42 replies to this topic

[angelfire]

I have been taking Carnosine for quite some time, at doses similar to those of LifeMirage. I have been happy with this, in an 'anecdotal experience' way.

I then came across reports written by Dr. E.K. Schandl, who I believe is the scientific director of LEF (a company which it seems most of you here have a lot of respect for).

His beliefs over Carnosine are well summarised by this link: http://caprofile.net...NEwarning1.html

This, and other of his reports, strongly imply to me that he is saying that too much carnosine can cause carnosinemia, which I thought was an inherited condition, (like eg Wilson's desease), and various other negative effects.

This seems misleading to me as a lot of the research he cites concerns people with the inherited condition, and I think he draws dubious analogies to things like excitory neurotoxins in artificial sweeteners.

I emailed him and he responded with what I thouht was a very insulting comment, to the effect: He hopes I take as much carnosine as I want in my lifetime and 'get what I deserve' from doing so.

I'd much appreciate anyone else's comments on this.
Am I wrong that he is associated with LEF? I would be very disappointed if I'm not.
Thanks.

[rfarris]

How much carnosine is too much? I take a gram per day.

[angelfire]

So do I.

They say dosage of 100-200mg are effective in humans while doses greater than 500 mg show adverse and reverse effects, and recommend either 100 to 150 mg a day or 100 to 250 mg doses taken a few days a week as safe and beneficial doses.

I really hope that's not true. Thought someone here might know better. I can find the writings if needed.
Can Carnosine (in someone without Carnosinemia genetically) develop such symptoms by taking too much (i.e. around 1g) of carnosine a day? I can't see how, but Dr Schandl says so.

[cesium]

Carnosinemia is a very rare inherited metabolic disorder, but apparently this Dr. is speculating that supplementing with enough carnosine to overwhelm the body's carnosinase could potentially have deleterious effects that would resemble the disease state. Something to consider I suppose, though this guy sounds like a jerk the way he comes off responding to you in his email. I was thinking of taking more carnosine myself until I came across this.

[Shepard]

I doubt he is the scientific director of LEF since LEF pushes carnosine in the 1000mg range.

[cesium]

Whatever his credentials, he does raise a valid point about what excess carnosine could potentially do to the body. I had never heard of Carnosinemia before this thread and actually was thinking of increasing my uptake of carnosine, but am having second thoughts about it now. I recall a LF article saying that to benefit from carnosine the amount to be taken had to be in excess of what the body would immediately metabolize with its carnosinase. So by overwhelming that enzyme on a chronic basis, you are essentially artificially inducing or mimicking the diseased state of Carnosinemia. There might very well be risks associated with doing that.

[Shepard]

There are risks associated with basically any type of supplementation. You weigh the odds and decide if you're willing to take the risks (some are so minute it is inconsequential, others have slightly higher risk). From the reading I've done on carnosine, I will continue to take 1 gram per day.

[FunkOdyssey]

Well, we can indirectly answer one of Dr. Schandl's conclusions with a solid argument from LEF's literature:

As a conclusion, those who are presently taking carnosine may, in fact, induce the potentially dangerous neurotoxic condition, carnosinemia. Therefore, it is not advisable to supplement with carnosine. In the light of all of the above, one can see one of the true benefits of a vegetarian diet. Patients with neurological disorders such as M.S., Parkinson's Disease, A.L.S. and Alzheimer's Disease could very well benefit from a vegetarian diet.

So does reduced intake of carnosine help out vegetarians like Schandl implies?

A fascinating paper recently published in the journal Mechanisms of Aging and Development presents an entirely new theory to explain why vegetarians do not live longer.41 It turns out that those who avoid eating beef suffer a deficiency of a nutrient (carnosine) that is critical to preventing lethal glycation reactions in the body.

For the benefit of new members, glycation can be defined as the toxic binding of glucose to the body’s proteins. Glycation alters the body’s proteins and renders them non-functional. While wrinkled skin is the first outward appearance of glycation, most degenerative diseases are affected in one way or another by pathological glycation reactions.

