Carnosine
jannis
Some days ago I did an inquiry over the net about carnosines health
benefits. I therefore sent an e-mail to some 13 expert scientists
currently doing research on the substance. Below I post the actual
letter I sent as well as the answers I got from three people (the
postings are of course with their consent). The rest of the contacted
experts did not respond. I hope they are of interest to you:
My inquiry:
"Dear Sir/Madam,
carnosine is a substance in which you have done extensive reseach.
Carnosine is also a substance that recently has become very popular as
a health supplement. It is used by many health conscious people on a
self medication basis: diabetics, alzheimers patients, people with
cardiovascular and occular disorders, athletes, supplement "freaks"
(whether this is good or bad is another question). Also within the
body-building community it has been widely used for many years,
actually long before many of it´s potentiall health benefits where
known or even anticipated. But there have always been some uncertainty
and dispute as to what should be considered a proper dosage. Currently
and to my knowledge two different positions are the most prevailing:
one advocates 100-200 mg per day and the other advocates 1000mg per
day (supposedly to saturate the enzyme carnosinase and thus make
carnosine truly available to the bloodstream). What is your
reckomendation on the dosage issue when it comes to generall health
enhancement and health maintainance for healthy individualls? Should
carnosine supplementation be encouraged at all? I am interested in
nutritional matters (for both lay and professional reasons) and
constantly stumble on this issue. People in general are starting to
become aware of carnosine. And nutritional facts are becoming harder
and harder to separate from promotional hype. I would therefore
appreciate any kind of advice. Thanks in advance"
Their replies:
"It is difficult to provide you with any specific information
about the bodily intake of carnosine and its possible effects.
I offer the following comments:
1) In human muscle it is present at about 0.5% wet weight, which
is about 5 gms a kilo. This is the concentration we used in our
experiments with cultured human cells, and also higher concentrations
(up to approx 1.25%).
2) This means that there is a lot in the whole body, and as you know
carnosine is synthesised in tissues by the enzyme carnosine
synthetase.
3) It is true that it is broken down by carnosinase in blood, but I do
not know how efficient this is. Very little is known about the
regulation
of the amount of carnosine in various tissues.
4) Oral uptake of carnosine could be beneficial, but my guess is that
the dose should be high, probably higher that I gram per day. At least
we know that it is non-toxic.
5) If you pick up any textbook of biochemistry or physiology, you will
find very little, if any, information about carnosine. For reasons
unknown it has not received the attention it deserves, so we need
much more research on its role in the body.
6) We do know that for such a small molecule it has remarkable
properties. It is an anti-oxidant; it inhibits the glycosylation of
proteins; it chelates some heavy metals; it acts as a buffer; it
reverses the major features of senescent human fibroblasts
in culture and can prolong their lifespan, and it can kill cancer
cells under conditions where normal cells are unaffected.
The properties listed in 6) have been documented in various
publications.
I hope these comments are of some interest".
Best regards
Robin Holliday
__________________________
"There is no evidence of any benefit to dietary carnosine".
Eric Decker
__________________________________
Dear Colleague,
thank you for your message of April 3, 2002 concerning
carnosine usage and appropriate doses for human beings. I think the
dosage depends very much on the reason to use this neuromodulator.
For every day use as a tonic it is enough to get 100-150 mg tablette
whereas
radioprotective or anti-ischemic effect is sugested to be pronounced
at 1-3 g
per day (twice a day with an equal halfs). Concerning athlets
(sportmen) I have
no expirience but one can think higher doses should be useful. [There
is an]...absence of information on negative effects of
carnosine...[and that]...is understandable because LD50 for this
compound...[is]...equal to 17-22g/kg (depending on the source of the
compound)...The high LD50 corresoponds to low toxicity of
carnosine,that's why if the effective dose is low enough we can
predict no toxic side effect of the compound...One Russian Company
produces carnosine as tablettes of 100 mg ane 250 mg as a food
additive and I think it should be very useful. Please don't hesitate
to disturb my any other questions concerning this matter because I
continue carnosine study for the last 40 years or so.
Truly yours -
Alexander Boldyrev
_____________________
Hal R. Parker
up and ask them why carnosinase exists, and whether it indicates that
there may be some hidden danger to carnosine.
I am tempted to try this stuff but the LD50 should not reassure us
that it is safe. And effectiveness in combatting senescence of cells
in culture is not convincing evidence of benefits to whole people. So
the evidence is a bit thin, isn't it?
Hal.
Ian Goddard
>Very interesting, and thanks for posting that. Why don't you follow
>up and ask them why carnosinase exists, and whether it indicates that
>there may be some hidden danger to carnosine.
IAN: I was taking carnosine for a while but what bothered
me was carnosinase. I stopped after reasoning that if the
body has a chemical, carnosinase, designed to breakdown
carnosine, there's the hypothetical possibility that if
I increase levels of carnosine my body will respond by
increasing levels of carnosinase, since it may have some
means of determining if carnosine is at the proper level.
Therefore, spending money on carnosine could be worthless,
or even worse, upregulation of carnosinase might continue
longer than the doses of carnosine, so taking carnosine
might result in periods of reduced of carnosine. ???
Of course that's all speculation, but it seems reasonable
not to take a supplement that's open to such speculation.
Is anyone aware of research refuting those speculations?
"To lengthen thy life, lessen thy meals." Ben Franklin
http://www.ultrahiq.net/Ubiquity/Winter02/CR.html
michaelprice
news:762f55a3.02041...@posting.google.com...
> Very interesting, and thanks for posting that. Why don't you follow
> up and ask them why carnosinase exists, and whether it indicates that
> there may be some hidden danger to carnosine.
Well, if it is a "hidden danger", they may not know about it....
I agree with your concerns, which is why I don't take carnosine.
Until we know why carnosinase exists then I think it is rather
risky taking the stuff.
Cheers,
Michael C Price
Thomas Carter
Hi Michael,
I understand your concern. But, it is synthesized in many
tissues, and is maintained at VERY high concentrations in the muscles
and brain, (20 mM in muscle and I think somewhat less in brain) these
are post mitotic tissues that produce a lot of free radicals. Taking a
gram a day is not likely to raise concentrations much. I wish I could
find a study on tissue levels in humans. Mice only maintain about 1mM.
There is another point of view to the failure to find the
"reason" for the synthesis of Carnosine in cells. Like the purloined
letter, the existance is right before our eyes. Namely it would be for
cellular homeostasis and the prolongation of life span. Thus the very
effects we see are the reason. Every day that goes by without finding
another reason makes this hypothesis more likely. My main concern is
somewhat the opposite of yours, that the gram/day I'm taking is not
enough to raise my tissue levels much. Here is a very small bit of the
info I have compiled on the substance.
