Intermittent Thoughts on Intermittent Fasting - Finally Getting Started - Setting Yourself Up For Success!

Image 1: Socrates unquestionably did not look like he knew anything about intermittent fasting or physical culture, but he knew a lot about how to unlock the potential of his students.

In the last parts of the series you have learned so much about the biochemical underpinnings of how your diet and exercise regimen can change the way you look, feel and perform that you should by now have a general idea of why people, like Duong, "all of a sudden" drop tons of body fat, without having to resort to the still much-heralded combination of low-intensity-steady state "cardio" sessions and frequent low-fat high carb mini-meals. You should, however, also have grasped the idea that copying Duong's or Adelfo's regimen probably won't get you where you want to be. My intention thus is (and has always been) to teach you all the stuff you will need to find your own way... just as children will not learn to read if you just read books to them, you will never be able to constantly progress unless you totally surrender yourself to the advice of a highly paid personal trainer who babysits you 24/7 or - and I would assume that this is the way more desirable alternative - learn how to do his job on your own. In this installment of the Intermittent Thoughts and probably a few follow ups, I am thus going to "think" about how you can decide on the necessary steps you have to achieve your personal goals.

Do you want to know how to set yourself up for failure?

If I wanted to make it easy for me, I would follow the example of many health and fitness authors and provide you with a 3-10 item list of how you can "set yourself up for failure". This is easy, because you do not even have to know what works. It is enough to now what does not work. Yet even though there are much more things that don't work, than things that do work,  the word(s) "overeating" or even "constant overeating" would be totally misplaced on the list of "don'ts" of a skinny person who insists to do an intermittent fast and still wants to gain weight. Without "constant overeating" in the restricted feeding windows this is not going to happen.

Image 2: The new "MyPlate" is probably the most prominent example of moribund one-diet-fits-them all solutions (even if it was not intrinsically flawed, as well)

As you may notice, it gets pretty difficult for me, not to set you up for failure, even if I am providing advice that would be spot on for 90% of my readers. This is why I will not give you any answers, at all, but ask questions. I will ask questions that will enable you (based on the information of the future installments and concrete examples I will weave into future Intermittent Thoughts) to come up with the answers yourself - in didactics, this is referred to as a "socratic dialogue" (Rose. 2001), where the lecturer is trying to ilicit information from students through a direct line of reasoning... I suspect that this may sound counter-intuitive, after all it sounds as if it implied that you already know what the answers would be. That, however, is not the case. Socrates made his pupils discover for themselves things they could know - and that is fundamentally different from inquiring about things you do know.

Who are You and what do You want to achieve?

As I am doing it at the beginning of each semester with my real world students, the first thing I will ask you to do is to introduce yourself. What relevant information would you have to provide? Are you being fed up of being the fat or skinny kid, the girl or guy who is always just "a friend", the last one to be picked when you are playing football with peers, the pre-diabetic who got scared, when the doctor told him that if he did not start jogging and eating "healthy" *haha* whole grains will sooner or later be injecting insulin? If you do not have an answer to this question, yet, chances are you won't be able to help yourself make a change - and if you do not want to change, why are you even contemplating an intermittent fast?

Image 3: Are you sure "getting skinny" is really what you want, former fat kid?

Outside of the realm or professional athletics, the issue we are approaching right now is something that is commonly overlooked by many trainees and oftentimes not accordingly valued by their trainers (if they have any) - it is the complex interrelation of personal motivation and goals. Let's assume you were the "fat kid" all your life. Is you goal actually to "get skinny"? Probably not. And in case it is - just stop eating. If you take in enough fluid, and maybe a protein shake with some olive oil from time to time, you will probably live long enough to see a skinny image of yourself in the mirror, someday. Will this provide the social acceptance you have been longing for, all these years? I don't think so. It would rather have you descend deeper into the social abyss...

Why are you here? What is it that motivates you to "study" at the SuppVersity?

The first step in setting yourself up for success is thus to set an appropriate long term goal. I know that each and every one of you will tell me that he is "freakin' motivated" and "ready to do whatever it takes" to achieve his/her goals... so!? Then give me the elevator pitch of what you want to achieve... if it took you longer than 2 seconds to put your main goals into a single sentence, I must tell you that you have not yet taken the first and most fundamental step to set yourself up for success. Even the slightest doubts on your part as far as your goal is concerned will eventually become major obstacles on journey to a "new" or "better" you. That does not mean that your goals cannot change in the course of your journey (it is very likely that they will and in most cases it is even necessary), but if you were not sure, whether you want to go to Canada or to the South Pole, don't you think it would be better to stay at home, then?

Figure 1: Initial motivation (as assessed by the MPAM-R questionaire on a 7-point Likert scale) of male and female trainees going to a commercial gym and correlation (r-values) with adherence to the exercise program (adapted from Ryan. 1997)

Maybe it will help you if we take a look at what others set out to achieve. In a 1997 study, Richard M. Ryan and his coworkers at the Universities of Rochester and Southern Utah conducted a study where they asked 66 male and 89 female gym-goers for their personal motives and correlated this information on initial motivation with the subjects adherence to their respective exercise programs. The results are quite interesting, because although physical fitness and appearance were ranked highest, they showed the least correlation with the individuals adherence to the exercise program. In the case of "appearance" - my often-cited "I just want to look good naked" - there was even no (statistical significant) correlation at all. In other words, it did not matter how bad people wanted to improve their physical appearance - if this was their main motive to go to the gym. It did not help them to stay on track. Or as the scientists put it:

The implications of these findings [...] suggest that body-related motives are not, on average, sufficient to sustain regular exercise regimens, and thus should not be made the most salient justification for engaging in exercise.

Image 4: For Arnold (you know he is my favorite ;-) "the pump is like cumming ... like having sex with a woman" ... well, we all know how much he enjoys both, and it was the former joy, the one from the pump, him on track and made him succeed (still from video).

The scientists suggest that trainers & trainees would be better off if they emphasized "the inherent enjoyment associated with physical activity and/or the growth of competences that exercise promotes". Now, think about yourself and the people surrounding you. Think about the "losers" and the ones who had success. Do you see a pattern? Think about their faces when they come to the gym. Think about how they approach the weight stack. Think about what they say and how they respond, when you ask them: "What do you train today?" Do you see the pattern? Think of Arnold

Your muscle get a real a tight feeling [...] that's the pump [...] it feels different, it feels fantastic [...] it is as having sex with a women [...] I am cumming day and night ... it's terrific, I am in heaven (if you don't believe he said that, watch the video)

Do you see the pattern? Think of the fat lady that was holding on to the inclined treadmill, trampling away sweating, when you were doing your HIIT on the stair-master. Do you see a pattern?

Well, obviously both Arnold and the lady wanted to improve their physique. For the Governator, however, it was a necessary consequence of his life-style, a life-style that was based on doing what he loved to do. For the lady you saw on the treadmill, on the other hand, it was something alien - a physique "those other all have", something "nature has given those skinny anorexic chicks", something she "can work for as hard as she wants, but will never achieve". Be honest with yourself: Who are you? Arnold or the lady on the stairmaster?

