Lose(!) 33% Body Fat in 10 Days!? The Heavy Metal Obesity Link: Study Shows "Preventive Role" for Inorganic Cobalt in Obesity-Related Diseases.

Image 1: Cobalt - certainly not what you would expect to see at a health food store or pharmacy; with Kawakami et al.'s study this may change in the future (img Alchemist-hp)

"We are living in a toxic world!" - you have probably heard or read this sentence more than once and while I cannot deny that the environmental load of, among others, heavy metals appears to be increasing, I can however tell you that, according to a recent study from scientists from the Tukushima Bunri University in Japan, exposure to some of those heavy metals produces quite unexpected results in a rodent model of the metabolic syndrome and in lean controls. Instead of making them gain weight even more rapidly, the "toxic" (maybe we will have to reconsider that, just as we did in the case of chromium) heavy metal cobalt did not only reduce the weight of the white adipose tissue of the rodents, it increased leptin, adiponectin, and HDL-cholesterol, as well, and thusly "may have a preventive role in obesity-related diseases" (Kawakami. 2011)

This is certainly the 1001st time I am writing this, but I cannot emphasize often enough that the "high fat diet" researchers use in their studies has (in most cases) nothing to do with the Atkins or even a low-carb diet. Its main characteristic is that it is hypercaloric and high in fat and carbs. Please keep that in mind whenever you read about another study on the detrimental health effects of "high fat diets".

For 24days Kawakami et al. fed a group of seven-weeks-old male mice either a standard diet with 357.6kcal/100g or a hypercaloric (cf. red box above) high fat diet (HFD), where the latter induced obesity and dislepidemia within 2 weeks. After this initial phase, i.e. when the HFD mice were already obese and metabolically deranged, the scientists injected the animals with Sodium Arsenite (NaAsO2: 1.0 mg/kg bw), Mercuric Chloride (HgCl2: 1.0 mg/kg bw), Manganese Chloride (MnCl2: 5.0 mg/kg bw), Cobalt Chloride (CoCl2: 0, 1.3, 5.0, 7.5 mg/kg bw) or saline (control).

Figure 1: Modulatory effects of 10 days of heavy metal injection in mice on a high fat diet; values expressed as changes relative to animals on a normal diet (data calculated based on Kawakami. 2011)

Now, if you look at the data in figure 1, you will notice that the administration of Mercuric Chloride may have been most "effective" in ameliorating the HFD-induced increase in white adipose tissue (WAT) mass (HFD +70%; HgCl2 -14% vs. normal fed control), but those "fat burning" effects went hand in hand with profound elevations of the liver enzymes AST, ALT (in this case we can safely assume that these were not coming from the muscle tissue of the animals) and the blood urea nitrogen (BUN) levels, which indicate deteriorations of the kidney metabolism. Manganese and cobalt, on the other hand, had negligible or even beneficial effects (compared to HFD alone) on liver and kidney health and ameliorated the weight gain to +10% and +17%, respectively.

Figure 2: Adiponectin and leptin serum levels and mRNA expression in mice after 10 days on a high fat diet with simulatenous injection of mercury or cobalt; data expressed relative to normal fed control (calculated based on Kawakami. 2011)

What is particularly interesting about cobalt, though, is that it did not simply starve out the adipose tissue by poisoning it (like that was probably the case for mercury), but triggered exactly those metabolic adaptations scientists have been trying to provoke with drugs for years now: elevations in adiponectin and leptin (cf. figure 2), the two adipokines, researchers currently believe to be essential for successful weight loss / maintenance.

Figure 3: pAMPK/AMPK ratio after injection of different dosages of Cobalt chloride (calculated based on Kawakami. 2011)

In a follow up experiment, the scientists, also found that cobalt dose-dependently increases AMPK phosphorylation (for more on AMPK, I would like to refer you to the Intermittent Thoughts series) in white adipose tissue (WAT), muscle and liver of the animals (cf. figure 3). Of the three tested dosages, administration of 5mg/kg CoCl2 per day resulted in the most beneficial AMPK response, while with the maximal dose of 7.5mg/kg the negative / toxic effects appear to prevail (another of these bell-shaped dose-response curves, I guess).

Figure 4: Glucose tolerance test in mice on high fat diet with or without cobalt injections compared to mice on standard diet (control); values in mg/dl (data adapted from Kawakami. 2011)

Now, you are probably asking yourselves: "So what's the catch?". A brief look at figure 4 tells you that is ain't glucose intolerance, as the cobalt treated animals had the exact same response to the glucose tolerance test, as the mice on the normal diet - in other words: cobalt completely reversed the HFD induced glucose intolerance, and it did so not only without negative effects on blood lipids, but in the presence of a profound elevation of HDL levels and a reduction in LDL levels (cf. figure 5).

Figure 5: Relative (to normal fed control) changes in blood lipid in mice on a high fat diet with or without heavy metal injections (calculated based on Kawakami. 2011)

And as if that was not enough, the cobalt injections also eradicated the iincreases in free fatty acids and ameliorated the increase in triglycerides.

From the lab to the bedside?

Last but not least, and I hardly dare showing you this graph, because I would expect that some of you will already be googling a source of injectable cobalt (which would be plain out stupid, before any reliable safety data and confirmation of these results in controlled human trials are available), cobalt had almost identical effects when it was injected to the mice on the normal diet.

Figure 6: Relative changes in body composition and liver and kidney parameters due to heavy metal injection in non-obese mice on a standard diet (calculated based on Kawakami. 2011)

As figure 6 goes to show the mice lost 33% of their white adipose tissue and liver, as well as kidney function did not take a beating (HDL stayed the same, LDL decreased by -1%). Whether we will see a obesity or even just a weight-loss drug based on cobalt in the near future, does yet still seem questionable. In view of the fact that the number of "bad things" (cobalt is in fact an essential nutrient as it is the active center of vitamin B12 = cobal-amin) that have unexpectedly positive health effects is increasing day by day, we do yet obviously have to ask ourselves, whether there may be some major flaws in our current understanding of how our body works and how it deals and is effected by "toxins", oxidants and co.

Ask Dr. Andro: Are Vitamin Supplements Bad For Me (2/2)? 3+1 = 666! The Raw Data Truth about the "Vitamins Kill!" Offspring of the Iowa Women's Health Study

Image 1: "Please Dr. Andro tell me I can keep taking my essential multivitamin! I am just too busy to eat healthy..."

I must admit that I feel kind of awkward as I am about to defend one of those supplements, I consider to be the most dispensable within the dietary regimen of a physical culturist: the so-called multi-vitamin! In essence these small, and lately more often than not large pills do not even fall into the category supplement. With dose-equivalents way beyond what you would actually need, "multivitamins" are not even "replacements", they are madness or, I should say, the mad outgrowth of the prevalent "more is more" mentality that is beginning to harm us on every level of our society... but I am digressing, here. Let's take a look at the actual study which brought about such an upheaval in the supplement-addicted health community on the Internet.

Dietary Supplements and Mortality Rate in Older Women

Image 2: Is this you? No? Maybe she is "The Average American", then? No? Well, but the study says "vitamins are bad for YOU" and she could be one of the subjects (img. medscape.org)

The title alone, actually made me click the study away, back in the day when I first hit upon it, on one of my regular searches for new stories on the medical databases of the World-Wide-Web; and unless you are an old women (I would hope there were some older women reading the SuppVersity, but I guess there are none), you should have disregarded the study, as well. After all, we all know how the game changes after menopause and guess what, of those women, 98.6% were post-menopausal (in case you ever see studies done on ovariectomized rodents, remember that those are "menopausal", too ;-). Ah, and in case you are a post menopausal women with Africa-American or Hispanic background, there is likewise little reason for you to read on, because 99.2% of the women in the study were white (if you question whether or not ethnicity really matters, when it comes to the health effects of vitamins, I suggest you take a look at some reviews like Carmel. 1999).

