Science Round-Up Seconds: 8 Nootropics to Combat Stroke, Alheimer's & Co and Boost Cognitive Performance. Plus: 7 Rarely Thought of Side Effects of High Dose Glutamine.

Effects of infusion times on phenol content of black tea (Ramalho. 2012)

If you have already listened to the podcast of yesterday's Science Round-Up on the Super Human Radio Website (click here if you haven't and wan't to know what the following is all about), I suppose you will not mind that I compiled some of the complex information about "optimal" tea brewing in the illustration to the right (based on Ramalho. 2012). The colored arrows indicate the time-points at which the given compounds in the tea achieved peak values. The exact time point is also given in minutes, so that a 9' in front of the green caffeine and on the left to the green arrow pointing at the 9 min point tells you "it took 9 minutes for the caffeine content to reach it's maximum in the British tea". The graph in the background shows the catechin concentration depending on the infusion time.

Cholinergenic nootropics - What a recent review says

I guess some of you will probably have heard about piracetam or lecithine as purported enhancers of cognitive function. According to a recent review in the Journal of Experimental Pharmacology those two are yet not the most prosing agents:

Eggs are rich in choline which is an essential nutrient and was abundant in the classic BB diets (rear more)

• Piracetam: no cerebroprotective effects in patients who have open heart surgery, but does help on non-open cardiopulmonary bypass surgery (Holinski. 2008), beneficial effects in response to cerbrovascular and cognitive disorders traumatic origin (Malykh. 2010), intravenous piracetam can prevent cognitive deficits in response to anesthesia (Fesenko. 2009)

• Lecitin: does not improve cognitive deficits in patients (Amenta. 2011; Parnetti. 2007)

More promising "nootropics" - specifically in view of what most people do actually expect, when they buy such products.

• Oxiracetam: improves cognitive performance except for patients with dementia (Malykh. 2010)

• Citocoline: general neuroprotective effects (Alvares-Sabin. 2011), improvements in cognitive performance in healthy and patients and patients with dementia (Secades. 2010), helps with cognitive dysfunction in Parkinson's (Vale. 2008), helps with cognitive function in dementia of neurodegenerative and vascular origin (Parnetti. 2007), prevents cognitive decline after a stroke (Alvarez. 2011), improves recovery after stroke (Garcia-Cobos. 2010) 

• Cerebrolysine: produces signifant cognitive improvements in vascular dementia (Guekht. 2011), effective for both cognitive function and behavioral symptoms in Alzheimer's (Alvarez. 2011), promising results in patients with Alzheimer's (Plosker. 2009)

And a couple of things you would not usually associate with nootropics:

• 

  Suggested read: Amino Acids for Super Humans on the effects and differences between the various forms of carnitine (read more).

  Acetyl-L-carnitine: improves cognitive performance in patients with encephalopathy, decreases anxiety and increases general energy and wellness, as well as fatigue and age-related cognitive deficits (Malaguernera. 2008, Liu. 2008),can reduce or block neuronal death in neurodegenerative diseases (Manusco. 2007), helps ammeliorate hyperammonemia (Cagnon. 2007)

• Saffron extract: beneficial effects in mild to modest Alzheimer's  (Akhondzadeh. 2010)

• DHA (fish oil): positive effects on verbal recognition memory in old subjects (Yurko-Mauro. 2010)

Interestingly, the most profound effects appear to be brought about by acetyl-l-carnitine. In that it's worth mentioning that the benefits could still be related to cholinergic mechanisms, since it has long been known that ALCAR can increase the expression of choline acetyltransferase activity in the central nervous system (Taglialatela. 1994). And the latter is, as the name implies, necessary to form the neurotransmitter acetylcholine .

Glutamine probably not suitable for chronic high dose supplementation

Czech scientists warn about the risks of chronic high dose glutamine supplementation. I know that many of you are still too bamboozeled by the "protein for everything and let the liver take care of any glucose demands I may have" theory, of which you could probably argue that it is the bastard child of the standard BB diet with low carb. Maybe the following recently published paper by a scientist from the Charles University in Prague can help cure this "disease" (and your cognitive problems, fatigue and brainfog).

According to Holecek, the chronic ingestion of glutamine / glutamine enriched diets in can lead to...

Figure 1: In the presence of high amounts of glutamine outside of the cell, the glutamine synthesis (GLN) and with it the ammonia detoxification from muscle tissue sucks (Holecek. 2012).

"(1) Alterations in amino acid transport-as GLN shares the transporters with other amino acids, enhanced GLN intake may impair amino acid distribution among tissues and their absorption in the gut and kidneys.

(2) Alterations in GLN metabolism-GLN supplementation may impair synthesis of endogenous GLN and enhance glutamate and ammonia production.

(3) Alterations in ammonia transport-GLN supplementation may impair ammonia detoxification and negatively affect the role of GLN as the carrier of ammonia among tissues.

(4) Abnormalities in aminoacidemia-increased plasma levels of GLN, glutamate, citrulline, ornithine, arginine, and histidine and decreased levels of valine, leucine, isoleucine, glycine, threonine, serine, and proline are reported.

(5) Alterations in immune system-as GLN has immunomodulating properties, the effect of chronic GLN consumption on the immune system needs to be assessed.

(6) Effect on tumor growth-it should be elucidated whether chronic intake of GLN increases the risk of cancer.

(7) Effect of the withdrawal of GLN supplementation-due to the adaptive response of the organism to enhanced GLN consumption, the withdrawal of GLN may enhance the risk of health problems resulting from GLN deficiency." (Holecek. 2012)

Remember the post on the ammonia induced peripheral and central fatigue with high dose chronic BCAAs supplementation?

In view of the fact that some people consumer up to 40g of glutamine regularly, Holecek demands that "long-term studies should be performed" to test the side effects and evaluate whether there is any benefit at all to justify chronic consumption of a GLN-enriched diet.