Carnosine (B-alanyl-L-histidine) is a naturally-occurring di-peptide
(a combination of two amino acids), found in muscle, brain and other
innervated animal and human tissues. It is formed by a process
involving the enzyme carnosine-synthetase which bonds the amino acids
alinine and histidine. This process occurs mainly in muscles and
brain. It is kept in equilibrium by the carnisinases which are enzymes
specifically aimed at inactivating carnosine in the tissues or in the
blood Human muscle contains 20 mM carnosine (Elsewhere I read 8mM
but the tissue was unspecified.)
Carnosine has a number of interesting actions,
1. it is a potent antioxidant, it helps to chelate ionic metals (i.e.
flush toxins from the body),
2. it has immune boosting properties (aids wound healing)
3. and is also known to reduce and prevent cell damage caused by beta
amyloid (the substance found in the brain of Alzheimer disease
patients). Carnosine helps protect neural tissues by blocking and
inactivating beta amyloid and therefore it could help protect tissues
against dementia
4. Carnosine's ability to help prevent glycosylation- the cross
linking of proteins (and DNA molecules) caused by sugar aldehydes
reacting with the aminoacids on the protein molecule and creating
Advance Glycosylation End-products (AGE's Such anti-glycosylation may
be beneficial for diabetes, cataracts, neuropathy, kidney failure and
skin conditions, as well as “general” anti-aging
properties.
5. In 1999, Australian researchers confirmed that carnosine increases
longevity of human fibroblast cells in the laboratory. Carnosine
extended the Hayflick limit (the maximum number of times a cell can
divide), from a “normal” 50 by up to an additional 10
times! Although not enough time has passed to test these results,
carnosine may be a supplement of choice for longevity.
6. a reduction of gastric ulceration (particularly when the ulcer is
related to stress), both by preventing the formation of the ulcer and
by healing it (carnosine increases the formation of granulation
tissue). It does not affect acid secretion.<O:P</O:P <O:P</O:P
7. , to lower blood pressure,
8. The result shows that carnosine gives a pronounced effect on
primary senile cataract, the effective rate being 100%. For mature
senile cataract, the effect rate is 80%, and positive effects were
observed with other types of cataract. It is significant that no side
effect has been found in the observed cases. During recent years, we
have also applied carnosine drops containing the same content to
nearly one thousand patients with senile cataract. Our research
findings (ready to be published) show similar result.
9. It is, however, striking that human muscle contains 20 mM
carnosine, whereas mouse muscle contains only 1 mM ([11], J.
Michaelis, personal communication). This suggests that carnosine may
have a more fundamental role in cellular maintenance, since it is well
established that the efficiency of maintenance in mammalian species is
correlated with lifespan [8, 12]. The proposed maintenance function
could include antioxidant activity, chelation of toxic metals, and the
inhibition of non-enzymic glycosylation of proteins and the
accumulation of AGEs (advanced glycation end products). These
high-molecular-weight aggregates are seen in several tissues in
senescent animals and obviously accumulate more rapidly in short-lived
animals than in long-lived ones.
Thomas
michaelprice
take carnosine!
My concern is still about the existence of these damned carnosinases. Why
if carnosine is so good - and it does look very promising - would we evolve
a range of carnosinases to degrade it? If fact, as the known benefits of
carnosine increase, so do my concerns that there must be some hidden
downside. I notice trawling PubMed that the carnosinases seem very
unspecific in their targeting (i.e. they each seem to degrade a number of
different substances). Is it possible that their action on carnosine is an
unfortunate and detrimental side effect, outweighed by the benefit in
degrading some hypothetical, putative toxin(s)??? In which case
supplementing with highdose carnosine to overwhelm our carnosinases would be
very beneficial. But if not it could be v.detrimental.
Cheers,
Michael C Price
Thomas Carter
Hi, Michael,
Carnosine is absorbed pretty well but is rapidly eliminated by
plasma carnosinase. I still can't find anything on the increase of
cellular levels by supplementaion. (1) My guess is very little in
muscle and brain, but perhaps more in other tissues. Carnosinase is
fairly specific for histidine containing dipeptides, so I doubt that
it serves a double purpose in detoxification. Carnosine is degraded to
some extent by other dipeptideases and the cellular levels could
easily be regulated by simple allosteric control of carnosine
synthase, so it is hypothesized that the reason for Carnosinease is to
rapidly provide histamine and alanine for wound healing and
immunoreactivity. (2),(3),(4). My question is why does carnosine
synthase exist? Why don't the cells simply pool histamine and alanine?
The answer could be for cellular homeostasis and longevity. (hope)
Someday people may be switching to N-acetyl-L-carnosine which is not
degraded by carnosiase. Lack of carnosinease in humans is very rare,
but causes high levels of carnosine and is assosciated with severe
neuropathology. I got most of this from a Medline search for
carnosinease which resulted in 86 hits. To be (taking), or not to be
(taking), that is the question. Whether 'tis better to suffer the
slings and arrows of outrageous aging, or to steer thine own course in
quest of better fate.
Thomas Shakespere
1. J Physiol 1991 Aug;439:411-22 Intestinal absorption of the intact
peptide carnosine in man, and comparison with intestinal permeability
to lactulose. Gardner ML, Illingworth KM, Kelleher J, Wood D.
Department of Biomedical Sciences, University of Bradford. 1. Healthy
humans ingested the dipeptide carnosine (L-beta-alanyl-L-histidine).
Their plasma levels and urinary outputs of carnosine and beta-alanine
were monitored over the following 5 h. 2. Large amounts of intact
carnosine (up to 14% of the ingested dose) were recovered in the urine
over the 5 h after ingestion. However, carnosine was undetectable in
the plasma unless precautions were taken to inhibit blood carnosinase
activity ex vivo during and after blood collection. 3. The amount of
carnosine recovered in urine varied substantially between subjects. It
correlated negatively with carnosinase enzymic activity in the plasma.