Now, if you are still with me at this point, I guess that you either are a post-menopausal white woman, or - and I suppose that this will be the case for the majority of you - you have been agitated by the heated debate on the net (and even regular mass-media) in the last couple of days and want someone to tell you that you did not reduce your life-expectancy by -15% by religiously taking your "essential" *rofl* multi-vitamin, everyday. We will see, whether I can be this person (in case it turns out I am not, I have seen more than enough "gurus" you will tell you exactly that, if you promise to buy their "all natural" or "superior source" product in the future).

The Iowa Women's Health Study - Mrs "not so average" American

So, let's see. What we have here is an offshoot of the Iowa Women's Health Study (IWHS), which is one of those highly over-estimate surveys, the media loves, because they boast of ten-thousands of "participants". In the case of the IWHS, "41836 women aged 55 to 69 years"... well, at least that were the women the scientists send their little questionnaires to back in 1986. Interestingly, this is also where the first bias (i.e. a deviation from "objectivity") came into play:

Respondents were slightly younger, had lower body mass index (calculated as weight in kilograms divided by height in meters squared), and were more likely to live in rural areas compared with nonrespondents.

So instead of the average American "older woman", the scientists suddenly had the "slightly younger" not just as obese, better off American older women, as their study object. Moreover, the number of participants dropped to 38772 women or, in other words, the scientists "lost" 7.3% of their study population even before the study actually began. Now, of those, the Mursu et al. selected 29230, who were the "elite" which responded to both the initial 1986 and the 2nd 1997 follow-up questionnaire.

Failure 1: Not representative of "The Average American"

"Ladies, give me as little information about your supplements as possible, please!"

The latter, i.e. the questionnaire, assessed the use of 13 supplements:

• multi-vitamins; 
• vitamins A, beta-carotene, B6, folic acid, B complex, C, D, and E; 
• iron, calcium, copper, magnesium, selenium, and zinc

Now, the scientists show off their wealth of knowledge and state that "[d]ifferent forms of vitamin D, cholecalcif-erol (D3) or ergocalciferol (D2), were not distinguished". While this is obviously important, it would have been even more important to distinguish between different forms of vitamin B6 (pyridoxin vs. P5P), B complex (you can have a complete one, one with equal doses, one particularly high in one B vitamin, etc.), vitamin E (I suppose you read the first installment?), iron (heme, non-heme, chelated, etc.), copper / magnesium, selenium, and zinc (oxide, chelated, etc.), because we know that these different forms of vitamins and minerals are not only differentially absorbed, but also exhibit differential effects on our health and well-being.

Failure 2: Ignorance towards the fact that
not all vitamins / minerals with the same label are created equal

And as if this had not been enough, the scientists did not even care if the ladies popped 1 or 23 of their beta carotene (I hope you do not still believe you can take endless amounts of that orange poison), magnesium, folic acid and B-complex pills.

Failure 3: Careless ignorance towards dosages

Raw foods are dangerous and so is raw data

Hence, the scientists got a set of data that was full of holes from a group of women who are by no means representative of "The Average American" (let alone every human being) - what did they do next? Well, obviously "raw data" is as dangerous as raw meat (or even raw milk), that is why the next step for every good scientists is data processing. In that Mursu et al. were particularly skilful as far as not revealing what they actually did was concerned:

In the minimally adjusted model, we adjusted the association for age and energy intake; 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. For multivariable adjusted model, version 2, we added intake of alcohol, saturated fatty acids, whole grain products, fruits, and vegetables.

Even, or I should say, especially for a physicist, who is a 75% mathematician, the idea that by some sort of mathematical magic you could reliable subtract out all those influence, so that you get the "real picture" of what is going on, with an average human being is so hilarious that I avoid any further comment. Everything that goes beyond the "minimal adjustment" is so full of speculative hypothesis and mainstream paradigms (like "Whole grains are good for you! The more, the better!") that I will simply ignore this data... unfortunately these results of "3+3 = 666" mathematical manipulation were what the scientists (in their press releases) highlighted as their main results and what was accordingly taken up by the laymen (initially I wanted to write idiots, but that would be unfair, because laymen they are) in the editorial offices of the mass media.

Failure 4: Over-"analysis" of the data

Let's get to the raw truth

This would not be the SuppVersity, if I did not have something to offer that goes beyond the angry rants and criticism (see above) you probably have read elsewhere, anyways. So, I went through the pains of compiling and comparing the "real", i.e. the N=X data and not the calculated hazard ratios for you.

Figure 1: Raw data and minimally adjusted (age and caloric intake) data on the effect of taking vitamin A, beta carotene, vitamin C, vitamin D, vitamin E, and finally the multivitamins on overall mortality (data calculated based on Mursu. 2011)

Now, I want you to take a close look at the data for vitamin A, beta carotene, vitamin C, vitamin D, vitamin E, and finally the multivitamins. I don't know what you see, but I see only vitamin A and beta carotene scratching at the increased mortality margin of 1.0 (cf. dotted red line in figure 1). And, just for a better understand, two examples:

• the 1.04 as for vitamin A (minimally adjusted) in 2004-08 indicates a +4% higher risk and 0.80,
• the 0.80 for vitamin E (raw data) in 2004-08 indicates a -20% decrease in mortality risk

So, what would you say, how "dangerous" is taking vitamin pills if you do not process the data to death? Interestingly, things get really nasty, from here. And moreover, they get nasty, where you probably would not have expected it unless you are a very diligent student of the SuppVersity and are thus aware that messing with the methylation cycle via B6 or folic acid supplementation for no reason is not a good idea.

Figure 2: Raw data and minimally adjusted (age and caloric intake) data on the effect of taking vitamin B6, folic acid, B-complex, calcium, and magnesium on overall mortality (data calculated based on Mursu. 2011)

Given the fact that an increasing amount of "old" people are taking magnesium supplementation, I would say that in this case the age-adjustment is probably necessary - if you also consider that back in the 1980s this bias was smaller, since people were not told that taking mg supplements would be necessary for older folks, the respective adjustment will be "too small" and thus I would simply ignore the fact that the 1996 value still signifies a +2% greater risk of dying when you take a magnesium supplement (add to that that the study participants could have taken magnesium in the 10x recommended dosage and the scientists would not know that /see comment on dosage, above). What really surprises me, though is the enormous benefit that is (even in the raw data) associated with calcium supplements - 22% reduced risk according to raw data and 21% reduced risk with age/energy adjustment - impressive!

Figure 2: Raw data and minimally adjusted (age and caloric intake) data on the effect of taking iron, copper, zinc, and selenium on overall mortality (data calculated based on Mursu. 2011)

Last but not least - the worst offenders, the dreaded "heavy metals" ;-) Ok, I guess iron really is a bad guy (at least for post-menopausal women), but even copper, which has gotten such a bad rep, lately turns out to come pretty handy in the female part of the aging American population, ... interestingly only in the early to late 2000s - how come? I'll leave it up to you to make up your mind on this and other questions, but I assume that now, that you know the raw truth, you will not blindly follow Bjelakovic's campaign to "wake up [regulatory authorities] to their responsibility to allow only safe products on the market" (Bjelakovic. 2011), but rather scrutinize his "invited comment" to the Mursu study, which was published in the same issue of the Archives of Internal Medicine and has caused such an upheaval among the increasingly health conscious American and International public.

Adelfo Cerame - Road to The Wheelchair Nationals '12: Leaner, Tighter, Stronger - And All That Despite a Novel Sugary Twist to the Uber-Technician's Diet.

Image 1: Just in case you didn't listen to Adelfo on SHR, last week - he is still single, ladies!

Another week, another Thursday; and although I suppose that more of you have been waiting for Adelfo's update than for my humble thoughts on the latest anti-multivitamin campaign... ah, I mean respectable research on multivitamins ;-), I just wanted to let you know that I am at it. Expect the second installment of the follow-up on "Ask Dr. Andro: Are Supplements Bad For Me (1/2)" either tomorrow or on Saturday... fortunately, future pro-wheelchair bodybuilders like Adelfo Cerame appear to be more reliable than muddle-headed pro-physicists, who spent most of their free-time either in the gym or blogging away on exercise and nutrition science. So, "now, without further delay, let's get to" (I bet some of you will recognize this slogan ;-) Adelfo's third week of what I believe is going to be his last contest prep as an amateur *thumbs up!*

Adelfo Cerame Jr., the uber-technician

Week 3 almost in the books and... I’m feeling great! I’m really having fun with my EDT (escalating density training) routines and tweaking it in to my own. Through trial and error, last week, I was able to pick and eliminate what EDT combinations worked and didn’t work for me. I narrowed it down to 5 exercises that work really well considering my mobility, where I can quickly move from one exercise to another during my EDT block. With some help of my friend Dr. Andro I have compiled a graphical overview for you, always pairing one chest and one back or one biceps and one triceps exercise.

