I just posted the following on the sci.life-extension group. Because I
think this is a very important finding I am posting it here too.


From: Olafur Pall Olafsson - view profile
Date: Fri, Aug 11 2006 8:37 am
Email: "Olafur Pall Olafsson" <olafurp...@...>
Groups: sci.life-extension

As the abstracts below show ingesting beta-alanine is very promising
for life-extension as it may be the most effective method available
today to increase carnosine levels in the body. It may also be of much
benefit to athletes due to the buffering capability carnosine has in
muscles.

Carnosine is a dipeptide composed of the amino acids beta-alanine and
histidine and is synthesized in muscles and cells of the central
nervous system by the enzyme carnosine synthetase. It's synthesis in
humans is limited by the availability of beta-alanine. This appears to
be caused by the low concentrations of beta-alanine in muscles and
plasma relative to it's high Michaelis constant towards carnosine
synthetase.

[Note: The Michaelis constant is an inverse measure of the affinity of a
substrate for the enzyme which uses it to synthesize a more complex chemical of
which the substrate is one moiety (part). --Paul]


Histidine on the other hand is much more abundant in
muscles and plasma and has a much lower Michaelis constant towards
carnosine synthetase than beta-alanine, and is therefore not rate
limiting for the synthesis of Carnosine under normal circumstances.
Consequently beta-alanine has been effectively used to stimulate
carnosine synthesis in humans in doses up to 6.4g daily distributed
throughout the day. To avoid symptoms of flushing it is advisable to
start with low doses and take beta-alanine in a distributed fashion.

BTW, beta-alanine is already available at a reasonable price at
1fast400.com: http://www.1fast400.com/?products_id=2318


J Neurochem. 1985 May;44(5):1459-64.

Carnosine synthesis in olfactory tissue during ontogeny: effect of
exogenous beta-alanine.

Margolis FL, Grillo M, Kawano T, Farbman AI.

Carnosine has now been demonstrated by chemical analysis to be
present in rat olfactory mucosa on day 16 of gestation. The tissue
content of this dipeptide then increases progressively during fetal
and postnatal life. Radioactive carnosine can be isolated from
cultured embryonic rat olfactory mucosa incubated with
[14C]beta-alanine as early as 13-14 days of gestation. The amount of
incorporation also increases progressively with the initial age of the
explant and with time in culture indicating in vitro maturation of the
carnosine synthesis capability of olfactory tissue. To test whether
the level of beta-alanine was limiting the synthesis of carnosine, we
evaluated the effect of elevated beta-alanine levels on tissue
carnosine content. Exogenous beta-alanine caused an increase in the
tissue content of carnosine at several ages in vivo and in vitro. In
adult animals this increase was observed in olfactory bulb, olfactory
mucosa, and skeletal muscle. However, there was no associated
alteration in carnosine synthetase activity. In addition, the
different half-lives of carnosine in olfactory tissue and muscle
seemed unaltered, arguing against any effect on degradative enzymes.
Thus, tissue carnosine levels are regulated, at least in part, by
substrate availability. The early appearance of carnosine synthetic
capacity during prenatal development indicates that this enzyme
activity should be a valuable aid in studying early events in
olfactory neuron maturation.

PMID: 3921664


Equine Vet J Suppl. 1999 Jul;30:499-504.

Influence of oral beta-alanine and L-histidine supplementation on
the carnosine content of the gluteus medius.

Dunnett M, Harris RC.

Department of Veterinary Basic Sciences, Royal Veterinary College,
Hatfield, Hertfordshire, UK.

