48 replies to this topic

[Mind]

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.

Great post Darryl. Another good thing to remember is the dose-response curve, or "the dose makes the poison". Many of the phytonutrients, spices, spice extracts, plant extracts, teas, resveratrol, etc...appear to operate on similar pathways. If you are taking every "supp" that some mouse study shows a small benefit, you are probably hammering a particular metabolic pathway with orders of magnitude more dose than needed to be healthy. A good chance you are destroying that particular metabolic process.

[albedo]

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.

So do you think there is no longer any evidence of benefit of taking both supplements together by healthy human subjects (and probably never was)? How about R-Lipoic alone? Thank you in advance.

[Michael]

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

That reply was sufficiently riddled with errors that when some of them were pointed out they took the post down. Edit: The reply in that link has its own problems, and isn't about the study under discussion.

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

Darryl, that was beautiful; thank you.

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.

So do you think there is no longer any evidence of benefit of taking both supplements together by healthy human subjects (and probably never was)? How about R-Lipoic alone? Thank you in advance.

I believe I already made my views on this to you clear in a post you quoted and my reply to your followup question/comment here. IAC: clearly, there never was any evidence of benefit of taking both supplements together or either alone by healthy human subjects: there was only evidence suggesting the potential of such benefit, such as the Hagen/Ames studies. But today, in addition to still having no evidence of benefit in healthy humans, we now have at least five studies (that I know of) in which RLA ± ALCAR has failed to extend lifespan in normal mice or rats(1-5) (and yes, (3) and (4) are separate studies), and in nondiabetic, nonobese, non-sugar-stuffed rodents RLA has no effect on heart mitochondrial superoxide production,(6) plasma and aortic CML,(6) fasting glucose,(6,7) fasting insulin,(6,7) VO2_max,(7) or insulin resistance;(6,7) it has only a transient effect on blood pressure that reverses itself within four weeks,(6) and if anything may worsen free fatty acids.(7)

References
1. Lee CK, Pugh TD, Klopp RG, Edwards J, Allison DB, Weindruch R, Prolla TA (Apr 15, 2004). "The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice". Free Radic Biol Med 36 (8): 1043–57. doi:10.1016/j.freeradbiomed.2004.01.015 . PMID 15059645.
2. Merry BJ, Kirk AJ, Goyns MH (June 2008). "Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span". Mech Ageing Dev 129 (6): 341–8. doi:10.1016/j.mad.2008.04.004 . PMID 18486188.
3. Spindler SR; Mote PL (2007). "Screening candidate longevity therapeutics using gene-expression arrays". Gerontology 53 (5): 306–21. doi:10.1159/000103924 . PMID 17570924.
4. Spindler SR; Mote PL; Flegal JM (2013 Dec). "Lifespan effects of simple and complex nutraceutical combinations fed isocalorically to mice". Age (Dordr). Online First. doi:10.1007/s11357-013-9609-9 . PMID 24370781.
5. Bruce N. Ames. Personal communication, 2003-09-21
6. Midaoui AE, Elimadi A, Wu L, Haddad PS, de Champlain J. Lipoic acid prevents hypertension, hyperglycemia, and the increase in heart mitochondrial superoxide production. Am J Hypertens. 2003 Mar;16(3):173-9. PubMed PMID: 12620694.
7. Saengsirisuwan V, Perez FR, Kinnick TR, Henriksen EJ. Effects of exercise training and antioxidant R-ALA on glucose transport in insulin-sensitive rat skeletal muscle. J Appl Physiol (1985). 2002 Jan;92(1):50-8. PubMed PMID: 11744642.

Edited by Michael, 16 February 2014 - 08:00 PM.

[Dorian Grey]

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

"That reply was sufficiently riddled with errors that when some of them were pointed out they took the post down".

Link still works... Post still up... A very good read! Am I missing something?

[Michael]

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

"That reply was sufficiently riddled with errors that when some of them were pointed out they took the post down".

Link still works... Post still up... A very good read! Am I missing something?

My error: I mistook you to be talking about the post on the study under discussion in this thread.

[Dorian Grey]

"That reply was sufficiently riddled with errors that when some of them were pointed out they took the post down. Edit: The reply in that link has its own problems, and isn't about the study under discussion".

I'm curious... About the problmes in the LEF rebuttal. Can you help?

