Amino Acids for Super Humans, Part IV - Purported Ergogenics (2/3): L-Carnitine, ALCAR, LCLT, GPLC & Co.

Image 1: Even bought in bulk,
the carnitines are not exactly
cheap, so you better read on
to gather whether ALCAR,
L-CAR, P-LCAR, L-CLT & Co
are worth spending money on.

Despite the fact that even my grandmother has heard of the miraculous energizing and fat-burning abilities of carnitine, most people - and even those who are buying those carnitine-enriched functional, or should I say disfunctional foods are not even aware that L-3-hydroxy-4-N,N,N-trimethylaminobutyric acid (l-carnitine) is a naturally occurring amino acid, all mammals (humans included) can synthesize from l-lysine or l-methionine in their livers and kidneys.

Necessary co-factors for carnitine synthesis are

• ascorbic acid (vitamin C), 
• pyridoxine (vitamin B6), 
• niacin (vitamin B3) and 
• S-Adenosyl methionine (SAMe)

Interestingly, supplementation of the EAA substrates and co-factors failed to raise carnitine synthesis and or serum levels in respective studies. Gamma-butyrobetaine, a down-stream metabolite in carnitine synthesis from lysine, on the other hand, doubled plasma, brain, kidney and liver levels of carnitine in juvenile mice; cf. Higashi. 2001).

Note: This is the detailed transcript of my show notes to "Amino Acids for Super Humans Part IV"
click here to download the podcast if you want to listen before / during / after you read the rest of the notes

In view of the limited capacity for endogenous biosynthesis of carnitine, it is not very surprising that mammals obtain the heat sensitive (at 284°F ~ 140°C carnitine starts to decompose) amino acidprimarily from their diet (Vaz. 2002); and in that, it is probably no coincidence that colostrum and breast milk are particularly high in l-carnitine, as the need for this essential metabolite in the mammalian energy metabolism increases in phases of rapid growth.

Did you know? The first soy-based baby formulas were low in carnitine, so that neonates who were fed respective products had 1/3 lower carnitine levels than babies who were breast-fed or received milk-based products. Even in the absence of symptoms of overt carnitine deficiency, sub-optimal carnitine levels put these children at risk of early or late metabolic complications (Olson. 1989). Consequently, almost all soy-based infant formulas are enriched with l-cartinine, today.

Vegetarians and Vegans generally have lower plasma carnitine levels

Table 1: Amount of carnitine in food;
meat, fish and dairy are particularly
good sources of dietary l-carnitine
(data adapted from wikipedia.org)

That's unfortunate news for all vegetarians and vegans out there, because as the data in table 1 shows, meat, fish and dairy are the richest dietary sources of l-carnitine. "Omnivorous humans generally ingest 2-12 µmol of carnitine per day per kg of body weight" (Vaz. 2002), which is up to 10x the estimated amount of our endegenous production (1.2µmol /kg/day). So that 75% of the well-stocked carnitine stores of meat-eaters come from dietary, and only 25% from de novo biosynthesis. Needless to say that, with an average daily carnitine intake of <0.1µmol /kg body weight, vegetarians and vegans are usually significantly lower than those of their omnivores fellow men (Rebouche. 1992).

Symptoms of overt carnitine deficiency, such as cardiomyopathy,
hepatomegaly, myopathy, recurrent episodes of hypoketotic
hypoglycaemia, hyperammonaemia and failure to thrive have yet not been observed in the absence of CDSP (primary carnitine defiency), a pathology that has been mapped to human chromosome 5q and is characterized by excessive renal and intestinal wastage of carnitine.

Attention Atkins dieters! In a German study (Liebhaber. 2006) the long-term effects of ketogenic diets on epileptic children, carnitine deficiency was detected in 57% of the patients who did not receive supplemental l-carnitine. There was a large interpersonal variety as far as the onset of carnitine deficiency was concerned. On average subjects developed carnitine defiencey after about 32 weeks, one subject was however carnitine deficient after only two days and one subject maintain sufficient carnitine levels for 248 weeks before carnitine deficiency was diagnosed. These observations stand in line with results of Stadler et al. (Stadler. 1999) who had previously established that a high fat intake increases carnitine excretion. Taken together, this data suggests that people who follow a high fat (not the high protein low carb diet everybody is on these days) would generally benefit from carnitine supplementation.

How carnitine facilitates "fat-burning"

Illustration 1: Carnitine is like the man who
shovels the coal. It's just a small wheel in the
mitochondrial fat burning machinery. Without
lipolytic activity (= free fatty acids floating aroun) and
a sufficient number of properly functioning
mitochondria, increased carnitine levels
won't translate into fat loss (picture in the back-
ground from Ptak Science Books. 2009)

The previous remarks on potentially low carnitine levels suggest the assumption that their diet puts this group of people at risk of high triglyceride levels, obesity and all other sorts of metabolic pathologies related to suboptimal fatty acid oxidation. There is however very little evidence that plasma l-carnitine is - under normal conditions - rate limiting in mitochondrial beta-oxidation. If you think of coal-fired steam engines of the Titanic, would the ship have been faster and thus be able to take the safer route and still win theBlue Riband of the Atlantic if there had been more workers to fire up the ovens? Probably not, because the engines were already running at full throttle... the same is true for your mitochondria, just because there is an overabundance of carrier molecules that does not mean that your "ovens",... pardon me..., your mitochondria will be able to oxidize more fat.