The aim of this work was to test the hypothesis that in vivo
carnosine biosynthesis is dependent upon endogenous beta-alanine
availability, by studying the effect of sustained dietary beta-alanine
supplementation in the horse on the carnosine concentration in types
I, IIA and IIB skeletal muscle fibres. The diets of 6 Thoroughbred
horses were supplemented 3 times/day with beta-alanine (100 mg/kg bwt)
and L-histidine (12.5 mg/kg bwt) for a period of 30 days. Percutaneous
biopsies of the m. gluteus medius from a depth of 6 cm were taken on
the days immediately before and after the supplementation period.
Heparinised blood samples were collected at hourly intervals on the
first and last days of supplementation, and on every sixth day during
the supplementation period, 2 h after each ration. Individual muscle
fibres were dissected from freeze-dried biopsies, weighed and
characterised histochemically. beta-alanine, histidine and carnosine
concentrations were measured in plasma. The areas under the plasma
concentration-time curves (AUC) for beta-alanine and histidine were
calculated as indicators of the doses absorbed. Carnosine
concentrations were measured in types I, IIA and IIB muscle fibres.
There was an adaptive response to sustained beta-alanine
administration resulting in mean +/- s.d. beta-alanine AUC increasing
significantly from 1130 +/- 612 mumol/l h (Day 1) to 2490 +/- 1416
mumol/l h (Day 30) (P < 0.05). This was probably due to increased
beta-amino acid transport across the gastrointestinal lumen. There was
no consistent increase in histidine AUC between Days 1 and 30, (mean
+/- s.d. values being 757 +/- 447 mumol/l h Day 1[ and 1162 +/- 1084
mumol/l h Day 30[ P > 0.05[). Type IIA fibre carnosine concentrations
increased from 59.9-102.6 to 76.2-112.2 mmol/kg dry weight (dw).
Increases were statistically significant in 2 of the 6 horses (P <
0.05 in both instances). Type IIB fibre carnosine concentrations
increased from 101.3-131.2 to 114.3-153.3 mmol/kg dw. Increases were
statistically significant in 5 of the 6 horses (P < 0.05 in 3 horses,
P < 0.01 in 1 horse, P < 0.005 in 1 horse). Changes in muscle
carnosine concentration appeared to be influenced by beta-alanine
bioavailability. Individual increases in muscle carnosine
concentration were significantly correlated with individual changes in
beta-alanine AUC (r2 = 0.973, P < 0.005). Increased muscle carnosine
concentrations lead to increased intramuscular hydrogen ion (H+)
buffering capacity.

PMID: 10659307


Amino Acids. 2006 May;30(3):279-89.

The absorption of orally supplied beta-alanine and its effect on
muscle carnosine synthesis in human vastus lateralis.

Harris RC, Tallon MJ, Dunnett M, Boobis L, Coakley J, Kim HJ,
Fallowfield JL, Hill CA, Sale C, Wise JA.

School of Sports, Exercise and Health Sciences, University College
Chichester, Chichester, U.K..

beta-Alanine in blood-plasma when administered as A) histidine
dipeptides (equivalent to 40 mg . kg(-1) bwt of beta-alanine) in
chicken broth, or B) 10, C) 20 and D) 40 mg . kg(-1) bwt beta-alanine
(CarnoSyntrade mark, NAI, USA), peaked at 428 +/- SE 66, 47 +/- 13,
374 +/- 68 and 833 +/- 43 microM. Concentrations regained baseline at
2 h. Carnosine was not detected in plasma with A) although traces of
this and anserine were found in urine. Loss of beta-alanine in urine
with B) to D) was <5%. Plasma taurine was increased by beta-alanine
ingestion but this did not result in any increased loss via urine.
Pharmacodynamics were further investigated with 3 x B) per day given
for 15 d. Dietary supplementation with I) 3.2 and II) 6.4 g . d(-1)
beta-alanine (as multiple doses of 400 or 800 mg) or III) L-carnosine
(isomolar to II) for 4 w resulted in significant increases in muscle
carnosine estimated at 42.1, 64.2 and 65.8%.

PMID: 16554972

Quotes from the full text article:

"In human vastus lateralis muscle carnosine ranges from 10.5 +/- SDind
7.6mmol x kg(-1) dry muscle (dm) in type I and 23.2 +/- SDind 17.8mmol
x kg(-1) dm in type II fibres (Harris et al., 1998), where SDind is
the estimated standard deviation in fibre content within an individual."

"In human vastus lateralis muscle the most frequently cited range for
the carnosine content is 17.5 +/- 4.8 mmol x kg(-1) dm in females to
21.3 +/- 4.2 mmol x kg(-1) dm in males (Mannion et al., 1992)."

"Carnosine is synthesized in muscle and cells of the CNS (Bakardjiev
and Bauer, 1984) although other cell types express a dipeptide
transporter enabling the molecule to be taken up intact (Hoffmann et
al., 1996; Dieck et al., 1999)."

"As the concentration of histidine in muscle (and plasma) is high
relative to its Km with muscle carnosine synthetase (CS) (Horinishi et
al., 1978), in contrast to the low concentration of b-alanine in
muscle which exhibits a much higher Km with CS (Skaper et al., 1978),
it was concluded that b-alanine was probably limiting to carnosine
synthesis in equine muscle."

"Subjects were staff and students of University College Chichester,
non-smokers and had not taken any dietary supplements 4 to 6 weeks
prior to the start of the relevant study. None of the subjects
recruited to the various studies were vegetarians."

