Caffeine Protects Brain Function Against Stress & SAD Diet; Coffee Withdrawal, Anxiety & More; Giardia, Messy Subtenant W/ Gusto For Arginine; Vit B6 & n6:n3 PUFA Ratio

19 Billion Euro that's the estimated 2011 financial burden due to lung cancer, alone, here in Europe and the On Short Notice figure of the week (information based on ESMO2012 press release)

Those of you who are also following the SuppVersity facebook news, will probably recognize the figure on the right: 16,000,000,000€ or $24,419,000,000, that's the estimated economical burden due to lung cancer, alone, here in Europe (cf. "Who cares if people are dying as long as the economy is thriving?"). An enormous financial loss, and still not the reason that this is my figure of the week. Rather than the financial damage, itself, it is the tragic fact that only the latter, yet not the fate of the patients and their families, would make a valid argument, when policy makers were debating a long overdue, total and all-encompassing public smoking ban... but now for a couple of more sciency, yet not less intriguing news from the past week.

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Problems thinking straight? Guess what: 3-4 cups of coffee could help :-) According to a soon-to-be-published paper by scientists from the Jordan University of Science and Technology in Irbid, Jordan, the ingestion of the human equivalent of approximately 3.8mg caffeine per kg body weight or 3-4 cups of coffee per day, can inhibit both, the stress, related as well as diet induced (we are talking of the "typical" Western diet (WD), that's both high in carbohydrates and fat) cognitive impairments (Alzoubi. 2012)... well, at least in the researchers 3-months rodent study it worked like a charm

• learning trial: animals in the caffeine/stress, caffeine/WD, and caffeine/stress/WD groups made fewer errors, than non-supplemented stressed or WD animals; overall their performance was comparable to those of the control
• memory tests: treatment reduced the number of error and restored short-term memory and long-term memory during chronic stress and/or WD (P < 0.05) to normal levels

With respect to the underlying mechanisms the scientists speculate that caffeine may "act mainly by inhibiting adenosine receptors" (Alroubi. 2012), which has in turn been shown to to inhibit long term potentiation (LTP) in rat hippocampal slices and disrupt the process of learning and memory at the synaptic level by blocking release of glutamate (de Mendonca. 1994).

Additionally, caffeine has also been shown to increases the expression of hippocampal brain-derived neurotrophic factor (BDNF) and its receptor, which is impaired in response to chronic stress and a hypercaloric Western diet (Aleisa. 2006; Molteni. 2004) and leads to deteriorations in cognitive performance. In the long run those effects could also contribute to the anti-dementia and anti-Parkinson's effects, I mentioned in the recent SuppVersity post on the insulin sensitizing effects of coffee.

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Figure 1: While the Hedonic tone and alertness reduced to baseline on day 5 of caffeine withdrawal, the habitual caffeine consumers had >15% higher anxiety scores on day 7 after giving up on their daily dose of methylxanthine (data calculated based on Smith. 2012).

Don't worry, caffeine will also work for humans. And what's best, upon short-term withdrawl (8 days) your cognitive performance is not going to suck - at least not as much as when you are stressed or living on pizza and French fries, only. All that and a couple of interesting other results have been published ahead of print in the online version of the Journal of Pharmacology (Smith. 2012).

To probe the effects of acute caffeine ingestion on cognitive performance and the influence of previous caffeine consumption and withdrawal, Andrew P Smith, Gary Christopher and David Sutherland recruited 70 volunteers (25 male, 45 female; mean age 22.8 years). The 35 consumers (>100mg caffeine /day, mean 300mg; range 110–600 mg) were put on withdrawal and tested on day 2, alone and without caffeine, and day 8 together with the non-consumers in a double-blind placebo-controlled fashion. During the caffeine challenge, the cognitive performance was tested twice, once before and once 30min after the provision of the caffeinated beverages.

Anxious, but smart: Caffeine gives you the edge

The results of the trial clearly indicate that the ingestion of 2 mg/kg of caffeine, which were served in decaffeinated coffee or tea 30min before the testing procedures, were associated with faster simple reaction times, fewer long responses, greater detection of targets in the cognitive vigilance task, and faster encoding of new information.