Illustration 1: Adelfo's favorite antagonistic supersets for his current EDT routine.

These are the 5 EDT antagonistic (push/pull) combinations that work real well for me, where I can quickly move from one exercise to another. I will try to get some video for next week (don't forget to come back ;-) with me doing one of my favorite EDT blocks.

Image 2: Adelfo's abs during a previous contest prep. Difficult to outdo, but he will do it ;-)

After the famine and with this escalation in training density, I am getting harder and stronger!

The videos probably won't be able to show that, but after the famine, I cribbed from Rob Regish's Blueprint and with the switch to this (for me) novel training style, I have also noticed that my body has gotten a lot harder, my skin feels tighter, and I feel a lot leaner... while this obviously is somewhat subjective, there is not doubt: I’m definitely getting STRONGER! Moreover, my waist is already at 31" and it looks like it can get down to 30" by next week… pure imagination? I wouldn't think so. I’ll try to take some quality photos of how my physique is looking for next weeks segment - promise!

My diet: A permanent construction site...

As for my diet… I have made some minor adjustments to keep things simple! When it comes to prep and my diet, I get really paranoid and over analyze everything from my nutrition to training. I don’t know why I get like this, but I always do every time I prep. The only way out of this misery is to keep things as simple as possible, so I decided to return to protein and fat (P+F), only, as the basis of the majority of my meals. The only meals that is going to have a "high" carbohydrate content (and low fat) will be my PWO shake and PWO meal. Knowing my own body best, I figured it would be wise to let it run on what it runs best, i.e. fats and give him those damn carbs it needs not to shut down and keep the performance up in the very window, where they will get stored, right where they belong, inside my muscle.

This also implies that I will stop doing my usual Sunday re-feeds for a while, because I feel that I get plenty of carbs post workout after this tweeks, so that - given my current caloric intake - I do not see any need for further refeeds (especially not carby ones). Up to know, this has worked out pretty well, I haven’t been feeling flat, my energy is up throughout the week, my metabolism seems to be up... moreover, I haven’t been feeling deprived of anything, so psychologically I’m fine, as well. The formula is easy:

no flat muscle + no lack of energy +  no metabolic shutdown + no cravings = no re-feeds

I am yet aware, that, eventually, somewhere down the road, I will start to incorporate re-feeds again. Probably every 2-3 weeks, at the latest, when I drop the carbs even in the post workout phase and switch to a strictly "ketogenic" diet.

Image 3: An image for those of you who forgot what table sugar looks like; and Alan Aragon's wisdom for those of you who still believe that only dextrose, or even waxy maize or Vitargo are tolerable PWO sugars.

A pros pos carbs, in case you are wondering what carbs we are talking about... we are talking about "white poison" - plain table sugar! I have been adding 5 tsp. of it to my post-workout shakes (and as you can see, I survived ;-) Originally, I wanted to use dextrose, but I really did not fell like forking over $6 for a pound of sugar. I’d rather spend that $6 on half a gallon of raw milk! [Comment Dr. Andro: A wise decision, but since I do not want to adorn myself with borrowed plumes, I just refer you to Alan Aragon's December 2008 Research Letter, where, in his article "An objective comparison of chocolate milk and Surge Recovery", he beautifully dissects, the dextrose (and other) myth(s).

So, what have I left to tell you? Ah, yes. As of lately I have come up with a new "all natural" growth promoting sleeping aid, it's a dessert I suppose the chefs among you will be interested in.

My pineapple chocolate cheesecake

Image 4: Healthy, all natural pre-bed nutrition - Adelfo Cerame's original Pineapple Chocolate Cheesecake (TM)

Ingredients:
• ½ c. cottage cheese
• 24g vanilla whey
• 1 tbs. heavy whipping cream
• ¼ c. of fresh chopped pineapples
• 1 tbs. of Walden Farms Calorie free chocolate syrup
• 1 tbs. coconut oil
  
  Macronutrient breakdown:
• 37g protein
• 10g carbs 
• 25g fat

How to do it:  Mix cottage cheese, vanilla whey and heavy whipping cream (you can blend it as well, if you prefer that). Pour Walden Farms Calorie free chocolate syrup over what you just mixed. Add the fresh pineapples on top, then pour 1 tbs. of melted coconut oil over your fresh pineapples and wait for the coconut oil to harden over the cold fresh pineapples (about 20 sec.) - You can wash this down with a cold glass of raw milk (which I do), and enjoy your anabolic sleep!

...hmm, what are you waiting for? I said "anabolic sleep!" ;-)

CoQ10 for Ultra-Endurance Athletes: 150mg of Ubiquinone Reduce Stress & Inflammation and Stabilize Cell Membranes in 52.4 Mile Torture from 640m to 3,393m!

Image 1: Susan Kokesh, blogger and the Crazy Running Mum at the Sierra Nevada ultra-endurance run a 52.4 miles "double marathon"
  in September 2010; I probably would not even have survived this torture - respect!

As a health conscious physcial culturist, you are probably aware that the vitaminesque nutrient CoQ10, which, due to its ubiquitous presence in all living beings, is also known as ubiqinone, plays a fundamental role in cellular bioenergetics. It is a necessary cofactor in the mitochondrial electron transport chain (i.e. your cell's way of "breathing", its respiratory chain) and is therefore essential for the production of ATP, the fundamental energy unit your cells are operating on. In that, CoQ10 works as a mobile redox agent that shuttles electrons and, interestingly, also protons (those little blue and red balls from Bohr's atom model ;-) in the electron transport chain. Within the health and fitness community, it is however better known for its antioxidant value, as in its reduced form, ubiquinol, it is a potent lipophilic (which means that it does not combine with fats) antioxidant, which is able to recycle and regenerate other antioxidants, such as vitamin E and vitamin C (Ernster. 1995). Moreover, CoQ10 participates in cell signaling and gene expression and has been used as a dietary supplement (among others) for the treatment of neurodegenerative diseases and statin-induced myopathies.

In view of its pluripotent influence on mammalian metabolism (on a side note: the "-10" in CoQ10 indicates the length of the isoprenoid sidechain that is attached to the common benzoquinone ring structure; the latter is unique and can be found in humans and a few other mammals only), it should thus not surprise you that Chavier Díaz-Castro and his collegues from the University of Granada report that the intake of 150mg of the natural version of CoQ10 (2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone; natural = has trans configuration), profoundly modulated "the undesirable effects of the evoked oxidative stress and inflammation signaling during high-intensity" (Díaz-Castro. 2011).

Illustration 1: Supplementational protocol used in the study; CoQ10 was administered as 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone in powder form in 30mg capsules.

As you can see in illustration 1, the 20 highly trained male amateur athletes (all had run The Sierra Nevada ultra-endurance race in the previous 2 years), who participated in the study were not given the whole dose of 150mg of CoQ10 at once, but followed what I would like to call a "loading protocol" in the two days before the event. The placebo group received an identically looking product containing beer yeast, cellulose,
acacia, silica stearic acid, magnesium stearate, cellulose gum, and maltodextrin.

The total distance of The Sierra Nevada run is >50km. It is considered one of the hardest trials worldwide, mainly because the run, in the course of which the participants "climb" from 640m to a final altitude of  3,393m is almost on a continuous incline! A 5.5 hour torture, for which the CoQ10 supplemented athletes needed on average ~25min less than the subjects in the placebo group. In this study, the exercise performance was yet of negligible importance. What the scientists were really interested were the markers of oxidative damage and inflammation and as the following data shows, those were markedly influenced by the ingestion of this rather "mediocre" (compared to what you see some "health-gurus" advocate) amount of CoQ10.