Did I just hear you say that "it is not my fault, Dr. Andro!"?

Image 5: "Good" or "bad" this DNA helix is a part of your setup for success. Trust me - a few pathologic exceptions aside - it will only hinder your success if you lull yourselves into believing that it does.

From the fact that you did not head right to the gym to jerk... ahh I mean pump off ;-) I gather that you are not on the extreme "arnold'esque" side of the continuum - in other words: Things have not worked out the way you intended in the past, have they? You know what? That's your advantage! Thusly you save yourself at least a few of the 1001 mistakes that lurk on the way that lies between the "old" you and the "new" one... which reminds me: Do you already have your elevator pitch ready? What? You still "just want to look good naked"? Well, that is fine with me. Just be aware that even if you went to bed tonight, woke up the next morning, stood before the mirror in your bedroom and ... finally looked good naked, it will probably only take few weeks to restore your looks to your old "inner self", which obviously would not have changed, when the beauty fairy struck you with her magic wand in that fateful night.

You need to realize that whatever the central aspect of your motivational elevator pitch is going to be ...

• looking good naked (how do you define that?)
• never being called "skinny bitch/bastard", again (are you sure that is only an issue of how you look?)
• not being the fat guy/girl, any more (what do you think will change, then?)
• eventually get rid of the constant fatigue (could the fatigue be the result of trying to achieve unrealistic aims?)
• adding +20lbs of lean muscle to my frame (what will you have achieved then? will this be enough? or are you going to want more?)
• losing -50lbs of fat (is it just the figure on the scale you are looking for?)
• getting off your diabetes drugs (do you have an idea why you maneuvered yourself into this situation in the first place?)
• living into your 100s (do you just want to live long or is this more about good health into the old age?)
• and so on and so forth

 ... chances are, you would already be there, or at least on your way to achieve them, if there was not this one person that was standing in your way: YOU! No excuses! Taking responsibility for where you are at now, regardless of which "bad advice" you have been following or "how bad your genes" may be - your status quo is the foundation on which you are going to reinvent yourself - not just your training or your "diet". If that works out, patience and perseverance will be the only thing it will take you to eventually arrive, where you see yourselves in your elevator pitch.

Homework for the next installment: Post your elevator pitch

Figure 2: Robb Wolf once mentioned the "performance - health - longevity triple point" in one of his numerous insightful blogposts on his webpage. In essence the figure above expands on his idea: You obviously cannot max out on all of the items. Notwithstanding, all of them are attached to the very same life-style foundation and the practical overemphasis of any of them may have pathological consequence (Adonis complex, depression, drug addiction, obesity, anorexia, ...).

As a  "homework" I want you to fine-tune and post your elevator pitch in the comment section of this post. Not only will you thusly make yourself accountable for what you will feel, look and perform in a few weeks or months from now, you will also help me tailor the next parts of this series, which are going to deal with the actual "programming of success" by making appropriate life-style interventions, to your goals. So don't miss out on this chance and give the world a preview of what the characteristic feature(s) of the "new you" is going to be.

And don't forget, where you came from. Maybe you've just been straying around, because your present elevator pitch incorporates two or more of the partly diametrically opposed extremes in figure 2? Think about it. Have you ever seen an Olympic athlete partying 5 days à week, who goes to bed at 4am has pizza for "breakfast" at 4pm and improves the world record at 8pm? Probably not. So incorporating diametrically opposed extremes into your elevator pitch is about as much a no-go as having none at all, remember that before you go public - I mean, what would the world think if your plan to have french fries instead of the pizza and them perform a new world record fails?

Astragalus membranaceus: Purported Telomerase Activator Increases Exercise Capacity by +56%, Fights Cancer and May Be a Healthy Adjunct to Chemotherapy and Vaccines

Image 1: Astragalus membranaceus, one of the 50 fundamental herbs in traditional Chinese medicine (TCM). A purported telomerase activator that contains potent antioxidants.

There is hardly one month passing without some media reports about a group of scientists who supposedly found the royal route to health and longevity. With all those potentially life-extending drugs, herbals and nutritional supplements that have thus surfaced in the course of the last decades, it is actually almost surprising that we still die like flies, isn't it? Well, one possibility would obviously be that the scientifically-backed wonder-potions you can buy in the snake-oil shops all over the Internet do not work at all - impossible? I don't think so. Consequently, I was and still am very skeptical about the dubious claims about the "life-extending" effects of a patented Astragalus membranaceus (also Astragalus propinquus) extract - and that despite or, I should say, because of its "scientifically proven" effect on telomerase length in 114 older (63 +/-12 years) subjects. After all, the respective study was not only by the owner of the company which holds the patent for T-65(R), a (I quote) ">95% pure single chemical entity isolated from a proprietary extract of the dried root of Astragalus membranaceus" (Harley. 2011), but the authors (guess what all somehow involved in the sale of the product) also use several more or less clever tricks to polish their results. While they have to admit that

Two independent measures of median or mean telomere length (by FlowFISH and qPCR) showed no consistent change with time on PattonProtocol-1 (data not shown).

they cleverly handpicked 7 out of 13 tested subjects in which the percentage of nuclei with short telomeres had declined at 12-18 months compared to baseline. Now, while this decline may be statistically significant (p<0.05, according to the scientists), I wonder what happened to the other 6 subjects... and even if you were among those lucky 7, this does by no means indicate that that will actually prolong your life.

Who wants to live forever, anyway...

That I did nevertheless dig a little deeper into the research on astragalus had two reasons. One was that I wanted to find any other data on its potential effects on telomerase length - and more importantly its practical outcome in rodents or even my "favorite" subject of medical research, the roundworm Caenorhabditis elegans, or "C. elegans" (do I have to say that there are no such studies?). The other reason was that astragalus membranaceus has been used in Traditional Chinese Medicine for centuries. So, even if it would not make you live forever there obviously had to be some benefits to this flowering plant from the family of Fabaceae. And as it turned out, Chinese researchers have been performing numerous studies into its antioxidant, anti-diabetic, anti-hypertensive, and immunomodulatory activity within the last decades, of which a very recent one could be of particular interest for fitness enthusiasts and even professional athletes.

... isn't performance the only thing that counts?

Image 2: While this is not the exact model that has been used in the study, this is what "exercise" looks like if you are one of those poor lab rats... well, not so much different from what a whole host of trainers still suggest their clients should do to lose weight... but I am digressing, here ;-)

If you look at the sales-ranks of various dietary supplements, it is quite obvious that (potential) long-term effects on health and longevity usually stand second to immediate benefits like increased energy, well being, weight loss or exercise performance. "If you don't feel it, it doesn't work!" is the mantra of many fitness enthusiasts; a montra on which the manufacturers of purported fat-burners and pre-workouts, 99% of which are only caffeine, geranamine and yohimbine loaden stimulants, monetize big time. And as long as those cheap stims keep the sales of their products up, the producers obviously would be stupid if they changed their formulas and included more expensive "adaptogens" - chances are the customers would not be willing to pay the price, anyway. Accordingly, you won't find references to studies like the one Deng and Hu recently published in the Academic Journals on any of the labels of the currently available mainstream supplements (Deng. 2011).