"The results confirmed previous findings, with ingestion of caffeine being associated with a faster simple reaction time, fewer long responses, more targets detected and faster encoding of new information. There were no main effects of consumer status, nor were there any significant interactions between caffeine and consumer status." (Smith. 2012)

Notwithstanding, I believe that many of you will probably be more interested in the effects of caffeine withdrawal on overall withdrawal symptoms (figure 1, top), as well as the alertness, hedonic tone and anxiety (figure 1, bottom) and the cognitive performance on day 2 of the withdrawal period (figure 2, left), than in any of the well-established performance cognitive performance boost, right?

Figure 2: Performance on day 2 of withdrawal phase (w/out caffeine) and on day 8 before (w/out caffeine) and after (w/ caffeine)the ingestion of decaffeinated tea or coffee with 2mg/kg caffeine in it (data based on Smith. 2012)

As you can see on the left-hand side of figure 2 there was a minimal performance decline on day 2 of the withdrawal phase, but the latter was statistically not significant and all measured markers of cognitive function had returned to normal on day 8 (remember longer response times = worse performance!), when the resumption or first time provision of caffeine spiked the reaction times and lowered the mistakes in all tests, irrespective of whether the subjects were former habitual consumers on withdrawal, or not.

Outside of controlled experiments "real" coffee and tea do at least as well

Since a large cup of coffee contains about the same amount of caffeine the scientists simply added to decaffeinated beverages, to ensure that the drinks could not be distinguished (by their smell for example), you can simply stick to your regular coffee and if you want to enjoy similar benefits. And to be honest, in view of the plethora of benefits of chronic low dose coffee consumption, I would not even think for a second about whether or not you may be missing out on the occasional boost, when you are not "going on withdrawal" from time to time...

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Figure 3: W/out arginine (Arg-) intestinal epithelial cells can't proliferate (graph based on Stadelmann. 2012)

Giardia eats away your guts arginine supply and makes itself at home within an increasingly morbid digestive tract! As a group of scientists from Sweden and Argentina reports in their latest paper, the protozoan parasite, Giardia intestinalis, feasts on the arginine your gut cells need to proliferate (Stadelmann. 2012). This will lead to reduced polyamine levels and upregulated cell cycle inhibitory genes, which will eventually disrupt the the cell cycle of the intestinal epithelial cells. The reduced intestinal epithelial cell proliferation, on the other hand, allows the gut pathogen to thrive and will, in the long run, disrupt the intestinal tissue homeostasis and thus initiate the decay of the intestinal epithelium  - a central feature of so many of the wide-spread gut pathologies.

Provision of additional arginine + citrulline can help ... in the short run

Now, the good news about all that is that the in-vitro data in figure 3 clearly suggests and anecdotal, as well as the effective therapy of diarrhea patients with arginine/citrulline actually confirm that the provision of supplemental arginine (or citrulline) constitutes a cheap and readily available way to ameliorate the decay, until the bugs have been eradicated by antimicrobial drugs.

A pros pos, antimocrobial drugs, with regard to latter, Noa Tejman-Yarden and Lars Eckmann write in a recent review of the latest drug innovations, that despite the fact that metronidazole and other antimicrobials are usually effective, "treatment failures are common and antimicrobia resistance occurs" (Tejman-Yarden. 2011), so that it would appear as if complex derivatives of 5-nitroimidazole and benzimidazole, which form the core structure of the most widely used antigiardial drugs, will replace them in the short-run. At least for so long, until several new classes of antigiardial drug candidates that have already been identity by high-throughput screening of large compound libraries, will eventually hit the market (Tejman.Yarden. 2011)

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More about vitamin B6: Helps with neurotransmitters synthesis; is involved in nerve function and necessary for normal brain development & function; influences mood, and melatonin production; effects circadian clock; is needed for B12 absorption and thus red blood cell production

When low: "Pins and needles" in extremities, mental disorders, seborrheic dermatitis, estrogenic PMS, dizziness, irritability, kidney stones, abnormal EEG, anemia, convulsions, edema (water retention), hypothyroidism, migraine-headaches, glossitis, lymphopenia

When high: Depression, suicidal tendencies, severe fatigue, mood swings, low blood sugar, migraine-headaches, heart palpitations, thyroid abnormalities (hyper- in the short, hypo in the long term), numbness in hands and/or feet, spinal / nerve degeneration, muscle spasms / cramps, osteoporosis, arthritis, higher blood pressure (short-term suppl.), lower blood pressure (long-term suppl.), mineral imbalances (high phosphor & magnesium vs. low sodium & calcium), restlessness, insomnia, vivid dreams, decreased estrogen & prolactin, depressive PMS.