The commonly touted "fat burning" effects of l-carnitine (and all other forms of carnitine) thusly belong to the realms of advertismental oversimplifications, or should I say frauds? Even taken poundwise carnitine by itself will neither empty, nor burn the contents of a single of your unaesthetic fat cells. On the other hand, a profoundly lowered carnitine levels as they were reported for elderly and obese patients by Noland et al. (Noland. 2009) could lead to or exasperate existing weight problems by compromising the transport of fatty acids from the cytosol, i.e. the intracellular fluid, into and back out of the mitochondria.

Figure 1: Free and bound (esterified) carnitine content in mg/kg of different meat products
(data adapted from Seline. 2007)

In and out that's the way things have to go

Image 2: Lipofuscin accumulation (fine
brown / yellow granular pigment)
in liver cells (photo by Nephron).

The latter, the transport of partly oxidized, "damaged fats", so called lipofuscins out of the mitochondria, may in fact be about as important for your overall metabolic health as the well-known transportation of esterified fatty acids into the mitochondria. Mitochondrial malfunction and failure aside, a way more visible effect of lipofuscin accumulation are the brown stains on old peoples skin. Of greater significance are yet the negative effects of lipofuscin depositions in the brain, which have been shown to be ameliorated by acetyl-carnitine supplementation (Kohjimoto. 1988). And it is likely that many of the established benefits of (acetyl-)l-carnitine supplementation stem from the clearance not the the entrance of fatty acids into the cells.

Inter-cellularly, carnitine also functions as a temporary buffer for the unused acetyl-CoA. The accumulation of respective acyl-carnitines within the mitochondrion, which goes hand in hand with a depletion of unbound l-carnitine that would faciliate the transport of fatty acids into the mitochondria, has been implicated as one of the confounding factors in the etiology of the metabolic syndrome. 

Figure 2: Simplified illustration of the underlying mechanism of carnitine mediated fatty acid transport in and out of the mitochondrion (The AOCS Lipid Library)

L-Carnitine as a selective glucocorticoid receptor modulator & useful tool in hyperthyroidism

Beside its effects on mitochondrial health, l-carnitine also exhibits anti-inflammatory properties by directly interacting with glucocorticoid receptors on immune cells (Manoli. 2006). In experiments Manoli et al. conducted back in 2006, l-carnitine in a glucocorticoid-like fashion "suppressed the lipopolysaccharide-stimulated release of tumor necrosis factor α and interleukin-12 from primary human monocytes". Despite its ability to stimulate glucocorticoid receptors (GR), and to reduce binding of the cortisol analogue ³H]-dexamethasone to GRs, LCAR apparently lacks the deleterious side effects corticosteroids have on other organs/tissues in the human body.
Moreover, a study by Benvenga et al. in which women received supraphysiological doses of the synthetic thyroid hormone levothyroxin (T4) to induce symptoms of hyperthyroidism confirmed previous observations that l-carnitine even at doses as low as 2-4g/day "antagonizes hyperthyroidism-related [...] symptoms and biochemical responses of thyroid hormone target tissues". Data from cell culture experiments suggest that it is the property to inhibit T3 and T4 entry into cell nuclei, which it at the heart of the anti-(hyper-)thyroid effect of l-carnitine, since l-carnitine supplementation does not substantially affect thyroid hormone levels or radioactive iodine uptake by the thyroid.

Did you know? Both full-blown hyper- as well as hypothyroidism have been associated with muscular carnitine depletion (Sinclair. 2005), as a consequence of insufficient synthesis (hypo-) and increased usage (hyper-) of carnitine.

In that, it is interesting to note that, vice-versa, thyroid hormone also influences the rate of carnitine synthesis (Galland. 2002), which, again, brings up the idea of tightly regulated, feedback-control mechanisms intended to keep the metabolic rate (including the mitochondrial beta oxidation of fatty acids) in a narrow physiological range, so that in people with high levels of thyroid hormones (not necessarily hyperthyroidism) and increased carnitine production, or in people with low levels of thyroid hormones (not necessarily hypothyroidism) and decreased carnitine production the respective ratios of carnitine / thyroid hormone could lead to similar cellular T3 / T4 uptake in the presence of fundamentally different serum levels of these hormones.

Carnitine intake and clearance - does supplementation make sense at all?

In healthy human beings, on the other hand, the main regulatory mechanisms take place in the kidney and a basic understanding of the relation of carnitine intake to urinary loss is of fundamental importance for anyone who does not want to feed his expensive carnitine supplements to sewer rats.

Figure 2: Free and bound (esterified) carnitine content in mg/kg of different milk products
(data adapted from Seline. 2007)

In general, dietary l-carnitine has a bioavailability of 54%-84% and is thusly much better absorbed than supplemental carnitine in powdered or capped form, for which Rebouche et al. report a bioavailability of meager 14%-18% (Rebouche. 2006). Ideally, you would thus get about 1.28g of carnitine from 1kg of Kangaroo steak, which turns out to be by far the best source of dietary l-carnitine.