So, relying on glutamine instead of carbs, as smart as this idea appears to be in the current carbophobia, could actually make you stupid due to the disruption of the intracellular ammonia detoxification, which is not a problem in muscle only, but also in the brain.

In the end, what we are seeing here is just another instance of a disruption in the natural balance of things. Ornithine, citrulline and arginine, for example are involved in the detoxification of ammonia via the urea cycle. They are however not the only bottleneck to the system.

Obviously your liver and kidneys will have to handle the clearance. People with liver problems (or persons taking "supplements" or NSAIDs that may impair the liver function) are therefore particularly prone to hyperammonemic encephalopathy (Kanamori. 1996; Lemberg. 2009)

Bottom line: Glutamine, just like everything else, in moderation and by no means so much that your body runs on glutamine as fuel. Aside from the mentioned amino acids that help the clearance of ammonia from the blood stream, taurine appears to exert a direct protective affect in the brain (Chepkova. 2006), and lactulose (a fermentable carbohydrate) can reduce the ammonia influx from ammonia producing bacteria in the gut (Vince. 1980). So if you want to wear a helmet when you bang your head against the wall, these would be suggested "take supplement B in order to counter the side effects of supplement A" - side effects of a supplement you would not even have to take, by the way (100% bro-logic ;-)

References: 

• Amenta F, Carotenuto A, Fasanaro G, Lanari A, Rea R, Traini E. Preliminary results of Ascomalva trial on the association of donepezil and choline alphoscerate in Alzheimer’s disease with associated cere-brovascular injury. G Gerontol. 2011;59:89–9.
• Akhondzadeh S, Shaf iee Sabet M, Harirchian MH, Togha M. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativusin the treatment of mild-to-moderate Alzheimer’s disease. Psychopharmacology (Berl). 2010;207:637–643.
• Alvarez XA, Cacabelos R, Sampedro C, et al. Efficacy and safety of cerebrolysin in moderate to moderately severe Alzheimer’s disease: results of a randomized, double-blind, controlled trial investigating three dosages of cerebrolysin. Eur J Neurol. 2011;18: 59–68.
• Alvarez-Sabín J, Román GC. Citicoline in vascular cognitive impair-ment and vascular dementia after stroke. Stroke. 2011;42(Suppl 1): S40–S43.
• Cagnon L, Braissant O. Hyperammonemia-induced toxicity for the devel-oping central nervous system. Brain Res Rev. 2007;56:183–197.
• Chepkova AN, Sergeeva OA, Haas HL. Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment. Neurobiol Dis. 2006 Sep;23(3):512-21.
• Fesenko UA. Piracetam improves children’s memory after general anaesthesia. Anestezjol Intens Ter. 2009;41:16–21. Polish
• García-Cobos R, Frank-García A, Gutiérrez-Fernández M, Díez-Tejedor E. Citicoline, use in cognitive decline: vascular and degenerative. J Neurol Sci. 2010;299:188–192.
• Guekht AB, Moessler H, Novak PH, Gusev EI; Cerebrolysin Investigators. Cerebrolysin in vascular dementia: improvement of clinical outcome in a randomized, double-blind, placebo-controlled multicenter trial. J Stroke Cerebrovasc Dis. 2011;20:310–318. 
• Holecek M. Side Effects of Long-term Glutamine Supplementation. JPEN J Parenter Enteral Nutr. 2012 Sep 18.
• Holinski S, Claus B, Alaaraj N, et al. Cerebroprotective effect of piracetam in patients undergoing coronary bypass surgery. Med Sci Monit. 2008;14:153–15.
• Kanamori K, Ross BD, Chung JC, Kuo EL. Severity of hyperammonemic encephalopathy correlates with brain ammonia level and saturation of glutamine synthetase in vivo. J Neurochem. 1996 Oct;67(4):1584-94.
• Lemberg A, Fernández MA. Hepatic encephalopathy, ammonia, glutamate, glutamine and oxidative stress. Ann Hepatol. 2009 Apr-Jun;8(2):95-102.
• Liu J. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res. 2008;33:194–203.
• Mancuso C, Bates TE, Butterfield DA, et al. Natural antioxidants in Alzheimer’s disease. Expert Opin Investig Drugs. 2007;16:1921–1931.
• Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue. Arch Gerontol Geriatr. 2008;46:181–19
• Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl-L-carnitine treatment in minimal hepatic encephalopathy. Dig Dis Sci. 2008;53: 3018–3025
• Malykh AG, Sadaie MR. Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders. Drugs. 2010;70:287–31
• Pantoni L. Treatment of vascular dementia: evidence from trials with non-cholinergic drugs. J Neurol Sci. 2004;226:67–70
• Parnetti L, Mignini F, Tomassoni D, Traini E, Amenta F.  Cholinergic precursors in the treatment of cognitive impairment of vascular origin: ineffective approaches or need for re-evaluation? J Neurol Sci. 2007;257:264–269.
• Ramalho SA, Nigam N, Oliveira GB, Alves de Oliveira P, Matos Silva TO, Passos dos Santos AG, Narain N. Effect of infusion time on phenolic compounds and caffeine content in black tea  Food Research International; 13 December 2012 [ahead of print]
• Secades JJ. Citicoline: pharmacological and clinical review. Rev Neurol. 2010;52 Suppl 2:S1–S62.
• Vale S. Current management of the cognitive dysfunction in Parkinson’s disease: how far have we come? Exp Biol Med (Maywood). 2008;233:941–951.
• Vince AJ, Burridge SM. Ammonia production by intestinal bacteria: the effects of lactose, lactulose and glucose. J Med Microbiol. 1980 May;13(2):177-91.
• Yurko-Mauro K. Cognitive and cardiovascular benefits of docosahexaenoic acid in aging and cognitive decline. Curr Alzheimer Res. 2010;7:190–196.