The study was divided into three parts, the last of which examined the
effects of beta-alanine supplementation on muscle Carnosine content.
Below are some quotes relating to the third part of the study:

"Study 3: The effect of 4 weeks dietary supplementation with
beta-alanine or carnosine on the muscle carnosine content

The main study was preceded by an investigation of 16 male subjects
(19.4 +/- SD 1.6 yrs; 79.5 +/- SD 9.3 kg) to assess the effects of
repeated administration of b-alanine on blood biochemistry and
haematology."

"Venous blood samples were taken at St. Richard's Hospital,
Chichester, at the start and end of the 4 weeks supplementation with 4
doses per day of 800mg of b-alanine (n=8) or a matching placebo (n=8).
Both treatments were provided as 2 x 400mg contained in gelatin
capsules. Subjects were instructed to take the 4 doses at
approximately 9 am, 12am, 3 pm and 6pm."

"Subjects ingested b-alanine daily using one of two regimens (I and
II, both n=5), L-carnosine (III, n=5) or placebo (IV, n=6) for 4 weeks:

I) 800mg of b-alanine was given 4 times per day (approximately 9 am,
12am, 3pm and 6pm) to give an average daily dose of 3.2 g and total 4
week dose of 89.6g.

II) used a more frequent dosage strategy in order to increase the dose
but not to exceed 800mg in any one dose. In week 1 subjects consumed
800, 400, 400, 400, 800, 400, 400 and 400mg at 9, 10, 11 and 12 am,
and, 3, 4, 5, and 6pm to give an average daily dose of 4 g. In week 2
the 11 am and 5 pm doses were increased to 800mg; in week the 10am and
4pm doses were similarly increased and in week 4 also the 12am and 6
pm doses. Thus in week 4 the average daily dose was 6.4 g. The total
dose over the 4 weeks was 145.6 g.

III) subjects ingested L-carnosine using a dosing strategy identical
to II) and where each individual dose was approximately isomolar with
respect to b-alanine. Thus where 400 and 800mg of b-alanine were given
in II), 1000 and 2000mg of L-carnosine were given in III). The total
given over the 4 weeks was 364 g of L-carnosine corresponding to 143.3
g of b-alanine.

IV) subjects were given capsules containing maltodextrin to match
those of II) and at the same frequency as given also in III).

"Mild symptoms of flushing were reported in week 2 by 4 of the
subjects given b-alanine (with fewer subjects in the other weeks) and
3 subjects in week 4 given carnosine. One subject given the placebo
also recorded mild symptoms of flushing."

"b-Alanine was below the limit of detection of 0.1–0.2mmol x kg(-1) dm
in most muscle extracts both before and following supplementation,"

"The mean carnosine content of all subjects prior to treatment was
22.69 +/- 1.11mmol x kg(-1) dm and the mean change over the 4 weeks in
the four groups was: I: +7.80 +/- 0.36 (P<0.05), II: +11.04 +/- 2.68
(P<0.05), III: +16.37 +/- 3.03 (P<0.05), IV:+1.87 +/- 1.73
(P>0.05)mmol x kg(-1) dm (Table 3)."

"The mean percent changes in the four groups (after exclusion of
subject J from group II) were: I: +42.1%, II: +64.2%, III: +65.8%, IV:
ţ9.9%."

"Transport of b-alanine into muscle cells has been shown in cultures
of embryonic chick pectoral muscle to be sodium and chloride dependent
and to show Michaelis- Menten kinetics with a Km of approximately 40
mcM (Bakardjiev and Bauer, 1994). Prior to administration of b-alanine
the plasma concentration was <0.5 mcM in all subjects but increased to
50 to 100 mcM within 30 min of ingestion of 10 mg x kg(-1) bwt (Figs.
2 and 6). This, however, subsequently fell 60% within 30 min and 95%
to an average of 12.8 mcM within 90 min. Within this range transport
of b-alanine will be concentration dependent fluctuating between 10
and 70% of Vmax. Nonetheless, 10 mg x kg(-1) bwt must be close to the
upper practical dose if symptoms of flushing are to be avoided.
Consequently in study 3 supplementation was provided 4 (group I) or 8
(groups II and III) times per day in order to provide a more even
concentration profile in plasma with a maximum concentration of 125 to
250% of the assumed Km of the transporter."

"Based on the affinity of CS for its two substrates – the Km for
b-alanine is 1.0–2.3mM (Ng and Marshall 1978; Skaper et al., 1973),
and the Km for histidine is 16.8 mcM (Horinishi et al., 1978) –
compared with the relative abundance of histidine in muscle and plasma
and the very much lower concentrations of b-alanine, it is probable
that muscle carnosine synthesis is limited only by the intracellular
availability of b-alanine. Where b-alanine is in abundance then
synthesis may be further limited by the activity of CS itself."


