I just recently posted the message below on the sci.life-extension
group. I decided it was worth posting here too particularly because of
the positive information on carnosine which I think might interest
morelife readers.

[Because this post from Olafur is a copy of what he has already posted to the
sci.life-extension newsgroup (available via Google Groups), I and Paul have not
corrected any spelling/typo errors or removed what we consider extraneous text.
**Kitty]


From: Olafur Pall Olafsson - view profile
Date: Mon, May 22 2006 12:14 pm
Email: "Olafur Pall Olafsson" <olafurp...@...>
Groups: sci.life-extension

A new deglycation process operating on Shiff bases (the first products
in the process of nonenzymatic glycation) has been discovered. The
first step in this deglycation process has been given the term
transglycation and occurs by transfer of the sugar moiety from the
Shiff base to one of the low-molecular weight intracellular
nucleophiles. Transglycating agents therefore reverse glycation in its
early stages. Any agent capaple of doing this, if potent, would be
very important for life-extension, since glycation in the body can
only be slowed down but not stopped. A few such agents have been found
but wether their role as transglycating agents is physiologically
important remains to be determined. As opposed to F3K and F3K-RP,
which are deglycating enzymes produced endogenously with apparently no
known ways for enhancement, some of the potential transglycating
agents can currently be provided exogenously or increased indirectly
by supplementation.

Carnosine and anserine have already been shown to operate as
transglycating agents in vitro but the fate of their transglycation
products (glucosyl-carnosine and glucosyl-anserine) is not known yet.
The same is true for glutathione. Other compounds which have been
hypothesized to act as transglycating agents in the body are
alpha-thiolamines such as N-acetyl-cysteine, cysteine, taurine,
cysteamine and penicillamine. In the case of cysteine,
glucose-cysteine, a cysteine transglycation product, is found in human
urine and is increased in diabetes.


Ann N Y Acad Sci. 2005 Jun;1043:845-64. Related Articles, Links
Click here to read
Transglycation--a potential new mechanism for deglycation of
Schiff's bases.

Szwergold BS, Howell SK, Beisswenger PJ.

Dartmouth Medical School, Remsen 311-314, HB 7515, Hanover, NH
03755, USA. Szwergold@...

Nonenzymatic glycation is believed to play a major role in the
development of diabetic complications. Over the past several years we
and others have shown that in cells this nonenzymatic process can be
reversed by an ATP-dependent reaction catalyzed by
fructosamine-3-kinase (FN3K) and possibly by its isozyme,
fructosamine-3-kinase-related protein (FN3KRP). In this study we
provide the first evidence that this FN3K-dependent deglycation,
acting on the Amadori products, is complemented by another deglycation
process operating on the very first product of nonenzymatic glycation,
glucosylamines (Schiff's bases). We postulate that the first step in
this Schiff's-base deglycation process occurs by transfer of the sugar
moiety from macromolecule-bound glucosylamine to one of the
low-molecular weight intracellular nucleophiles-in particular,
glutathione. We term this reaction transglycation, and in this study
we demonstrate that it occurs readily and spontaneously in vitro. We
further propose that one of the spontaneously formed
glucose-glutathione adduct(s) is subsequently removed from cells by a
multidrug-resistance pump (MRP, MDR-protein, ATP-binding-cassette
protein), metabolized, and excreted in urine. In support of this
latter contention, we show that at least one transglycation product,
glucose-cysteine, is found in human urine and that its concentrations
are increased in diabetes.

PMID: 16037312 [PubMed - indexed for MEDLINE]


Biochem Biophys Res Commun. 2005 Oct 14;336(1):36-41. Related
Articles, Links
Click here to read
Carnosine and anserine act as effective transglycating agents in
decomposition of aldose-derived Schiff bases.

Szwergold BS.

Department of Medicine, Dartmouth Medical School, Hanover, NH,
USA. Szwergold@...

There are numerous publications describing the positive effects of
carnosine (beta-alanyl-histidine) and anserine
(beta-alanyl-1-N-methyl-histidine) on cell and organ function. Of
special interest to us is the fact that these dipeptides act to retard
and (in one instance) reverse non-enzymatic glycation. To date, the
primary explanation for these anti-glycating effects has been the fact
that carnosine and anserine can serve as alternative and competitive
glycation targets, thereby protecting proteins from this deleterious
process. In this paper, we document another mechanism by which these
two peptides can retard or reverse glycation. The process involves
decomposition of the very first intermediates of the non-enzymatic
glycation cascade (aldosamines a.k.a. Schiff bases) by nucleophilic
attack of carnosine and/or anserine on the preformed aldosamine such
as glucosyl-lysine. If future research shows this reaction is to be
physiologically important, this mechanism could explain some of the
beneficial effects of carnosine and anserine as anti-glycating agents.