RDA (adults): 1.3 mg*
*higher for pregnant women & >50y

Upper tolerable limit: 30-100mg*
*depending on the source of information

Food sources: chicken, turkey, tuna, salmon, shrimp, beef liver, milk, cheese, lentils, beans, spinach, carrots, brown rice, bran, sunflower seeds, wheat germ, and whole-grain flour

n6:n3 ratio does not depend on dietary intake alone: A marginal deficiency in vitamin B6 will skew your serum PUFA levels towards the N6-side That's the long and short of the results of a study that's going to be published in the October issue of the Journal of Nutrition.

Mei Zhao and her colleagues analyzed the fatty acid profiles in plasma, erythrocytes, and peripheral blood mononuclear cells (PBMC) of healthy men and women who had been fed a low-vitamin B-6 (pyridoxine) diet for 28 days and observed that contrary to the plasma HDL and LDL cholesterol concentrations, the amount of free fatty acids (FFA) in the blood and the erythrocyte and PBMC membrane fatty acid compositions, neither of which showed any statistically significant changes, the amount of all long-chain polyunsaturated fatty acids, i.e. arachidonic acid (n6) and EPA and DHA (n3) decreased from 548 ± 96 to 490 ± 94 μmol/L, 37 ± 13 to 32 ± 13 μmol/L, and 121 ± 28 to 109 ± 28 μmol/L, respectively.

The subsequent 8% increase in the total n6:n3 PUFA ratio from 15.4 to 16.6 is not alarming, but if this trend would continue linearly, it would certainly become problematic, in the long run. Moreover, the decrease in both n6 and n3 long-chain PUFAs (of which people tend to forget that the "inflammatory" arachidonic acid is as vitally important as its "anti-inflammatory" omega-3 counterparts) could provide an alternative / complementary mechanistic explanation for the increased cardiovascular disease risk that has been associated with vitamin B-6 deficiency.

In view of the fact that the RDA is not exactly high and can easily be achieved from dietary sources, along (as long as you follow a diversified whole foods diet), and considering the fact that high levels of B6 have been associated with more negative side-effects than B6 deficiency (see infobox on the right; please note that I collected the information on a couple of trustworthy websites on RDAs & co and did not verify the research on each of them!), I would however caution against the typical Western "more helps more" supplementation mentality.

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Figure 4: Easy come, easy go - the mass you gain and the fat you lose by doing nothing than simply injecting testosterone is lost / regained within 6 months after discontinuation of the "testosterone therapy" (Forbes. 1992); read more about the role of testosterone in skeletal muscle hypertrophy in the Intermittent Thoughts on Building Muscle

In view of the fact that (a) today's short news items are pretty long(ish) and you still got a couple of interesting facebook news to check out, such as...

• health related: "Vitamin D: We probably won't know before 2017, whether supplementation is advisable", "Aromatase inhibitors to treat endometriosis", or 
• muscle related: "The muscle sparing effects of CLA + Omega-3" and a true classic "Muscle mass gained on injectable testosterone is lost, when injections are seized", 

... and a plethora of additional gems from the realms of health, exercise, nutrition & supplementation, I will call it a day for today and save the exercise and a couple of other exciting On Short Notice items for later next week.


References:

• Aleisa AM, Alzoubi KH, Gerges NZ, Alkadhi KA. Chronic psychosocial stress-induced impairment of hippocampal LTP: possible role of BDNF. Neurobiology of Disease 2006;22:453–62. 
• Alzoubi KH, Abdul-Razzak KK, Khabour OF, Al-Tuweiq GM, Alzubi MA, Alkadhi KA. Caffeine prevents cognitive impairment induced by chronic psychosocial stress and/or high fat-high carbohydrate diet. Behav Brain Res. 2012 Sep 20.
• ESMO. Press releases related to the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna.
• Forbes GB, Porta CR, Herr BE, Griggs RC. Sequence of changes in body composition induced by testosterone and reversal of changes after drug is stopped. JAMA. 1992 Jan 15;267(3):397-9.
• de Mendonca A, Ribeiro JA. Endogenous adenosine modulates long-term potentiation in the hippocampus. Neuroscience 1994;62:385–90.
• Molteni R, Wu A, Vaynman S, Ying Z, Barnard RJ, Gomez-Pinilla F. Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor. Neuroscience 2004;123:429–40.
• Smith AP, Christopher G, Sutherland D. Acute effects of caffeine on attention: a comparison of non-consumers and withdrawn consumers. J Psychopharmacol. 2012 Sep 19.
• Stadelmann B, Merino MC, Persson L, Svaerd SG. Arginine Consumption by the Intestinal Parasite Giardia intestinalis Reduces Proliferation of Intestinal Epithelial Cells. PLoS ONE. 2012; 7(9): e45325. 
• Tejman-Yarden N, Eckmann L. New approaches to the treatment of giardiasis. Curr Opin Infect Dis. 2011 Oct;24(5):451-6.