Diabetics suffer from accelerated glycation that contributes to the secondary diseases that result in premature death.42,43 For instance, glycation’s destructive effect on the arterial system results in a loss of elasticity, hypertension, and atherosclerosis.44-47 Glycation is involved in disorders as diverse as cataract, cancer, and Alzheimer’s disease.48-57

Unless aggressive steps are taken, many aging adults will suffer the devastating effects of glycation to proteins throughout their bodies. This fact was established recently when it was shown that even healthy people with slightly elevated glycation levels are at higher risk for heart attack.

Vegetarians have higher levels of advanced glycation end products (AGEs) in their blood compared to those who eat meat.58,59 This is because an exclusively vegetarian diet would lack carnosine, nature’s most potent anti-glycating agent.

For vegetarians who fastidiously adhere to a diet devoid of meat, their “Achilles’ heel” may be lack of carnosine. This was confirmed in a paper published in October 2005 titled, “Glycation, ageing and carnosine: Are carnivorous diets beneficial?”41
Does Beef Supply Enough Carnosine?

A recent study of 18 people sought to determine carnosine concentrations in blood plasma after eating beef.60 Each 7.1-ounce serving of ground beef used in this study naturally contained 248 milligrams (mg) of carnosine.

In the study’s first phase, meat foods were removed from the diet for 48 hours. When fasting blood levels were measured, no carnosine was present. After the subjects ate 7.1 ounces of ground beef, carnosine was detected in the blood within 15 minutes and continued to increase for several hours. After 5.5 hours, there was again no carnosine in the blood. This study clearly showed that 248 mg of carnosine does not provide the body with all-day protection against glycation reactions.

The reason carnosine disappears so quickly from the blood is the presence of an enzyme (carnosinase) that naturally degrades carnosine in the body. This new study on carnosine blood levels confirms what Life Extension published five years ago. Back in 2000, we advised members that at least 1000 mg a day of carnosine is needed to overwhelm the carnosinase enzyme and protect against toxic glycation reactions.61,62

Commercial supplement companies are still selling 50-mg carnosine capsules and claiming that this low dose is effective. Based on this recent study showing that the body degrades 248 mg of carnosine within 5.5 hours, consumers who take these 50-mg carnosine capsules are obtaining virtually no benefit.

They found 248mg of carnosine in 7 ounces of ground beef. Assuming other meats also contain significant quantities of carnosine, many people are probably getting 200-400mg of carnosine a day from diet already. With this in mind, 1000mg/daily supplementation doesn't sound so unreasonable.

[DukeNukem]

Good digging, Funk.

[FunkOdyssey]

If the body degrades 248mg in 5.5 hours, what would be the best way to take 1000 or 1500mg daily? Would you get more "area under the curve" by taking it all in a big shot, or dividing it up throughout the day? Possibly take a larger dose of it near bedtime to maintain blood levels until the morning dose?

300mg with breakfast, lunch, and dinner, and 600mg at bedtime for example...

[FunkOdyssey]

Or, is it important to give your body an opportunity to clear the carnosine from the blood completely? It occurs to me that my proposed dosing scheme above might lead to cumulatively higher levels of carnosine each day and eventually the supplementation induced carnosinemia Schandl warns of. Maybe a compromise would be 300mg at each meal and 300mg at bedtime. Sometime in the few hours before you awake the body would have cleared out all the carnosine, and it wouldnt be that important at that point anyway because you are in a fasting state of low blood sugar.

I tentatively like that.

[mitkat]

As I understand it, a vegetarian diet totally lacks carnosine. What would be the your "optimum" dosage to have in your body, since there would be little or none to start with?

Maybe intermittent, lower doses would be best.

[FunkOdyssey]

Maybe intermittent, lower doses would be best.

That would be a good way to mimic the pattern of carnosine intake of a diet that includes meat. I feel that maintaining a relatively constant amount of carnosine in the blood throughout most of the day is probably beneficial above and beyond that.

[trh001]

per http://caprofile.net...NEwarning1.html

"It should be realized that an overload of substrate, i.e. carnosine in the present case, will cause the inhibition of the degradation/detoxifying enzyme, carnosinase."