Note: According to the data from Rebouche et al. you wanted to get the same 1.28g of carnitine from a supplement, instead of a 3-4 dilicious steaks, you would  have to consume 7-9g of supplemental carnitine in pill or capsules for the same amount of l-carnitine to hit your blood stream!

A vegan, who abstains from eating meat, fish and dairy, on the other hand, would have to eat his share of 60kg of mushrooms to get an equal amount of 1.28g of carnitine. Although the act of eating 60kg of mushrooms would already border the supernatural, the of 320kg of carrots you would have to eat, alternatively, are merely hypothetical.

Figure 3: Free and bound (esterified) carnitine content in mg/kg of different mushroom, vegetable and fruit products
(data adapted from Seline. 2007)

Unfortunately things do not turn out to be that easy as the above calculations would suggest, because, as we physicists use to say, bioavailibilty B(m, C, F) "is a function of body weight m, carnitine availability C and the form of carnitine F" and thus depends on how much you weight, how much carnitine you eat in a single sitting, how much carnitine is already floating around in your blood stream and what form of carnitine (free l-carnitine or esterified carnitines, such as acetyl-l-carnitine or (glycine-)propionyl-l-carnitine, you ingest. Add to that some interpersonal variability and plot the total ingested and absorbed amounts of l-carnitine from a previous study of Rebouche et al. (Rebouche. 1999) in a graph and you get something that looks like this:

Figure 4: Total ingested (full bars) and absorbed (blue part of the bar) amount of dietary carnitine in mg/kg body weight
(data adapted from Rebouche. 1999 & Rebouche. 2006)

It's quite obvious that - despite all interpersonal variety among the 12 test subjects - the relative amount of carnitine that actually hits the circulation decreases with increasing amounts of carnitine in the diet.

Did you know that multiple small doses of carnitine are way superior to a single large dose if your aim is to persistently increase serum carnitine levels? In contrast to Rebouche et al. (Rebouche. 2006), who achieved relatively stable carnitine levels >50% above baseline by having their subjects take their 2g of carnitine in three divided doses (at 8am, 12pm, and 6pm) trials using a single, large bolus of l-carnitine (orally and even intraveniously) did not produce sustainable elevations in plasma carnitine levels. Furthermore, the addition of carbohydrate (96g glucose in addition to 3g l-carnitine/day) and the concomitant insulin release have been found to decrease uriniry carnitine clearance, or, converesely, increase carnitine retention by ~40% (Stephens. 2007).

The decreased absorption of dietary carnitine from the gut goes hand in hand with a decreased reabsorption of  carnitine in the kidneys. At low to normal serum carnitine levels the latter conserve 90-99% of the circulating carnitine. When carnitine levels increase, however, the clearance rate increases way beyond the 1-3 mL/min that would leave your body in the form of urinary losses under "normal" circumstances. Thusly, increased carnitine levels, as they are the result of an intravenous infusion of 0.5g of carnitine, return to baseline in less than 12h, with a rapid decline (-80%) in the first hour after administration. Whole body turnover, i.e. the "renewal" of creatine stores, in slow (muscle) and fast turnover (liver, kidney, and other tissues) stores is estimated to take about 38-119h (Rebouche. 2006).

On the different forms of carnitine

The absorption issue immediately reminds me of the bro-scientific mambo-jambo about the bioavailability of different forms of carnitine you can find wherever L-CAR, ALCAR, P-LCAR, LCLT & Co are sold.  In most cases the the individual bioavailibility appears to depend on the venue the respective vendor will get from the different forms of carnitine. In that, supplement manufacturers cash in on the lack of scientific studies comparing the absorption kinetics of the various commercially available forms of carnitine in a single objective model. In this context it is also noteworthy that both commercially available carnitine-esters, i.e. acetyl-l-carnitine (ALCAR) and (glycine-)propionyl-l-carnitine (PLCAR, (G)PLC), are no invention of the supplement industry, but naturally occurring forms of carnitine, the pharmacokinetics of which have been studies by Cao et al. after oral administration of 2g of l-carnitine to 12 healthy volunteers (Cao. 2009).

Table 2: Pharmacokinetics of l-carnitine (L-CAR), acetyl-l-carnitine (ALCAR) and propionyl-l-carnitine (PLC) after oral administration of 2g of l-carnitine to 12 healthy volunteers (data adapted from Cao. 2009)

As it was to be expected both, the maximal, as well as the absolute plasma concentration of l-carnitine of l-carnitine are greater than that of its esters. Yet despite the sudden spike in l-carnitine levels, the clearance rate for ALCAR and PLC were greater. Conversely, the carnitine-esters have a -40% (ALCAR) and -57% shorter half-life than the free form of carnitine. In that, the high 24-h urinary excretion of ALCAR, which equals about 2x the area under the curve suggest that both long PLC esters that have previously been broken down to shorter acetyl-esters, as well as "used" and thus esterified l-carnitine are excreted as acetyl-l-carnitine.