The bottom line in your original post was: "The results are consistent with epidemiological studies suggesting that dietary supplements are not beneficial and even may be harmful for otherwise healthy individuals"

If I understand correctly, the topic is: Supplement Stacks Still a Squader... Don't believe I've strayed too far off topic.

I feel the LEF rebuttal refuted the variables where most studies on this topic go astray. Can you point out where the LEF rebuttal goes wrong?

Edited by synesthesia, 17 February 2014 - 12:15 AM.

[timar]

I agree that much of the overdosed and overpriced stuff the LEF, AOM, etc. sell is probably rather harmful than beneficial.

There's still compelling evidence though, that a relatively low-dose multivitamin/mineral supplement is beneficial. But you have to look close enough to see the important nuances and let neither the puffy LEF propaganda nor the recent anti-vitamin media hysteria blur your vision...

Edited by timar, 17 February 2014 - 08:00 AM.

[BlueCloud]

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.

Niner, have you tried contacting Spindler to suggest including C60 in his experiments ?

[Dorian Grey]

I agree that much of the overdosed and overpriced stuff the LEF, AOM, etc. sell is probably rather harmful than beneficial.

There's still compelling evidence though, that a relatively low-dose multivitamin/mineral supplement is beneficial. But you have to look close enough to see the important nuances and let neither the puffy LEF propaganda nor the recent anti-vitamin media hysteria blur your vision...

Thank you for this timar... I lived on junk food, beer and cigarettes for about a quarter of a century when I was young, and still prefer meat and potatoes to grazing on kale and lentil soup. Supplemented my way all through life to fill in the nutritional gaps, and feel I'm still in good shape (at 58) largely because of this.

I look around me and see a substantial percentage of the population my age in very bad shape and just have to shake my head in astonishment. What the heck has gone wrong with all these folks in such a dreadful state of health. I simply don't believe its all in the genes. I simply don't believe essential nutrients aren't really "essential", and if you don't get them through dietary means its better to simply go without them.

I feel anti-supplement preachers do the world a great disservice by scaring the masses away from supplements, literally with threats of an early death from even the most basic nutritional supplementation. I may be wrong, but I truly believe supplements are what saved me from the fate of ill health so many suffer from today.

We all live and learn, but learning the hard way essential nutrients really are essential after all is a fate I wouldn't wish on my worst enemy.

Edited by synesthesia, 17 February 2014 - 01:39 PM.

[Michael]

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

That reply was sufficiently riddled with errors that when some of them were pointed out they took the post down. Edit: The reply in that link has its own problems, and isn't about the study under discussion.

I'm curious... About the problmes in the LEF rebuttal. Can you help? [...]

I feel the LEF rebuttal refuted the variables where most studies on this topic go astray. Can you point out where the LEF rebuttal goes wrong?

Well, let's start with the fact that their core argument is based on a notion that is not only complete speculation, but is actually completely opposite to the actual study details:

It’s a sad fact that most common diseases of aging are preventable, yet most people don’t engage in healthier lifestyle choices until after serious illness manifestation.

The classic example is an individual who never swallowed a single dietary supplement until they’re diagnosed with cancer. They then go from zero to low intakes of supplemental nutrients to swallowing 40 or more pills a day in what too often is a futile attempt to cure advanced stage disease.

In the Iowa Women’s Health Study,[(1) below] the authors admit they did not factor in the increased intake of dietary supplements that occur in response to the development of symptoms or diagnosis of serious disease. Stated differently: If a woman was diagnosed with stage 4 breast cancer and began ingesting 40 supplements daily, but died six months later, she would have been counted as being a heavy supplement user who died prematurely.

In other words, women who did not begin supplementing until after symptoms and/or disease manifested would have been classified from a statistical standpoint as being part of the group that ingested large quantities of supplements but died early nonetheless.

All emphasis in original. First, note that this is complete speculation: they have no data to show that many women did this in this study, that many people do it in general, or that such people are, in fact, responsible for the excess mortality.

