--- In morelife@yahoogroups.com, Ólafur Páll Ólafsson <olafurpall@...>
wrote:
>
> [Thanks for posting this, Olafur. It is important information,
> although I do not think that it is as important as you seem to think.
> I have been aware of the rate-limiting nature of beta-alanine for
> carnosine synthesis for sometime, and if I was not getting my
> carnosine at no cost from LEF, I might have purchased some at
> 1fast400.com since I already buy piracetam from them. However, I had
> not seen these latest two papers which shed more light on the
> relationship, particularly with respect to comparing supplementation
> of both. Maybe I have missed something, but my interpretation of these
> studies is that supplementing beta-alanine would give no advantage
> over supplementing carnosine except perhaps for cost, particularly on
> a molar basis. I had thought that beta-alanine might be superior
> because it would not increase histidine levels and therefore might
> lead to less histamine release and consequent flushing, but these
> papers do not appear to support that view. --Paul]

You're absolutely right. After examining this in more detail I've
realised that it probably isn't as important as I initially thought.
Beta-alanine appears to have no advantage over carnosine as a
supplement except for it's much lower cost and possibly less risk with
respect to the concern of overriding the carnosinase enzyme, as it
mainly raises carnosine levels inside cells and is therefore less
subject to serum carnosinase.

[Yes, I had not considered that potential advantage of beta-alanine. However,
that potential disadvantage of high dose carnosine is also an advantage of
N-acetyl-L-carnosine given that its absorption is comparable, since it will
mostly get into cells before being deacetylated and thus hydrolyzable by the
carnosinase enzyme. --Paul]


And as I just posted on the
sci.life-extension group carnosine has some benefits over beta-alanine.

Here is a quote from the full text article of PMID: 16341596:

"Comparison of the different cell culture systems revealed not only
considerable differences in their capacity to synthesize
x-aminoacyl-amino acids (muscle cells exhibit by far the highest
activities of carnosine synthetase) but also with regard to the
release of these dipeptides into the culture medium. As expected from
the high concentrations of carnosine in skeletal muscle, carnosine was
not released into the medium of cultured muscle cells. Carnosine
synthesized by the glioma C-6 cell line also remained within the cells
whereas the dipeptides synthesized by astroglia- rich and
oligodendrocyte-enriched cultures were readily released into the
culture medium (6,8)."

This quote seems to suggests that once synthesized inside cells most of the
carnosine stays there and therefore that much of the benefits of increased
synthesis caused by beta-alanine supplementation may be localised to the tissues
in which carnosine is synthesized, namely muscle tissue and cells of the central
nervous system. However in addition to the cells that synthesize it there are
some cells that cannot synthesize carnosine but can take it up from the
circulation, so carnosine would probably be more beneficial than beta-alanine in
the circulation and in cells that cannot synthesize it but can take it up.

[Which means that for general anti-glycation and longevity purposes (which
affect all cells) carnosine (or perhaps better N-acetyl-L-carnosine) will be
better than beta-alanine, albeit more expensive. --Paul]


> IMO, the most important aspect of the papers is the verification of
> the clear need to supplement either beta-alanine or carnosine very
> frequently during the day. The papers also very clearly make a case
> for supplementing larger quantities of either because the breakdown of
> carnosine by the carnosinase enzyme will not, in the end, cause any
> loss of activity since the beta-alanine released will then allow more
> carnosine to be synthesized in the muscles where it is most needed
physiologically. --Paul]

I think the case for supplementing with larger quantities is
particularly true for beta-alanine as it raises carnosine levels
by increasing its synthesis similarly to what exercise has been
safely shown to do (PMID: 14610252 PMID: 1910085). This can be thought
of as a more natural way to increase carnosine levels compared to
supplementing high doses of carnosine. For this reason even for young
people I do not think there is any good reason to recommend against
supplementary doses of beta-alanine as high as used in these studies
as long as the dose is increased gradually and distributed throughout
the day to avoid flushing.

[Agreed. --Paul]


> OTOH, the muscles are not the only or even the major place where one
> would want the antiglycation effects of carnosine to be applied.
> Therefore, there may still be a case for supplementing carnosine
> instead of beta-alanine and even moreso for supplementing
> N-acetyl-L-carnosine which will avoid decomposition by the carnosinase
> enzyme and will be more slowly converted to carnosine to the extent
> that is is absorbed. --Paul]

I totally agree. I would only suggest to stop taking carnosine and
replacing it with beta-alanine to people who have no interest in
life-extension but only in increased sport performance, since for that
purpose beta-alanine should be just as effective as carnosine while
being much cheaper. For those who are interested in life-extension on the other
hand, I would suggest beta-alanine as an addition to carnosine, serving as a
cost effective measure to further increase carnosine levels in those tissues
where it is synthesized.