Figure 1: Effects of CoQ10 supplementation of total bilirubin, triglycerides and urinary creatinine in 20 ultra-endurance runners (data calculated based on Díaz-Castro. 2011)

As you can see in figure 1, CoQ10 induced a significant reduction in urinary creatinine even before the race started (figure 1, left column). Moreover, there were significant differences in the bilirubin (indicates heme catabolism), triglycerides and (again) creatinine (indicates net protein catabolism):

Intense physical exercise resulted in an increase in net protein catabolism and an increase in
creatinine excretion in the PG after the physical test (p < 0.001); however, the urinary levels of creatinine were lower (p < 0.05 before and p < 0.001 after the physical test) in the CoQ10 treated group. Other interesting result was that although there was an increase in urinary creatinine in the CG, it was lower than in PG (38.77 ± 10.20 vs. 88.23 ± 11.21, p < 0.05). We also observed a decrease in the bilirubin concentrations in the CG after the run (p < 0.001) with lower values compared to PG group.

There were also significant differences in the inflammatory response, with (statistically significant, p<0.05) lower values of interleukin 6 (IL-6; -32%) and TNF-alpha (-23%) before the start of the race, and -22% lower TNF-alpha values after the "torture". Moreover, the basal hydroper-oxide content in the erythrocyte membranes, the scientists measured as an indicator of the degree of oxidative stress were lower before and after the exercise test, as the scientists call it.

Taken together, these results suggest that the addition of a small dose of CoQ10 to your supplemental regimen could induce unexpectedly profound cell-stabilizing benefits, of which it would yet be interesting to see how those translate into performance benefits, health and longevity, in the long run.

Cordyceps Sinensis - Another Supplemental Non-Starter: Human Data Shows No Increase in Testosterone, No Strength Gains, No Improvements in Body Composition.

Image 1: As it turns out it's not necessary you start eating parasites (img nepaliproducts.com)

In view of the public attention adaptogens have gotten, ever since everyone is self-diagnosing him- / herself with "Central Fatigue Syndrom", I assume you will be aware that the parasitic fungus, Cordyceps sinensis (CS) that is found on larvae of Lepidoptera, and has been used for centuries in traditional Chines medicine as a tonic, has lately been marketed as powerful modulator of the hypothalamus-thyroid-pituitary axis (HTPA). Extracts from cordyceps have in fact been shown to have various biological and pharmacological actions on the liver, the kideys, the endocrine and the vascular system. It appears to stimulate erythropeoiesis (production of red blood cells) and haemopoiesis (formation of blood cellular compounds), and it exhibits immunomodulatory and anti-tumor activities.

Within the health and fitness community Cordyceps sinensis has yet been touted as "natural HCG" (human chorionic gonadotropin), because, just like the latter, it stimulates the release of luteinizing hormone and thus testosterone secretion in rodent models (mice and rat; cf. Huang. 2001; HSU. 2003; Huang. 2004). Not long ago, scientists have identified cordycepin as the active ingredient in the parasite extract - an ingredient, which, according to Pan et al., does not only stimulate steriodogenesis, but also exhibits anti-cancer effects by inducing apoptosis in MA-10 mouse Leydig tumor cells (Pan. 2011).

Illustration 1: Training protocol the subjects in the study performed  3x à week for a total of 8 weeks.

With its endocrine and haematopoietic effects, cordyceps looks like the perfect substitute for what you may call the "Tour de France performance package", i.e. the combination of testosterone (e.g. Landis) and erythropoietin (e.g. Riis). Consequently, one should expect that an 8-week (3 training sessions per week)randomized double-blind place-controlled study with sixteen previously not resistance-trained young volunteers (male, age: 19-25; BMI: 24kg/m²; body fat: 14.65%), like the one performed by Hsu et al. at the Graduate Institute of Sports Science at the National Taiwan Sports University, should show at least some measurable effects on strength and muscle gains and/or body composition of the subjects.

Figure 1: Muscle strength as maesured by 1RM after 8 weeks of strength training with (CS) and without (PL) Cordyceps sinensis supplementation (data based on Hsu. 2011).

Figure 1, however, shows no greater strength improvements in the Cordyceps sinensis (6 caps à 400mg of an extract containing 0.33% soluble protein, 5.81% sugars, 5.92µmol/g adenosine derivatives (5.92 µmol/g), 1.23µmol/g cordycepin and 8.81 µmol/g ergosterol) supplemented strength trainees (CS) compared to the subjects in the placebo group (PL). And even the +7% greater increase in 1RM strength on seated rows does not reach statistical significance.

Figure 2: Changes in body composition after 8 weeks of strength training with (CS) and without (PL) Cordyceps sinensis supplementation (data based on Hsu. 2011).

Similarly, the cordyceps supplement had no measurable beneficial effects on the accrual of lean or the loss of fat mass in the course of the 8-week strength training protocol (cf. figure 2). Although statistically non-significant, the subjects who received the CS supplement did in fact lose some lean mass and gain some fat mass... certainly not what you would have expected from the purchase of a "testosterone boosting adaptogen"!?

Figure 3: Testosterone levels after 8 weeks of strength training with (CS) and without (PL) Cordyceps sinensis supplementation (data based on Hsu. 2011).

A pros pos "testosterone boosting", as the data in figure 3 clearly shows, there was a "boost", but the latter was identical between groups and - as the body composition data in figure 2 shows - the placebo group, whose baseline testosterone levels were 7% lower than those of the subjects in the CS group, took greater advantage from this probably exercise-induced and in view of the diurnal fluctuations of serum testosterone statistically non-significant increase.

Figure 4: Changes in serum levels of BUN, Creatinine, ALT and AST after 8 weeks of strength training with (CS) and without (PL) Cordyceps sinensis supplementation (data based on Hsu. 2011).

It would be unfair though to say that the ingestion of 2.4g of Cordyceps sinensis was totally pointless. After all there was a non-negligable decrease in the purported "liver values" ALT and AST. Now, as a diligent reader of the SuppVersity you are among the few chosen ones who outsmart 99% of the general practitioners and know that the enzymes ALanine Transaminase (ALT) and ASpartate Transaminase (AST) are by no means "liver values", i.e. liver-specific. In fact, their elevation in hard training athletes is completely normal and an indicator of muscular, not hepatic, damage, as both, ALT and ALT, are expressed in skeletal muscle, as well (Petterrson. 2007). This does not change that - once again - beneficial effects that have repeatedly been observed in rodent studies did not translate to humans, but it could explain why Quinc, senior member on the Mind and Muscle Forum and a true believer in the potency of cordyceps maintains:

I can't say I have noticed any 1RM gains, but I have noticed a quicker recovery time between sets and more endurance. (Quinc. 2011)

In view of the beneficial effects on the amino acid transferase enzymes, it may well be that the scientists just measured the wrong parameters. If their subjects had participated in the Tour de France, it could well be that the CS group had survived a few kilometers more, before they had had to be picked up by one of the team vehicles ;-)

Inflammation Is a True Fat Burner: BSO-Induced Glutathione Depletion Wards off Fat Gains on Hypercaloric Diet

Image 1: This little bugger obviously has too little inflammation going on ;-)

Are you "on fire"? Inflammation has been implicated as the root cause of almost all modern disease: obesity, diabetes, heart disease, cancer, you name it. Soothing the flames via natural and supplemental anti-oxidants has thusly been proposed and marketed as a solution for many of the aforementioned health problems.

Yet, despite tons of vitamins, anti-oxidants and all the other "healthy" stuff we are taking and consuming on a daily basis, the number of morbidly obese people, diabetics and heart attack patients appears to be ever-increasing... how can that be?

A possible answer to that question comes from scientists from the Saha Cardiovascular Research Center at the University of Kentucky College of Medicine in Lexington, Kentucky, US (Findeisen. 2011) - we simply got everything wrong! The observation that insulin resistance and beta-cell dysfunction usually occur in the presence of large amounts so-called reactive oxygen specimen (ROS) lead scientists to propose that there was a causative relationship between these two events, of which the data only shows that they are corollary.