In what they themselves claim is one of the few studies (to my mind the first to be published in an international journal) investigating the effects of Astragalus membranaceus polysaccharides (AMP) on exercise performance, the scientists from the Kunming University in China orally administered 50, 100 or 200mg/kg of previously extracted pure astragalus polysaccharides to 6-8 week old male Sprague-Dawley rats for 30 successive days. In the course of the last week of the experimental period the rats, who had been fed ad-libitum for the whole study period, were accustomed to running on a treadmill for 15-20min at 15-30 m/min (=0.9-1.8km/h), so that they would be able to perform an exercise test that consisted of running on a 10° incline (30m/min, ~75%VO2Max) until exhaustion on day 30.

Figure 1: Running time to exhaustion (in s, left) in rats who received either saline control or astragalus membranaceus polysaccharides at a dosage of 50, 100 or 200mg /kg per day and the extrapolated dose-response relationship (data calculated based on Deng. 2011)

As the data in figure 1 shows, the supplemental regimen, which had no effects on the body weight of the then 12-week old rats, significantly improved the running endurance of the laboratory animals. Interestingly, the extrapolation of the dose-dependency suggests that dosages above 300mg/kg (human equivalent ~50mg/kg) will probably not yield much better results than the 200mg/kg maximal dose that was used in the study (human equivalent ~35mg/kg).

Figure 2: Effects of astragalus supplementation on anti-oxidant enzymes after exhaustive endurance training in rats; values expressed relative to unsupplemented control (data calculated based on Deng. 2011)

The post-exercise glutathione peroxidase (GSH-Px) activity exhibits a similarly logarithmic dose-response relation (cf. figure 2). The decreases in malondyaldehyde (MDA), as well as the increase in superoxide dismutase (SOD), on the other hand appear to be almost linear. And, lastly, the lower increase in catalase (CAT) in the high dose astragalus group could be a consequence of the fact that, with GPH-Px and CAT both being responsible for the catalyzation of hydrogen peroxide to water, there simply was no need for additional cat activity, when the GPH-Px activity already increased by >100%.

If (the big if ;-) those results could be confirmed in human trials, the +56% increase in exercise endurance in the 200mg/kg (i.e. 35mg/kg for humans) of astragalus could in fact be the "next big thing" in terms of natural ergogenics. For the time being, it is yet only another item on the list of purported benefits, I am now going to conclude on another anon more health related note.

Beyond exercise performance: Cancer protection and immuno-modulation

While I initially voiced some doubts with regard to the purported longevity effects of astragalus, its relatively well-established anti-carcinogenic effects could well help many of us to substantially prolong our lives. After all, numerous studies have established the anti-cancerous activity of various natural constitutents of astragalus. Among the cancer cell lines that were tested were  

• colon cancer cells (Tin. 2007, Auyeung. 2010),  
• breast cancer cells (Zhou. 2009; Gülcemal. 2011),  
• cervical cancer cells (Yalcin. 2011), 
• human gastric adenocarcinoma cells (Auyeung. 2011),  
• human hepatocellular carcinoma (HCC) cells  (Hu. 2009; Auyeung. 2009)

If you look a the publication dates and authors, you will notice that despite its longstanding tradition within TCM scientists have only lately begun to realize that we could have overlooked a vital contribution in the ongoing battle against cancer - and what's more, the studies are mostly done by TCM practitioners at the School of Chinese Medicine, who certainly ain't under suspicion to be interested in monetizing on a new drug. After all, natural medicine is not patentable.

From the petri dish to the bedside: APS improved quality of life in cancer patients.

Image 3: Astragalus has already proven its usefulness as an adjunct to the toxic cocktail cancer patients receive as part of their chemotherapy

In a first trial (Guo. 2011), the intravenous administration of astragalus polysaccharides (APS) at 250mg/day in connection with chemotherapy for 7 days lead to statistically significant improvements in the overall quality of life of advanced non-small-cell lung cancer patients. Personally, I find it most remarkable that it reduced the chemotherapy induced fatigue by >50% (as measured by a standardized Quality Of Life questionnaire). The objective response rate to chemotherapy was higher, as well: 42.64% (29/68) in the APS supplemented patients vs. 36.76% (25/68) in the control arm of the study, but these effects did not reach statistical significance (P = 0.483, indicating that chances are about 43% that this was just "conincidence").

In view of the immune-weakening effects of chemotherapy, it may also be important that astragalus has established anti-viral effects. It has been tested as an adjunct to interferon alpha-2b in anti-herpes therapy (Zhang. 1998) and against (chronic) hepatitis B infections (Wu. 2001; Dang. 2009) - the effects are yet rather mediocre and may be mediated by the same general immune-stimulatory effects of the herb (Block. 2003; Jiang. 2010). In this context, it is particularly noteworthy that a paper on herbal medicinces for viral myocarditis published in the reputable Cocraine Database of Systematic Reviews that ...

[..a]stragalus membranaceus (either as an injection or granules) showed significant positive effects in symptom improvement, normalisation of electrocardiogram results, CPK levels, and cardiac function.

And with the current vaccination-hysteria, we may soon see the practical realization of a proposal that has been made by Lin et al. in a recent paper on the effects of Astragalus polysaccharides (APS) on foot-and-mouth disease in swine (Lin. 2010), i.e. the addition of APS as an immuno-modulator for various vaccines (I guess it would certainly be better than mercury, don't you think ;-).

Conclusion: A promising herb... without a future?

Image 4: If all the info got you interested, Carl Lanore from Super Human Radio has recently sourced a bulk powdered version of astragalus. The bulk source is probably the only way not to run out of money before you notice any effects ;-)

Despite the accumulating evidence for the many health benefits that could be derived from the administration of crude extracts or isolated fractions of astragalus, chances that it will make it from Carl Lenore's Super Human Radio shop to the mass market are low ... or I should say non-existent, as long as the latter is still controlled by BigPharma and their right-hand men and women in the bureaucracy. After all, Astragalus membranaceus is not only non-patentable, it also does not appear to have any side-effects, the pharma companies could monetize on ;-) So regardless of whether future studies will validate or maybe falsify the hopes many naturopaths and TCM practitioners are pinning on this herb, MDs who follow the official guidelines, which state that the...

evidence for using astragalus for any health condition is limited. High-quality clinical trials (studies in people) are generally lacking (NCCAM. 2010),

will probably never prescribe it to their patients... unless, well unless some genius of a molecular biologist in one of the pharma-companies applies a few minor melcular tweaks to some of the active ingredients of astragalus, so that his company can file a patent application that goes beyond the extraction technique that has been patented for Harley's (questionable) T-65(R).