Highest carnosinase activities were observed in those subjects who
regularly underwent physical training. 4. Urinary recovery of the
disaccharide lactulose also varied considerably between subjects, but
was substantially lower than that of carnosine. There was no
significant correlation between the recoveries of carnosine and
lactulose. 5. When lactulose was ingested with a hypertonic solution,
the urinary recovery of lactulose was generally increased. When
carnosine was ingested with a hypertonic solution, the urinary
recovery of carnosine was reduced: hence the paracellular route
probably is not dominant for absorption of intact carnosine. 6. Intact
carnosine must have crossed the intestine to an extent much greater
than hitherto recognized. Rapid post-absorptive hydrolysis is a severe
obstacle to quantification of intact peptide absorption. PMID: 1910085
2. Eur J Pharmacol 1984 Mar 16;99(1):79-84 Enhanced carnosine
(beta-alanyl-L-histidine) breakdown and histamine metabolism following
treatment with compound 48/80. Greene SM, Margolis FL, Grillo M,
Fisher H. We have previously suggested that carnosine may serve as a
reservoir for histidine to be used as a source of histamine in the
trauma response of rats. In this study we report the effect of
stimulation of histamine-forming capacity by compound 48/80 on muscle
carnosinase (C'ASE) and histidine decarboxylase (HDC) activities as
well as on muscle carnosine and histamine concentrations. Male rats
(180 g) were injected i.p. with 5 mg/kg bw of compound 48/80 and C'ASE
and HDC activities as well as carnosine, histidine and histamine
concentrations were monitored over a 72 h period post-injection. This
treatment resulted in an 120% increase in muscle HDC activity and an
110% increase in muscle histamine concentration at 15 min
post-injection, followed by an 80% increase in muscle C'ASE activity
at 1 h and a 100% reduction in muscle carnosine concentration at 24 h
post-injection when compared to control animals injected with 0.9%
saline. Histidine concentration was not affected by treatment. The
time frame of response, a rapid increase in muscle HDC activity and in
muscle histamine concentration followed by an increase in muscle C'ASE
activity and a later decrease in muscle carnosine concentration,
suggests that carnosine is hydrolysed to liberate histidine and that
carnosine, as a reservoir for histidine, is mobilized to maintain a
constant muscle concentration of histidine for histamine synthesis.
PMID: 6723792
3. Acta Otolaryngol 1994 Mar;114(2):193-8 Cellular localization of
carnosinase in the human nasal mucosa. Chen Y, Getchell TV, Sparks DL,
Getchell ML. Department of Surgery, University of Kentucky College of
Medicine, Lexington 40536. The cellular localization of the enzyme
carnosinase in human nasal mucosa was investigated using
immunoperoxidase and double-staining immunoflourescence techniques. In
the olfactory mucosa, carnosinase immunoreactivity was localized in
the sustentacular cells, the acinar cells of Bowman's glands, and the
perinuclear region of a small subset of olfactory receptor neurons. In
the respiratory mucosa, carnosinase immunoreactivity was identified in
the secretory vesicles of the epithelial goblet cells as well as in
the respiratory glands. There was an age-related trend toward a
decrease in the intensity of carnosinase immunoreactivity in the
olfactory mucosae of older subjects. These results suggest that the
role of carnosinase may be to provide the amino acids histidine and
beta-alanine, the products of carnosine hydrolysis, to the amino acid
pool for protein synthesis in the cells that secrete nasal mucus and
in olfactory receptor neurons. PMID: 8203202
4. Surgery 1986 Nov;100(5):815-21 Action of carnosine and
beta-alanine on wound healing. Nagai K, Suda T, Kawasaki K, Mathuura
S. In rats treat-given hydrocortisone to suppress healing, tensile
strength of the skin at the site of an incision wound was
significantly higher in rats locally treated with carnosine than in
untreated animals. Similar effects on the tensile strength of the skin
were observed by the administration of beta-alanine and histidine, but
not of beta-alanine alone. Exogenous carnosine was degraded in the
body by carnosinase and histidine decarboxylase to yield histamine.
Since beta-alanine, the other degradation product of carnosine, was
found to stimulate the biosynthesis of nucleic acids and collagen,
histamine derived from carnosine is considered to have enhanced the
process of wound healing by stimulating effusion at the initial stage
of inflammation. Thus, the enhancement by carnosine of wound healing
may be ascribed to stimulation of early effusion by histamine and of
collagen biosynthesis by beta-alanine. The wound-healing effects of
carnosine were further demonstrated by the observation that carnosine
significantly increased granulation suppressed by cortisone, mitomycin
C, 5-fluorouracil, and bleomycin. PMID: 3095942
5. Other roles ascribed to these dipeptides include actions as
neurotransmitters, modulation of enzymic activities and chelation of
heavy metals PMID: 9765790
6. Ann Clin Biochem 1986 Mar;23 ( Pt 2):190-4 Reduced serum
carnosinase activity in hypothyroidism. Bando K, Ichihara K,
Shimotsuji T, Toyoshima H, Koda K, Hayashi C, Miyai K. Carnosinase
hydrolyses carnosine in muscle, and its deficiency is associated with
extensive neuromuscular abnormalities. We measured serum carnosinase
activity in patients with thyroid dysfunction which often involves
neuromuscular systems. In hyperthyroidism, the carnosinase activity
was not significantly different from that in normal subjects. In
hypothyroidism, however, it was significantly lower than that in
normal subjects. The activity examined in five patients with
hypothyroidism returned to normal after replacement therapy. In
hypothyroidism, the carnosinase activity showed significant
correlation with concentration of serum thyroxine and negative
correlation with serum creatine kinase activity. This finding may be
of practical importance in the differential diagnosis of disorders
causing carnosinase deficiency. PMID: 3767265
7. These results indicate that carnosinase enzyme is primarily
located in the soluble (cytoplasmic) fraction of rat liver. PMID:
3233742
michaelprice
Does this mean we should be taking N-acetyl-L-carnosine,
not carnosine? Would NALC suppress carnosine synthesis?
Cheers,
Michael C Price
michaelprice
Suggests that acetylcarnosine is not so effective in preventing
cell death as carnosine. Is this a problem?
Neuroscience 1999;94(2):571-7
Carnosine protects against excitotoxic cell death independently of effects
on reactive oxygen species.
Boldyrev A, Song R, Lawrence D, Carpenter DO.
International Center for Biotechnology and Center for Molecular Medicine, MV
Lomonosov Moscow State University, Department of Biochemistry, School of
Biology, Russia.
The role of carnosine, N-acetylcarnosine and homocarnosine as scavengers of
reactive oxygen species and protectors against neuronal cell death secondary
to excitotoxic concentrations of kainate and N-methyl-D-aspartate was
studied using acutely dissociated cerebellar granule cell neurons and flow
cytometry. We find that carnosine, N-acetylcarnosine and homocarnosine at
physiological concentrations are all potent in suppressing fluorescence of
2',7'-dichlorofluorescein, which reacts with intracellularly generated
reactive oxygen species. However, only carnosine in the same concentration
range was effective in preventing apoptotic neuronal cell death, studied
using a combination of the DNA binding dye, propidium iodide, and a
fluorescent derivative of the phosphatidylserine-binding dye, Annexin-V. Our
results indicate that carnosine and related compounds are effective
scavengers of reactive oxygen species generated by activation of ionotropic
glutamate receptors, but that this action does not prevent excitotoxic cell
death. Some other process which is sensitive to carnosine but not the
related compounds is a critical factor in cell death. These observations
indicate that at least in this system reactive oxygen species generation is
not a major contributor to excitotoxic neuronal cell death.