Amino Acids. 2006 Jul 28;

Influence of beta-alanine supplementation on skeletal muscle
carnosine concentrations and high intensity cycling capacity.

Hill CA, Harris RC, Kim HJ, Harris BD, Sale C, Boobis LH, Kim CK,
Wise JA.

School of Sports, Exercise & Health Sciences, University of
Chichester, Chichester, U.K..

Muscle carnosine synthesis is limited by the availability of
beta-alanine. Thirteen male subjects were supplemented with
beta-alanine (CarnoSyntrade mark) for 4 wks, 8 of these for 10 wks. A
biopsy of the vastus lateralis was obtained from 6 of the 8 at 0, 4
and 10 wks. Subjects undertook a cycle capacity test to determine
total work done (TWD) at 110% (CCT(110%)) of their maximum power
(W(max)). Twelve matched subjects received a placebo. Eleven of these
completed the CCT(110%) at 0 and 4 wks, and 8, 10 wks. Muscle biopsies
were obtained from 5 of the 8 and one additional subject. Muscle
carnosine was significantly increased by +58.8% and +80.1% after 4 and
10 wks beta-alanine supplementation. Carnosine, initially 1.71 times
higher in type IIa fibres, increased equally in both type I and IIa
fibres. No increase was seen in control subjects. Taurine was
unchanged by 10 wks of supplementation. 4 wks beta-alanine
supplementation resulted in a significant increase in TWD (+13.0%);
with a further +3.2% increase at 10 wks. TWD was unchanged at 4 and 10
wks in the control subjects. The increase in TWD with supplementation
followed the increase in muscle carnosine.

PMID: 16868650

Quotes from the full text article:

"Twenty-five physically active male subjects, mainly undergraduate and
postgraduate students at the University of Chichester, volunteered to
participate in the study. None of the subjects were actively involved
at the time in a structured training programme."

"None of the subjects were vegetarian and had estimated daily intakes
of b-alanine from the digestion of histidine dipeptides in meat of
250–750mg daily (estimates based on values of histidine dipeptide
contents in Abe, 2000)."

"Following a cycle performance test subjects were supplemented for 4
or 10 weeks with either b-alanine (b-Ala, n=13) or a matching placebo
(P, n=12). Allocation to treatments was randomized. b-alanine
(CarnoSynTM) was obtained from Natural Alternatives International, San
Marcos, USA. Details of the specific dosing strategies employed for
both groups are provided in Table 2. As in a previous study (Harris et
al., 2006), b-alanine was administered each day as 8 divided doses,
with the dose increasing during the first 4 weeks. 800mg b-alanine
corresponds to the amount in dipeptide form available from 100 g of
whale beef, 150 g turkey breast meat (Abe, 2000) or 100 g
north-Atlantic seaprawns (unpublished observations)."

"Carnosine increased in both fibre types (p<0.01) and to the same
extent with supplementation representing a doubling in the content in
type I fibres and a 50% increase in type IIa fibres. At this time the
mean content in IIa fibres was 1.43 +/- 0.14 times higher than that in
type I fibres (p<0.05) (Table 3)."

"TWD was significantly increased following 4 and 10 weeks of b-alanine
supplementation (+7.3 +/- 1.3 [+13.0%] and +8.6 +/- 3.1 [+16.2%] kJ,
respectively; Fig. 5) compared with no change in P (+1.1 +/- 1.1
[+2.3%] and +1.7 +/- 1.5 [+3.3%], respectively) [2-way rm-ANOVA:
p<0.015; Zp 2 =0.37; observed power=0.731]. The corresponding changes
in exercise times from the initial mean of 156.5 s were +11.8 +/- 3.2%
and +15.9 +/- 5.1%, and, +0.2 +/- 1.5% and +0.6 +/- 1.3%, respectively."

"In agreement with a previous study (Harris et al., 2006),
supplementation was not associated with any reduction in muscle
taurine arising from increased competition between b-alanine and
taurine for transport into muscle cells (Jessen, 1994; Ramamoorthy et
al., 1994)."

"As carnosine has been implicated in a number of physiological
actions, several explanations for the increase in performance are
possible. The most likely would seem to be a change in Ca2ţ
sensitivity, E-C coupling (Lamont and Miller, 1992; Batrukova and
Rubtsov, 1997) and increase in intracellular buffering. Of these, we
would favour the latter."


[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.

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. 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]