But it's worse than that: the rebuttal claims that "In the Iowa Women’s Health Study, the authors admit they did not factor in the increased intake of dietary supplements that occur in response to the development of symptoms or diagnosis of serious disease." But that's absolutely untrue: the authors explicitly state that they did factor this phenomenon in, and it had no impact on the results:

An intermediate event, such as CVD or cancer, can induce a change in supplement use and confound the exposure-outcome association. In our data, the use of supplements was not modified by a pre-baseline diagnosis of CVD, diabetes mellitus, or cancer. Furthermore, intermediate cancer did not alter the supplement-taking pattern. ... In sensitivity analyses excluding women who had CVD or diabetes mellitus (n=5772) or cancer (n=3523) at baseline, the results were not materially changed. For example, for iron, the multivariable adjusted HR for total mortality was 1.13 (95% CI, 1.05-1.22). Parallel to the situation with total mortality rate, most supplements were unrelated to or showed higher cause-specific mortality rate in multivariable adjusted model version 2, although risk patterns varied across causes (Table 3). (1)

So: they looked, and saw that women who developed one of these diseases were no more likely to start or stop taking supplements after diagnosis than the women in the rest of the study -- and just to be sure that any such effect was not biasing their results anyway, they did an analysis where they just threw all such women out of the study, and it had no effect on the results: depending on the supplement, either harm or no effect of supplementation in healthy women without pre-existing disease.

So LEF's core argument is both false (they DID "factor in the increased intake of dietary supplements that occur in response to the development of symptoms or diagnosis of serious disease") and had no effect on the results. But now, let us (for the sake of argument) pretend that the authors had not done this, or that it had exerted a material effect on outcomes. LEF goes on to say,

This flaw by itself could render the overall findings of the Iowa Women’s Health Study meaningless because much of the lay public today mistakenly associates dietary supplements as something very important to initiate after serious disease appears.

Wha ...? If indeed "much of the lay public today mistakenly associates dietary supplements as something very important to initiate after serious disease appears," and if indeed there were excess mortality caused by taking supplements under those conditions (especially if (per LEF's false speculation) there was not such excess mortality, or a positive countervailing benefit, in women who had started taking them while healthy)), then this would make the results even more meaningful, because those would be exactly the conditions under which the lay public would be most likely to take them!

(By the way: LEF has done plenty to encourage people with pre-existing disease to load up on supplements: their website and protocol book is loaded with advice to take a variety of supplements if you have various diseases, particularly cancer: see eg. here, here, and here. So there's hypocrisy mixed in with their (conscious or unconscious) misrepresentation of the study analysis).

They then go on a long tear about confounding by hormone therapy:

In the Iowa Women’s Health Study, about twice as many women who took multivitamin/mineral supplements also took non-bioidentical hormone replacement therapy which is associated with early mortality. In numerical terms, 13.5% of the supplement users took hormone therapy at baseline compared to only 7.2% of non-supplement users. This ratio showing more supplement users taking hormone drugs persisted to the end of the observational period.

In technical terms, this is known as a ‘confounding factor’ because the increase in mortality caused by these dangerous hormone drugs would skew the results in a way that would show higher death rates in women taking these hormone drugs who also happened to be taking a multivitamin/mineral supplement.

Sure: this is absolutely an important consideration. So what do you do with a potential confounding factor? You perform an adjusted analysis to take the disproportionate use out of the picture. LEF (intentionally or due to failure to read the study) neglects to mention that the authors adjusted for use of HRT:

in multivariable adjusted model, version 1, we additionally adjusted for educational level, place of residence, diabetes mellitus, high blood pressure, body mass index, waist to hip ratio, hormone replacement therapy, physical activity, and smoking status.(1)

The result? The magnitude of the increased mortality for multivitamin use went up, not down: in the basic analysis (adjusted only for age and energy intake), multivitamin users appeared to possibly be 2% more likely to die over the course of the next 19 years, but it was not statistically significant and might have been statistical noise or residual confounding; in multivariate-adjusted model 1, they were a statistically-significant 6% more likely to die.

That's the other thing. Notice that risk went up after adjusting for "educational level, place of residence, diabetes mellitus, high blood pressure, body mass index, waist to hip ratio, hormone replacement therapy, physical activity, and smoking status".(1) The most likely reason is that users of supplements were leading healthier lives all around at baseline and at followup .

