elderly populations should include the possibility of the "Geritol Effect", which would effectively sabotage any benefit they may have derived from their supplementation through the negative effect of throwing boatloads of additional iron into geriatric bodies.

[timar]

Meanwhile, the LEF has published a comment on Spindler's study.

It's surprisingly weak and factually incorrect. I would have expected a better piece of sophistry. In particular I would like to comment on this statement by LEF

Indeed -- it's actually shocking how incorrect it is. There is, literally, nearly not a single sentence in the rebuttal that is factually accurate and non-misleading, when taken in context. I'm gearing up for travel, but may make a post with corrections on the site if someone (Kismet?) doesn't have time to do so first.

Some members here tend to be somewhat agitative when it comes to the LEF. I think from their perspective - which is of course heavily biased towards (their) supplements - they wrote a fair comment on Spindler's study, puting it into context. The factual error they seem to have made with critizing the intervention group size, pointed out by kismet, is indeed annoying. I wish I had access to the full text of the study so I could judge for myself, but I referenced kismet's post on the LEF forum. Let's see how they react...

@Darryl: Good point. I think many supplements, particulary phytochemicals, should be taken intermittently rather than continously. At least if they are taken in doses significantly higher than those obtained through the diet. Of course that calls the concept behind supplements like the Life Extension Mix into question.

Edited by timar, 04 January 2014 - 08:52 PM.