Science Round-Up Seconds: Are Statins Good for Your Brain? Or Have the Scientists Just Forgotten About the Risks?

Brainy question of the day: Will statins revive or criple your brain?

Those of you who made it in time for yesterday's live-show, will already know that I have "postponed" publishing the (by then) commented list of dietary supplements to improve and maintain insulin sensitivity to Sunday.

It was my original plan to publish this list along with three suggested supplement stacks on Sunday and sticking to it has the advantage of a "true" ending to the "Maintain and Improve Your Insulin Sensitivity" series (read previous posts) - there is already enough chaos among the 1351 published SuppVersity posts ;-).

Furthermore, it will unquestionable be good for your brain, if I do not flood it with an informational overload by trying to cram all the information about the insulin sensitizers, as well ;-)

Download!

Don't forget to download the podcast: If you have not already done so, I suggest you download and listen to the show. With Carl's questions and comments the radio show does also deliver some extra information that is not part of this summary.

I have to admit that I must have over-read the original article a listener who goes by the name "Rad Fox" referenced in an email he send to onair@superhumanradio.com (feel free to bother us with questions for future episodes). In this email "Rad" referenced an article which turned out to be one of these notorious copy + paste pieces of a press release. The latter came from John Hopkins Medicine and discussed the results of an as of now unpublished paper about the incidence of dementia in patients on statin therapy.

This is not the first review that connects statin use to brain health!

Despite their bad reputation within the health and fitness community, the use of statin drugs has in fact been shown in numerous studies to keep your brain on top of the game. Another very recent meta-analysis of data from studies with 2851 cases and 57020 participants, for example, says that statin use is associatied with a statistically significant -48% reduction in dementia risk (Song. 2013). Similarly, Steenland et al. write in a paper that's been published roughly a month ago:

"Research volunteers with normal cognition at baseline evaluated an average 4.1 times over 3.4 years (1,244 statin users, 2,363 nonusers) and with mild cognitive impairment (MCI) at baseline evaluated an average 3.9 times over 2.8 years (763 users, 917 nonusers)." (Steenland. 2013)

Irrespective of the high number of empirical studies that seem to support the efficacy of statins as "anti-dementia" drug, I did not even have to bother with PubMed or any other medical database to find trials that suggest that the use of statin drugs will have the exact opposite effects. I just had to scroll down to the end of the article, where I found a news report on an study that claims that Pravachol, obviously likewise a statin drug, would be "linked to memory impairment" (read the news story).

Beneficial or detrimental? Which results can you trust?

Your body does in fact produce i's own anti-dementia "drug": Melatonin. With the natural decline of the metlatonion production with age, it is thus only logical that you develop dementia, only in your older age - learn how to protect yourself with melatonin

I know it can be enervating at time, but it's one of the central characteristics of science that it's results are usually ambiguous and far from achieving the status of "undebatable truths". If you've been around the SuppVersity for some time now, you should by now have overcome this naive understanding of the nature of science by now, anyways.

"The promising results obtained in vivo and in epidemiological studies are generally not in accordance with those of placebo-controlled randomized clinical trials." (Silva. 2013)

You should also be aware that the best way to reconcile these discrepancies between epidemiological and experimental evidence is to identify the underlying mechanism behind the effects statins exert on the build-up of neuronal plaque. As soon as we know exactly what's happening we may well be able to decide whether the protective effects we see are "real" or just an "epidemiological Fata Morgana".

The most important question we have to answer is: "HOW?"

Unless we have a rationale explanation for the protective effects statins may have on the brain of (elderly!) individuals, we can file the claim "statins protect elderly brains against cognitive decline" in the "still to be investigated" folder and let it rest there until we have a verifiable theory (= sum of hypothesis) to explain how the use of a drug that was originally designed to block the endogenous production of cholesterol could have such an effect on the brain.

Dietary vs. endogenously produced cholesterol: I know that most of you will be aware that statins reduce your bodies own (=endogenous) production of cholesterol. Most of you will probably also know that it is this endogenously produced cholesterol that is - if any form of cholesterol - to be held responsible for coronary heart disease and (purportedly) the formation of plaque in the brain.

If you are not a narrow-minded text-book physician, you will have to acknowledge that eggs promote an anti-artherogenic cholesterol profile and will thus probably have anti-Alzheimer's and anti-dementia effects (learn more)

For the average human being, his dietary cholesterol intake will have no or only minor influence on the serum levels of cholesterol and cholesterol rich foods such as eggs, have actualle been found to exerd positive effects on the cognitive function of elderly individiuals (Aparicio. 2013); and despite the fact that the results did lose their significance, when they were stratified for total energy intake and education level, the Aparicio study should remind us that the role cholesterol rich foods do not necessarily increase your dementia risk, even if cholesterol was mechanistically involved in the etiology of dementia - even if studies in rodents and rabbits who were fed with synthetic high cholesterol diets suggest otherwise (learn more about the problems with synthetic diets).

And what about saturated fat? In a study from Japan (the Hisayama Study; cf. Ozawa. 2013), the consumption of a diet with a normal amount of saturated fat in it and not the allegedly healthier "almost zero SFA" pattern were associated with reductions in all cause (-34%), Alzheimer's (-35%) and vascular dementia (-55%) - a direct negative effect of saturated fats is thus unlikely. A negative impact of certain foods that happen to have a high amount of saturated foods in them, on the other hand, cannot be excluded.