PMID: 10579217 [PubMed - indexed for MEDLINE
Cheers,
Michael C Price
Thomas Carter
Hi Michael,
I just plain don't know the answer to your questions or what to make
of the abstract. Maybe someone can help us out. For now I will not
take NALC. I don't even know if its available for ingestion.
Thomas
jannis
carnosine research has stil a long way to go before conclusive
evidence is at hand then the way is even longer for NALC and it might
well lead nowhere. All the research showing consistant health benefits
from carnosine has been done, to my knowledge, on L-carnosine and it
is doubtful if they can be transfered on to NALC. Carnosine is what we
should take. NALC might well be unable to produce the health benefits
documented for L-carnosine. The encouraging thing is that there is
quite a lot of carnosine research going on so the answers we are
looking for might well be around the corner.
"michaelprice" <michae...@ntlworld.com> wrote in message
news:<trmu8.17707$tZ1.5...@news2-win.server.ntlworld.com>...
Rodney Reid
It is only available in eyedrops to my knowledge. BAC has a 'brite-eyes'
product listed that contains it.
...Rodney
Tom Pall
his wife take it. They might be able to point you to a source.
"Rodney Reid" <rr...@tsoft.com> wrote in message
news:ubmq6g4...@corp.supernews.com...
tintinet
> Last time I checked Tom Mathiew's website, http://www.morelife.org, Tom and
> his wife take it. They might be able to point you to a source.
They might be able to provide a source; however, according to the
above website (Morelife, they don't currently take NALC orally. AFAIK,
they haven't yet, either.
jannis
"There are a number of evidence that [the] main therapeutic effect of
carnosine is provided by carnlosine itself, not by its constituents,
however some side effects (also positive) can be explained by
beta-alanine and histidine.
Because of carnosinase, whos activity decelerates carnosines effect,
it is recommended to use carnosine several times a day by small
portions of 200-250 mg instead of usage of 1 daily dose of the same
weight.
Truly -
Boldyrev"
jann...@hotmail.com (jannis) wrote in message news:<be137038.02041...@posting.google.com>...
Tim
consuming about a pound of meat a day, as mammalian skeletal muscle
contains about 200 mg per 100 g of meat. My concern is that it may be
generally rather ineffective at this dose anyway. SAM mice (a strain
of mice that age rapidly and live less than half as long as wild-type
mice) showed about a 20% increase in longevity when fed huge amounts.
LEF's claim that carnosine is the most important anti-aging supplement
IMO is totally unfounded. Humans already have about 20 times higher
tissue levels of carnosine than mice. This link will give you the
amount of carnosine present in various types of meat.
www.fao.org/docrep/V7180E/V7180E08.htm
...or can be found in the LEF forum under the thread "How much
carnosine in beef/meat?"
Tim
Thomas Carter
Hi Tim,
I agree the effective human dose may be much larger than a gram. I
hope they come out soon with some studies of tissue levels vs
supplementaion amounts. They would be easy to do and the longer we
don't see them, the more curiouser it gets.
There is hope tho. The hi tissue levels quoted for humans are
mostly skeletal muscle and brain. Other tissues have much less. I
wonder what the tissues levels are in epithilial cells, whose
malfunction cause 70-90% of death in older people, and whose
replicative life span (youth span??) has been extended in vitro by
carnosine, and whose carnosine levels may rise more than those in
muscle and brain due to lower natural levels. I would like to see
answers in the next couple of years, followed by some upper safe limit
info.
Meanwhile the carnosine in Chronoforte from LEF is almost free if
you already were taking the other ingredients.
Thomas
PS Nice work on the GH posts. I'd say the book is about closed on it,
barring supprising new positive info.
Tim
recall that some of the metabolites also had some beneficial effects.
Histidine as well has many of the reported benefits of carnosine
(.ie., is an antioxidant, chelates metals, etc.). Really the cell
culture research probably doesn't mean much. It seems to be generally
accepted now that what happens in culture isn't what happens in vivo
and the view that the Hayflick limit was of monolithic importance was
sort red herring that tended to mislead thinking on aging. What I
would like to see is actual research on dosage and effect in humans,
That is if carnosine is doing all these wondrous things in the human
body that they do in a test tube.
Tim
Tim
membranes
thereby increasing the potency of its effect. (e.g., acetylating
cysteine allows it to pass through the lipid membranes of the cell
rather than requiring
active transport, if two acetyls are added to morphine, a water
soluble substance, you end up with diacetylmorphine, "heroin," which
is 2-3 times more potent) So NALC should presumably be more potent and
accessible to the cell and particularly the brain at lower dosages.
Tim
Craig Hollander
brain. (Horning, Blakemore et al. 2000; Trombley, Horning et al. 2000)
Carnosine has also been shown, in vitro, to inhibit non-enzymic
glycosylation and cross-linking of proteins induced by reactive aldehydes,
including aldose and ketose sugars, certain triose glycolytic intermediates,
and malondialdehyde (MDA, a lipid peroxidation product). Carnosine also
inhibits formation of MDA-induced protein-associated advanced glycosylation
end products (AGEs) and formation of DNA-protein cross-links induced by
acetaldehyde and formaldehyde. (Munch, Mayer et al. 1997; Hipkiss 1998;
Hipkiss, Preston et al. 1998; Preston, Hipkiss et al. 1998)
A study tested the effect of carnosine on life span and indicators of aging
in senescence-accelerated mice. Carnosine extended the life span of the
treated mice by 20% on average, compared to the mice not fed carnosine. The
mice given carnosine were about twice as likely to reach the "ripe old age"
of 12 months as untreated mice.
Carnosine did not alter the 15 month maximum life span of the
senescence-accelerated mouse strain, but it did significantly raise the
number of mice surviving to old age. Carnosine distinctly improved the
appearance of the aged mice, whose coat fullness and color remained much
closer to that of young animals. Significantly more carnosine-treated mice
had glossy coats (44% vs. 5%), while fewer had skin ulcers (14% vs. 36%).
The researchers also measured biochemical indicators associated with brain
aging. Carnosine treated mice had significantly lower levels of toxic MDA
(malondialdehyde) in their brain cell membranes. MAO-B (monoamine oxidase B)
activity was 44% lower in the carnosine-treated mice, indicating maintenance
of youthful dopamine metabolism. Aging humans produce too much MAO-B, and
this is thought to contribute to certain types of brain cell damage.
Glutamate binding to its cellular receptors nearly doubled in the carnosine
treated group, which may explain the more normal behavioral reactivity of
the carnosine-fed mice.
This longevity study showed that carnosine significantly improved most
measures of appearance, physiological health, behavior and brain
biochemistry-as well as extending life span. The researchers concluded that
"carnosine-treated animals can be characterized as more resistant to the
development of features of aging."