SuppVersity Science Round Up Seconds: Wheat Gluten Hydrolysates Fail, Exposure to Air Pollutants During Workout Reduces Brain Benefits, Homocysteine, B-Vitamins, Cognitive Impairment and Mortality

Before the profound weight loss (A) you don't see any of the glucose sucking and fad burning brown fat depots (black spots in B) on the neck of the in (B) 'foermerly obese', now only 'overweight' subject (also take a look at how the visceral fat in the abdominal region in (A) is actually pushing the organs upwards; img Vijgen. 2012)

Those of you who have listened to yesterday's show will have noticed that despite its flow the number of things you can discuss in a 1h podcast is simply very limited, to say the least. This is also why these Friday posts are probably never going to be simple summaries of the SuppVersity Science Round Up of the day before. The same is true for today and still I decided not to use the allegedly lame logo I did for the first two installments, but provide you with some 'real science' evidence of the absence of brown adipose tissue on the obese and it's magical reappearance after shedding 100lbs+ subsequent to a gastric bypass operation, instead (see image on the right).

Assuming that you have no idea what this "evidence" is for, I would suspect that you missed the live show yesterday and also did not find the time to download and listen to the podcast, yet -- right? Well, you should either download and listen to the show now and digest the Seconds later, or you read the following paragraphs first and download the podcast later.

What is not an option, however, is to miss one or another - I mean you can hardly want to eat the seconds if you have not had the main dish yet... and after listening to the podcast, I cannot imagine you don't want at least some seconds. Apropos seconds, here are today's seconds...

• Wheat gluten hydrolysate is not the new goto protein supplement - certainly not for female distance runners and probably not for anyone else, either! These are the kinds of studies that really annoy me. Studies that start out with blatant statements like "WGH [Wheat gluten hydrolysate] has been reported to suppress post-exercise rises in serum creatine kinase in male distance runners" (Hirao. 2012).
  
  

  

  Figure 1: CK, AST, ALT response in the "success trial" with men. In women even the miniscule beneficial effect on CK was not there. No reason to even think about buying a gluten hydrolysate as you new go-to protein supplement with only 5.6g of leucine/100g (whey has 50% more) and almost no GSH replenishing cysteine in it (0.9g vs. 3g+ in whey, which is more than +200% more).

  Sentences like that make the null-results of the study they precede look like the exception to the rule and are still nothing but a concession to a bias (let's hope not due to the grant from Nisshin Pharma Inc. which was the manufacturer of the wheat gluten hydrolysate used in this study). A bias, due to which an isolated observation as the slightly blunted increase in CK is blown up as if a slightly lower CK level was what could turn a sedentary pencil pusher into the next Hussein Bolt (Aoki. 2012).
  
  So, even if you are not afraid of the evil in gluten (which I believe not everyone has to), I strongly caution against making the switch from a high EAA protein with ton's of GSH boosting cysteine in it like whey to a mediocre grain protein, which is a potential allergen and contains tons of glutamine your body will readily turn into glucose, once it passes through the portal veign into the liver (I bet a large part won't even make it into systemic circulation).
  
  And as far as the purported "gender difference" goes the study at hand tries to blame the null result on (Hiriao. 2012), I suspect that it is rather the indisputable difference between the long-distance running at a continuous pace the women in the study at hand did, versus the totally different strains the guys in the previous study were exposed to during a soccer training + mini-match, which made the difference.
• Working out next to a street takes away some of the beneficial cognitive effects due to ultrafine particulate matter (UFPM) exposure. "Working out in the fresh air will promote weight loss more than working out inside." You heard me state that in one of the previous installments of the SuppVersity Science Round Up on Super Human Radio. Now this is still correct and based on sientific evidence, but at least as far as the cognitive benefits are concerned, working out outside does also have its downsides - at least for those of you who live in the inner city area.
  
  

  

  You better watch what you breath while you run.

  During a 12-week program the researchers from the Universiteit Brussel, the Hasselt University and the Royal Military Academy measured the improvements in physical performance, changes in serum markers and corresponding ultrafine particulate matter (UFPM) concentrations in the enviromnent in which their 15 previously untrained subjects conducted their aerobic training program thrice a week (Bos. 2012). What Bos et al. found was that the UFPM levels were signfificantly higher in the urban compared to the rural environment and that the higher UFPM exposures correlated with increases in leukocyte counts (p = 0.02), neutrophil counts (p = 0.04), and eNO levels (p = 0.002) that were exclusively observed in the group that trained in the urban environment.
  
  With the latter being markers of inflammation which exert their effects systemically, i.e. not just in the lung or musculature of which you may be thinking now, but also in the brain, it is no wonder that
  

  "reaction times on the Stroop task improved in the rural group (p = 0.001), but not in the urban group" (Bos. 2012). 

  What's comforting, though, is that the physical fitness did increase to a similar extend in both arms of the study.
• Homocysteine levels, mortality, cognitive impairment and which nutrients can offer some protection. I am not sure about what your impression is, but for whatever reason homocystein seems to be 'out of vogue' -- probably no room for it on the research agenda with all the hype surrounding vitamin D. It used to be all the rage in CVD risk research and today's news item is actually ain't about cardiovascular health, either.
  
  What the researchers from China and Taiwan actually were interested in was the correlation of high and low homocysteine levels with cognitive impairment and the corresponding nutrient intakes. In that Xiu et al. paid particular attention to the "B-vitamins" and found the following correlations between the mortality, cognitive status, homocystein levels and nutrient intake of their 1412 study participants (Xiu. 2012):
  

  • 

    Figure 2: Unadjusted mortality in the four quartiles of homocysteine levels (top); mortality according to homocysteine levels in subjects with different degrees of cognitive impairment (based on Xiu. 2012)

    if you go by the unadjusted data in figure 2, it's plain obvious that the all-cause mortality increases linearly from one quartile to the other 
  • this relation between plasma homocysteine levels and all mortality remained statistically significant after adjustments for age, sex, smoking status, BMI, physical function and general health were made
  • of the general foods, the scientists assessed, only regular fish intake had a statistically significant effect on homocysteine levels, with higher intakes being associated with lower homocysteine levels
  • of the b-vitamins choline was the only one with a significant association with plasma homocysteine levels (suggested read "Old School Supplement Choline Could Save Your Live and Liver!") 
  • neither betaine, nor vitamin B1, B2, B3 or B6 intakes did show statistically significant correlations with plasma homocysteine (not even "borderline significant; p > 0.15 for all, most way hither)
  • of the plasma markers, folate showed a highly significant correlation with homocysteine (14.4 nmol/L in the lowest HCY and 8.70 nnmol/L in the highest HCY group)
  • PLP, the active form of vitamin B6, came in close second with 70.3 nmol/l in the lowest HCY quantile and only 44.4 nmol / l in the highest quantile.
  Now, if you consider the fact that higher intakes of B-vitamins are probably not doing much to lower homocysteine levels int he elderly (at least not dose-dependently, when they are already getting enough) oddity #1, another look at the data in figure 2 will reveal oddity #2: The surprisingly high mortality in the lowest homocysteine quartiles in the patients with severe cognitive decline - how come? I mean, with low homocysteine they should not be at risk of having severe cognitive decline, anyway - right?
  