The most straightforward explanation for the beneficial effects scientists observed in numerous epidemiological studies would obviously be a direct one: "Statins take away a substrate that's necessary for the amyloid plaque to form." This hypothesis would also be supported by significant correlations between elevated serum cholesterol levels and plaque build-up in the brain, as they were observed by (among others) by Matzusaki et al. in who used the same cohort Ozawa et al. analyzed in their study on the influence of certain dietary patterns on the risk of developing dementia (see red box above). In the corresponding paper Matzusaki et al. report:

Table 1: Official "normal" levels for total, LDL & HDL cholesterol, as well as triglycerides (based on AHA recommendations)

• 23x higher risk for total cholesterol > 5.8mmol/L
• 13x higher risk for LDL > 4.02 mmol/L
• 70% higher risk for HDL < 1.04 mmol/L (p > .5)
• 3.5x higher risk for triglycerides >1.56mmol/L
  that's compared to Q1 <0.51mmol/L
• 7x higher risk for LDL / HDL > 3.48 mmol/L
• 3.1x higher risk for “non-HDL” > 4.61 mmol/L

What makes Matzusaki et al.'s observation particularly interesting is the fact that they are based on 147 autopsies that were performed between 1998 and 2003. Autopsies? Yes, I know that sounds gross and irrelevant, but it has the advantage of

• being able to measure the amount of plaque directly,
• having physical and quantitative data, and
• not being limited to diagnosed cases of dementia.

In other words: Your data is not going to be skewed by analyzing only those who are already sick enough to be treated, when you are able to look at the brains of a representative sample of the population after they died.

Dead or alive, there is more than one hypothesis

Remember: We are inclined to forget that the only difference between "effects" and "side effects" is our assessment of the latter. The beneficial effects statins have on the expression of AGE receptors, for example would be  "side effects" for a classic statin which is obviously supposed to lower cholesterol and nothing else. In the context of dementia prevention, this side effect it is the intended effect and the cholesterol lowering effects of statins are the "side effects".

In view of the myriad of already discovered and hitherto undiscovered "side effects" of statins it is however just as likely that the reduced dementia risk is a result of  ...

• a reduction in advanced glycation end product receptors in the brain and thus a protection against the negative effects AGEs exert on the brain (Liu. 2012; Deane. 2012).
  On a side note: If you want to counter the production of endogenous AGEs you can do so with taurine (Nandhini. 2004). This would obviously render the use of a statin to reduce the receptor density obsolete.
• a blockade of the “maturation” from plague precursors to amyloid beta plaque (Hosaka. 2013)

... or a combination of all these effects with the direct and indirect role cholesterol plays in the formation of plaque in the brain (Fantini. 2013; Hung. 2013).

Whether we will ever really know that it is that appears to protect statin users from dementia is thus obviously still anybody's guess. What is not "anybody's guess" is whether it makes sense to take a statin solely to protect yourself from developing dementia. That would - in my humble opinion - rather be a sign of existing cognitive decline than a protection against its development ;-)

Bottom line: Despite the fact that I have never been a statin advocate it is difficult to argue with the current epidemiological evidence: People who take statins have a lower incidence of dementi *fullstop* Whether this is even related to cholesterol is however as questionable as Carl's suggestion that it's an overall reduction in inflammation as it has been observed by Reis et al. (2012) in the context of Malaria infections, where statins appear to be able to sooth the "brainflammation" that's behind the beneficial effects of statin drugs.

Those who take statins can benefit from eating pomegranate | learn more

What is more or less undebatable, though, is that "there is insufficient evidence to recommend statins for the treatment of dementia" (McGuinness. 2013). I will leave you with this conclusion from the latest Cochrane review and a discreet reference to the influence of APO-E phenotypes on both baseline cholesterol levels and the development of Alzheimer's disease. Who knows? If we controlled for the APO-E4 allele, we may well find that carriers of the AA (=2x positive) form of the APO-E4 gene, of which a recent study from the University of Toronto suggests that having this homozygous APO-E4 gene poses a 56.0x higher risk (no typo!) of developing dementia (all forms), benefit from taking a statin while others don't? I will obviously keep you posted on all future developments.

References: 

• Aparicio Vizuete A, Robles F, Rodríguez-Rodríguez E, López-Sobaler AM, Ortega RM. Association between food and nutrient intakes and cognitive capacity in a group of institutionalized elderly people. Eur J Nutr. 2010 Aug;49(5):293-300.
• Barberger-Gateau P, Letenneur L, Deschamps V, Pérès K, Dartigues JF, Renaud S. Fish, meat, and risk of dementia: cohort study. BMJ. 2002 Oct 26;325(7370):932-3.
• Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, Love R, Perry S, Paquette N, Deane RJ, Thiyagarajan M, Zarcone T, Fritz G, Friedman AE, Miller BL, Zlokovic BV. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest. 2012 Apr 2;122(4):1377-92. 
• Fantini J, Yahi N, Garmy N. Cholesterol accelerates the binding of Alzheimer's β-amyloid peptide to ganglioside GM1 through a universal hydrogen-bond-dependent sterol tuning of glycolipid conformation. Front Physiol. 2013;4:120. doi: 10.3389/fphys.2013.00120.
• Liu R, Wu CX, Zhou D, Yang F, Tian S, Zhang L, Zhang TT, Du GH. Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE)-independent signaling pathways and regulating mitochondrion-mediated apoptosis. BMC Med. 2012 Sep 18;10:105. 
• Hosaka A, Araki W, Oda A, Tomidokoro Y, Tamaoka A. Statins reduce amyloid β-peptide production by modulating amyloid precursor protein maturation and phosphorylation through a cholesterol-independent mechanism in cultured neurons. Neurochem Res. 2013 Mar;38(3):589-600.
• Hung YH, Bush AI, La Fontaine S. Links between copper and cholesterol in Alzheimer's disease. Front Physiol. 2013;4:111. 
• Matsuzaki T, Sasaki K, Hata J, Hirakawa Y, Fujimi K, Ninomiya T, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T. Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study. Neurology. 2011 Sep 13;77(11):1068-75.
• Nandhini AT, Thirunavukkarasu V, Anuradha CV. Stimulation of glucose utilization and inhibition of protein glycation and AGE products by taurine. Acta Physiol Scand. 2004 Jul;181(3):297-303. 
• Ozawa M, Ninomiya T, Ohara T, Doi Y, Uchida K, Shirota T, Yonemoto K, Kitazono T, Kiyohara Y. Dietary patterns and risk of dementia in an elderly Japanese population: the Hisayama Study. Am J Clin Nutr. 2013 May;97(5):1076-82.
• Reis PA, Estato V, da Silva TI, d'Avila JC, Siqueira LD, Assis EF, Bozza PT, Bozza FA, Tibiriça EV, Zimmerman GA, Castro-Faria-Neto HC. Statins decrease neuroinflammation and prevent cognitive impairment after cerebral malaria. PLoS Pathog. 2012 Dec;8(12):e1003099.
• Silva T, Teixeira J, Remião F, Borges F. Alzheimer's disease, cholesterol, and statins: the junctions of important metabolic pathways. Angew Chem Int Ed Engl. 2013 Jan 21;52(4):1110-21.
• Song Y, Nie H, Xu Y, Zhang L, Wu Y. Association of statin use with risk of dementia: A meta-analysis of prospective cohort studies. Geriatr Gerontol Int. 2013 Mar 6.
• Steenland K, Zhao L, Goldstein FC, Levey AI. Statins and cognitive decline in older adults with normal cognition or mild cognitive impairment. J Am Geriatr Soc. 2013 Sep;61(9):1449-55.