I don't think this can be defended. M-Menton kinetics shows that in the presence of excess substrate, enzyme turnover of substrate reaches "steady state". There is no 'inhibition', via substrate -- it wouldn't be a substrate...it would be an inhibitor. This is how drugs are developed, for example - modify a substrate to block the active site of an enzyme. This isn't what's happening here.

I also call into question carnosinase as a 'detoxification' enzyme: seems an attempt to inflame, and put negative spin, is taking place wrt this statement.

Sounds less than objective. Someone should do a lit. search to look for dosing studies in animals.

[trh001]

Also, carnosine is interesting due to repeated studies, such as the one below, showing it affects telomere shortening, and this is a critical target in cell and tissue aging, especially long lived tissues. If you want to protect yourself from glycation (AGE's) then Benfotiamine and Thiamine might be a better bet, but carnosine has unique properties beyond interfering with non-enzymatic glycation:

Biochem Biophys Res Commun. 2004 Nov 12;324(2):931-6. Related Articles, Links

L-carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts.

Shao L, Li QH, Tan Z.

Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, PR China.

Telomere is the repetitive DNA sequence at the end of chromosomes, which shortens progressively with cell division and limits the replicative potential of normal human somatic cells. L-carnosine, a naturally occurring dipeptide, has been reported to delay the replicative senescence, and extend the lifespan of cultured human diploid fibroblasts. In this work, we studied the effect of carnosine on the telomeric DNA of cultured human fetal lung fibroblast cells. Cells continuously grown in 20 mM carnosine exhibited a slower telomere shortening rate and extended lifespan in population doublings. When kept in a long-term nonproliferating state, they accumulated much less damages in the telomeric DNA when cultured in the presence of carnosine. We suggest that the reduction in telomere shortening rate and damages in telomeric DNA made an important contribution to the life-extension effect of carnosine.

[trh001]

Also, the concentration of carnosine ranges from 1-25mM. The molarity is pretty small for a dipeptide, so we'll call it about 1400 GMW. Assuming an average cross compartment concentration throughout the body of 1mM, and a body volume of 30 liters (is that too high or too low?) then you get 30mmols total, on the low end.
At 1400mg/mmol, that's 42,000mg or 42 grams of carnosine in the human body (?). If that's anywhere near correct, then adding a gram in, per day, is only 2.4% added carnosine.

Another way to look at it would be to assess the added carnosine as a function of the amount already eaten in the daily diet. Meat eaters get plenty of carnosine...but how much? If the daily intake is already in the gram range I'd say the supplement isn't a concern. It may also not be worth the money, arguably, but then I don't eat meat, and only occasional fish.

[trh001]

As I understand it, a vegetarian diet totally lacks carnosine. What would be the your "optimum" dosage to have in your body, since there would be little or none to start with?

Maybe intermittent, lower doses would be best.

The body synthesizes carnosine, so one won't be "malnourished" on a vegetarian diet.

[trh001]

Here's an old but good reference to oral dosing in food in SAM. The dose was 100mg/kg body weight...and it increased life span in both SAM and control mice. That's about 6grams for a human, equivalent dosing, so taking an extra gram still seems reasonable.

----------------
Biosci Rep. 1999 Dec;19(6):581-7. Related Articles, Links


Carnosine, the protective, anti-aging peptide.

Boldyrev AA, Gallant SC, Sukhich GT.

Center for Molecular Medicine, Department of Biochemistry, Biological Faculty, MV Lomonosov, Moscow State University, Vorobjovy Gory, Russia. aab@1.biocenter.bio.msu.ru

Carnosine attenuates the development of senile features when used as a supplement to a standard diet of senescence accelerated mice (SAM). Its effect is apparent on physical and behavioral parameters and on average life span. Carnosine has a similar effect on mice of the control strain, but this is less pronounced due to the non-accelerated character of their senescence processes.

[FunkOdyssey]

The body synthesizes carnosine, so one won't be "malnourished" on a vegetarian diet.