  Actually if you follow this rationale you can almost answer the question yourself. If you have low homocysteine and severe cognitive decline, the severe cognitive decline can hardly be from high homocysteine levels, so it must have another obviously pathological reason, or as the scientists have it
  

  "The joint effects of the 2 variables [homocysteine and cognitive decline] were most pronounced with severe cognitive impairment where mortality HRs ranged from 5- to 18-fold across a wide range of homocysteine concentrations. The findings with hypohomocysteinemia provide some insight into what might be an optimal range for this analyte in peripheral blood and tissues. The low concentrations may be seen with severe illness and malnutrition, and our study population comprises the health-vulnerable aged. For these reasons, we adjusted these associations for BMI (using the World Health Organization chronic energy deficiency category of, 18.5 kg/m 2 ), and we excluded those who died in the first year of follow-up. The findings were unchanged. Because mortality among the very old may have skewed the joint effects, these are presented for those ≤75 years and over, but again with similar findings." (

  A sarcastic person would now probably say: "We all have to go some time!" and just wave his hands at these results. True! And I am the last to advice you to become over-anxious. Yet in the mean time it would appear prudent to make sure to get your homocysteine levels checked from time to time, not to forget that choline is a b-vitamin as well and not to fall for the idea that you cannot overdose on B-vitamins - I don't have to remind you of the negative effects, specifically folic acid supplementation can have on all sorts of cancer (e.g. breast cancer, where a high folic acid intake from foods and supplements is associated with a +30% risk of cancerous growth; cf. Kim. 2006).

In case you are looking for the post on "ammonia accumulation brain-fog, toxicity, liver 'pathologies' and workout performance", yeah it was on the list, but I decided it would be a shame to tackle that within a short two paragraph seconds items. Don't worry I am not going to forget about it, after all its in my humble opinion one of the main reasons the diets and workout regimen of the many ambitious physical culturists fail. If you are still looking for more and have not listened to the podcast, yet, this would be the right moment to download the file from the Super Human Radio Network server (click here to download), otherwise the latest short news on the SuppVersity Facebook Wall may offer some diversion ;-)

References:

• Aoki K, Kohmura Y, Suzuki Y, Koikawa N, Yoshimura M, Aoba Y, Fukushi N, Sakuraba K, Nagaoka I, Sawaki K. Post-training consumption of wheat gluten hydrolysate suppresses the delayed onset of muscle injury in soccer players. Exp Ther Med. 2012 Jun;3(6):969-972. Epub 2012 Apr 3.
• Bos I, De Boever P, Vanparijs J, Pattyn N, Panis LI, Meeusen R. Subclinical Effects of Aerobic Training in Urban Environment. Med Sci Sports Exerc. 2012 Oct 15.
• Cankurtaran M, Yesil Y, Kuyumcu ME, Oztürk ZA, Yavuz BB, Halil M, Ulger Z, Cankurtaran ES, Arıoğul S. Altered Levels of Homocysteine and Serum Natural Antioxidants Links Oxidative Damage to Alzheimer's Disease. J Alzheimers Dis. 2012 Oct 29.
• Guest PC, Urday S, Ma D, Stelzhammer V, Harris LW, Amess B, Pietsch S, Oheim C, Ozanne SE, Bahn S. Proteomic analysis of the maternal protein restriction rat model for schizophrenia: Identification of translational changes in hormonal signalling pathways and glutamate neurotransmission. Proteomics. 2012 Oct 16.
• Hirao T, Koikawa N, Aoki K, Sakuraba K, Shimmura Y, Suzuki Y, Sawaki K. Female distance runners show a different response to post-workout consumption of wheat gluten hydrolysate compared to their male counterparts. Exp Ther Med. 2012 Apr;3(4):641-644.
• Kim YI. Does a high folate intake increase the risk of breast cancer? Nutr Rev. 2006 Oct;64(10 Pt 1):468-75.
• Vijgen GH, Bouvy ND, Teule GJ, Brans B, Hoeks J, Schrauwen P, van Marken Lichtenbelt WD. Increase in brown adipose tissue activity after weight loss in morbidly obese subjects. J Clin Endocrinol Metab. 2012 Jul;97(7):E1229-33. Epub 2012 Apr 24.
• Xiu LL, Lee MS, Wahlqvist ML, Chia-Yu Chen R, Huang YC, Chen KJ, Li D. Low and high homocysteine are associated with mortality independent of B group vitamins but interactive with cognitive status in a free-living elderly cohort. Nutr Res. 2012. Ahead of print.

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.

Pharmacological Starvation: 30% Increased Life Expectancy w/ Still to be Developed FGF21 Analog - The Royal Road To Longevity? Plus: Ground Yourself It's World Nutrition Day!

Do you really think this kid cares whether there is fructose in his/her banana? Think about that before you delve into the next religious discussion about whether or not food a is legit to eat, "not paleo" or "too high in carbs" *thank you*

It's World Food Day and I thought it may be nice to remind everyone about the hilariousness of such "important" first world problems as "eating X bananas a day is bad foryou", the notion of "non paleo" foods and the rest of the vitally important topics the blogosphere is so fond of, these days. Allegedly, neither the bloggers, nor the facebookers or forum posters, who spend so much time and energy debating these and similarly worldshaking issues, will be among the 24,000 human beings who are dieing each and every day from hunger, but maybe one or another of you, of whom I am sure that they don't belong to the group of real notorious nitpickers, will have a similar "grounding experience", from just being reminded of this figure, as me, when I heard it on the radio earlier this morning.

Don't get me wrong, I am not intending to point with a finger at anyone (if anything I would have to start with pointing at myself), but if one or another of you would pause for a second or two and have a similar "grounding experience" as I had, I would be happy.

From real starvation to starvation science
 
Although this prelude appears to segue quite nicely into today's science post, I am not sure if that's even a good thing... be that as it may, after listening to the news on the radio I was quite annoyed, when I read about a recent study by Zhang, Kliewer et al. on the wonderful effects of the "starvation hormone" FGF21 (fibroblast growth factor 21; the effects were observed in mutants who overexpressed FGF21, by the way) on yet another of those awful copy & paste items on Science Daily that are 99% hype and 1% science (in the scientists' defense it must be said that I am well aware of the fact that our, i.e. university or institutionalist, press offices are writing this stuff together in this way on purpose and are not really interested in the actual science background, though). With statements such as "[the mice] got the benefits of dieting without having to limit their food intake" (UT Southwestern Medical Center. 2012) the "article" tailors perfectly to the demands of the glutenous Westerner who applies his "the more the better" principle to all areas of his super sized life that people will probably already be emailing Dr. Kliever about the release date of the drug he surely must be working on.