At baseline, compared with nonusers, supplement users had a lower prevalence of diabetes mellitus, high blood pressure, and smoking status; a lower BMI and waist to hip ratio; and were less likely to live on a farm. Supplement users had a higher educational level, were more physically active, and were more likely to use estrogen replacement therapy (Table 1). Also, supplement users were more likely to have lower intake of energy, total fat, and monounsaturated fatty acids, saturated fatty acids and to have higher intake of protein, carbohydrates, polyunsaturated fatty acids, alcohol [don't scream "aha!": we're talking 3.9 vs. 3.6 grams of alcohol a day, or about a third of a standard drink -MR] , whole grain products, fruits, and vegetables. Similar patterns were seen in the 2004 questionnaire among 19 124 women (Table 1) and for individual supplements (eg, iron and calcium) (eTable 1; http://www.internmed.com).(1)

The whole "sick-user bias" thing is, in other words, not only (a) untrue and (b) irrelevant to the results — it's the reverse of the case. The vitamin users were healthy lifestyle people, who should if anything have had lower mortality rates. And disease onset did not change their supplement use either way. Indeed, that has been the case in every study I've ever seen of suppelment users: uniformly, supplement users are not unhealthy people who pop pills either to make up for a bad lifestyle or in response to disease diagnosis, but are (mild to extreme) health nuts, who exercise more, eat better diets, are thinner, better-educated, consume less saturated fat, etc etc (eg. (1-9)). Far from a "sick user" confounder, there is if anything a "healthy user" confounder: if anything, epidemiological studies should find (as indeed many of them do, especially in unadjusted or poorly-adjusted analysis) that supplement users live longer, due to all the other healthy stuff they're doing.

Indeed: when LEF argues that

The Iowa Women’s Health Study initially showed that women who supplemented with vitamins C, D, E and calcium had significantly lower risks of mortality.

The study authors then blended this positive data with the negative results of iron and copper use and other multivariable adjustments to conclude increased mortality associated with multivitamin/mineral supplementation.

These “multivariable adjustments” were at the discretion of the study authors and could have been skewed either way to show positive or negative outcomes. Based on the negative remarks expressed at the beginning of the report, there appeared to be author bias against the use of multivitamin/mineral supplements.

Now, first, you can't have it both ways. You can't bitch about the confounding by the fact that the supplement users were more likely to use HRT (and ignore/fail to mention that HRT was adjusted for), and then bitch that the illusory protective effect of various supplments vanished after adjustmentfor the various ways that supplement users were different from nonusers (mostly, again, in a healthy rather than unhealthy direction).

But second, these multivariable adjustments were not "at the discretion of the study authors" (except in the trivial sense that no one was holding a gun to their heads to force them to do them): the authors looked, saw the various ways in which users were different from nonusers (younger, thinner, eating more veggies, exercising more, etc etc), and adjusted for the observed confounders. If they had not done so, LEF would have been justified in their (in the event, vapid) outrage over HRT confounding -- and other critics would have been justified to be outraged by failure to adjust for the healthier lifestyles of the users.

There's more bunk about the "European study," and embedded under "Too Much Vitamin A!!", "The Problem with Questionnaires," and "This Study Has Nothing to Do With Life Extension Members" (= "Move along; nothing to see here" = "Fnord!" = "Pay no attention to that man behind the curtain"), but I don't have all day ...

There's still compelling evidence though, that a relatively low-dose multivitamin/mineral supplement is beneficial. But you have to look close enough to see the important nuances and let neither the puffy LEF propaganda nor the recent anti-vitamin media hysteria blur your vision...

While interesting and non-crazy (and non-venal ...), I don't really find that terribly compelling evidence ... and while I don't have time for a microdissection of your analysis there, I will emphasize again that the "sick user" bias is really not present in (either the great majority, or all) epidemiological studies of supplement users vs. nonusers: again, the normal (universal?) pattern is the reverse.

References
1: Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR Jr. Dietary supplements and mortality rate in older women: the Iowa Women's Health Study. Arch Intern Med. 2011 Oct 10;171(18):1625-33. doi: 10.1001/archinternmed.2011.445. PubMed PMID: 21987192.

2: Dickinson A, Mackay D. Health habits and other characteristics of dietary supplement users: A review. Nutr J. 2014 Feb 6;13(1):14. [Epub ahead of print] PubMed PMID: 24499096.

3: Touvier M, Kesse E, Volatier JL, Clavel-Chapelon F, Boutron-Ruault MC. Dietary and cancer-related behaviors of vitamin/mineral dietary supplement users in a large cohort of French women. Eur J Nutr. 2006 Jun;45(4):205-14. Epub 2006 Jan 2. PubMed PMID: 16382374; PubMed Central PMCID: PMC1973945.