Calcium, Magnesium, Potassium & Co in Food, Water & Supps - Getting Enough is Easy, Knowing How Much Is Not!

Image 1: "Minerals? Yeah that's the stuff you need to avoid cramping" While this is certainly true, the mineral loss during "normal" workouts is largely overblown, the most important and actually only necessary ingredients in respective drinks, even for Ironman Triathletes, are salt, water and sugar and what's worse this prejudice conceals the importance of electrolytes for our general health.

While it is Thursday, it is plain to see that this is not Adelfo Cerame's weekly SuppVersity post. There have been a couple of issues with the promised workout videos and neither I nor Adelfo wanted to postpone them yet another week so that we decided to rather publish videos + Adelfo's weekly update tomorrow instead of a reduced snippet today. To make sure you have more than enough food for thought to bridge the time, I applied a coupe of tweaks to a longer snipped from the next installment of On Short News that dealt with the protective effects of high(er) intakes of calcium, magnesium and potassium on the incidence of vascular dementia (=dementia in response to low blood flow to / oxygenation of the brain) and Alzheimer's dementia (=dementia due to the build up of plaque in the brain). As you may already have seen, the result got somewhat epic, so let's not waste anymore time and get straight into the original data before it's too late and we have already become demented ;-)

Don't forget your minerals or they'll soon be just one of the many things you tend to forget

While the studies and reviews on the effects of minerals, especially calcium (and as of late also magnesium), on cardiovascular health is about as abundant as the assessments of their individual and joint benefits and / or pitfalls, their role in the etiology of another, quieter, but not less prevalent pandemic is still insufficiently studied. Against that background, the results Ozawa et al. present in a recently published paper in the Journal of the American Geriatric Society could well provide some novel insights on whether or not forgetting to keep an eye on your mineral intake now will make you forget more than just a couple of minerals in the more or less distant future - and that even if none of the 1081 community dwelling elderly (>60y) Japanese the scientists followed up for 17 years is even remotely related to you ;-)

Figure 1: Hazard ratios for all-cause, vascular and Alzheimer's dementia for patients in the lowest to highest quartiles of potassium (≤1,856 / 1,857–2,149 / 2,150–2,559 / ≥2,560), calcium (≤431 / 432–531 / 532–638 / ≥638) and magnesium (≤147 / 148–169 / 170–195 / ≥196) intake in mg/day (top) and difference in intake of selected foods in the highest vs. lowest quantile of overall mineral intake (bottom; all calculated based on Ozawa. 2012)

Aside from the general association of higher potassium, calcium, and magnesium intake with lower incidence of dementia, which was - given the overall low median intake - more or less to be expected, there are a couple of other very noteworthy things I want you to take note of (see figure 1; data adjusted for age; sex; low education; history of stroke; hypertension; diabetes mellitus; total cholesterol; body mass index; smoking; alcohol intake; regular exercise; and energy, vitamin C, cholesterol, saturated fatty acid, monounsaturated fatty acid, and polyunsaturated fatty acid intake):

• a higher mineral intake was had a more pronounced beneficial impact on vascular compared to Alzheimer's dementia (-77% vs. -46% max. reduction)
• for potassium and calcium the general rule of thumb is "the more, the better" (the deviation from that rule in the individual analysis for Alzheimer's is statistically nonsignificant), but I don't this is mediated by the overall low intake of both and thus only valid within the given range of ~700-900mg of calcium and ~2600-3000mg of potassium - intakes you can by the way easily get from your diets alone
• aside from the usual suspects, i.e. (green) vegetables, fruits and fish, dairy is among the most important source of minerals and high dairy eaters tend to be high mineral consumers, while low / no dairy eaters tend to be in the lowest quartiles of overall mineral intake

as well as a couple of things you cannot read off the graphs, e.g.:

• women had  significantly higher mineral intakes than men, i.e. 68.3% of the persons in Q4 for overall mineral intake were women
• age had no effect whatsoever on the overall intake of potassium, calcium and magnesium
• a low(er) education (<6 years of schooling) was a good predictor of low total mineral intakes, just as it is by the way in view of an overall worse diet quality (this is however less pronounced than conventional wisdom would suggest)
  
• intriguingly, people with diabetes had on average higher mineral intakes than people without diabetes, almost certainly a non-causative relationship that is probably mediated by supplements and nutritional counseling the diabetics received
• contrary to the US, there was no association between high salt and low Ca, Mg, or K intakes, this is also surprising because the "average" middle aged Japanese consumes way more than 5g of salt (Nagata. 2004) and thus 2x more than the US "tolerable upper intake level" of 2300 mg (Cogswell. 2012)

Apropos US, in view of a couple of other studies that have only recently provided support for the widely held, but in fact rarely scrutinized believe that, the lack of adequate amounts of potassium and magnesium, in particular, is associated not only with the age-related cognitive decline and even dementia, but also with such profane things as "simple" obesity, e.g. ...