And in fact, the actual results of the study (Zhang. 2012), the press release specifies by quoting Kliever who said "Male mice that overproduced the hormone had about a 30 percent increase in average life span and female mice had about a 40 percent increase in average life span" sound intriguing. After all this would mean that you would have a realistic chance of making it to the magic 100, when you would otherwise have died at the age of 77.

Starvation, real or hormonal is not the way to healthy longevity!

Nonetheless, the price you would have to pay to "starve yourself into this biblical age" - pharmacologically, of course since (a) otherwise no one could make money on it and (b) no one would want to do it - is high. And I am not sure any of you is willing to pay it.

Figure 1: What do you call it, when mice simply won't grow and end up as a small copy of their normal counterparts with identical body composition, but virtually no bone mass? Right! That's failure to thrive. Now, what do you call the same phenomenon, if the poor critters live 30% longer? Yeah, righ! That's a scientific break through!

I guess you could say you can cope with being a shrimpy weed (or a tiny version of yourself, which is actually what what you would be if you had half your current weight and the same totally average body composition; see figure 1), if that means that you can see your grand grand children rise, but your chances that this is going to happen outside of a wheelchair are not particularly high for men and the chance of seeing them at all is non-existent for women.

The combination of low bone mass and infertility should actually ring a bell with everyone who has been following the Athlete's Triad Series.

Why is that? Well, next to being a pathetic weed, your bone mass and density would be so low that the chances of literally breaking apart are probably way higher than the already low chance that any of these results do even translate to human beings.

And while men who like to gamble may want to make this bet with the pharmaceutical devil, the antifertility effect of FGF21 would not allow any women making the same bet to even have children. Which does obviously not make it very likely that they will ever get to see the children of their grand children - regardless of whether they become 200 years old, by the way.

I am therefore not so sure whether the mere fact that the FGF21 mutants' mobility was not effected is evidence enough of "living a nice, long life", as Kliewer is pointing out (UT Southwestern Medical Center. 2012).

There is no way this drug will be gluttony and thus "Western lifestyle" compatible 

Figure 2: Don't be fooled! The small "g/g body weight" makes all the difference! If you weigh half of a normal human being thanks to whatever patented FGF21 derivate you take, you better make sure you eat like half a human being, as well, if you don't want to shorten your life by 30%, instead of prolonging it!

And as far as the implicit promise of being able to eat "as much as you want" goes, it may be correct that "there were no differences in food intake, physical activity, oxygen consumption or respiratory exchange ratio" (see figure 2) but if you scrutinize the caption of the Y-axis you'll see the bad, bad letters "g/g body weight". And this label means nothing else than that whoever has written the press release has been trying to fool you, when he or she wrote

"The mice that overproduced FGF21 in this latest study were lean throughout their lives and remained lean even while eating slightly more than the wild-type mice, the researchers said." (UT Southwestern Medical Center. 2012)

The truth is, they ate almost half as much as the normal animals, so where on earth was this not a starvation diet? I mean, all of you who have read parts (better the whole) SuppVersity Athlete's Triad Series will be well aware that bone loss and infertility are hallmark features of in this case exercise induced "starvation".

And let's be honest, unless Mc Donalds is going to produce XXS Menues for people on FGF21, I can guarantee you that the only effect any future drug analog of this hormone is going to have is to make people's lives even more miserable than they already are... longevity? No way! After all, this is not going to correct the dietary induced failure of our natural satiety response that constantly drives us to overeat on all those things the people who are now probably lining up in front of Mr. Kliewer's office to be part of the earliest trial are not willing to give up, although they know that they are thus easily reducing their maximal life-expectancy by 30%!

The unsexy, since inconvenient truth is missing from the mainstream science breakdown

In view of the fact that neither the press guy (or girl) nor the scientists appear to have a wested interest to tell you that FGF21 activity is "paradoxically elevated in obese conditions" (Fletcher. 2012) and that something as awfully inconvenient (and moreover non-patentable!) as exercise is the best way to normalize not only the skewed FGF21 levels, but also to increase the expression of the "longevity factor" clotho (30-50% in a classic rodent model; cf. Fletcher. 2012), I consider it my duty to let you know that you neither have to resort to the exogenous provision of drugs, nor starve yourself and can still be sure to benefit from the effects of FGF21: Either by its modulation via exercise if you are obese as the aforementioned rodents or, more importantly, by its upregulation in normal weight individuals, like the 60 sedentary young women Cuevas-Ramos et al. put on a two week exercise regimen earlier this year, only to find that their

"[s]erum FGF21 levels significantly increased after two weeks of physical activity [and that this 66%! increment in FGF 21] correlated positively with clinical parameters related to the adrenergic and lipolytic response to exercise." (Cuevas-Ramos. 2012)

Now, I don't know about you, but I, for my part, would probably risk to make a bet with the devil (pharmacological or not) that anyone who is willing and able to appropriately fuel his workouts, get his share of anabolic and restorative sleep and refrain from overtraining, will get all the benefits, the press release aptly ties solely to the unquestionable pharmacological "separation of the hormone’s life span-extending effects", Kliever is cited for in the last paragraph of the copy & paste job, without any of the downsides.

The SuppVersity Approach to Longevity is therefore simple, cheap and 100% healthy: Work out, eat healthy and get your daily dose of SuppVersity news to know how you can optimize your training, nutrition and supplementation regimen ;-)

References:

• Cuevas-Ramos D, Almeda-Valdés P, Meza-Arana CE, Brito-Córdova G, Gómez-Pérez FJ, Mehta R, Oseguera-Moguel J, Aguilar-Salinas CA. Exercise increases serum fibroblast growth factor 21 (FGF21) levels. PLoS One. 2012;7(5):e38022.
• Fletcher JA, Meers GM, Laughlin MH, Ibdah JA, Thyfault JP, Rector RS. Modulating fibroblast growth factor 21 in hyperphagic OLETF rats with daily exercise and caloric restriction. Appl Physiol Nutr Metab.
• UT Southwestern Medical Center. Newsroom. Starvation hormone markedly extends mouse life span, without need for calorie restriction. Oct 16, 2012. < http://www.utsouthwestern.edu/newsroom/news-releases/year-2012/october/starvation-hormone-mangelsdorf-kliewer.html > retrieved Oct 16, 2012.
• Zhang Y, Xie Y, Berglund ED, Coate KC, He TT, Katafuchi T, Xiao G, Potthoff MJ, Wei W, Wan Y, Yu RT, Evans RM, Kliewer SA, Mangelsdorf DJ. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. elife. 2012;1:e00065. doi: 10.7554/eLife.00065.