To inhibit AGEs, 1000mg per day (minimum) should be considered.Refer to the
above studies.
"Tim" <timo...@my-deja.com> wrote in message
news:6da4c14.02042...@posting.google.com...
john-knows-nothing
receiving 100mg/K of bw of carnosine and SAMP mice are far from the
best way to measure its effect on normal aging, mice already have far
lower levels of tissue carnosine than humans. All of the research I am
aware of on glycation etc. were in vitro. What I would like to see is
measures of its benefits on human subjects. I know several researchers
have proposed it as an anti-aging therapy but it seems to me premature
until we have hard evidence of its benefits in humans, not to sy that
it will not be eventually forthcoming.
Some of the articles for those interested can be found at this
website
www.protein.bio.msu.su/biokhimiya
Tim
Tom Matthews
Thomas Carter wrote:
First, I think the reason for the results in Michael's abstract above is because
NALC is only slowly converted to carnosine, thereby acting as a kind of
time-release carnosine. In fact, this is the reason why it appears to be far
better for the eyes (it does not turn as quickly in the the potentially eye
damaging histamine and penetrates better before it converts to the beneficial
carnosine).
Because I think it will be much more effective than carnosine at far lower
dosages and without the need to swamp the carnosinase enzyme, I have been
searching for a source of NALC (without success) for several months now.
There are also many people who cannot take large doses of carnosine because of
histamine reactions particularly in their sinuses. (Kitty has such problems from
time to time.) Only NALC will do for these people.
In summary, it is my conjecture that NALC will penetrate to more parts of the
body before it is more slowly converted to carnosine which may then be cleaved
by the carnosinase enzyme. In this matter, it will be more distributed and more
effective over a longer period of time.
Sometime soon, I will have a webpage at my site documenting the story of
L-carnosine, the carnosinase enzymes and N-acetyl-L-carnosine.
--Tom Matthews
MoreLife for us all - http://morelife.org
Reality based tools for More Life in quantity & quality
Tom Matthews
Exactly!
And the "deacetylation" is a ubiquitous process which can take place anywhere.
Tom Matthews
> I haven't really been following carnosine research, but I think I
> recall that some of the metabolites also had some beneficial effects.
> Histidine as well has many of the reported benefits of carnosine
> (.ie., is an antioxidant, chelates metals, etc.).
The papers which I have read do show that some of the effects of carnosine
are also effects of its two constituent amino acids. However, this is not
true of all of its effects.
> Really the cell
> culture research probably doesn't mean much. It seems to be generally
> accepted now that what happens in culture isn't what happens in vivo
> and the view that the Hayflick limit was of monolithic importance was
> sort red herring that tended to mislead thinking on aging. What I
> would like to see is actual research on dosage and effect in humans,
> That is if carnosine is doing all these wondrous things in the human
> body that they do in a test tube.
>
>
> Tim
I am also waiting impatiently to see such work.
Here is a new paper which relates the antisenescent activity of carnosine to
that of N-tert-butyl-hydroxylamine.
Ann N Y Acad Sci 2002 Apr;959:285-294
Reaction of Carnosine with Aged Proteins: Another Protective Process?
Hipkiss AR, Brownson C, Bertani MF, Ruiz E, Ferro A.
GKT School of Biomedical Sciences, King's College London, Guy's Campus, London
Bridge, London SE1 1UL, United Kingdom.
Cellular aging is often associated with an increase in protein carbonyl groups
arising from oxidation- and glycation-related phenomena and suppressed
proteasome activity. These "aged" polypeptides may either be degraded by 20S
proteasomes or cross-link to form structures intractable to proteolysis and
inhibitory to proteasome activity. Carnosine (beta-alanyl-l-histidine) is
present at surprisingly high levels (up to 20 mM) in muscle and nervous tissues
in many animals, especially long-lived species. Carnosine can delay senescence
in cultured human fibroblasts and reverse the senescent phenotype, restoring a
more juvenile appearance. As better antioxidants/free-radical scavengers than
carnosine do not demonstrate these antisenescent effects, additional properties
of carnosine must contribute to its antisenescent activity. Having shown that
carnosine can react with protein carbonyls, thereby generating "carnosinylated"
polypeptides using model systems, we propose that similar adducts are generated
in senescent cells exposed to carnosine. Polypeptide-carnosine adducts have been
recently detected in beef products that are relatively rich in carnosine, and
carnosine's reaction with carbonyl functions generated during amino acid
deamidation has also been described. Growth of cultured human fibroblasts with
carnosine stimulated proteolysis of long-labeled proteins as the cells
approached their "Hayflick limit," consistent with the idea that carnosine
ameliorates the senescence-associated proteolytic decline. We also find that
carnosine suppresses induction of heme-oxygenase-1 activity following exposure
of human endothelial cells to a glycated protein. The antisenescent activity of
the spin-trap agent alpha-phenyl-N-t-butylnitrone (PBN) towards cultured human
fibroblasts resides in N-t-butyl-hydroxylamine, its hydrolysis product. As
hydroxylamines are reactive towards aldehydes and ketones, the antisenescent
activity of N-t-butyl-hydroxylamine and other hydroxylamines may be mediated, at
least in part, by reactivity towards macromolecular carbonyls, analogous to that
proposed for carnosine.
PMID: 11976203
Tim
The metabolites I was referring to (Offhand I don't remember all
the transformation steps and products and don't have the chart at
hand) were anserine, homocarnosine etc. that also exhibit
anti-glycating and antioxidant properties for the hydroxyl radical,
singlet oxygen and perhaps some others. A quote from one of the
articles:
"Of eight derivatives examined histidine,Gly-His,carnosine and Ala-His
inhibited the inactivation of the enzyme (Cu,Zn SOD) and
Gly-His,Ala-His,anserine,carnosine and homocarnosine exhibited a
marked protective effect against inactivation of glycoaldehyde."
So "swamping" the carnosinases may not be necessary or even desireable
for any possible benefit. For those interested in further information
a brief Medline search turned up the following abstracts among others.
PMID: 11911459
PMID: 1186617
PMID: 10079975
PMID: 9111930
Tim
michaelprice
> In summary, it is my conjecture that NALC will penetrate to more parts
> of the body before it is more slowly converted to carnosine which may
> then be cleaved by the carnosinase enzyme. In this matter, it will be more
> distributed and more effective over a longer period of time.
If the only action of NALC is via deacetylation to carnosine then it
may alsoshare its putative drawbacks - the existence of carnosinase
still worries me. Interestingly, levels of carnosinase rise during
childhood, from almost zero, indicating that this is probably not just
some fetal developmental problem. Carnosine is linked with mental
retardation (see the 8 studies below).