[Agreed. --Paul]


I personally am now looking into adding beta-alanine to my regimen to
complement the 500mg of carnosine I take daily. However beta-alanine
is not even listed on the Icelandic drug administration's web site, and as they
told me in an email, until they have reviewed it it will be categorized as a
drug and is therefore illegal to purchase
individually. I suspect that it will be categorized similarly to most
amino acids here in Iceland which are not allowed individually but are
allowed if combined with protein or some other ingredients. I found a
product here in Iceland which contains beta-alanine in addition to
other ingredients but that product is not only very expensive but it
contains a ton of sugar for every gram of beta-alanine, so there is no
way I'm buying that one. Therefore my best bet is probably to try to
get trueprotein.com to add it to their supplement line and take it as
a part of a protein mixture as I do with all the amino acids I
currently take.


BTW I would like use the opportunity to share some information on
histidine I just came across and posted on the sci.life-extension
group, as I think it is relevant to this discussion. I was just
reading the full text article of the abstract below:

Life Sci. 2004 Jul 30;75(11):1379-89.
Anti-crosslinking properties of carnosine: significance of histidine.
Hobart LJ, Seibel I, Yeargans GS, Seidler NW.
Department of Biochemistry, University of Health Sciences, 1750
Independence Avenue, Kansas City, MO 64106-1453, USA.

Carnosine, a histidine-containing dipeptide, is a potential
treatment for Alzheimer's disease. There is evidence that carnosine
prevents oxidation and glycation, both of which contribute to the
crosslinking of proteins; and protein crosslinking promotes
beta-amyloid plaque formation. It was previously shown that carnosine
has anti-crosslinking activity, but it is not known which of the
chemical constituents are responsible. We tested the individual amino
acids in carnosine (beta-alanine, histidine) as well as modified forms
of histidine (alpha-acetyl-histidine, 1-methyl-histidine) and
methylated carnosine (anserine) using glycation-induced crosslinking
of cytosolic aspartate aminotransferase as our model. beta-Alanine
showed anti-crosslinking activity but less than that of carnosine,
suggesting that the beta-amino group is required in preventing protein
crosslinking. Interestingly, histidine, which has both alpha-amino and
imidazolium groups, was more effective than carnosine. Acetylation of
histidine's alpha-amino group or methylation of its imidazolium group
abolished anti-crosslinking activity. Furthermore, methylation of
carnosine's imidazolium group decreased its anti-crosslinking
activity. The results suggest that histidine is the representative
structure for an anti-crosslinking agent, containing the necessary
functional groups for optimal protection against crosslinking agents.
We propose that the imidazolium group of histidine or carnosine may
stabilize adducts formed at the primary amino group.

PMID: 15234195

I had read the abstract before so I was well aware of histidine's
anti-glycative potential but I do not remember having read the full
text article before. Below are two quotes from the full text article
the first of which suggests that histidine is slightly better at
protecting against crosslinking of glyceraldehyde 3-phosphate (G3P)
than carnosine is when they are at a ratio of 20 to 1 to G3P. What I
found most interesting however is the second quote below. It suggests
that histidine is an effective anti-glycative agent at much lower
concentration than carnosine is, at least with respect to it's ability
to prevent G3P induced crosslinking. You need a 10 to 1 ratio of
carnosine to G3P to prevent crosslinking but histidine is effective at
a 1 to 1 ratio. It is worth mentioning however that G3P is not the
only or even the most important crosslinking agent in humans so this
does not necessarily mean that overall histidine is a better
antiglycative agent than carnosine. It only is with respect to
glycation of G3P. But it does suggest that histidine would be
beneficial as an antiglycative supplement and a good addition to any
life-extenison regimen, as long as one does not take so much of it
that one gets allergic reactions from it's conversion to histamine.

"Interestingly, the anti-crosslinking activity of histidine was
greater than that of carnosine (P < 0.005) (Fig. 3). Histidine
exhibited 60% and carnosine 50% protection against
glyceraldehyde-induced crosslinking (protective agent to glycating
agent RATIO = 20:1; GLYCERALDEHYDE = 1.0 mM)."

"Carnosine is a dipeptide that contains a ß-alanine, whose carboxyl
group is amide-linked to histidine (Fig. 1). Hence, our immediate
interest was in testing the two amino acids separately. Our data
suggest that histidine is a representative anti-crosslinking agent.
Foremost, histidine exhibited greater anti-crosslinking activity than
carnosine (Fig. 3). Additionally, histidine was effective at
preventing crosslinking even at 1:1 ratios of histidine to
crosslinking agent (Fig. 4). Previously we showed that a 10:1 ratio of
carnosine to glyceraldehyde 3-phosphate is necessary to prevent
protein crosslinking (Seidler, 2000)."

[Yes, this information about histidine is very interesting. Perhaps you could do
some research on just what is the likelihood or relevant conditions of
conversion of histidine to histamine. It seems to me that for a healthy person
it may be possible that this does not happen sufficiently to be of any harm and
that any concern about taking high dose histidine may be false. --Paul]

[I'll look into this and report back if I find something of interest about this.
-°Olafur]