Here is LEF's explanation:

Vegetarians have higher levels of advanced glycation end products (AGEs) in their blood compared to those who eat meat.58,59 This is because an exclusively vegetarian diet would lack carnosine, nature’s most potent anti-glycating agent.

For vegetarians who fastidiously adhere to a diet devoid of meat, their “Achilles’ heel” may be lack of carnosine. This was confirmed in a paper published in October 2005 titled, “Glycation, ageing and carnosine: Are carnivorous diets beneficial?”41

Here are the studies in the order in which they are referenced:

Physiol Res. 2002;51(3):313-6.  Related Articles, Links
    Click here to read
    Advanced glycation end products and nutrition.

    Krajcovicova-Kudlackova M, Sebekova K, Schinzel R, Klvanova J.

    Institute of Preventive and Clinical Medicine, Bratislava, Slovak Republic.

    Advanced glycation end products (AGEs) may play an important adverse role in process of atherosclerosis, diabetes, aging and chronic renal failure. Levels of N(epsilon)-carboxymethyllysine and fluorescent AGE values were estimated in two nutritional population groups--alternative group (vegetarians--plant food, milk products, eggs) and traditional group (omnivorous subjects). Vegetarians have a significantly higher carboxymethyllysine content in plasma and fluorescent AGE values. Intake of proteins, lysine and monosaccharides as well as culinary treatment, consumption of food AGEs (mainly from technologically processed products) and the routes of Maillard reaction in organism are the substantial sources of plasma AGEs. Vegetarians consume less proteins and saccharides. Lysine intake is significantly reduced (low content in plant proteins). Subjects on alternative nutrition do not use high temperature for culinary treatment and consume low amount of technologically processed food. Fructation induced AGE fluorescence is greater as compared with that induced by glucose. It is due to higher participation of a more reactive acyclic form of fructose. Intake of vegetables and fruit with predominance of fructose is significantly higher in vegetarians. Comparison of nutrition and plasma AGEs in vegetarian and omnivorous groups shows that the higher intake of fructose in alternative nutrition of healthy subjects may cause an increase of AGE levels.

In that one, the researchers think the extra fructose in the vegetarian diet is responsible for the increase in AGEs.

http://www.clinchem....t/full/49/6/983
More evidence that vegetarians have higher levels of AGEs, although the focus of the study is on rampant vegetarian B12 deficiency and high homocysteine

Here's the one that I think LEF is basing their "vegetarians don't live longer because they don't get carnosine" conclusion on (they referenced several studies showing that vegetarians didn't live much longer, this is the one that provides a possible carnosine link):
http://www.biovita.f...ni_hipkiss.html

I have to admit, the explanation that vegetarians have more AGEs because they simply eat more fructose and other carbs does seem very plausible.

[trh001]

RE. vegetarians having a defecit of carnosine, it's entirely possible. I know carnosine is a peptide, composed of beta-alanine, and L-histidine, and it's synthesis is part of our basic biochemistry. Wether it's conditionally essential, is an open question. I don't know what contribution meat might have, wrt dietary carnosine (interesting that the meat itself would increase the glycation burden) and the issue of extra fructose is plausible, though there's so much fructose in high fructose corn syrup products (all processed foods) that anyone on a standard western diet is over-exposed to fructose.

I take a gram a day via LEF's Mitochondrial Energy Optimizer. As noted in a previous post, I'm unclear on it's contribution to the total pool of carnosine in my body, but the studies suggest it's in the range of what might have an impact.

[nbourbaki]

I've tried to take carnosine three times. All three times my sinuses just absolutely plugged up. I tried to lessen this effect by taking anti-histamines and increasing the amount of Vit C I would normally take but without luck. Even at 250 mg per day, my sinuses plug up. My body seems to convert the L-histidine to histamine very efficiently.

[angelfire]

I was interested in carnosine due to it's (apparent) ability to 'revitalise' aging cells, decrease cellular aggregation, etc..., but there are other benefits such as decreasing lipid peroxidation catalysed by Cu2+

But the article (the one I referenced to was simply the most concise of Dr. E.K. Schandl's arguements I could find) still worries me.