For the moment I shall stay clear of carnosine, until we know more.
Cheers,
Michael C Price
A search on "carnosine" and "mental retardation" yields:
1: Gjessing LR, Lunde HA, Morkrid L, Lenney JF, Sjaastad O.
Inborn errors of carnosine and homocarnosine metabolism.
J Neural Transm Suppl. 1990;29:91-106.
PMID: 2358806
2: Cohen M, Hartlage PL, Krawiecki N, Roesel RA, Carter AL, Hommes FA.
Serum carnosinase deficiency: a non-disabling phenotype?
J Ment Defic Res. 1985 Dec;29 ( Pt 4):383-9.
PMID: 4093964
3: Bondarenko TI, Makletsova MG, Sukhomovskii BI
[Concentration of free amino acids and homocarnosine dipeptide in the
cerebrospinal fluid of children with hydrocephalus]
Zh Nevropatol Psikhiatr Im S S Korsakova. 1983;83(10):1484-8. Russian.
PMID: 6659780
4: Wisniewski K, Fleisher L, Rassin D, Lassmann H.
Neurological disease in a child with carnosinase deficiency.
Neuropediatrics. 1981 May;12(2):143-51.
PMID: 7266778
5: Fleisher LD, Rassin DK, Wisniewski K, Salwen HR. Related Articles
Carnosinase deficiency: a new variant with high residual activity.
Pediatr Res. 1980 Apr;14(4 Pt 1):269-71.
PMID: 7375183
6: Sjaastad O, Berstad J, Gjesdahl P, Gjessing L. Related Articles, OMIM
Homocarnosinosis. 2. A familial metabolic disorder associated with spastic
paraplegia, progressive mental deficiency, and retinal pigmentation.
Acta Neurol Scand. 1976 Apr;53(4):275-90.
PMID: 1266573
7: Gjessing LR, Sjaastad O. Related Articles, OMIM
Letter: Homocarnosinosis: a new metabolic disorder associated with
spasticity and mental retardation.
Lancet. 1974 Oct 26;2(7887):1028. No abstract available.
PMID: 4138320
Thomas Carter
> "Tom Matthews"
> > In summary, it is my conjecture that NALC will penetrate to more parts
> > of the body before it is more slowly converted to carnosine which may
> > then be cleaved by the carnosinase enzyme. In this matter, it will be more
> > distributed and more effective over a longer period of time.
>
> If the only action of NALC is via deacetylation to carnosine then it
> may alsoshare its putative drawbacks - the existence of carnosinase
> still worries me. Interestingly, levels of carnosinase rise during
> childhood, from almost zero, indicating that this is probably not just
> some fetal developmental problem. Carnosine is linked with mental
> retardation (see the 8 studies below).
>
> For the moment I shall stay clear of carnosine, until we know more.
>
> Cheers,
> Michael C Price
Hi Michael,
Low serum carnosinase activity is widely accepted to be a result of
neuronal damage rather than a cause, and is thought to have to have
deleterious effects on GABA levels independantly of its effect on
carnosine levels. Curiously it is not strongly assosciated with long
term very high tissue carnosine levels. I have read definitive papers
on this I believe, but I didn't save them. Below, I attach what I
have.
Thomas
Front Biosci 1999 Aug 1;4:e58-66 Oxidants, antioxidants and alcohol:
implications for skeletal and cardiac muscle. Preedy VR, Patel VB,
Reilly ME, Richardson PJ, Falkous G, Mantle D. Department of Clinical
Biochemistry, Guy's, King's and St Thomas's Medical School, King's
College London, Bessemer Road, London SE5 9PJ, United Kingdom.
victor...@kcl.ac.uk The chronic form of alcoholic skeletal
myopathy is characterized by selective atrophy of Type II fibers and
affects up to two thirds of all alcohol misusers. Plasma selenium and
alpha-tocopherol are reduced in myopathic alcoholics compared to
alcoholic patients without myopathy. Plasma carnosinase is also
reduced in myopathic alcoholics, implicating a mechanism related to
reduced intramuscular carnosine, an imidazole dipeptide with putative
antioxidant properties. Together with the observation that alcoholic
patients have increased indices of lipid peroxidation, there is
evidence suggestive of free radical (i.e., unpaired electrons or
reactive oxygen species) mediated damage in the pathogenesis of
alcohol-induced muscle disease. Protein synthesis is a multi-step
process that encompasses amino acid transport, signal transduction,
translation and transcription. Any defect in one or more of the
innumerable components of each process will have an impact on protein
synthesis, as determined by radiolabelling of constituent proteins.
Both acute and chronic alcohol exposure are associated with a
reduction in skeletal muscle protein synthesis. Paradoxically,
alcohol-feeding studies in rats have shown that the imidazole
dipeptide concentrations are increased in myopathic muscles though
alpha-tocopherol contents are not significantly altered. In acutely
dosed rats, where protein synthesis is reduced, protein carbonyl
concentrations (an index of oxidative damage to muscle) also decline
slightly or are unaltered, contrary to the expected increase.
Alcoholic cardiomyopathy can ensue from heavy consumption of alcohol
over a long period of time. The clinical features include poor
myocardial contractility with reduced left ventricular ejection
volume, raised tissue enzymes, dilation of the left ventricle, raised
auto- antibodies and defects in mitochondrial function. Whilst oxidant
damage occurs in experimental models, however this issues remains to
be confirmed in the clinical setting. In the rat, circulating
troponin-T release increases in the presence of ethanol, a mechanism
ascribed to free radical mediated damage, as it is prevented with the
xanthine oxidase inhibitor and beta-blocker, propranolol. However,
whilst propranolol prevents the release of troponin-T, it does not
prevent the fall in whole cardiac protein synthesis, suggestive of
localized ischemic damage due to ethanol. Publication Types: Review
Review, Tutorial PMID: 10430553
Stroke 1996 Nov;27(11):2064-8 Serum neuron-specific enolase,
carnosinase, and their ratio in acute stroke. An enzymatic test for
predicting outcome? Butterworth RJ, Wassif WS, Sherwood RA, Gerges A,
Poyser KH, Garthwaite J, Peters TJ, Bath PM. Stroke Research Group
(Department of Medicine), King's College School of Medicine and
Dentistry, London, UK. BACKGROUND AND PURPOSE: Few admission variables
adequately predict neuronal damage and prognosis in individual
patients after stroke. Therefore, there is a need for a reliable
non-invasive surrogate measure of clinical outcome. METHODS: We have
developed a surrogate measure of stroke outcome using the ratio of
serum neuron-specific enolase (NSE) to human serum carnosinase (HSC)
in 124 patients with acute ischemic or hemorrhagic stroke and 61
matched control subjects. Serum NSE is known to rise and HSC to fall
after neuronal injury such as cerebral ischemia. RESULTS: Serum NSE
levels were significantly higher and HSC levels lower in the patient
group. The NSE/HSC ratio was elevated in patients with stroke: median
(semiquartile) hemorrhages, 0.072 (0.033); infarcts, 0.039 (0.026);
and control subjects, 0.019 (0.014), P = .0001. Patients with a
primary intracerebral hemorrhage had nonsignificantly higher ratios
than those with an infarct (P = .082). The NSE/HSC ratio was
significantly associated with 90-day outcome measured in two out of
three disability and handicap scales: modified Barthel Index (rs =
-.34, P = .001), modified Rankin Scale (rs = .30, P = .002), and
Lindley Score (rs = .19, P = .057). Patients who died or were
institutionalized had higher ratios than those who were discharged
home: 0.069 (0.043) versus 0.038 (0.024), P = .011. Correlations
between the NSE/HSC ratio and outcome were comparable to those between
patient age or consciousness level on admission and clinical outcome.