Intermittent Thoughts On Intermittent Fasting - AMPK II/III: Leucine, HMB and a Glimpse on Other AMPK Modulators

Image 1: You pick a health, diet or diabetes supplement and I find the study that shows that in one way or another its effect is related to AMPK ;-)

I ended yesterday's installment of the Intermittent Thoughts on Intermittent Fasting Series on a pretty bold statement about the benefits of preworkout BCAA supplementation that would, at first sight, contradict common sense, or rather what common sense would dictate based on all you have read about the beneficial effects of BCAA supplementation on mTOR-related muscle protein synthesis (MPS) and the complementarity of mTOR and AMPK as regulators of anabolic (e.g. MPS, adipogensis ,etc.) and non-anabolic "scraping, rebuilding, recycling and repairing" processes. Since, after all, Bomb Jack, who posted a comment on last weeks installment of this series, is right: It would be logical that supplementation with BCAAs (he mentions HMB specifically) during the fast should result in dephosphorylation (~deactivation) of AMPK and thus negate its desirable effect on (metabolic) health.

And in fact, in the Wilson study I wrote about on Saturday the postprandial increase in AMPK phosphorylation, was blunted by the provision of carbohydrates, leucine or a combination of both (cf. yesterday's news) and you would assume that HMB supplementation would do the same, but the latter is - at least for chronic supplementation with low amounts (320mg/kg in rats ~ 52mg/kg in humans) of HMB - not the case (Pimentel. 2011), as the data I plotted in figure 1 clearly shows:

Figure 1: Effect one month of saline (control) or 80mg/day HMB on mTOR and AMPK phosphorylation and GLUT-4 expression in extensor digitorum longus (EDL) muscle of rats (Pimentel. 2011).

In the Pimentel study, there was, if anything, a non-significant increase in the AMPK and its purported downstream effect on GLUT-4 mediated glucose uptake  - both of which common sense would have told us to be compromised by HMB supplementation. While the lack of information on the "timing" or, more specifically, the interval between the last feeding and the intragastric administration (gavage) of 320 mg/kg body weight of HMB is a drawback in view of the significance of these results in an intermittent fasting context, rats usually eat at night and thus the administration of the 80mg of HMB (the rats weighed only 250g) "daily at the same time (during the light period)" will probably have coincided with a "fasting" period.

How can we explain that mTOR expression increased, while AMPK remained constant?

Are the different result a consequence of the metabolic magic of HMB? Well, before we analyze that in detail, there is another significant difference, we have to account for - in fact, a much more obvious one, which the amount of amino acids the rats were given in the Wilson and the Pimentel study, respectively (cf. figure 2).

Figure 2: Dosage, not type of supplement would be the most probable explanation for the different effects of leucine and HMB supplementation on AMPK phosphorylation in the Wilson vs. the Pimentol study.

I hope you did not already forget that, the main function of AMPK is to prevent that your cells run out of fuel or, to be precise, to avoid the ratio of "used" energy ADP and AMP (adenosine di- and monophospate) to ATP (adenosine triphospate) to continue to rise beyond a tolerable level. I further assume that you will be familiar with the fact that branched-chain amino acids bypass oxidation in the liver and thus become readily available energy sources for skeletal muscle (Renny. 2011). Now, if you put one and one together the answer seems pretty obvious: If the dosage of amino acids is sufficient (remember that those 270mg leucine are 4x more leucine than the the rats in the Wilson study got for "breakfast") to restore ATP levels to "appropriate" levels, the decrease in the ADP/ATP ratio will allow part of the AMP-activated protein kinase to be dephosphorylated.

According to our current understanding, BCAAs in general and leucine in particular trigger the ATP related decrease in AMPK and the complementary increase in mTOR by two distinct pathways, of which Tokunaga et al. write (Tokunaga. 2004)

[...]leucine stimulates p70α phosphorylation via mTOR pathway, in part, by serving both as a mitochondrial fuel through oxidative carboxylation and an allosteric activation of glutamate dehydrogenase. This hypothesis may support an idea in which leucine modulates mTOR function, in part by regulating mitochondrial function and AMPK.

In plain English: Leucine increases ATP when it is "burned" as fuel and it docks directly to the the non-active site of glutamate dihydrogenase enzyme and thusly increases the conversion of glutamate to alpha-ketoglutarate which in turn can be fed into the citric cycle to ultimately produce ATP.

Is it all about (cellular) energy ...

Figure 3: AMPK phosphorylation in Escherichia coli at different ADP/ATP ratios (data adapted from Xiao. 2011)

In April 2011 Xiao et al. published a study in Nature with some interesting quantitative data on the ADP/ATP ratio, on the one hand, the phosphorylation status of AMPK, on the other (Xiao. 2011). As my plot of the data in figure 3 shows, with increasing ATP levels (at constant ADP levels of 30µM) the phosphorylation of AMP-activated protein kinase in Escherichia coli BL21 cells declines by roughly -20% from 44% at a 30/0 ADP/ATP ratio to 22% at a 30/800 ADP/ATP ratio.

Yet, although these results would confirm the hypothesis that the main reason for the discrepancy is dose, or rather, energy related, and each and every nutrient that could potentially raise ATP levels, would eventually decrease AMPK, this still does not explain the increase in mTOR Pimentel et al. observed, despite (statistically non-significant) increases in AMPK.

... or is there a place for the "magic" of HMB?

As you probably know, beta-hydroxy-beta-methylbutyrat (HMB) is an oxidation product of leucine and / or its keto-acid alpha-ketoisocaproate (KIC) (Koevering. 1992). In 1998 Lembert et al. found that even KIC is not a direct substrate for ATP production, instead "KIC must transaminate with glutamate or glutamine to yield alpha-ketoglutarate and leucine" (Lembert. 1998). We may thus assume that similarly HMB cannot be used (directly) to restore cellular ATP pools. Moreover, HMB is thought to be the second (non-energetic) pathway by which leucine acts on protein synthesis / breakdown. According to a 2011 review of the literature by Zanchi et al. (Zanchi. 2011)

Nissen et al. (1996) suggested that HMB or some other metabolite (since there is no specific inhibitor to BCAT) is the main component responsible for the anti-catabolic effects of HMB because when adopting inhibitors of BCAA transamination, the only BCAA capable of anti-proteolytic effects is leucine, which undergoes a process capable of generating HMB (Slater and Jenkins 2000). Such effects were not observed when other BCAAs were tested (isoleucine and valine), suggesting that HMB or some metabolite may be the key element in promoting the [anticatabolic] effects.

When usually 5% of the dietary leucine is metabolized into HMB (Wilson. 2008), and these 5% are responsible for the non-ATP dependent effects on phosphorylation of mTOR, p70^S6k, and 4E-BP1 of leucine (Eley. 2007), it is no wonder that chronic intake of 80mg of HMB did stimulate mTOR in the absence of increased ATP levels (which would obviously have led to a decrease in AMPK expression that was not present in the Pimentol study), while 270mg leucine, yielding only 13.5mg HMB, did not stimulate mTOR, but was (ab-)used as a substrate to increase cellular ATP levels, thusly reduced AMPK levels and increased protein anabolism - different pathways, similar results: an increase in net protein synthesis.