The results of Cao et al. stand in line with findings of Eder et al. (Eder. 2005), who used a pig model ( which is pretty reliable when it comes to modeling the human digestive system) to estimate the bioavailability of various L-carnitine esters (acetyl-L-carnitine and lauroyl-L-carnitine) and salts (L-carnitine L-tartrate, L-carnitine fumarate, L-carnitine magnesium citrate) and found that

AUC [aera under the curve] values, calculated for the time interval between 0 and 32 hours, for both free and total carnitine were similar for base of free L-carnitine and the three L-carnitine salts (L-carnitine L-tartrate, L-carnitine fumarate, L-carnitine magnesium citrate) while those of the two esters (acetyl-L-carnitine, lauroyl-L-carnitine) were lower.

In that, it is of particular interest that l-carnitine-l-tartrate (LCLT), which is heavily promoted as the "best" carnitine supplement, did in fact "yield a higher plasma free carnitine AUC value for the time interval between 0 and 3.5 hours than [any] of the other compounds." The faster absorption of LCLT aside, the data of this (unfortunately) unique study would suggest that the fancy "L-carnitine salts have a similar bioavailability" as the way cheaper free form of carnitine (l-carnitine) and both appear to be better absorbed than any of the l-carnitine esters .

Did you know? Gram per gram the tartrate salt of carnitine (LCLT) provides only 40% carnitine. If, for example, you wanted 2g of pure carnitine, you would have to take 5g of LCLT.

Acetyl l-carnitine the one and only (?) brain booster

In the case of ALCAR, for example, it is well established that its oral bioavailability is decreased due to increased hydrolysis. Oral bioavailability, on the other hand, is only one of the attributes the addition of the acetyl ester to the free form of carnitine changes. For example, it is often cited that ALCAR would be the only form of carnitine that is able to pass the blood-brain-barrier (BBB) in mammals. This statement is simply false! While it is true that the acetylated form of carnitine passes enters the brain more easily, i.e. it takes lower concentrations outside the barrier to achieve the same levels of carnitine within the brain, the difference in K(m) values, which area a measure of the concentration of substrate required to produce 50% of the maximal uptake, is only 5% (K(m)_Alcar=31.3 vs. K(m)_Carn=33.1, cf. Kido. 2008).

Anyway, at least those of you who have some sort of cognitive / neurological problem, probably won't really care if ALCAR is actually the only, or maybe just the favorable form of carnitine to treat neurological diseases, as long as it will help mitigate your problems - and indeed, ALCAR appears to be a formidable "brain nutrient" which has been used succesfully in a variety of brain-related clinical conditions (Alternative Medicine Review. 2010):

• Alzheimer's disease
• Depression
• Attention deficit / hyperactivity disorder (ADHD) and Fragile X Syndrome
• Peripheral (diabetic, antiretroviral and chemotherapy-induced) neuropathy
• Cerebral ischemia and reperfusion
• and others

The underlying mechanisms of action most likely are:

• Increasing neural energy production
• Protecting neurons from toxins
• Maintaining neuron receptors
• Increasing availability of the neurotransmitter acetylcholine
• Decreasing accumulation "damaged fats" (lipofuscins) in brain tissue

If administered orally, dosages usually range from 2.0-5.0g of ALCAR, mostly taken in divided doses. Reports on side effects are scarce, and generally limited to agitation, nausea and vomiting, so that ALCAR is generally considered safe, even wit long-term administration  (Spagnoli. 1991).

(Glycine) propionyl l-carnitine the one and only (?) nitric oxide booster

Image 3: Molecular structure
of the bulky 3-Propanoyloxy-
4-(trimethylazaniumyl)butanoate
molecule which usually goes by
the name Propionyl-L-carnitine, or
its abbreviations PLC or PLCAR.

GPLC, i.e. glycine propionyl l-carnitine certainly is the fancier of the two readily available carnitine esters. I mean, who cares about brain health, if GPLC promises huge pumps? The target group of the colorful ads in the bodybuilding magazines probably doesn't. Yet while studies from the Department of Health and Sport Sciences at the University of Memphis (Bloomer 2007; Bloomer. 2009), the Department of Exercise Science and Health Promotion at the Florida Atlantic University (Jacobs. 2009) support the claim that the combination of glycine and propionyl l-carnitine can increase nitric oxide production, decrease lactate accumulation and increase performance in high intensity exercises such as sprinting, the exact underlying mechanism remains questionable. Especially in view of the fact that Bloomer et al. (Bloomer 2007) administered glycine (1g) and the carnitine ester PLC (3g) in an unbound form, further investigation, whether co-administration of glycine and l-carnitine would not produce similar, yet more cost effective results, are warranted.

Note: I assume, you have also heard of the paradoxical effect 4.5g of GPLC had on sprint performance in a 2010 follow-up study of Jacobs et al. (Jacobs. 2010). In contrast to what the scientists had expected based on previous results (Jacobs. 2009), long-term supplementation of a high dose (4.5g vs. 1.5g) of glycine propionyl l-carnitine did not only fail to improve sprint performance beyond what was achieved with 1/3 of the dosage, the huge pump, the athletes were complaining about, even compromised their performance. If you are an athlete, exceeding a dose 1-2g of GPLC per day would thus be more than a waste of money, it could actually cost you your victory. Remember: With most supplements taking more does not equal greater benefits!