4: White E, Patterson RE, Kristal AR, Thornquist M, King I, Shattuck AL, Evans I, Satia-Abouta J, Littman AJ, Potter JD. VITamins And Lifestyle cohort study: study design and characteristics of supplement users. Am J Epidemiol. 2004 Jan 1;159(1):83-93. PubMed PMID: 14693663.

5: Ishihara J, Sobue T, Yamamoto S, Sasaki S, Tsugane S; JPHC Study Group. Demographics, lifestyles, health characteristics, and dietary intake among dietary supplement users in Japan. Int J Epidemiol. 2003 Aug;32(4):546-53. PubMed PMID: 12913027.

6: Kirk SF, Cade JE, Barrett JH, Conner M. Diet and lifestyle characteristics associated with dietary supplement use in women. Public Health Nutr. 1999 Mar;2(1):69-73. PubMed PMID: 10452734.

7: Lyle BJ, Mares-Perlman JA, Klein BE, Klein R, Greger JL. Supplement users differ from nonusers in demographic, lifestyle, dietary and health characteristics. J Nutr. 1998 Dec;128(12):2355-62. PubMed PMID: 9868181.

8: Patterson RE, Neuhouser ML, White E, Hunt JR, Kristal AR. Cancer-related behavior of vitamin supplement users. Cancer Epidemiol Biomarkers Prev. 1998 Jan;7(1):79-81. PubMed PMID: 9456246.

9: Houston DK, Johnson MA, Daniel TD, Poon LW. Health and dietary characteristics of supplement users in an elderly population. Int J Vitam Nutr Res. 1997;67(3):183-91. PubMed PMID: 9202979.

Edited by Michael, 18 February 2014 - 03:39 PM.

[timar]

All emphasis in original. First, note that this is complete speculation: they have no data to show that many women did this in this study, that many people do it in general, or that such people are, in fact, responsible for the excess mortality.

Well, although not referenced in that LEF article, there are at least the results of a high quality German cohort study (EPIC-Heidelberg) which strongly support that somewhat speculative argument:

PURPOSE: To prospectively evaluate the association of vitamin/mineral supplementation with cancer, cardiovascular, and all-cause mortality.
METHODS: In the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg), which was recruited in 1994-1998, 23,943 participants without pre-existing cancer and myocardial infarction/stroke at baseline were included in the analyses. Vitamin/mineral supplementation was assessed at baseline and during follow-up. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
RESULTS: After an average follow-up time of 11 years, 1,101 deaths were documented (cancer deaths = 513 and cardiovascular deaths = 264). After adjustment for potential confounders, neither any vitamin/mineral supplementation nor multivitamin supplementation at baseline was statistically significantly associated with cancer, cardiovascular, or all-cause mortality. However, baseline users of antioxidant vitamin supplements had a significantly reduced risk of cancer mortality (HR: 0.52; 95% CI: 0.28, 0.97) and all-cause mortality (HR: 0.58; 95% CI: 0.38, 0.88). In comparison with never users, baseline non-users who started taking vitamin/mineral supplements during follow-up had significantly increased risks of cancer mortality (HR: 1.74; 95% CI: 1.09, 2.77) and all-cause mortality (HR: 1.58; 95% CI: 1.17, 2.14).
CONCLUSIONS: Based on limited numbers of users and cases, this cohort study suggests that supplementation of antioxidant vitamins might possibly reduce cancer and all-cause mortality. The significantly increased risks of cancer and all-cause mortality among baseline non-users who started taking supplements during follow-up may suggest a "sick-user effect," which researchers should be cautious of in future observational studies.

It is also worth noting that other, much more impartially authorties (which are quite far from being a supplement-sales business) like the Harvard School of Public Health and the Linus Pauling Institute basically share the view brought forth by the LEF, at least with regard to basic multivitamin supplements. I can't find the citation right now, but I remember that Walter Willet himself once very explicitly criticized the Iowa Women’s Health Study findings for their alleged poor methodological quality and "sicker-user" bias.

I have the impression that you are on a one man crusade against the LEF, Michael. I'm not exactly an LEF fanboy, I am usually put off by the blatant sales show on their website and magazine and the often ridiculously exaggerated articles, with every second word bolded (you also have a tendency to do that ), and the wacko libertarian paranoia twist. However, sometimes I find valuable information burried in all the marketing fluff and some of their dogmatic positions actually to be a balancing counterpoint against oposing dogmatic positions held by official insitutions. I think they have their part in the great dialectic game...