As for dosage, I think LifeMirage recommends Carnosine to be taken in one dose, specifically to bypass the Carnosinease.

I'm also interested in whether one can bypass the need to take Carnosine by taking it's two constituent amino acids (alanine & histidine?), as it can be made from these in the body.

As for the link between Dr. E.K. Schandl and LEF, I may be wrong, but "Dr. E. K. Schandl, scientific director of the Life Extension Foundation" is from here:
http://search.lef.or.....0E.K. Schandl
Thanks.

[trh001]

Beta-alanine (I believe it's derived from a nucleic acid pathway?) is distinct from L-alanine, however, L-histidine was reported to raise carnosine levels in oral dosing in horses (I'll need to dig up the reference). I take 125mg of L-his 4x per day.

However, L-histine is functional in many respects, and carnosinase cleavage of carnosine to it's component parts doesn't destroy all aspects of carnosine function in that they remain, to a degree via functional amino groups in b-ala and L-his. For example, see Alan R. Hipkiss, Mechanisms of Aging and Development 126 (2005) 1034-1039, for speculation along these lines, and there are papers that compare certain carnosine functions wrt potency with it's component L-his, and speculate on biological relevance.

Finally, I found this recently, which is rather interesting from the pharmacokinetic standpoint and leads me to think oral dosing with a modest 250mg 4x per day may be a better way for me to go wrt LEF's MEO (vs. their recommended 1X dosing to 'overwhelm' carnosinase) supplement carnosine content:

J Agric Food Chem. 2005 Jun 15;53(12):4736-9. Related Articles, Links


Quantitation of carnosine in humans plasma after dietary consumption of beef.

Park YJ, Volpe SL, Decker EA.

Department of Food Science, Chenoweth Lab, University of Massachusetts, Amherst, Massachusetts 01003, USA.

Carnosine (beta-alanyl-L-histidine) is a dipeptide found in the muscle foods that has been postulated to be a bioactive food component. The objective of this research was to determine the concentration of carnosine in human plasma after ingestion of beef. Nine males and nine females were recruited for the study. Food devoid of meat products was given to the subjects so that they did not consume carnosine for 48 h prior to the test. Subjects fasted for 12 h and then had blood withdrawn prior to a meal containing 200 g of ground beef. Additional blood samples were collected over the following 24 h and carnosine concentrations were determined by HPLC. The cooked ground beef used in the study contained 52% water, 24% protein, 22% fat, and 124 mg of carnosine/100 g of beef. No plasma carnosine was detected in subjects before the consumption of the beef. Carnosine was detected in plasma 15 min after beef consumption. Plasma carnosine concentrations continued to increase with a maximum (32.7 mg of carnosine/L of plasma) being recorded 2.5 h after consumption. Carnosine concentrations then decreased until no carnosine could be detected at 5.5 h postconsumption. These results indicate that dietary carnosine is absorbed into human plasma after the consumption of beef. Since carnosine has several potential health benefits, evidence of its bioavailability suggests that it could be a bioactive food component.

PMID: 15941308 [PubMed - indexed for MEDLINE]

Now the above doesn't take into account the food mass and gastric emptyring, which would not be a variable if one doses as LEF suggests, on empty stomack. One might see much higher blood levels more quickly, on an empty stomack. I known there are other oral dosing studies. Need to dig out. Still, this suggests one can ingest it with food, unless there are precursor forms in beef with different pharmacokinetics, which perhaps the authors are not taking into account.

So, in summary, of the above dosing is representative of the pharmacokinetic coverage one might achieve with pure carnosine, the 4x per day with 250mg (via LEF product) would give complete coverage leading to 24 hour increased plasma levels of carnosine.

[trh001]

This also, I think, puts into grater perspective the concern about carnosinemia, given the dietary carnosine one gets as a meat eater being in the range of what users (many vegetarian and/or low meat intake) are ingesting, and suggesting a 1g supplement would only bring low meat intake users up to perhaps 2x-4x the dose of what a regular meat eater might take in. As well, wrt a genetic trait that diminishes carnosine breakdown, one would have ever increasing levels of carnosine, vs. a higher steady state concentration. A higher steady state of, say, 2x-4x, would be much different than ever increasing levels to, say, 10x, 100x, 1000x, etc. It's still a debatable point, but it seems increasingly marginal.