• Donfrancesco et al. report higher potassium and magnesium intakes were associated with lower BMIs in 1168 men and 1112 women aged 35-79 yrs from 12 Italian regions (Donfrancesco. 2012)
• almost identical results in a study by Shay et al. that found associations with lower BMIs for potassium and magnesium 1794 men and women (ages 40-59 y) from 8 US population samples (Shay. 2012)

... it would unquestionably make sense to eventually stop bashing on sodium and start promoting the consumption of magnesium- and potassium-rich foods, instead.

Figure 2: Percentage of the population mineral intakes below the EAR for individuals aged ≥2y (data from NHANES 2003–2006; n = 16,110; Fulgoni. 2011).

Did you know that according to latest data from the CDC (Cogswell. 2012) less than 2% of US adults meet the dietary recommendations for potassium (≥4700 mg K/d) and that the lack of potassium was even more pronounced in the elderly (0.5% of the >72y-old US citizens meet the dietary requirements) and obese (0.7% meet the recommendations. With two out of five Americans also failing to meet even the required amount of magnesium in the diet, it appears more than questionable why the good-meaning (I don't doubt they are but too often they are mislead of have the good of the wrong people in mind) policy makers don't put magnesium and potassium into the water supply instead of toxic junk such as chlorine and fluoride...

I mean, you will probably remember from "On Short News on July 28, 2012" that each milligram of magnesium per liter drinking water could decrease the heart disease risk of people with an unbalanced mineral intake by 5%! But, alas, who am I to make such bold suggestions?

Now, while the importance of watching your dietary magnesium and potassium are pretty obvious and probably nothing you have not heard before, there is still one question left to be answered - a question that will point us away from RDAs and EARs and back to foods, which never contain only one of the aforementioned minerals in isolation. So here is the question: What do we make of calcium? In the Ozawa study it appeared to be clearly useful, but that was with intakes of >638mg/day in the highest quintile of the study population! The average European citizen, on the other hand, consumes roughly 1g = 1,000mg, i.e. 36% more than the Japanese and still we (us Europeans) are about as sick, if not sicker than the average Japanese? How come?  

Potassium, check; magnesium, check; calcium, ... wait a minute! What about phosphorus? 

Aside from the mere possibility that we could already be consuming way too much calcium (which is not supported by science as long as those 1,000mg come from your diet and not from supplements; cf. "Higher Calcium Intake Greater Fatty Acid Oxidation"), the most straight forward explanation would be an imbalanced intake of phosphorus. For the average European the latter is at about 1,675mg/day (mostly from dairy, cereals and meats - 27.9, 23.4, 17.4.% of daily intake, respectively) and thus clearly twice the amount our (the European) version of the well-meaning policy makers are telling us each and every one of us should be consuming on a daily basis.

Figure 4: Relative potassium intake in European countries according to source; note: with 4,110mg/day the average potassium intake in the Euopean Union is much higher than in the US, highest intakes were observed in Spain, lowest in Germany (Welch. 2009)

Did you know that the average magnesium intake in Europe (409mg/day) is much higher than in the US? And guess what, the usual suspects, i.e. dairy and cereals aside, non-alcoholic beverages are the #2 source (19% of total mg intake) of dietary magnesium in Europe! I would, an observation Welch et al. attribute just like the almost "optimal" (wrt to the US recommendations) average potassium intake of 4,110mg/day to the high quality tap and bottled mineral water, and other non-alcoholic beverages (and certainly not to reverse osmosis or the consumption of mineral-free distilled water, which is something you can use to satisfy the water requirements of your radiator or  iron, but not those of your body ;-).

Figure 3: Hazard risk analysis based on the Cholesterol and Recurrent Events (CARE) study (n = 4127; Tonelli. 2005)

In fact, we have broached on another of these imbalances in the context of the effects that were observed with higher magnesium : calcium ratios in drinking water (cf. red box above + "On Short News on July 28, 2012"), before. With phosphor we have yet another "antagonistic partner" of calcium, of which Ritz et al. have only recently argued that its increasing use as a food additive (check out the label of whatever processed food you buy, chances you find a XZY-phosphate on it are >50%) poses a serious health risk. To support their argument, the researchers cite data from a 2005 study by Tonelli et al. that indicates that even serum phosphor levels that are well within the normal range (2.0-4.0mg/dl) were associated with significantly increased CVD risks (cf. figure 3; suggested read: "Does Low Vitamin D Protect Us From Dietary Phoshporus Overload?").

These are only two selected examples of the available evidence that suggests that we are still totally underestimating the effects of "electrolytes", in general, and their ratios, in particular, on our neurological and metabolic health - and, even worse, doctors, policy makers, experts and gurus keep making mostly unwarranted recommendations to increase our intake of one and decrease the intake of another mineral, when in fact the lack of synergists (e.g. normal amounts of dietary magnesium to complement calcium) and absence or abundance of antagonists (e.g. potassium and magnesium for salt and calcium, magnesium and potassium for phosphorus) are the actual problems we are dealing with.