L-carnitine l-tartrate the one an only (?) testosterone booster

Image 4: "Supported" studies make
LCLT highly marketable (Lonza, Inc)

Based on what you (should) have learned from the previous paragraphs, you should not be surprised to hear that l-carnitine l-tatrate at dises of 5g (equiv. to 2g of carnitine), just as his "brethren" l-carnitine, acetyl- and propionyl l-carnitine may be considered a scientifically proven ergogenic. Ester (ALCAR, PLC) or salt (L-carnitine L-tartrate, L-carnitine fumarate, L-carnitine magnesium citrate), after all, its all carnitine... that being said, I do not question any of the highly marketable results Kraemer, Volek and the other scientists from the Human Performance Laboratory, Department of Kinesiology at the University of Connecticut have produced. I am just asking myself, why none of these studies compared the expensive tartrate salt, L-Carnipure® tartrate, the scientists received along with research grants from Lonza, Inc, to the much cheaper non-patented free form of carnitine. You do not have an answer, do you?

Did you ever think of the remote possibility that the "subtle yet significant" effects l-carnitine l-tartrate had on androgen receptor expression and testosterone in the heavily cited 2006 study by Kraemer et al. (Kraemer. 2006), may come from the tartrate and not the carnitine? Me neither, but the idea Owner (pseudonym) from the Mind&Muscle boards brought up, back in the days, is not totally devious. Join the smartest BB-community on the net and revive the discussion, if you will!

Conclusion

Do you remember? This write-up started out with the purported fat-burning effects of carnitine, established that carnitine is a necessary, but not sufficient co-factor in mitochondrial beta oxidation and clearance of fatty acid, elaborated on the metabolic and neurological health benefits of carnitine and concluded on the true ergogenic value of what turned out to be a whole group of quite expensive amino acids, the use of which you should take into consideration only after you got your (carnivorous) diet, your training regimen and your basic supplement protocol (protein, creatine + facultative EAA/BCAA) in check.

Amino Acids for Super Humans, Part IV - Purported Ergogenics (1/3): Beta Alanine, The New Creatine?

Image 1: Despite its presence in meat,
fish and dairy, it is near impossible to
achieve supra-physiological and thus
ergogenic carnosine levels without
supplemental beta alanine.

Beta alanine, unlike l-alanine is one of the "beta-amino acids", indicating that it is neither essential nor proteinogenic, i.e. it is not built into proteins or used in the synthesis of major enzymes. Nevertheless, beta alanine plays a major role with regard to health in general and brain health and muscular performance, particular.

Taken orally, as a supplement, beta alanine (BA) has a slight sweet taste to it (the artificial sweetener suosan is derived from BA). It is highly water soluble and the funny tingles, which can be avoided by either taking it with food or by taking smaller servings (e.g. 5x 800mg for a total of 4g, which would be a reasonable amount for carnosine "loading") multiple times a day, aside, it is virtually side effects free (some people also develop benign allergic skin or mucosal reactions and/or diarrhea). 

According to Jeffrey R. Stout from the University of Oklahoma, who is one of the scientists behind many of the the commonly cited studies on beta-alanine and exercise performance, humans, in contrast to other mammals, cannot synthesize beta alanine (PerfNut. June, 2006). Humans get their beta-alanine directly from BA-containing dipeptides in our food:

• Carnosine (beta-Alanyl-L-histidine), 
• Anserine (beta-Alanyl-N(pi)-methyl-L-histidine) and 
• Balenine (beta-alanyl-N tau-methyl histidine)

are dietary sources of beta alanine. All three are particularly high in meat, eggs, dairy, which is why vegetarians tend to have significantly lower beta alanine intakes. With beta alanine being a non-essential amino acid, low intakes of beta alanine would not be a problem, if it were not the rate limiting substrate in muscular (and cerebral) carnosine synthesis.

Note: This is the detailed transcript of my show notes to "Amino Acids for Super Humans Part IV"
click here to download the podcast if you want to listen before / during / after you read the rest of the notes

Beta alanine, the rate-limiting substrate in carnosine synthesis

Carnosine, i.e. beta-Alanyl-L-histidine (C9H14N4O3), is a dipeptide which was first isolated by Gulewitsch and Amiradzhibi at the dawn of the 20th century. Yet, science begins only recently to grasp all the remarkable health and performance benefits, its presence in muscle, nerve and other tissues may provide. In the following I will summarize the most relevant facts and findings:

• carnosine levels are particularly high in brain tissue and fast-twitch muscle fibers (Harris. 1998)
• mean concentrations are 17.5 ± 4.8 mmol kg−1 dm in females and 21.3 ± 4.2 mmol kg−1 dm in males (Mannion. 1992),
• interestingly muscle carnosine levels of sprinters and other sports with short bursts of high intensity work are elevated compared to non-athletes and athletes from endurance-oriented sports such as marathon runners
  
  carnosine & the brain
  
• carnosinemia (a rare condition of low carnosine levels) effects almost exclusively the brain, which indicates that it is of utmost importance to brain health
• carnosine levels (in all tissues) decline with age; scientists speculate about the role of low carnosine levels in dementia and other age-related neurological diseases
• carnosine's antiglycation effect makes it a promising therapeutic agent in the treatment of AGE-related (AGE = advanced-glycation-end-products) pathologies such as Alzheimer's (Reddy. 2006)
  
  carnosine & athletic performance



Figure 1: In one of the most recent studies
beta alanine supplementation @ 4g/day
significantly improved performance and
body composition in trained football
players and wrestlers (Jun 13, 2011)



• carnosine appears to have general anti-oxidant capacity and could thus protect athletes from exercise induced oxidative stress
• carnosine has a PH of 6.9-7.0, which is identical with the normal intracellular PH level of 7.0 (cf. blood PH is higher: 7.4); similar to bicarbonate (PH ~8.0) which is an excellent extra-cellular buffer, carnosine can act as a buffer on the cellular level
• by buffering H+ ions which are produced in the course of strenuous exercise sessions, it reduces the buildup of lactic acid, which other than its base, lactate cannot be readily "recycled" as fuel (Catham. 2002), but contributes to exercise induced and acidosis and consecutive performance decrements (Böning. 2008)

Increasing carnosine levels by beta alanine supplementation

I has been shown, that oral beta alanine supplementation can elevate carnosine levels (in muscle) by up to 80% (Derawe. 2010). The beneficial effects of the practice of what I would like to call carnosine loading (via BA supplementation) have been confirmed by numerous studies in the course of the last decade. In a 2010 review of the literature Sale et al. conclude:

β-Alanine supplementation has consistently been shown to augment muscle carnosine concentrations in man [...] There is now a growing body of evidence to show that β-alanine supplementation of 4 weeks or longer evokes significant improvements to exercise capacity, especially when that performance is likely to be limited by the accumulation of H+ ions in the skeletal muscle (i.e. in high-intensity exercise tests lasting between 1.5 and 4 min)

In that, it is important to note that the immediate effects, many fitness enthusiasts report on the health and body building boards on the Internet, are probably placebo and/or psychological effects related to the tingling sensation, most people get from beta alanine intakes in the range of 1g+.

Muscle carnosine levels rise gradually, a sensible supplementation regimen would thus span 4-6 weeks with a daily intake of 3-5g of beta alanine per day - preferably in divided doses to avoid the tingling and ensure proper absorption.

Studies show that after a certain time-frame, which varies according to interpersonal differences and training modalities, carnosine levels saturate. Whether or to which extent continuous supplementation makes sense in these circumstances has not yet been elucidated and would certainly depend on the individual athletic demands.

Tingles, flushing and myocardial suffocation

Regardless of whether they enjoy or hate the tingling sensation that comes with higher doses of beta alanine, neither the "lovers" nor the "haters" can provide a 100% scientifically proven explanation for their occurrence. A common theory relates to the process of carnosine synthesis, of which you have already learned that it involves two amino acids: beta alanine and l-histidine. The latter is abundant in muscle tissue and the generally accepted hypothesis is that it is released in the presence of beta alanine in order to form carnosine. If a sudden spike in serum beta alanine levels occurs, the amount of histidine that is released from the muscle tissue could either surpass the amount of beta alanine that is actually there to recombine to carnosine, which would subsequently be stored within the muscle (or other tissue), or there is simply not enough carnosine synthetase (the enzyme which catalyzes the reaction of beta alanine + l-histidine to carnosine) available. In both instances there would be a net increase in "free floating" l-histidine in the blood stream, which in turn could undergo decarboxylase by the respective enzyme, L-histidine decarboxylase. The histamine produced in this reaction could then activate histamine receptors at the tissue level and provoke an "allergic" reaction that feels like a tingling sensation. Both, the non-occurrence of the tingling as well as the few reported instances, where the latter are accompanied by a rash on the tingling body parts, would support the histamine-hypothesis.

In Joe Antonio's Performance Nutrition Podcast, back in 2006, however, Jeffrey R. Stout suggested another possible mechanism (PerfNut. June, 2006). According to Stout, a direct interaction of the beta-alanine molecules with neurons in the respective tissue would be responsible for the (un-?)comfortable sensation. 

And, to make things even more complicated, I would like to suggest a third hypothesis: Those of you who have had thequestionable experience of (over-)consuming GABA orally, may have noticed that, the shortness of breath aside, the activation of peripheral GABA receptors can provoke a feeling which is not all too different from the BA-tingles. With beta alanine being a GABA-A & GABA-C agonist, this would be another, yet possibly the least likely, explanation.

Beta Alanine & Taurine - archenemies or synergists?

Figure 3: The structural difference in their
molecular structure is the outward sign of
the very different biological functions of
alanine (left) and beta-alanine (right);
one part of the energy supply chain,
the other a potent H+ buffer

Whatever the reasons for the tingles are, they are just as benign as oral beta alanine supplementation in general. In this respect, any possible concerns, my report on the hypoxic consequences of beta alanine induced taurine depletion in isolated cardiomyocytes might have brought up, would be inappropriate. Other than cells in a petri dish, your heart, or rather your whole body can very well take counter-measures against overtly high beta alanine levels and consequent cellular taurine depletion. The latter could at worst become an issue, if you decided do lace all your foods, drinking water and whatever else you consume with tons of beta alanine for weeks to deliberately deplete your taurine stores.