Image 2: Whenever there is a fire, the firefighters are not far away, but does this correlation indicate that all firefighters are firebugs? (img texarkanagazette.com)

Despite the fact that the distinction between correlation and causation should be obvious, correlations have a long history of being mistaken as causative factors in the history of science. The corollary elevation of total cholesterol in heart disease patients, for example, is the reason that millions of well-educated people world-wide still believe that cholesterol would cause heart disease - an erroneous conclusion for which my friend, Carl Lenore, has coined a very fitting analogy (actually the analogy spans all those "corollary causation"): When there is a fire in down-town New York, it won't take long until the place is packed with firefighters, nevertheless, no sane observer would get the idea that the corollary appearance of firefighters on the scene would be the reason for the fire.

Here, at the SuppVersity, you have already learned that a group of researchers from Germany has invested a lot of work into research on the beneficial effects of inflammation (Ristow. 2010). Now, with the data from Hannes M. Findeisen (who unquestionably is a German or has German ancestors, as well ;-) et al., evidence begins to accumulate that the role of reactive oxygen specimen in glucose homeostasis could in fact be a beneficial and not a detrimental one. After all, Findeisen and his colleagues were able to show that the pharmacological depletion of glutathion, our natural broadband fire-extinguisher, made mice resistant to diet-induced obesity, increased energy expenditure and enhanced insulin sensitivity.

If you have listened to all the installments of the Amino Acids for Super Humans Series on Carl Lenore's Super Human Radio, you will already have heard me mention that a methionine/cysteine-free diet has been shown years ago to have profound fat-burning, or I should say, weight-reducing effects on mice - no wonder, with methionine and cysteine being essential substrates for mammalian gluthation production, a lack of these dietary sulfur-amino acids induced a similar glutathion depletion as the addition of 30mmol/l BSO to the drinking water of the mice in the Findeisen study (for more on the glutathion depleting effects of BSO, cf. Skapek. 1998; Mira. 2002; Cattan. 2008)

Even before the works of Ristow et al. and now Findeisen et al., it has been well-established that reactive oxygen specimen, the purported villains of the 21st century, enhance cellular signaling (Veal. 2007). About a year ago, Chang and Chang  reported that H2O2, in particular, is a potent activator of protein signaling pathways, including insulin signaling and can even mimic insulin's effects by the inhibition of oxidation-sensitive protein tyrosinases (Chang. 2010). With glutathion being the primary H2O2 scavenger in mammalian tissue, it is thus not surprising that the BSO treated and thusly glutathion depleted mice in the Findeisen study displayed a more favorable response to a glucose tolerance test after 6 weeks of treatment with BSO and a 45%(high)-fat diet (cf. figure 1).

Figure 1: Glucose levels in mg/dl after oral glucose tolerance test in mice after 6 weeks on a high-fat diet (47% fat) with or without 30mmol/L BSO in their drinking water (data adapted from Findeisen. 2011)

These results are surprising, also because the daily food and water intake of the mice was identical. The latter cannot be said of their calorie-expenditure, daily activity level (cf. figure 2) and the activity of the "fat burning" uncoupling protein UCP2 (+100%), the elevation of which increases thermogenesis and energy expenditure.

Figure 2: Relative changes in energy expenditure and daily activity due to BSO induced glutathion depletion in mice on a high fat diet compared to non-treated control (data calculated based on Findeisen. 2011)

Now, most importantly for you, as a physical culturist, may be that glutathione depleted mice did not simply fail to thrive or shrivel away - they were, as Findeisen points out...

completely protected from diet-induced obesity, despite similar food intake and water consumption. Analysis of body composition in mice fed a HFD diet confirmed significantly decreased fat mass in BSO-treated mice without significant differences in lean body mass, indicating that the difference in body weight was due to reduced fat mass in BSO-treated mice.

If you don't believe the words, I suggest you take a look at the data in figure 3 - while the control mice had a body fat percentage of whopping 32% the mice on BSO with their ~16% body fat were well within the normal range for lab-mice.

Figure 3: Fat and lean mass (in g) of mice from the control group and the glutathion-depleted group after 6 weeks on a hypercaloric high fat diet (data adapted from Findeisen. 2011)

Even the researchers appeared to be surprised by the profound effects glutathion depletion had on the rodent's ability to accumulate body fat. As far as the underlying reasons are concerned, they speculate that it was ...

[...] possible  that  the  observed  increase in the expression of UCP-2 and UCP-3 in BSO-treated mice induced  mitochondrial  uncoupling [...] Alternatively, the enhanced energy expenditure in BSO-treated mice  might  be  the  result  of  increased  locomotor  activity.  In skeletal muscle, ROS are necessary for optimal contractile function, force production, and exercise-induced adaptations. Furthermore, particularly H2O2 is increasingly recognized as
a potent neuromodulator. It is therefore conceivable, that glutathione depletion may lead to activity-stimulating changes in the redox environment of muscle or brain.

Now, it is however questionable in how far any of these three phenomena would occur in human beings, as well. While the lack of large amounts of UCP-sensitive brown adipose tissue would decrease the UCP induced thermogenic response to glutathione depletion, locomotor activity is something that appears to be completely blocked in the modern couch potato, anyways. It would thus warrant further research (and studies into the general safety of this approach) before it would appear warranted that you take a spoon of BSO with every meal to counter the negative effects of your last binge ;-)

Intermittent Thoughts On Intermittent Fasting - Exercise (1/3): Cycling, Powerlifting and Lean Gaining ;-)

Image 1: It may be more effective than your usual "eat half as much diet", but even with intermittent fasting exercise is compulsory, not facultative.

In the last installments of this series we have analyzed the natural interplay between AMPK and mTOR, have learned that chronic over-expression of either of the two can be detrimental to the way you look, feel and perform and have scratched on the surface of how intermittent fasting and the use of AMPK and/or mTOR promoting supplements can restore and amplify the natural up and down on the AMPK/mTOR seesaw and thus promote fat loss and and gains in lean body mass - not at the same time, but cyclically. In this episode it is high time to take a closer look on how exercise, the one and only true "body recompositioning agent", plays into this.

Tell me who you are and I tell you how your body will respond to exercise.

What we already know is that the exercise induced depletion of intra-cellular ATP and the corresponding increase in ADP and AMP levels will produce profound(!) increases in AMPK phosphorylation. In a recent study on the effects of a 30s Wingate test (a sprinting test on a cycle ergometer with breaking loads equivalent to 10 and 8% of body weight for men and women), for example, scientists from Gran Canaria found increases in AMPK phosphorylation vs. baseline of +495% - 98% for the ten women in the study and +278% - 33% for the 17 (cf. figure 1)

Figure 1: Relative changes in AMPK phosphorylation in response to 30s Wingate sprint test in 17 male and ten female subjects (data calculated based on Fuentes. 2011)

As you can see there is a huge (and statistically significant) gender difference in the initial AMPK(-alpha) response to sprinting, the difference at 30min and 120min post exercise on the other hand did not reach statistical significance (p<0.05). In an aerobic exercise scenario (90min at 60%VO2max), however, Roepstorff et al. PK came up with the exact opposite results (Roepstorff. 2006):

A 198% increase (P < 0.001) was observed from rest to 90 min of exercise in men, whereas in women the exercise-induced 74% increase in αAMPK Thr¹⁷² phosphorylation was only borderline-significant.

The different fiber-composition of the male and female subjects could provide an adequate explanation for this phenomenon. With a +23% higher ratio of slow twitch type I to fast twitch type II fibers, the women in the Roepstorff study were, on a pound per pound base, more effective endurance athletes than the men. Consequently, they did not run out of fuel so fast and thusly there was no need for their bodies to ramp up AMPK by the same 198% as the bodies of the men did.