Figure 5: Don't forget that there are personal, regional and historical difference in total and relative mineral intakes and never supplement, high amounts of isolated minerals simply because Mr or Mrs average would benefit, without checking how "average" you actually are in terms of your solid, fluid and supplemental mineral intake (data for image based on Crawford. 1971; data on US water hardness according to the Water Research Center)

Implications: I guess based on all the information on the allegedly complicated interactions between the different minerals, you will by now have realized that statements like "everybody will benefit from taking 300mg of supplemental magnesium" let alone "everybody must take at least 300mg of supplemental magnesium" are about as useful as the constant advice to cut your salt, cut your fat and cut your calories people are confronted with on a daily basis. The chances that person X may benefit are probably high, but they are certainly much lower than the chances that you will survive the sting of a bee - and even that will still kill 53 US citizens per year.

Individualization, evaluation are therefore obligatory steps which must necessarily come before supplementation, which would - as some of the data in the figure 4 did already suggest - rarely be necessary, if the average inhabitant of the Western hemisphere did not top his sugary, salty and phosphate-laden fast-food diet with beverages that are either devoid of any minerals or will simply exasperate the existing imbalances.

Too many people (and I believe this is particularly true for the US) seem to have forgotten that we have not always been forced to filter all the minerals out of our water just to make the chlorinate, fluorinated, and "estrogenated" sludge that streams out of the faucet suitable for human consumption. Think of that and the data in figure 5, the next time the as of late often second-guessed recommendation that you got to have "at least X cups of water per day" resurfaces and of how little use each of them is, when it does not contain any of the electrolytes your body needs to handle the water appropriately.

References:

• Cogswell ME, Zhang Z, Carriquiry AL, Gunn JP, Kuklina EV, Saydah SH, Yang Q, Moshfegh AJ. Sodium and potassium intakes among US adults: NHANES 2003-2008. Am J Clin Nutr. 2012 Aug 1. 
• Crawford MD, Gardner MJ, Morris JN. Cardiovascular Disease and the Mineral Content of Drinking Water. Br. Med, Bull. 1971; 27,1: 21-24.
• Donfrancesco C, Ippolito R, Lo Noce C, Palmieri L, Iacone R, Russo O, Vanuzzo D, Galletti F, Galeone D, Giampaoli S, Strazzullo P. Excess dietary sodium and inadequate potassium intake in Italy: Results of the MINISAL study. Nutr Metab Cardiovasc Dis. 2012 Jul 24.
• Fulgoni VL 3rd, Keast DR, Bailey RL, Dwyer J. Foods, fortificants, and supplements: Where do Americans get their nutrients? J Nutr. 2011 Oct;141(10):1847-54.
• Ozawa M, Ninomiya T, Ohara T, Hirakawa Y, Doi Y, Hata J, Uchida K, Shirota T, Kitazono T, Kiyohara Y. Self-Reported Dietary Intake of Potassium, Calcium, and Magnesium and Risk of Dementia in the Japanese: The Hisayama Study. J Am Geriatr Soc. 2012 Aug 2. 
• Ritz E, Hahn K, Ketteler M, Kuhlmann MK, Mann J. Phosphate additives in food--a health risk. Dtsch Arztebl Int. 2012 Jan;109(4):49-55. Epub 2012 Jan 27. 
• Shay CM, Van Horn L, Stamler J, Dyer AR, Brown IJ, Chan Q, Miura K, Zhao L, Okuda N, Daviglus ML, Elliott P; for the INTERMAP Research Group. Food and nutrient intakes and their associations with lower BMI in middle-aged US adults:  the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP). Am J Clin Nutr. 2012 Aug 1. 
• Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G; Cholesterol And Recurrent  Events Trial Investigators. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation. 2005 Oct 25;112(17):2627-33. 
• Water Research Center. Hard Water  Hardness Calcium Magnesium - Water Corrosion Mineral Scale. < http://www.water-research.net/hardness.htm > retrieved Aug 16, 2012.
• Welch AA, Fransen H, Jenab M, Boutron-Ruault MC, Tumino R, Agnoli C, Ericson U, Johansson I, Ferrari P, Engeset D, Lund E, Lentjes M, Key T, Touvier M, Niravong M, Larrañaga N, Rodríguez L, Ocké MC, Peeters PH, Tjønneland A, Bjerregaard L, Vasilopoulou E, Dilis V, Linseisen J, Nöthlings U, Riboli E, Slimani N, Bingham S. Variation in intakes of calcium, phosphorus, magnesium, iron and potassium in 10 countries in the European Prospective Investigation into Cancer and Nutrition study. Eur J Clin Nutr. 2009 Nov;63 Suppl 4:S101-21.

Supplemental Melatonin Protects Against Alzheimer's and Has The Highly Desirable "Side Effect" of Reducing Body Fat Percentages by More Than 50%!

Image 1: If you don't want your brain to shrivel up like that, I suppose you better get more than just an occasional night of good night's sleep and (not or) think about taking some supplemental melatonin.

Those of you who are also following me on facebook, will probably have seen the link to the study a group of Indian scientists conducted to assess the effect of melatonin supplementation in overiectomized (=model for human menopause) rats (Baxi. 2011). Much to my own surprise, the melatonin supplement did not only eradicate all the majority of overiectomy-induced metabolic changes, it was also more potent than the standard estrogen treatment that served as a control! And that in the absence of any of the side-effects of regular estrogen therapy. In that, the Baxi study is only one out of a handful of recently published paper, which suggest that melatonin is probably one of the most underrated supplements you can still (as soon as the FDA realizes what this stuff can do, they will probably ban it) buy without a script.

Don't let your brain shrivel away!

Published in the December issue of Neurobiology of Aging is a paper that investigated the effects of six months of high dose (10mg/kg) melatonin supplementation and/or exercise on six-month-old 3xTg-AD mice. Due to their specific genetic make-up, these mice are prone, or rather destined to develop Alzheimer's at a pretty young age. Based on previous research on the effects of exercise and the anti-oxidative properties of melatonin, the researchers speculated that if each of them could exert beneficial effects on the development of the Alzheimer's-inducing plaque in the brain of the mice, the combination of exercise + melatonin should be even more protective.