Figure 4: Simplified illustration of the two distinct pathways by which leucine can work its muscle protein synthetic (MPS) magic and a hint on the compensatory (/) / amplifying (+) effects of exercise.

There is however, a third major pathway to the metabolic effects that are brought about by common intermittent fasting programs and this third player makes things even more complicated (cf. figure 4) - it's exercise! You probably remember from yesterday's installment that

1. during exercise in the fasted state temporarily AMPK increases and the energetically costly muscle protein synthesis (MPS) is reduced, while
2. after exercise (regardless of whether it was performed fasted or not, cf. "Glycogen-Free Growth") muscle protein synthesis increases due to an exercise-induced stimulation of the mTOR protein synthetic cascade

Before we dig deeper into this modulatory effects of different modes of exercise in the next installment of the Intermittent Thoughts on Intermittent Fasting, however, I want to conclude today's thoughts with a preliminary list of supplements / medications that have been shown to modulate the phosphorylation state of 5' AMP-activated protein kinase.

Image 2: If you insist on trying HMB, don't be stupid and buy a capped products, the prices for bulk HMB powder have lately been crushed - a major European carrier, for example, sells 250g at <13€ atm; HMB is thus cheaper than BCAAs, which cost 16Euros in the small 250g pack - did you hear me say that even 13€ is too much, no - you must be mistaken ;-)

"Should you prefer HMB over leucine as a dietary supplement to promote lean mass gains and prevent muscle loss during the fast?" I assume this is a question many of you will now be pondering about. My answer to this question would be "NO!" Firstly, if you are no construction worker or pursue a similar physically demanding profession, the fear of losing muscle (which is different from "feeling flat", my bodybuilding friends ;-) during a ~16h fast is hilarious, which means that BCAA, Leucine or HMB supplementation, while you sitting fasted at your desk in the office is simply unwarranted. Secondly, when you are exercising the increased energy demand will negate / compensate the negative effect the increase in ATP has on AMPK activity. And thus, thirdly, a large bolus of leucine (or a complete BCAA or EAA product) taken pre-workout will not only ward off proteolysis (as HMB would do) it will also provide the necessary energy to train harder and thus help to increase the exercise induced stimulus on protein synthesis.

All that and the absence of conclusive scientific evidence that would demonstrate the superiority of HMB supplementation over the provision of adequately dosed BCAA or EAA mixtures (it stands to reason that you cannot compare 3g of HMB to 3g of BCAA) are arguments against the use of β-Hydroxy β-methylbutyric acid. If you wanted to try it, anyway (and have no problem swallowing a powder that tastes like poison), the prices for bulk-powders have gone through the floor, lately ;-)

How to modulate AMPK "artificially" -  supplements, medications, hormones and more

In view of the fact, that the discussion of the effects of leucine (BCAAs and HMB) alone took much longer than I had expected and this whole episode took a different turn than I would have expected, the following list is more a preliminary overview than a comprehensive explanation of the effects of various supplements, medications, hormones and hormone-like substances on the AMPK. The latter will follow, as promised, but for today, you will have to content yourselves with what I would like to call a sneak peak on the AMPK-mTOR modulation handbook of which I hope that it will be one of the outcomes of all the past and future work that is going into this series ;-)

AMPK promoters:

• Adiponectin (Yamauchi. 2002; Handy. 2010; Iwabu. 2010)
• Alpha lipoic acid (Lee. 2005; Wang. 2010; Packer. 2011)
• Artemisia sacrorum Ledeb (Yuan. 2010)
• Aspirin (Sung. 2011)
• Astragalus (Zhou. 2009)
• Berberine (Ma. 2011)
• Brain-derived neurotrophic factor (Matthews. 2009)
• Caffeine (Jensen. 2007; Spirydopulos. 2008; Egava. 2009) 
• Capsaicin (Kim. 2010)
• Catechins / green tea (Huang. 2009; Murase. 2009; Reiter. 2010)
• Chromium (Wang. 2009)
• Ciliary neurotrophic factor (CNTF) (Watt. 2006)
• Cinnamon (Huang. 2011)
• Conjugated Linolic Acid (CLA) (HSU. 2011)
• Coptidis Rhizoma (CR), the dried rhizomes of Asian herbs (Egawa. 2011) 
• Cordiceps sinensis (Wong. 2010)
• Creatine (Ceddia. 2004)
• Curcumin (Kim. 2010)
• DHA (Jing. 2011)
• Ecklonia Cava (Kim. 2010)
• Garlic (Lee. 2011)
• Ginseng (Juang. 2010)
• Glucosamine (Kong. 2009)
• Grape seed extract (Meeprom. 2011)
• Hibiscus sabdariffa extract (Yang. 2010)
• Interleukin-6 (Kelly. 2009)
• Kidney bean extract (Lee. 2009)
• Malva verticallata seeds (Jeong. 2011)
• Metformin (Zhou. 2001; Freyer. 2002; Ohira. 2009)
• Mulberry extract (Tsuduki. 2009)
• Nicotine (Cheng. 2007)
• Prostaglandin E2 (Zhu. 2011) 
• Pu-erh tea (Way. 2009) 
• Quercitin (Jung. 2010)
• Raishi Mushroom (Lane. 2011)
• Resveratrol (Fullerton. 2010; Lin. 2010; Breen. 2008)
• Tiozolidinediones (diabetes meds. like rosiglitazone) (Freyer. 2002; LeBrasseur. 2005; Yang. 2011) 
• Vanadium (Hwang. 2011)

I still have two things to add to this list, firstly, this list is the result of a VERY cursory and 100% random search and is not even intended to be complete (at this time ;-). The intention (at least for in this installment) is to show you that an overwhelmingly large percentage of purported health supplements, diabetes and obesity treatments work via the AMPK pathway. And, secondly, I decided to limit the references to 1-3 per compound, even if in cases such as Metformin, ALA & Co the number of relevant studies is probably >500. Therefore you better consider the given references as evidence that I did not make up any associations between compound X and AMPK phosphorylation - and, if you want to know more before the release of the next installment, I suggest you go to PubMed and enter the respective keywords and do some digging on your own (your SuppVersity homework of the day - so to say ;-)

I hope you do not mind that I did not manage to tackle the effects of sleep and exercise in this installment, as I had originally intended. It is, after all, the central characteristic of this series that I sit down in front of the computer and start thinking at point "A", then I dig, here, get distracted there and follow up on "A1" to "A743", so that the output is by no means as structured and straight forward as my lectures and seminars or my SuppVersity blogposts on isolated topics... so, I can only hope that you enjoyed the turn this installment took (at best, because you learned something new) and in the unfortunate case that you did not enjoy what you have just read, you can at least look forward to the next episode of the Intermittent Thoughts on Intermittent Fasting Series ;-)