Figure 2: Fat oxidation (in kcal/kg per min) calculated based on respiratory exchange ratio in male and female participants of a 90min cycling bout at 60% of their individual VO2Max (Roepstorff. 2006)

It is important to note that despite lower AMPK activiation in the female participants of the Roepstorff study, the women (due to their high ratio of type I fibers with +25% higher capillarization) had statistically significantly higher fatty acid oxidation rates (i.e. they burnt more fat) than their male counterparts (cf. figure 2)! This goes to show you that the metabolic scene, which is set by AMPK, is not the sole determinant of substrate metabolism. In the end, the capacity of the mitochondrial furnaces decides how much energy from fat you will be able to burn. For subjects with a high amount of type I fibers whose primary objective is to actively burn additional fat calories, aerobic exercise may thus well be a viable alternative for intense HIT regimens, of which Astorino et al. have recently shown that the rate of fatty acid oxidation in recreationally active men and women is identical within the statistical margins (Astorino. 2011).

Conversely, the higher type II to type I fiber ratio of men makes them better sprinters. That and their overall larger muscle mass could have allowed them to perform the 30s sprint on the cycle ergometer without having to resort to extra-muscular energy stores, which would explain why we did not see a significant increase of AMPK immediately after sprinting. Its occurrence 30 minutes after the sprinting exercise does yet go to show that even very short exercise bouts can trigger pretty profound AMPK responses, of which I would speculate that they facilitate post-exercise glycogen repletion via "energy-repartitioning".

Why cyclists should powerlift and powerlifters should cycle

Illustration 1: Differential response of cyclists and power lifters to strength and endurance training; statistically significant increases are highlighted in green, statistically significant decreases in red (data compiled from Coffey. 2005)

With regard to the differential response to different exercise modalities we also know from a 2005 study by Coffey et al. (Coffey. 2005) that muscle from strength-  and endurance-trained individuals respond very differently to endurance (1 h cycling at 70% VO2peak) or resistance training (8 sets of 5 maximal repetitions of isokinetic leg extensions).

I've gone to all the bother of compiling the extensive data on muscle protein synthesis and related signalling proteins from the study into a single chart (cf. illustration 1), where statistically highly significant increases are highlighted in green and statistically significant decreases are highlighted in red. Thusly, you should be able to see that if the goal is to increase AMPK, cyclists have to strength train, while powerlifters will have to get into the saddle of an elliptical or ergometer.

What appears paradoxical at first, is the result of adaptation processes: Only novel and unaccustomed stimuli trigger further adaptation... and "novelty" is such a profound trigger of adaptational responses that - under the assumption that p70S6K phosphorylation is a reliable measure of the protein synthetic training response - cycling causes almost comparable increases in protein synthesis as resistance training in powerlifters, a group of athletes who are not exactly known for doing large amounts of "cardio" training.

Since this is not exactly "intermittend fasted" related, I leave it up to you to interpret the rest of the data. Before I "think on", I do yet want to caution you against getting stuck in doing the same type of exercise over and over again - there is a reason that 99% percent of the figure athletes, bodybuilders, fitness models or whatever other athletes and celebrities you think have an aesthetic body, incorporate some form of aerobic training into their regimens, as well (if you read the latest posts on HIIT training, you will be familiar that "aerobic" does not always mean steady state endurance training ;-)

Training fasted? Maybe, for athletes and performance oriented amateurs.

While the previously discussed studies showed that AMPK/mTOR responses to different exercise regimes largely depend on who you are and what type of training you have conditioned your body to, it did not answer the question that appears to be preying on everyone's mind, which is "Do I do my aerobic and or resistance training in a fasted (no food at all), semi-fasted (only protein and maybe some fat), or fed state?" Or in other words: "Do I break the fast before or after training?"

Image 2: Ramadan fasting can serve as a relatively particularly well studied "model" of intermittent fasting. You can find more information about the strengths and limitations of this model, please read Part 2 and Part 3 of this series.

A brief reminder for all who of you who missed the first installments of this series and may now wonder why I am, without further explanations, referring to studies on Ramadan fasting as if it was intermittent fasting - in essence it is! This is why I have already discussed a handful of studies that investigated the effects of Ramadan fasting on Muslim athletes, in the initial installments of this series. In that context, I have also pointed out why the Ramadan "protocol" is an acceptable model of intermittent fasting and where it deviates from what we are seeing in the dietary regimens with which Adelfo and Duong get to grips with the little fat that is still left on their athletic bodies. For more information on that I would like to refer you to Part 2 and Part 3 of this series, in particular.

If you are a competitive athlete, who follows the advice of the establishment, the answer is easy - EAT, EAT, EAT! And do not even think of fasting! On the other hand, even experts openly admit that despite the fact that it is (Maughan. 2010).

often automatically assumed that intermittent fasting will lead to decrements in exercise performance. [...t]he available evidence does not entirely support this view, but there is little or no information on the effects on elite athletes competing in challenging environments.

With respect to the lack of data, we are in the fortunate position that the Olympic Games 2012 coincide with the Ramadan period from July 21 to August 20, 2012, i.e. right in the heart of the Games. Meanwhile we do yet have to resort to the little reliable data there is and of which Maughan et al. writes in another article that it "suggests that effects of Ramadan-style fasting on exercise performance are generally small." And a pretty recent study which investigated the effects of Ramadan fasting on performance and body composition of 16 young soccer players (17.4±1.2 years, 175.4±3.6 cm, 69.6±4.3 kg and 5.1±1.3 years of training experience) corroborates this assertion.

Study shows: You can improve body composition and performance if you train intermittendly fasted, but not in a fasted state 

Alpay Güvenc from the School of Physical Education and Sports at the Akdeniz University in Antalya, Turkey, assessed body composition, hydration status, dietary intake and sleep duration of his 16 male subjects, who continued their regular pre-season soccer training during the four weeks of Ramadan, on four occasions: before Ramadan, at the beginning of Ramadan, at the end of Ramadan and 2 weeks after the end of Ramadan. The training sessions were yet postponed, so that the soccer players could have a snack or meal before they took to the field - they were thus intermittendly fasting, but not training in a fasted state!

Figure 3: Relative changes in RD: running distance, RT: running time, RV: running velocity and
RV4.0: running velocity at 4.0mmol.L-1 lactate concentration due to Ramadan fasting during the pre-season preparations in 16 male soccer players (data calculated based on Güvenc. 2011)

As figure 3 goes to show, there was an initial decline in exercise performance in the first week of Ramadan (=intermittent) fasting. In the last week of Ramadan, the maximal running distance, the running time and velocity and the RV4 (running velocity at 4.0mmol.L-1 lactate concentration) had improved - only by 3%, 3%, 1% and 2% over baseline, but nevertheless statistically significantly. Now, what may be even more interesting for professional athletes is that these beneficial effects continued well into the post-Ramadan phase - how much of this has yet to be ascribed to the training regimen (remember the soccer players were in their pre-season preparation) could only be determined if half of the kids had been Christians and had served as a non-intermittendly-fasted control.

Figure 4: Changes in total body water (TBW in L), fat free mass (FFM in kg), body fat (in kg) and  the sum of skin-fold measures (in mm) due to Ramadan fasting during the pre-season preparations in 16 male soccer players (data calculated based on Güvenc. 2011)

In a similar vein, we cannot say for sure, whether there had been comparable improvements in body composition (as evidenced by the statistical significant reduction in skinfold measures, i.e. -2.2% by week 4 of Ramadan fasting; cf. figure 4), if the players had just continued their usual pre-season training without fasting intermittendly. What we can say for sure though, is that they achieved the latter without any major changes in their overall caloric intake or macronutrient composition (cf. figure 5)
And that the fasting had no negative effects on the subjects sleep duration (~8.7h) or their hydration status. So that, it would appear that during a metabolically demanding pre-season training a non-specific intermittent fast works just / at least as good as a normal diet, as long as the athletes meet their training induced caloric demands.

Training fasted? Yes, for lean gains.

Image 3: For some "lean gains" happen only in their heads (img muscle.iuhu.org)

Now, while "exercise performance" obviously is an important variable, I assume most of you who are toying around with the idea of doing an intermittent fast, are more interested in its effect on body composition and would tolerate a dip in "exercise performance" (whatever type of exercise that may be in your case) if only those love handles finally disappeared and allowed your ever-increasing muscle mass to shine... or are you interested in the potential (largely AMPK-related) health benefits intermittent fasting has to offer in a world, where nutritional abundance is a 24/7 phaenomenon and the world "bulking" is often misinterpreted as taking advantage of the former as often as possible?