Edited by timar, 18 February 2014 - 05:20 PM.

[Kevnzworld]

I agree that for people with a healthy lifestyle and diet a multivitamin isn't going to prevent or cure disease.
I know that targeted use of specific supplements can and do lower some risk factors for various disease. I know this because I've been testing my blood semi annually for ten years. I have and lived a fairly balanced and healthy life at baseline ten years ago.
I lowered my homocysteine from above 13 to about 7
I lowered my inflammation ( CRP ) from approx 1.4 to .4
My fasting glucose went from the mid 90's to the mid 80's. Post prandial from as high as 130 to now mid 90's
My HbA1C glycation level dropped from as high as 5.5 to the current 5.0
I normalized my hormone levels like DHEA and Testosterone
My lipid/ cholesterol numbers are much better , my blood pressure is lower.
My vitamin D status went from deficient to normal, though I live in the desert and walk daily.
My PSA has stayed .9-1.0. It had gotten to 1.2. I'm 57 yo
I believe that the science supports the supplementation of some minerals like Magnesium, and iodine.
I believe that the science supports a longevity benefit of the supplementation of polyphenols like GTE, curcumin and resveratrol.
I believe the risk/ benefit analysis supports the use of products like Metformin, PQQ, ubiquinol, fish oil etc.
I agree that LEF can and does make some exaggerated claims. I do think overall they offer useful information, it's up to the individual to sort through the science and make intelligent decisions based on their personal lifestyle, age and most importantly blood tests.
PS. I should also say the following. Unlike some of our friends here that believe that any supplementation is bunk, and only CR is effective, I think my personal experience refutes that. I also believe in quality of life. I could never employ strict CR, I enjoy food too much. I'm in Napa as I write this enjoying food and wine ( in moderation ) . And I don't want to weigh 115 lbs.......

Edited by Kevnzworld, 18 February 2014 - 05:42 PM.

[Dorian Grey]

Thank you for your analysis of the LEF rebuttal Michael... Some interesting points I hadn't considered.

So what would your advice be to a 20 something young man reading this who's living on "fast food, beer and cigarettes" and has no intention of changing his lifestyle for another decade or two?

Does heavy alcohol consumption burn through B Vitamins? Should these (B Vitamins) be supplemented in those who drink a six-pack every night after work?

Is fatty liver ever a problem for heavy drinkers? Is Vitamin E an "essential nutrient" that helps prevent lipid peroxidation in fatty livers? If this guy is getting getting almost no vitamin E from his diet, would supplementation not provide a desirable risk/reward ratio?

Does smoking not deplete Vitamin-C? Is Vitamin-C an optional nutrient, or will this guy's health suffer if dietary vitamin C is nearly non-existent and not supplemented.

Do you feel a little B-Complex, C & E would actually hurt this guy? Maybe cause him to die early?

Should he avoid foods fortified with added thiamine or other nutrients? The vitamins they fortify food with are not naturally occurring... Are these dangerous too?

Inquiring minds want to know!

Edited by synesthesia, 18 February 2014 - 09:44 PM.

[timar]

So what would your advice be to a 20 something young man reading this who's living on "fast food, beer and cigarettes" and has no intention of changing his lifestyle for another decade or two?

You asked Michael but here is my short answer: he should stop visting this forum and to maintain any ambitions regarding healthy aging or even life extension. There is simply no way to be serious about health and longevity for someone living on "fast food, beer and cigarettes". Period.

[Dorian Grey]

Abandon hope all ye who party their youth away? Jeanne Calment (oldest person who ever lived) smoked all her life... Churchill drank throughout the day every day most all his life (worked till 80, lived to 90). Don't suppose these two ate a lot of junk food though.

I lived on fast food, beer & cigarettes for over a quarter of a century myself... Managed to clean up my act about 10 years ago and am healthy as a horse today. I've always supplemented my atrocious diet with critical nutrients, and credit this with surviving my mis-spent youth relatively unscathed. I'll bet there are millions who have gone down similar paths in their lives, with many probably living this lifestyle today. Some will come through this phase without much damage, while others will emerge chronically ill.

I'm wise enough now to know better than to try and tell young adults how they should be living, at least in regards to diet and alcohol. I just hope they aren't scared off a few key supplements that would help support health in their long suffering little bodies until they reach maturity. I'm afraid the constant drumbeat of anti-supplement propaganda will do these guys far more harm than good.