CONCLUSIONS: We believe that measurement of NSE, HSC, or their ratio
may be useful in the assessment of patients with acute stroke with
respect to diagnosis and prediction of clinical outcome.
(Here is a quote lifted from the discussion area of the full
text).
HSC (EC 3.4.13.4) is a dipeptidase that hydrolyzes the three
dipeptides carnosine (ß-alanyl-L-histidine), anserine
(ß-alanyl-L-methylhistidine), and homocarnosine (-amino butyric acid
[GABA]-histidine). HSC is a brain-derived enzyme synthesized within
the brain and secreted through the CSF into the serum.18 The enzyme
may have several functions in the central nervous system including the
hydrolysis of homocarnosine producing the neurotransmitter GABA. This
forms an alternative pathway to its production through the direct
decarboxylation of glutamic acid. Both homocarnosine and HSC can be
detected throughout the brain in close proximity by immunostaining.19
Second, carnosinase may be important in olfactory pathways as both the
enzyme and the substrate carnosine are found in the olfactory areas.20
We found that HSC activities were significantly lower in stroke
patients, and it is possible that death of carnosinase-producing cells
reduces the secretion of this enzyme into the plasma. However, if this
were the case, then the largest infarcts would be expected to have the
lowest activities, and this was not seen in our study. An alternative
explanation is that the regulation of HSC release is altered after
neuronal insult. Within the stroke population studied, the lowest HSC
activities correlated with the worst outcome. It is possible that
these patients were unable to hydrolyze sufficient homocarnosine to
produce enough of the inhibitory neurotransmitter GABA after a stroke.
It is known that neurons produce excitatory neurotransmitters such as
glutamate after an ischemic insult and that this can lead to further
cell death. Thus, after stroke, limited GABA supplies secondary to low
HSC activities may exaggerate glutamate-induced neuronal damage and
death.
PMID: 8898817
Clin Chim Acta 1994 Feb;225(1):57-64 Serum carnosinase activities in
central nervous system disorders. Wassif WS, Sherwood RA, Amir A,
Idowu B, Summers B, Leigh N, Peters TJ. Dept. of Clinical
Biochemistry, King's College School of Medicine and Dentistry, London,
UK. Serum carnosinase activity was assayed in five groups of patients
with neurological disorders. Enzyme activities in patients with
idiopathic epilepsy (mean +/- S.E.M., 148 +/- 11 nmol/ml per min) and
motor neurone disease (155 +/- 15 nmol/ml per min) were similar to the
control group (161 +/- 7 nmol/ml per min). Reduced serum carnosinase
activity was observed in patients with Parkinson's disease (109 +/- 11
nmol/ml per min, P < 0.005), multiple sclerosis (82.5 +/- 10.0 nmol/ml
per min, P < 0.005) and patients following a cerebrovascular accident
(74.6 +/- 5.4 nmol/ml per min, P < 0.001) compared with the control
group. Carnosinase activity, 5-10% of that found in serum, was
detected in CSF samples. The cause of reduced serum carnosinase
activities in central nervous system disorders is unclear, although
anoxic damage to carnosinase-producing cells or disruption of the
blood-brain barrier may be responsible. PMID: 8033354
Tim
and I would think that NALC would do so better. This may or may not be
a good thing. Here's an abstract comparing the rate of hydrolysis of
carnosine and NALC
(and some other derivatives) by the carnosinases.
Comp Biochem Physiol B Biochem Mol Biol 2000 Dec,127(4)443-6
Hydrolysis of carnosine and related compounds by mammalian
carnosinases.
Boldyrev A.
Comparative study of the hydrolysis of carnosine and a number of its
natural derivatives by human serum and rat kidney carnosinase was
carried out. The rate of carnosine hydrolysis was 3-4 fold higher than
for anserine or ophidine. The rate of homocarnosine, N-acetylcarnosine
and carcinine hydrolysis were negligible by either of the enzymes
used. Our data show that methylation, decarboxylation, or acetylation
of carnosine increases resistance of the molecule toward enzymatic
hydrolysis. Thus metabolic modification of carnosine may increase its
half-life in the tissues.
PMID: 11281261
Tim
Tim
transformation of carnosine.For example recent research has found
anserine,which is formed by
methylation of carnosine, is effective as an antioxidant against
peroxynitrite,
H2O2, the Hydroxyl radical and singlet oxygen and is also reactive
with
aldehydes and chelates copper and is a more stable product against
hydrolytic
degradation. Histidine itself has these properties but can also be
used for the
synthesis of carnosine, a recent report found that histidine
supplementation
alone could increase skeletal muscle levels of carnosine. Interesting
replies you received concerning possible dosages for humans. A recent
paper on the synthesis, release and uptake of carnosine in cell
culture of neural and muscle cells, can be found here.
www.protein.bio.msu.su/biokhimiya/contents/v65/full/65070917.htm
More References
PMID: 11911459
PMID: 11964132
PMID: 10079975
Tim
Tim
taken up by certain cell types and if they are not would it be wise to
do so, presuming NALC would be an effective way to do so particularly
in cells that don't have an active dipeptide transporter or synthesize
it. It may also be that the serum carnosinases are splitting carnosine
into its constituent amino acids beta-alanine and histidine which are
then transported intracellularly for synthesis in certain cell-types
(amino acids generally require active transport and the article I cite
above suggests that cells that synthesize carnosine should have an
active transporter for beta-alanine) There doesn't seem to be a lot of
information about cellular uptake. For example the tripeptide
glutathione taken orally is ineffective at raising cellular
glutathione levels but oral consumption of either of its rate-limiting
essential amino acids glutamine and cysteine (or better yet
N-acetyl-l-cysteine)does so effectively. The article also seems to
infer that NALC doesn't have antiglycating properties (for information
of NALC's relatively long half-life see message 23 on this thread).