In both cases the results of a 2010 study from the Human Performance Laboratory in Leuven, Belgium (not the one in Canada!) would be relevant for you. In that study (Van Proeyen. 2010), Van Proeyen et al. had 27 healthy male volunteers consume a hypercaloric high-fat diet (∼+30% kcal/day; 50% of kcal from fat) for 6 weeks. Additionally 20 of the subjects had to participate in 4 training sessions per week (2x90min and 2x60min) consisting of cycling at 70-75% of the individual VO2Max and running at 85% of the maximal heart rate. 10 of the subjects (CHO; n=10) had yet had breakfast (~90min before training; 675 kcal, 70% carbohydrates, 15% fat, 15% protein), the rest (fasted; n= 10) reported to the lab after an overnight fast.

Figure 4: GLUT4 and AMPK expression in 10 healthy male subjects before and after 5 weeks on a hyper-caloric high-fat diet with or without (control) exercise in the fasted or fed (CHO) state  (data calculated based on Van Proeyen. 2010).

As the asterisk in figure 4 indicates, the exercise induced increase in GLUT4 (responsible for muscular glucose uptake) and AMPK expression is significant (p<0.05, i.e. chances that this is only coincidence <5%) only in the subjects which trained in a fasted state. Moreover, only the group which trained in the fasted state had neither statistically significant weight increases, nor statistically significant increases in the sum of the skinfold measurements (a relative reliable marker of body fat levels). The unexercised controls and the CHO group (training in fed state), on the other hand, gained 3kg and 1.4kg body weight (both p<0.05). Interestingly, though only the control group experienced a statistical significant increase in the sum of their skinfold measures of +15.1%! (+1.1% in fasted; +5.4% in CHO).

This study for the first time shows that fasted training is more potent than fed training to facilitate adaptations in muscle and to improve whole-body glucose tolerance and insulin sensitivity during hyper-caloric fat-rich diet. (Van Proeyen. 2010).

Obviously, we are dealing with a very different situation, when an intermittent fast is combined with a caloric deficit - yet in view of the idea to use intermittent fasting as dietary strategy on a "lean bulk", the results of the Van Proeyen study could be of great importance. Not only in view of keeping the fat gains at bay, but also with regard to potential negative health effects of deliberate overeating and subsequently compromised insulin sensitivity.

A pros pos "lean bulk", I suggest you do come back next week if you want to know more about when and what to eat right after what type of workouts in order to maximize muscle and minimize fat gains when you train intermittendly fasted. For now, I wish all of you a sunny Sunday (here it is one) and an intense week at the gym, regardless of whether you train (intermittendly) fasted or not ;-)

Ask Dr. Andro: Are Vitamin Supplements Bad For Me (1/2)? The "wrong" Vitamin E Supplements Increase Cancer Risk.

Figure 1: This is where you, my American friends (and most Europeans), should and would get your "E's" from - it's called "food" (Eitenmiller. 2004)

With the recent publication of two studies on increased all-cause mortality in older women (Bjelacovic. 2011; Mursu. 2011) who took multivitamins (+2.4%), vitamin B6 (+4.1%), folic acid (+5.9%), iron (+3.4%), magnsium (+3.6%), zinc (+3.0%), and the "killer" copper (+18%) and increased risk of prostate cancer due to selenium and/or vitamin E supplements (Klein. 2011) on a regular basis and the huge media attention these studies,

• "Certain Dietary Supplements Associated With Increased Risk of Death in Older Women, Study Suggests"
• "Vitamin E Supplement May Increase Prostate Cancer Risk, National U.S. Study Finds"

have received, I got interested in taking a closer look at what I would usually have discarded as epidemiological guesswork and scare tactics, anyway.

How can a vitamin be bad for you? It's supposed to be a vital nutrient, goddammit!  

In that, I want to start with the 2nd of the two studies, i.e. the one on Vitamin E, which also happens to be a "true" Ask Dr. Andro question. After all, Steven Acerra posted a whole bunch of related questions on my Facebook page (remember you can always send in questions you want to have answered in this column!)

Image 1: Conflicts of interest, as declared in the paper by Klein et al.

Are medical studies "objective"? Being a scientist (in a whole different area of research, though), myself, I am well aware that financing expensive cutting edge science with the meager support from national agencies is impossible, these days. Therefore, I refuse any rash prejudgements based on the openly stated potential conflicts of interest (cf. image 1), as Steven put them forward in a follow-up comment on my facebook page. If you want to blame someone, blame the influential editors of the large journals, including the JAMA, where Klein's paper was published. Their acceptance of a paper determines whether a study appears on the SuppVersity, "only", or is taken up by a journalist from a major popular scientific magazine or, as in this case, even the Health Podcast of Time Magazine.

Other than Steven suspected, the study by Klein et al. that was published in the latest issue of JAMA (the Journal of the American Medical Association which is not particularly well know for being independent of the pharma lobby, cf. red box ;-) - despite its size - actually is a "controlled" trial... Well, as controlled as a study with 34 887 men who were randomly assigned to receive selenium (n= 8752), vitamin E (n=8737), vitamin E + selenium (n=8702) or placebo (n=8696), can be. It is part of, or  I should say, the final outcome of the so called SELECT trial, a large scale intervention that was conducted in the United States, Canada, and Puerto Rico. Data acquisition started on August 22, 2001 and ended three months ago, on July 5, 2011. The fact that the study is over is good news for all participants, because, as the bold headlines would have it, all treatments increased the participants' risk to develop cancer. Yet, what mainstream media didn't tell you is that (I quote directly from the detailed results in the paper; Klein. 2011):

The rate of prostate cancer detection was greater in all treatment groups when compared with placebo* but was statistically significant only in the vitamin E alone group. After adjustment for the marginal effects of vitamin E and selenium, the interaction between vitamin E and selenium was statistically significant (P=.02), indicating no increased risk of prostate cancer when vitamin E and selenium were taken together. The risk of Gleason 7 or greater disease was higher for all 3 interventions [vitamin E + 16%; selenium +21%; combination: +23%] but did not reach statistical significance for any group.

* I suspect this is probably about as far as most journalists read - if they even had the fulltext of the study, when they wrote their sensational and fearmongerish articles

If you compare the real findings to what you may have read in the course of the last week, it is quite obvious that half of the media reports got the results completely wrong. A quarter of the reporters obviously did not know the meaning and importance of "statistical significance" and the lousy rest does not care about information, anyway, as long as a headline could potentially increase sales or pageviews, it makes it into the magazine or onto the website.

No matter what the press says: You better know your vitamins E before taking the wrong one

Figure 2: Natural RRR alpha-tocopherol and synthetic SRR alpha tocopherol which is one of the isomers in the -50% less potent all-rac-alpha tocopherol, which is the "vitamin E" the 34,887 men in the large scale trial conducted by Klein et al. have received at a dose of 400IU per day  (figure from Traber. 2011)

This leaves us with just one "unexpected" result to be explained, i.e. a statistically significant increase in cancer risk with 400IU of supplemental "vitamin E" per day. In case you've noticed the quotation-marks before and after vitamin E, in the previous sentence, you already know where this is heading. After all, you would assume that the scientists would use the most potent weapons from their arsenal in their battle against prostate cancer - wouldn't you? Trial "S0000 Selenium and Vitamin E in Preventing Prostate Cancer" (clinical trials identifier: NCT00006392) sponsored by the Southwest Oncology Group, however, relied on the cheap all-rac-alpha-tocopheryl acetate of which Max K. Horwitt had shown back in 1980, already, that "all-rac-alpha-tocopheryl acetate may have no more than half the biological potency of d-alpha-tocopheryl acetate" (Horwitt. 1980). About, 19 years later Horwitt, then over 90 years old (!), was still fighting a fight against the medical establishment who maintained that the cheap synthetic form of vitamin E would have at least a 73.5% the activity of the naturally occurring form. In a letter to the editors of the American Journal of Clinical Nutrition he writes (Horwitt. 1999):

Now in my 90th y, I doubt whether I will ever see the proper correction made in the official values of the tocopherols. Having introduced the term equivalent as used by committees of dietary allowance, I prefer that this designation be used to describe the potency of the tocopherols. In the recommended dietary allowances, l mg RRR-a-tocopherol has a biological value of 1.0 a-tocopherol equivalents. Accordingly, in modified US Pharmacopoeia vitamin E units, RRR-a-tocopherol should have a value of 1.0, all-rac-a-tocopherol a value of 0.5, RRR-a-tocopheryl acetate a value of 0.91, and all-rac-a-tocopheryl acetate a value of 0.455.