Some essential nutrients truly are essential, and if you're not getting them through diet, the risk/reward ratio of supplementation becomes a no-brainer. I would hope those who know better wouldn't spread false wisdom on this matter if they can help it.

Edited by synesthesia, 18 February 2014 - 10:54 PM.

[albedo]

I try to be balanced on all this. Let's say, on one side I stand very much with kevnzworld, also based on my own experience, even if I am doing it not so damn well as he does; otos I cannot argue with Michael, his huge knowledge and the logic in analyzing scientific results and rebuttals. I feel both are right and we will never get to end the discussion. I feel we will need new approaches and maybe help of technology for a targeted supplementation to your personalized needs (genomic data, blood test, lifestyle etc.).

[Michael]

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) -- ...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 [this is wrong: see below -MR] and required less caregiver time [this part is true -MR] 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. ...

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 ...

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. ...

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

A promising study for people suffering with AD and their families. It strengthens the ambiguous results of a previous trial of megadose alpha-tocopherol in patients with AD,(5) whose primary results were null, but which found that alpha-T slowed the progression to the composite outcome of "death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia" in a secondary analysis adjusting for baseline score on the Mini-Mental State Examination (MMSE).

As briefly noted in parentheses in my quote of the pop press report, the pop press story is wrong that vitamin E slowed the rate of cognitive decline in this new study. In fact, there was no effect at all on MMSE, and "Alpha tocopherol vs placebo treatment differences before adjustment for multiple comparisons favored alpha tocopherol on both the [Alzheimer Disease Assessment Scale–Cognitive score] and the CAS, but these differenceswere not statistically significant after adjustment for multiple comparisons (Table 2)." See also the interview transcript below. The benefit was in functional decline alone — still, nothing to sniff at in a disease with no disease-modifying therapies. Megadose E also seems to have reduced mortality, which is again very good news.

But note that both of these trials (the new one and (5)) were in people with existing Alzheimer's disease — not (as one might misinterpret "Delay Alzheimer's" in the pop-press headline) to prevent or delay the onset of AD in healthy people, the latter of which is closer to the context we're discussing. In fact, multiple clinical trials of vitamin E in normally-aging people(1-3) or even in people with mild cognitive impairment(4) have found no benefit of vitamin E in slowing cognitive decline or delaying conversion to dementia.

Indeed, the lead author of the new study was clear in recommending that healthy people without dementia should not take pharmacologic vitamin E supplements (all italicized emphasis below mine):

Vitamin E and Alzheimer
[Investigator] Maurice Dysken: Vitamin E had been tested in Alzheimer's patients in 1997, showing that it delayed progression by about seven months over a two-year period in Alzheimer's patients with moderately severe dementia. Vitamin E had been tested also in patients with mild cognitive impairment. Vitamin E was not effective in slowing the rate of conversion from mild cognitive impairment to Alzheimer's disease.

[Radio Host] Norman Swan: And in fact there's quite a lot of evidence that taking vitamin E to preserve your brain function doesn't really work. So there's this paradox. It seems to work in moderate to severe Alzheimer's disease once you've got the problem, but it doesn't seem to preserve brain function when you are pretty much okay.

Maurice Dysken: I would agree with you. So our population was in between. The mild to moderate group had not been tested for vitamin E. [...] Caregivers were spending at the beginning of the trial about three hours a day taking care of patients, and we knew that during the trial that time would probably increase. The increase in that time was least in the vitamin E group.

Norman Swan: But it made no difference to their thinking and memory ability, so functional decline was reduced but not through their thinking and memory ability.

Maurice Dysken: You're absolutely right. [...] I'm happy to tell you that the mortality was the lowest in the vitamin E group. [...]

Norman Swan: So, bottom line, you're pretty confident that this changes practice, that if you've got mild to moderate Alzheimer's disease it's worth going on 2,000 units a day of the vitamin E in two split doses, obviously in collaboration with your physician, but if you've got normal function or you're just getting a bit forgetful, forget about the vitamin E, it's not worth it.

Maurice Dysken: We think that there is real benefit for patients in the mild to moderate group. I think as the disease progresses, if you get to a point where you are six months away from going into a hospice, many caregivers will say why prolong this at all? But for this population I think there is benefit, it's safe, and I should also mention it's very inexpensive. This is not a prevention trial that we did, and one of the cautions here is we don't want people who don't have this illness to go to the drug store and buy a lot of vitamin E in anticipation of preventing it. It's not recommended.