In the aforementioned study the scientists found that "buffering" (remember these experiments were done in a petri dish) the beta alanine with equal amounts of taurine, i.e. one taurine molecule for each beta-alanine molecule. If you wanted to mimic this equilibrium state in your supplemental regimen, the higher molecular weight of taurine (125.15 g mol−1), as opposed to beta alanine (89.09 g mol−1), would dictate a ratio of about 3:5. A reasonable way of achieving this could be 1.5g of beta alanine upon waking, 1.5g before workout, 2.5g taurine post-workout and another 2.5g before bed. 

Personally, I do not think that supplementary taurine intake would be necessary (assuming you keep your beta alanine intake in the suggested range of 3-6g per day), but since both amino acids appear to have ergogenic potential (and taurine is also involved in many other metabolic processes) it may make sense to supplement both, anyway. Whether would be necessary or even beneficial to take them one at a time in order to avoid competitive absorption is yet questionable. Under the assumption that the ratio is not totally off - like 15g of bet alanine and 500mg of taurine - I assume that you will absorb reasonable amounts of both, even when you take them together.

Beta alanine, does it have endocrine effects as well?

Aside from the neurological effects of beta alanine (Tiedje. 2010) there is yet another hitherto hardly recognized effect of 3-Aminopropanoic acid (BA) in mammals: Beta alanine appears to modulate estrogen metabolism. A 2010 study by Yang et al. (Yang. 2010) found that beta alanine significantly (-18%) decreased estradiol levels in adult rats. This is an interesting observation, especially if one takes into account the results of Walter et al. (Walter. 2010) who recorded a significant weight gain in 44 women supplemented with 1.5g of beta alanine for 8 weeks. In contrast to other studies on male subjects, the weight gain was not due to superior increases in lean mass (measured, unfortunately, by air displacement instead of DEXA), as the latter increased similarly in the control group.

Note: The study by Yang et al. does not conflict with existing human data from Hoffman 2006 and Hoffman. 2008, who found no increase in testosterone, growth hormone or cortisol response to exercise in football players and experienced resistance trainers after 10, respectively 4 weeks of beta alanine supplementation. Those endocrine parameters remained unchanged in the Yang study, as well.

It is common knowledge that the reduced estrogen production at the onset of menopause is partly responsible for the weight gain women experience at that age. That the opposite, i.e. weight loss, and more specifically, fat loss, is a consequence of lower estradiol levels in men is yet less well known. And despite the fact that this hypothesis warrants experimental verification, it may be possible that small, yet statistically significant endocrine modulations due to beta alanine supplementation may in part explain both, the weight gain the women in the Walter study experienced (Walter. 2010), as well as the improvements in fat loss and retention of lean mass in dieting wrestlers in the recently published study by Kern et al. (Kern. 2011).

Bottom line: Although beta alanine is the next "big thing" since protein and creatine supplements, it probably is a way smaller "big thing". If you got to chose and are no athlete competing in weight classes, creatine will probably provide greater benefits in view of performance increases and body recomposition or muscle building. If you can afford taking both, however, do not hesitate! Studies like Hoffman 2006 make it quite clear that the combination of creatine and beta alanine, which work via distinct mechanisms of action, is the way to go for the non-drug taking athlete who is looking for the slight edge which so often decides on victory or defeat.

Show Notes: Amino Acids for Super Humans. Part III - Sulfur, More Than Just Rotten Eggs.

Amino Acids for Super Humans. Part III

Sulfur, More Than Just Rotten Eggs

Episode available for download, now!

notice! this are 100% uncorrected show notes not originally intended for publication

In this episode we are going to tackle:

• methionine (essential amino acid, EAA)
• cysteine (conditionally essential amino acid)
• n-acetyl cysteine (acetylated variety of cysteine, not found in food sources)
• taurine (non-essential amino acid)

SHR & BodyRX: Exercise & Nutrition Science that Goes Right From Your Ears into Your Brains.

I hope you did not plan otherwise, because I just scheduled two appointments for you: At 12pm (EST) you got to tune in live and listen to me & Sean Casey from Casey Performance @ Carl Lenore's Super Human Radio to learn more about the Science of Self Education ...

The Science of Self-Education
How to Read a Research Study
update: Podcast available for Download

Listen live to SHR @ 12:00PM ET

After that you may have a brief launch break to fuel the gray matter between your ears, in order to then tune in to Dr. Scott Connelly's BodyRX Show for the second installment of the "Hardgainer Episode" @ 3pm (EST)

Are We all Hardgainers - Part II
Muscle building strategies for those not part of the genetic elite
update: Podcast available for Download
 

Tune in live @ 3pm (EST)

Beyond Building Blocks: Amino Acids for Super Humans. Part I of an SHR Series on Metabolic, Endocrine and Neurocrine Functions of Amino Acids

This relevant for all of you - regardless of whether you can or cannot spare the time: Tune in live and listen to me @ Carl Lenore's Super Human Radio to learn that amino acids are far more than just the building blocks of the proteins of your body...