Meanwhile, the USDA has changed their calculations in the USDA National Nutrient Database for Standard Reference, according to release #20 (USDA. 2008), the all-rac-alpha-tocopheryl acetate 
is now officially classified as -55% less potent than natural tocopherol. Now, the chance to pick the worst of the four vitamin E's was 25% and *bang* Klein et al. nailed it. Can this be coincidence - I guess if it was you could call it "bad luck".

Supplementation may offset the natural balance by exchanging natural gamma tocopherols for cheap synthetic alpha-tocopherols

"Bad luck", also because supplementation with high doses of alpha-tocopherol has been shown to hinder "normal" incorporation of gamma-tocopherols into VLDL particles, to increase hepatic clearance of gamma-tocopherols and, in the end, to deplete plasma gamma-tocopherol levels, as well (Jiang. 2011). Now, if you have a less potent type of vitamin E, you obviously have to supplement more (to achieve a potency equivalent to 400IU you obviously need +55% more all-rac than natural tocopherol!)... but does that really matter? Oh yes it does! As gamma tocopherol and not alpha-tocopherol is "the vitamin E" which inhibits cyclooxygenase activity and, thus, possess heart-healthy anti-inflammatory properties. No wonder that Jiang et al. report in a 2001 review that...

1. plasma gamma-tocopherol concentrations are inversely associated with increased morbidity and mortality due to CVD. 
2. serum concentrations of  gamma-tocopherol, but not of alpha-tocopherol, were lower in CVD patients than in healthy control subjects. 
3. in a concomitant cross-sectional study of Swedish and Lithuanian middle-aged men,  plasma gamma-tocopherol concentrations were twice as high in the Swedish men, but that the Swedish men had a 25% lower incidence of CVD-related mortality. In contrast, this inverse correlation was not observed with alpha-toco-pherol. 

... and the list goes on. Now, you will probably say "But Dr. Andro, those men got cancer from vitamin E, not cardiovascular disease!" and, as always, you are right, BUT the evidence that gamma- not alpha-tocopherol (or at least a "natural" mix of both) is cancer protective is even more conclusive than the one on the CVD-protective effect of the former.

What are normal ratios of alpha- to gamma-tocopherol? While we hardly can say which ratios are optimal, we know that the "normal" ratio of serum alpha- to gamma-tocopherol levels for Americans who do not take any supplements is 5:1 (alpha:gamma). According to Chopra and Baghavan his ratio further increases to greater than 20-fold in people taking vitamin E supplements (Chopra. 1999).

High gamma-tocopherol levels reduce risk of prostate cancer by -500% [no typo!]

In 2000 Helzlsouer et al. analyzed the blood of 10 456 male residents of Washington County and found that (Helzlsouer. 2000)...

For gamma-tocopherol, men in the highest fifth of the distribution had a fivefold reduction in the risk of devel-oping prostate cancer than men in the lowest fifth (Ptrend = .002).

With p = 0.002 the chance that this was "coincidence" is exactly  125x smaller (0.2%) than Klein et al.'s chance (25%) to pick the worst alpha-tocopherol variety there is for their large scale intervention. And while this is only an epidemiological study, we have more than enough in-vitro and animal data to confirm the anti-cancer effect of gamma-tocopherol:

Prostate cancer:
• Jiang. 2004:  "... gammaT and mixed vitamin E forms induce cell death by interrupting the de novo sphingolipid pathway in a prostate cancer cell line"
• Campbell. 2009: Growth arrest (40%) in PC-3 prostate cancer cells through the regulation of fatty acid metabolism and PPAR gamma mRNA and protein upregulation was achieved with gamma-tocopherol within 6 h.
• Jiang. 2011: Sphingolipid promoting effects of gamma-tocopherol induces apoptosis and autophagy in prostate cancer cells

Colon cancer:
• Campbell 2006: In-vitro study on human colon-cancer cell lines; "treatment with RRR-gamma-tocopherol resulted in significant cell death for all cancer cell lines tested, while RRR-alpha-tocopherol did not [...] RRR-gamma-tocopherol may aid chemotherapy without toxic effects to normal cells demonstrated by most chemotherapeutic agents"

Other cancers:
• Yu. 2009: Mouse model (human breast cancer) + in-vitro studies > "α-tocopherol not only failed to exhibit anticancer properties but it reduced anticancer actions of γ-tocopherol in vivo and γ-tocopherol and α-TEA in vitro."; what is important to note, though is that the all-trans-variety used in the Klein study did at least inhibit proliferation and increase apoptosis (programmed cell death) in vivo.
• Yang. 2010: "[I]nhibition of inflammation as well as of cancer formation and growth in the lung and colon in animal models" by tocopherol supplement with  57% gamma-T
• Ju. 2010a: "In cell culture, the growth of H1299 cells [lung cancer] was inhibited by tocopherols with their effectiveness following the order of delta-T > gamma-TmT > gamma-T, whereas alpha-T was not effective."
• Ju. 2010b: "... recent results have demonstrated that a gamma-tocopherol-rich mixture of tocopherols inhibits colon, prostate, mammary and lung tumorigenesis in animal models, suggesting that this mixture may have a high potential for applications in the prevention of human cancer"

And directly referring to the "partly negative" outcomes of studies into the potentially beneficial effects of "vitamin E" supplements (which were almost exclusively conducted with alpha-tocepherol-only products), Reiter el al. wrote in a 2009 review (Reiter. 2009):

As pointed out in this review, more and more evidence indicates that γT and other vitamin E forms than αT have unique bioactivities that may be important for maintaining and improving human health (Dietrich et al. 2006; Jiang et al. 2001). For example, γT is a stronger inhibitor of cyclooxygenase and possibly lipoxygenase than αT. Furthermore, γT traps reactive nitrogen species more efficiently than αT. Some of these in vitro effects are slowly being confirmed in vivo, but more studies are needed here. In addition, γT but not αT exhibits anti-proliferative and pro-apoptotic effects on cancer but not normal epithelial cells (Jiang et al, 2004). [...] Thus, despite the undisputed anti-inflammatory effects of α- and γT, the recent large-scale interventional studies aimed at reducing diseases associated with chronic inflammation have been disappointing, but may be explained by the complex interaction of the different vitamin E forms with inflammatory signaling, xenobiotic transformation, and as yet undefined pathways.

I think I do not have to point out that with what we know today about the necessary synergy of the vitamins E (including the tocotrienols, which I deliberately left out, in order not to overcomplicate things) and the results of a 2003 study by Huang (Huang. 2003), which showed that supplementation with 400IU of RRR-alpha-tocopheryl acetate (remember due to the fact that this is the more potent variety, the actual dose in µg was -50% lower than in the Klein study)

reduced serum gamma-tocopherol concentrations by a median change of -58% [95% CI = (51%, 66%), P < 0.0001], and reduced the number of individuals with detectable delta-tocopherol concentrations (P < 0.0001),

initiating a similar study as Klein et al. did 10 years ago, would border physical injury resulting from negligence, today. And although the use of isolated forms of vitamin E, which you will find in most of the cheap multivitamin tablets you can buy at the supermarket, could also be involved in the negative effect "certain dietary supplements" (including multivitamins) were reported to have on the health of "older women" in the 2nd study, I mentioned in the introduction, I will address this issue in an individual installment in a follow up to this post in the course of the next week. So stay tuned for more.