References
1: Cetin E, Top EC, Sahin G, Ozkaya YG, Aydin H, Toraman F. Effect of vitamin E supplementation with exercise on cognitive functions and total antioxidant capacity in older people. J Nutr Health Aging. 2010 Nov;14(9):763-9. PubMed PMID: 21085907.
2: Kang JH, Cook NR, Manson JE, Buring JE, Albert CM, Grodstein F. Vitamin E, vitamin C, beta carotene, and cognitive function among women with or at risk of cardiovascular disease: The Women's Antioxidant and Cardiovascular Study. Circulation. 2009 Jun 2;119(21):2772-80. doi: 10.1161/CIRCULATIONAHA.108.816900. Epub 2009 May 18. PubMed PMID: 19451353; PubMed Central PMCID: PMC2752297.
3: Kang JH, Cook N, Manson J, Buring JE, Grodstein F. A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med. 2006 Dec 11-25;166(22):2462-8. PubMed PMID: 17159011.
4: Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ; Alzheimer's Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005 Jun 9;352(23):2379-88. Epub 2005 Apr 13. PubMed PMID: 15829527.
5: Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997 Apr 24;336(17):1216-22. PubMed PMID: 9110909.

Edited by Michael, 30 March 2014 - 05:31 PM.

[Dorian Grey]

Great Find Michael... Thanks for this.

With well over 70 million baby-boomers in America (450 million world wide) headed into Alzheimer's Territory, we need to use every tool in the box if we are to head off the most expensive healthcare catastrophe (boomer end of life care) the world has ever known.

Generation X/Y/Z/Millennials may well be enslaved by the Medical Industrial Complex if swift progress is not made in treating geriatric maladies.

I'll still supplement E though, as it is the most common vitamin deficiency, and it is an essential nutrient. Though early studies on the prophylactic value for dementia may not look promising at this time, the evidence does not yet appear to be conclusive to me. Hard to believe if Vitamin-E is the "best medicine" for Alzheimer's, it would be contraindicated as a prophylaxis.

How 'bout B-Complex as a good prophylaxis against age related dementia?
http://www.reuters.c...E6875CL20100908
B vitamins found to halve brain shrinkage in old

(Reuters) - "Daily tablets of large doses of B vitamins can halve the rate of brain shrinkage in elderly people with memory problems and may slow their progression toward dementia"

Perhaps combining B-Complex and E might be the one-two punch we're looking for that will save the world from boomergeddon?

Edited by synesthesia, 30 March 2014 - 06:15 PM.

[Castiel]

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.

Interesting, but glycine supplementation did increase lifespan in mice by 30%.   OR was it flawed or were the methionine restriction studies flawed?

As for supplements resveratrol did improve some parameters in healthy humans in  double blind trial

Resveratrol Decreases Inflammation
Study evaluates the effects of resveratrol supplementation on inflammatory cytokines in professional male basketball players
Using a randomized, double-blind, placebo-controlled clinical trial, this study examined the effects of trans-resveratrol on the plasma levels of tumor necrosis factor-α and interleukin 6 in male professional basketball players.
However, at the end of the 6-week intervention, the men in the resveratrol group had a significant decrease in tumor necrosis factor-α and interleukin 6 compared to the placebo control group.-link

It also increased physical performance in a step test significantly above placebo also in a double blind human trial iirc.

It also triples human cell survival to gamma radiation, and activates many of the genes of calorie restriction(though not all.)

LEF now has a formula with like 5 different substances that partially mimic CR gene activation patterns.   I'm not sure but if the substances complement their differences in partial activation well enough and do a complete or near complete mimic as a whole.  If they do complement well they could extend lifespan.    But that would depend on how thorough the induced activity changes are.

 

you are probably hammering a particular metabolic pathway with orders of magnitude more dose than needed to be healthy. A good chance you are destroying that particular metabolic process.

Calorie Restriction extends life all the way up to 65%, iirc.  And no further because of death via starvation.   For all we know targetting the upper regulatory molecules of it could push the pathway further and produce even more radical extension.

In c elegans I think combinations of two interventions with modest life extension together produced exponential increase in lifespan, due to synergy.   So while there may be detriments to combinations there are also possible potential benefits if targetting differing pathways.