Here's a relevant abstract:
Neurosci Lett 1996 Aug 30;215(1)29-32
Carnosine synthesis in cultures of rat glial cells is restricted to
oligodendrocytes and carnosine uptake to astrocyte.
Hoffmann AM et al
...carnosine was found to be taken up effectively only by astrocytes
but not by oligodendrocytes.
PMID: 8880746
Perhaps Jannis will be kind enough to query Boldyrev or Halliday for a
more definitive answer to what happens to carnosine after its ingested
and where it goes, if they in fact know.
Tim
Chris Allen
> Here is a new paper which relates the antisenescent activity of carnosine to
> that of N-tert-butyl-hydroxylamine.
>
> Ann N Y Acad Sci 2002 Apr;959:285-294
> Reaction of Carnosine with Aged Proteins: Another Protective Process?
> Hipkiss AR, Brownson C, Bertani MF, Ruiz E, Ferro A.
> GKT School of Biomedical Sciences, King's College London, Guy's Campus, London
> Bridge, London SE1 1UL, United Kingdom.
Actually, I read the paper, Tom, and it's only a review, not new
research. However, it _is_ a kickass review and I think the same goes
for the whole book:
http://www.annalsnyas.org/content/vol959/issue1/
..asskickingsnip..
Annals of the New York Academy of Sciences
INCREASING HEALTHY LIFE SPAN: CONVENTIONAL MEASURES AND SLOWING THE
INNATE AGING PROCESS
Volume 959 published April 2002
Editors:
Denham Harman
../asskickingsnip..
Here's a snip from the carnosine article:
..snip..
CARNOSINE AND AMINO ACID DEAMIDATION
Deamidation of asparagine and glutamine residues in proteins is
another source of age-related aberrant protein. Deamidation results in
production of l or d forms of aspartic and glutamic acids, as well as
isopeptide conformations where the side-chain carboxyl group (ß or ,
respectively) becomes incorporated into the polypeptide backbone.32
That a partial repair mechanism for this process33 is widely
distributed in nature indicates the biological importance of this type
of postsynthetic change. Mice defective in the gene coding for the
enzyme that initiates the repair, protein isoaspartate methyl
transferase (PIMT or PCMT), accumulate large amounts of aberrant
protein in their brains and usually die prematurely.33
It appears that carnosine may intervene during deamidation. Recent
observations from food science show that covalent adducts between
carnosine and polypeptide are found in beef soup preparations.26,34
Further studies showed that if present during heat-induced deamidation
of asparagine and glutamine, carnosine can react with the carbonyl
species produced following loss of the amino group from the amide side
chain of the amino acids generating ß-aspartyl-carnosine and
-glutamyl-carnosine adducts, respectively.26 It appears that
carnosine's amino group can form ß- or -peptide bonds to the side
chain carbonyls of the amino acids.26 Interestingly, formation of the
carnosine adducts proceeded about fourfold faster with asparagine
deamidation than with glutamine.26 A number of other products were
also detected that contained either ß-alanine or histidine, suggesting
that cleavage of the peptide bond between ß-alanine and histidine can
occur. In the case of asparagine, 14 adducts were detected, whereas
only 10 were detected when glutamine was incubated with carnosine.26
It may be significant that three of the extra peptide adducts detected
following asparagine's reaction with carnosine were particularly
enriched with ß-alanine, which could indicate that the peptide bond
between ß-alanine and histidine becomes particularly labile
during/following the dipeptide's reaction with the asparginyl carbonyl
derivative. This observation might explain the absence of
ß-aspartyl-carnosine adducts in the beef preparation, whereas
-glutamyl-carnosine adducts were readily observed26 as well as adducts
containing ß-alanine and histidine. Indeed is has been suggested that
the presence of carnosinase, an enzyme that cleaves the bond between
ß-alanine and histidine, could influence carnosine's reactivity in
vivo.23
..snip..
ACTION OF ANTISENESCENT AGENTS IN VIVO
Carnosine and PBN have all been reported to delay senescence in
senescence-accelerated mice (SAMP),40,41 although better antioxidants
than carnosine and PBN do not seem to possess antiaging activity in
vivo. Assuming that the active agent of PBN in vivo is
N-t-butylhydroxylamine,36 the possibility arises that the antiaging
mechanism of PBN and carnosine could reside at least partly in an
ability to react with protein carbonyls, in addition to any
antioxidant function. Such activity could explain the PBN-induced
disappearance of protein carbonyls from gerbil brains and their rapid
reappearance following its withdrawal.42
Kinetin also suppresses senescence in cultured cells and appears to
possess both anti-oxidant and antiglycating activities.43 As aging is
multifactorial, pluripotency may therefore be a necessary quality for
antiaging activity,8,27 which PBN, kinetin and carnosine appear to
possess.
Caloric restriction is the only reproducible method by which the
average and maximal life span of many species can be extended.44
Although many mechanisms have been proposed as explanations, few have
been totally convincing, although the inhibitory effects of persistent
hyperinsulinemia on proteasome activity in ad libitum fed animals45-47
is attractive. Moreover maintenance of proteasome activity is
important for DNA repair48 and cell division,49 and both show an
age-related decline. The possible effects of carnosine, kinetin,
aminoguanidine, and PBN in suppressing proteasome inhibition outlined
above are consistent with such an explanation.
..snip..
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../snip..
-Chris
Chris Allen
> consuming about a pound of meat a day, as mammalian skeletal muscle
> contains about 200 mg per 100 g of meat.
Since much of this is already in the form of adducts, it may be as
useless for anti-aging as iron would be for nuclear fuel (i.e. both
are spent {since iron sits at the very bottom of the curve of binding
energy, energy can only be lost instead of gained by trying to fuse or
fission it -- hence it's essentially the ashes of nuclear reactions}):
http://www.annalsnyas.org/cgi/content/full/959/1/285
..snip..
CARNOSINE AND PROTEIN OXIDATION
Not only can carnosine prevent generation of carbonyl groups on
proteins induced by malondialdehyde, hypochlorite, and
methylglyoxal,12 but it may also react directly with protein carbonyl
groups (Ref. 22 and Tables 2 and 3), producing
protein-carbonyl-carnosine adducts or "carnosinylated" proteins,23
thereby preventing cross-linking to other, unmodified protein.22
Indeed -glutamyl-carnosine adducts have recently been detected by
Karuda et al.26 in beef products; conceivably the adducts derive from
reaction of carnosine with glutamyl-semialdehyde in proteins formed
from oxidation of arginine and proline residues.
Alternatively/additionally carnosine may be involved in deamidation of
asparagine and glutamine residues (see below).
../snip..
-Chris