Listen live to SHR @ 12:00PM ET

Beyond Building Blocks:
Amino Acids for Super Humans.
(update: click here to download podcast)
Metabolic, Endocrine and Neuroendocrine Functions of Amino Acids

In the first installment of the series we will lay the foundations. What is an amino acid? What does it do, but being incorporated into proteins? How do we get (enough) amino acids? What on earth does our body do, once those little nitrogen containing molecules enter our blood streams?

As always, I will do my best to provide relevant examples and relate the theory to practical advice. The magic of individual amino acids will be tackled in the shows to come.

Update: The show is now available for download.

Fukushima & You: Understand What's Going On & How to Protect Yourself.

I am back on SHR - this time talking about a very serious topic: The meltdown at the nuclear power plant(s) in Fukushima.

"What the Fukushima Is Going On?"

Update: Download Podcast

Listen live @ 9:00AM AM/12:00PM ET

Tune in live and listen to some solid background info that will help you understand what's going on in Japan, California and the rest of the world.

Follow Up on Set-Point Theories: Could Royal Jelly Help With Obesity / Diet Induced Structural Brain Changes?

The colleagues over at ergo-log.com dug up a 2009 study (Narita. 2009) on the endocrine effects of royal jelly supplementation on rats. You may now wonder "Why is he suddenly beginning to writing off information about old studies on other sites?" Well, my interest in this study relates to my recent appearance on Carl Lenore's Super Human Radio show (I know, I promised a write-up /just have to find the time ;-) and diverges from the original interpretation the anonymous author over at ergo-log provided.

As you may have heard on the podcast, the most significant finding of the Ravussin study (Ravussin. 2011) was the down-regulation of pro-opiomelanocortin [POMC] neurons in the hypothalamus, which went hand in hand with weight gain and weight loss and is associated with a reduction of the metabolic rate to levels at which further weight loss or even weight maintenance become a significant challenge. Here, the findings of the aforementioned study on royal jelly, "a honey bee secretion that is used in the nutrition of larvae, as well as adult queens" (Wikipedia), come into play. As can be seen from in figure 1, 7 months supplementation with 5% Royal Jelly produced profound effects on the expression of the rats' pituitary hormone genes, one of which (you will have guessed that) is POMC.

Figure 1: Expression of Pituitary Hormone Genes in Middle-Aged Female Rats Fed a 5% Royal Jelly Diet for 7 Months. (Narita. 2009)

Now, one could speculate that despite the fact that a ~10% increase in POMC expression could not compensate for the obesity induced loss of 50% of excitatory POMC neurons observed by Ravussin et al., the combined effect of increased POMC expression and a rise in thyroid stimulating hormone TSH could eventually turn out to be beneficial for someone, who has maneuvered him or herself in a metabolic state, where effective weight loss, i.e. the loss of body fat and conservation of muscle mass, is nigh on impossible.
Yet, before you break into the next beeyard, you should consider that...

1. the amount of royal jelly the rats consumed in the study, i.e. 5% of their daily food intake is almost impossible to achieve without plundering beeyards all over the country (for the same reason it is no practical alternative to medications for "rejuvinating the pituitary" which the author of the ergo-log post seems to imply in the headline of his post)
2. an upregulation in gene expression alone does not guarantee an increase in metabolic rate (the increase in the thyroid (pre-)hormone T4, for example, was non-significant, despite a significant increase in TSH related gene expression)

Basically, this means that you should get accustomed to the idea that the damage years of overeating and/or crash- & yoyo-dieting has inflicted to your body are unlikely to be repaired within weeks or even months by just popping pills or eating some kind of superfood, no matter how "royal" it may be. In the end, it will come down to making a decision to change your life (nutrition and exercise) and to stick to this decision, no matter how hard it may seem.

Want to Stay Lean on a High-Fat Diet? Consume Whey Protein Everyday.

Listeners of Carl Lenore's Super Human Radio already know: Dr. Paul Arciero of Skidmore College is going to publish a study the results of which confirm that obese individuals can lose weight and improve markers of metabolic health by just adding a 20g shake of whey protein 3x a day.

While you still have to wait for the detailed results of this study to be published, another group of scientists (Shertzer. 2011) derived similar results from a study on mice. Despite being on a high fat diet, mice who received 100mg of whey protein isolate (WPI) per liter of their drinking water (WPI group) ...

had lower rates of body weight gain and percent body fat and greater lean body mass, although energy consumption was unchanged. These results were consistent with WPI mice having higher basal metabolic rates, respiratory quotients, and hepatic mitochondrial respiration. [...] Livers from WPI mice had significantly fewer hepatic lipid droplet numbers and less deposition of nonpolar lipids. Furthermore, WPI improved glucose tolerance and insulin sensitivity.

While you are waiting for the human study to be published (the SuppVersity will have it first ;-), get yourself some tasty whey protein and listen to Dr Arciero on Super Human Radio!