Long Chain Triglyceride Feeding Reduces Exercise Performance by >55% - Cambridge Scientists Find Reduced Mitochondrial Efficiacy in Rat Hearts.

Image 1: The ketogenic diet is also
referred to as the long chain
triglyceride diet by some dieticians
(image from fingercandymedia.com)

In view of the current low-carb hype, people tend to forget that, after all, carbohydrate consumption has been shown time and again to improve the performance of endurance athletes. And despite the existence of a few studies about "fat adaption" which report equal or even improved endurance performance in athletes on low carb diets, previous findings of Murray and his colleagues from the Department of Physiology, at the University of Cambridge clearly showed detrimental effects of short term high fat feeding (9 days) on the exercise capacity of rats. These results are corroborated by findings of Holloway et al. (Holloway. 2011) who found cardiac high-energy phosphate metabolism and cognitive function to be impaired in healthy human subjects on a high-fat diet. Now, it is quite obvious that these findings stand in contrast to all the beneficial effects about which you have read at the SuppVersity and even much more mainstream scientific webpages, such as Science-Daily, lately. Well, I guess this makes the results of Murray et al.'s latest study particularly interesting (Murray. 2011b).

Illustration 1: Study design.

In order to find out what the differential effects of medium and long chain triglyceride feeding on rats were the scientists allocated 33 rats to one out of six groups (cf. illustration 1), of which three were allowed to live a lazy rat-life, while the other three groups (the exercise groups)

... were habituated to a motorised treadmill (Columbus Instruments, OH, USA) over a 14 day period, running at gradually increasing belt velocities

until the rats were "proficient at running on the treadmill for 5 min at a velocity of 10 m/min on a 5° incline". And while I do not think you would call running on a 5° incline at a speed of 10m/min (=0.6km/h or 0.37miles/h) exactly "athletic" in human terms, this was only the initial speed the treadmill was set to in the exercise tests in the course of which the speed was increased by an additional 1 m/min with each minute until the rat fatigued.

Other than one may have expected, none of the fat-feedings induced significant changes in body weight in the sedentary rats, when compared to their chow fat controls (cf. figure 1). The +59% increase in visceral (epididymal) fat, the LCT fed rats experienced, is however a clear marker of impeding metabolic derangement and indicates, in the presence of otherwise unchanged bodyweight, a significant loss of lean body mass in the long chain triglyceride fed rats.

Figure 1: Selected biomarkers of sedentary and exercised rats after 15 days of standard chow, high medium chain triglyceride or high long chain triglyceride diet in comparison to chow fat, non-exercised control
(data calculated based on Murray. 2011b)

In the exercised rats, on the other hand, medium chain triglyceride feeding had quite similar effects (+44% vs. sedentary chow fat control), although the shorter MCTs did not exert any significant detrimental effect on the exercise capacity of the rats.

Image 2: Current research
suggests that MCT oils are
probably not useful to athletes
who are not on a very low
carbohydrate diet. The replacement
of long chain with these shorter
chain triglycerides, on the other
hand, could make sense from a
performance point of view

Medium Chain Triglycerides, the performance fats? While there was no decrease in performance observed in the MCT group in the study at hand, the performance increase some supplement companies will promise in order to sell their MCT oils and/or MCT-enriched supplements, was non-existent as well. In this regard, Murray et al. remark that

[i]t has been theorised that MCT-rich diets might improve energy utilisation during exercise, perhaps through increased ketogenesis, however there is little conclusive evidence for this.

Interestingly, one study that is often cited in this context (Fushiki. 1996) in which the swimming endurance capacity of mice fed an MCT-rich diet over 6 weeks increased, used a LCT-fed mice as controls. In view of the results of the study at hand, this "ergogenic effect" of MCTs has to be reevaluated. It is in fact much more likely that MCT-fed rats just avoided the detrimental effect of the LCT diet.