If one were concerned, the above reference suggests one can model one's intake on the above, and ingest, say, 125-250mg once or twice a day, and be in the range of a meat eater's intake. If one already eats meat, one might only take the supplement on days when one does not ingest meat, or for meals where one does not ingest meat.

[FunkOdyssey]

So, in summary, of the above dosing is representative of the pharmacokinetic coverage one might achieve with pure carnosine, the 4x per day with 250mg (via LEF product) would give complete coverage leading to 24 hour increased plasma levels of carnosine.

Thats correct... however, there might be some risks associated with maintaining supraphysiological levels of carnosine around the clock. If you read the first page of this topic, the 5.5 hour clearance time of 248mg and its implications have already been discussed, along with a dosing scheme similar to yours except with consideration of the potential for developing carnosinemia.

[trh001]

Thats correct... however, there might be some risks associated with maintaining supraphysiological levels of carnosine around the clock.  If you read the first page of this topic, the 5.5 hour clearance time of 248mg and its implications have already been discussed, along with a dosing scheme similar to yours except with consideration of the potential for developing carnosinemia.

Agreed. But see second post, as this I think addresses your valid. One could model one's dosing in a manner that reflects any coverage one considers reasonable.

[trh001]

Whoops, I am sorry! I didn't see your reference to this publicaiton above. Will be more careful next time.

[trh001]

For what it's worth, 800mg/day for 8 weeks, in children. Still working on finding long term dosing studies.

One cautionary interpretation of the abstract below would be that at 800mg/day, one is seeing statistically significant neurological effects. A further negative spin might be -- "this means one is moving from the dietarily significant to the pharmacological". While I suspect some in this group are reasonably comfortable with knowing that much of what they ingest as "supplements" are actually well into the range of pharmacologica agents, using the reference below, and combining it with the beef ingestion study (ca. 250 mg >> 5.5 hours coverage) one might be inclined to cut back to a few hundred milligrams per day, in single dose, if one wanted to bias one's intake toward what's more dietarily relevant.

On the other hand, clearly 800mg per day is having some neuropharmacological effect, per the study below.

---------
J Child Neurol. 2002 Nov;17(11):833-7. Related Articles, Links


Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders.

Chez MG, Buchanan CP, Aimonovitch MC, Becker M, Schaefer K, Black C, Komen J.

Research Division, Autism and Epilepsy Specialty Services of Illinois, Ltd, Lake Bluff, IL 60044, USA. mchezmd@interaccess.com

L-Carnosine, a dipeptide, can enhance frontal lobe function or be neuroprotective. It can also correlate with gamma-aminobutyric acid (GABA)-homocarnosine interaction, with possible anticonvulsive effects. We investigated 31 children with autistic spectrum disorders in an 8-week, double-blinded study to determine if 800 mg L-carnosine daily would result in observable changes versus placebo. Outcome measures were the Childhood Autism Rating Scale, the Gilliam Autism Rating Scale, the Expressive and Receptive One-Word Picture Vocabulary tests, and Clinical Global Impressions of Change. Children on placebo did not show statistically significant changes. After 8 weeks on L-carnosine, children showed statistically significant improvements on the Gilliam Autism Rating Scale (total score and the Behavior, Socialization, and Communication subscales) and the Receptive One-Word Picture Vocabulary test (all P < .05). Improved trends were noted on other outcome measures. Although the mechanism of action of L-carnosine is not well understood, it may enhance neurologic function, perhaps in the enterorhinal or temporal cortex.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 12585724 [PubMed - indexed for MEDLINE]

[FunkOdyssey]

After I get some carnosine in bulk, I'm going to do 300mg at 8am, 1pm, 6pm, and 11pm. I'll let you guys know how that turns out. [thumb]

[mitkat]

Let us know, funk - cause now i'm in a funk about my current lack of carnosine.