Figure 1: Amyloid- beta and phospho-tau in the cerebral cortex of nontransgenic mice (control) mice, 3xTg-AD (Tg) mice, and Tg mice treated with melatonin, physical exercise, and melatonin plus exercise (data adapted from Garcia-Mesa. 2011)

And in fact, if you take a closer look at the data on the formation of "plaque" (Ameloid-beta and Phospho-Tau) in the brains of the Alzheimer's mice (figure 1), it becomes quite obvious that the effects of exercise and melatonin may both be overall "ameliorative", a distinct reduction in both markers of Alzheimer's disease can only be seen in the melatonin group. In the exercise group (voluntary running on treadmill; ~20-25km/week), on the other hand, there was even a slight (and statistically non-significant increase) over the "sedentary" control Alzheimer's prone animals.

Figure 3: Effects of different treatments on cerebral cortical redox status of 3xTg-AD (Tg) mice; * p < 0.05, *** p < 0.001 compared with healthy control; # p < 0.05, ## p < 0.01, ### p < 0.001 compared with Alzheimer's prone control; & p < 0.05, && p < 0.01 compared with melatonin alone; $ p < 0.05 compared with exercise alone (data calculated based on Garcia-Mesa. 2011).

Similarly, both treatments ameliorated changes in the cerebral cortical redox status (figure 2) of the 3xTG-Ad mice. In that it is noteworthy that the different effects both treatments and their respective combination had on the measured redox parameters in the brain of the mice actually reflect in the overall outcome of the study:

Six-month chronic treatments began at a moderate pathology phase, when animals already present cognitive loss and brain pathology. Overall, both melatonin and exercise groups showed a remarkable amelioration of cognitive and brain redox states up to NTg mouse levels. Differential neuroprotection was obtained against other alterations. Namely, behavioral and psychological symptoms of dementia were protected by exercise and senescence parameters by melatonin. Interestingly, the combined treatment induced neuroprotective effects against brain mitochondria deterioration.

The last observation, that only the combination of both treatments could protect the mice against brain mitochondria deterioration is actually particularly interesting with regards to the concept of mitohormesis and the issue of "how much stress is too much stress", I have broached in a number of previous blogpost. If we took the results of the study at hand as a reference, the answer to this question would be as much exercise induced and thusly beneficial stress as your antioxidant system can handle ... and the capcity of the latter was obviously profoundly upregulated in response to the high dose melatonin supplement the mice received in their drinking water.

The treatment was yet not without (un-?)wanted side-effects

Now obviously almost no effective drug, or in this case a hormone, is without side-effects and you should thusly not be surprised that the 10mg/kg melatonin the mice consumed on a daily basis (this is a human equivalent of ~65g!) were not completely side-effect free.

Figure 3: Relative changes in body weight, white adipose tissue (%), brown adipose tissue (%) and thymus (%) vs. healthy control (data calculated based on Garcia-Mesa. 2011)

So, just to make sure how dangerous this hormone (all MDs please cry out loud, now ;-) actually is, I have compiled the data on the nasty side effects in figure 3 (remember: these are reduction vs. the normal not the Alzheimer's control!):

• - 61% reduction in white adipose tissue mass,
• -9% in brown adipose tissue mass, and
• 16% less reduction in thymus mass

If that sounds "scary", I suppose you are the CEO of one of the big pharma companies, because I guess neither of their drugs would be capable of similarly beneficial side-effects while still effectively battling the causes and symptoms of Alzheimer's.

Melatonin as an ergogenic weight loss adjuvant?

If you have been following my blogposts for quite some time now, you will already be aware that melatonin is far more than your bodies natural sleeping pill. On June, 4, 2011 I discussed the results of an amazing study, where a funky melatonin-loading-protocol effectively reduced the profound increase of inflammatory markers following an ultra-endurance race (cf. "More Than Restorative Sleep in a Pill"). In a more recent paper that is going to be published in the January edition of the Journal of Pineal Research, Germaine Escames et al. speculate about another exercise-melatonin interaction, the effects of which could be much more pronounced than the potential ergogenic effects in the aforementioned study: The exercise induced depletion of inodole, which is used to combat the oxidative stress, and the subsequent depletion of melatonin could in fact have negative impacts on the circadian system of which we are just beginning to realize that it has profound effects on how we look, feel and perform (Escames. 2012), so that strategic supplementation with melatonin could eventually turn out to be of particular importance for the overall health, not just the performance of athletes.

Figure 4: Body weight (left axis) and liver and intra-abdominal fat weight (right axes) after 4 weeks on control or high fructose diet without melatonin and after two additional weeks with daily injection of 1mg/kg or 10mg/kg melatonin (data adapted from Kitagawa. 2012)

And while I am still waiting for respective research on the optimal dosing scheme for athletic purposes, I can already tell you now that based on the results of Akira Kitagawa, Yoshiji Ohta and Koji Ohashi, the beneficial metabolic effects and subsequent reductions in body weight do occur at much lower doses than the ~60mg human equivalent from the Alhzeimer's study (cf. figure 4). Yet while both the low = 1mg/kg (human equivalent: 0.2mg/kg) and high = 10mg (human equivalent: 2.1mg/kg) reduced the intra-abdominal fat in both the rats on the normal, as well as on the high fructose diet,  "the higher serum insulin response curve in the oral glucose tolerance test and insulin resistance [after] 6-wk high fructose feeding" was reduced more effectively by the higher dose.

In view of these recent studies, I am pretty sure that we are soon going to see more research - including human data - on the subject. And I guess that I don't have to tell you that the SuppVersity is where you will find the detailed analyses of the results of those trials first, do I ;-) ?