So what does all that go to say for you, as an active or even athletic human being who is trying to find the appropriate and delicate balance between health, looks and performance? A fundamentally important observation was made in this context by the same group of Cambridge scientists a few month before (Murray. 2011a), when they found that endurance exercise training blunts the deleterious effect of high-fat feeding on whole-body energy efficiency and mitochondrial respiration - much to the scientists surprise highly trained endurance athletes appeared to even thrive on the "bad" high fat diet.This is an observation I would attribute to what I initially referred to as "fat adaption", i.e. an improvement in both rate and energy efficacy of fatty acid oxidation in a group of people whose bodies are used to literally "run out of carbs", no matter how many energy gels they are consuming in the course of a competition.

With regard to the fatty acid specific differences Murray et al. observed, one could speculate that in an intermediate phase, i.e. for example in the first 2 weeks of low-carb dieting, where most dieters complain about low energy levels, brain fog and other symptoms of suboptimal energy metabolism, the use of MCTs to provide "carb-like instant energy" could provide an adequate strategy to bridge the time-gap your body needs to ramp up mitochondrial fatty acid oxidation in order to fuel your metabolic demands from dietary fats, alone.

If you have read the Amino Acids for Super Humans write-up on l-carnitine, you are probably already aware that supplementation with L-3-hydroxy-4-N,N,N-trimethylaminobutyric acid (l-carnitine) could help to speed up / sustain your ability to use (long chain) triglycerides as fuel by shuttling the fatty acids into and (this is commonly overlooked) out of your cellular power plants (if you want to know more about LCAR, ALCAR, LCLT & co, read Part IV of the Amino Acids for Super Humans Series).

That being said, it would be interesting to see a similar LCT feeding study with appropriate adaptation times in order to decide whether the rats just were not accustomed or generally unable to efficiently metabolize the long chain triglycerides and to access what the long-term consequences of the upregulation of PPAR-gamma and UCP3 in the heart muscle will look like. I'll keep you updated!

Ketogenic Dieting and Vitamin & Mineral Imbalances!? Differential Effects of Classical Ketogenic and Medium Chain Triglyceride Ketogenic Diet on Vitamin and Mineral Status in Children

"Keto diets are unhealthy! You simply do not get enough quality nutrients if you do not eat your healthy pasta, bread and other starchy carbs." I suppose many of you - just like me - cannot tolerate the black-and-white thinking of either of the two, the high or the low/no carb camp and are thus as interested in the recently published results from a 12 month dietary intervention using either a classical ketogenic diet (Christodoulides. 2011), which uses long chain triglycerides as its primary source of fatty acids, or a medium chain triglyceride ketogenic diet, where the majority of fatty acids came from MCT oils [unfortunately the scientists used Liquigen or MCT oil (both SHS International) instead of a natural source of MCTs, like coconut oil] on vitamin and mineral status of 49 children (age 2-16 years).

Although the results are somewhat skewed due to the extensive use of supplements - apart from the MCT oil in the MCT group, all children received an additional mulit vitamin [either Forceval Junior capsules (Unigreg, Morden, UK) or Phlexy-vits powder sachets (SHS International)], the results (cf. figure 1) suggest that, after all, ketogenic dieting cannot be that detrimental to you vitamin and mineral status as one might expect.

Figure 1: Effects of 12 month on classical or MCT based ketogenic diet on vitamin and mineral status in 49 children.
(data adapted from Christodoulides. 2011)

It is particularly interesting that while vitamin E increased dramatically in the long-chain fatty acid fed "classical keto" group (no wonder in view of the amount of vitamin E present in most long-chain seed oils), the vitamin A level in that group dropped similarly dramatically.

In comparison, the changes in Zinc, Selenium and Magnesium appear to be negligible. In the case of magnesium the observation that

the pairwise comparison with baseline in children who provided data at both time points showed a significant decrease at 3 and 6 months and a highly significant decrease [of magnesium levels] at 12 months

especially in the classical diet is a cause of concern for "those using the diet to treat children with intractable epilepsy", where low(er) magnesium levels appear to correlate with seizures and magnesium supplementation is used as part of the common treatment strategy.

I leave it up to you to decide, whether your think that either a classical or, let alone, a MCT based (with MCTs from supplements instead of whole food sources) diet can be more than a temporary intervention or treatment strategy. Despite the positive evidence that you won't die from mineral insufficiencies or vitamin deficiencies within 12 month of vitamin and mineral supplemented (I assume every keto dieter will take a good multi vitamin anyway) ketogenic dieting, I am still not even remotely considering this to be an option for me.