PMID: 16112643 [PubMed - indexed for MEDLINE]

Quotes from the full text article:
"Results of our experiments indicate that both carnosine and anserine
act as efficient transglycating agents. This suggests that some of the
positive effects of these peptides in inhibiting non-enzymatic
glycation and improving cell function may be due to their
transglycating potential."

"Regarding the fate of glucosyl-carnosine and glucosyl-anserine, there
are at present no data but it is possible that such adducts could
either be transported out of cells or metabolized further, providing
thereby an irreversible set of reactions for removal of aldosamines
from proteins and phospholipids such as phosphatidylethanolamine and
phosphatidylserine."


Med Hypotheses. 2006;66(4):698-707. Epub 2005 Dec 15. Related
Articles, Links
Click here to read
Alpha-thiolamines such as cysteine and cysteamine act as effective
transglycating agents due to formation of irreversible thiazolidine
derivatives.

Szwergold BS.

Department of Medicine, Dartmouth Medical School, Remsen 311-314,
HB 7515, Hanover, NH 03755, USA. Szwergold@...

Non-enzymatic glycation of proteins and some phospholipids is
considered to be an important factor in the genesis of diabetic
complications. While this process has been viewed traditionally as
entirely non-enzymatic and unidirectional, the discovery of
fructosamine-3-phosphate (FN3K) and identification of FN3K-mediated
deglycation mechanisms have made it apparent that non-enzymatic
glycation is not unidirectional and that it can be reversed by
deglycation reactions. While FN3K operates on ketosamines, the second
intermediate in the non-enzymatic glycation cascade, we recently
identified another potential deglycation mechanism that can operate on
Schiff bases, the first intermediates of the non-enzymatic glycation
process. The initial step in this postulated deglycation process is a
transglycation reaction between a L.M.W. intracellular nucleophiles
and a macromolecule-bound aldosamines, which regenerate unmodified
proteins or phospholipids with a concomitant production of
aldose-nucleophile transglycation byproducts. In vitro, transglycation
occurs readily with amino acids, polyamines, thiols and thiolamines.
There are indications that this reaction also occurs in vivo since in
an initial GC/MS analysis of human urine we detected significant
amounts of a transglycation product, glucose-cysteine (G-Cys), which
was markedly increased in diabetics. Despite these encouraging early
data, it is not yet clear to what extent transglycation is important
in vivo and which intracellular nucleophiles are most relevant to this
process. As discussed by us previously in this journal, one likely
candidate for this role is glutathione since it is distributed
universally and since there are well described mechanisms for removal
of S-linked glutathione adducts from cells by the
multi-drug-resistance (MDR) pumps. In this paper we report on another
class of likely transglycating agents, alpha-thiolamines such as
cysteine and cysteamine. While concentrations of these compounds in
tissues are significantly lower than those of GSH, they react with
Schiff bases more rapidly than GSH and, most significantly they form
stable and irreversible thiazolidine products such as glucose-cysteine
(G-Cys) and glucose-cysteamine (G-Ctm) that can subsequently be
removed from cells. The possibility that alpha-thiolamines may play a
physiological role as deglycating agents in vivo is very attractive
since it suggests a possible strategy for inhibiting nonenzymatic
glycation and diabetic complications that could be readily implemented
through nutritional or pharmacological approaches. Such intervention
is eminently feasible since there are at least three thiolamines
already approved for human use. These include cysteamine used for the
treatment of cystinosis; N-acetylcysteine utilized as a mucolytic and
antioxidant agent, in the therapy of acetaminophen poisoning and
radiocontrast-induced nephrotoxicity; and penicillamine used for
treatment of Wilson's disease. Consequently, determining whether these
compounds have the expected anti-glycating effects in vivo should be
relatively straightforward.

PMID: 16359826 [PubMed - in process]

Quotes from the full text article:

"In this report we propose that, in addition to glutathione,
a-thiolamines, such as cysteine, are also good candidates to fulfill
the role of general transglycating agents due to the facts that, like
GSH, they are also universally distributed and that they readily form
irreversible thiazolidine products such as glucose-cysteine that
appear to be exported out of cells and organisms (G-Cys is present in
human urine)."

"Supplementation of cells, organs and organisms with transglycating
nucleophiles such as a-thiolamines should protect against the adverse
effects of hyperglycemia. While, we do not yet have independent data
on this matter, a significant number of reports on the
anti-hyperglycemic effects of penicillamine [31], N-acetyl-cysteine
[32] and [33], glutathione [34], taurine [35] and carnosine and
anserine [36] tend to support this notion."

[Thanks for the good research work, Olafur. Since aminoguanidine also operates
to stop glycation at the Schiff base stage of the process (before the
spontaneously irreversible Amadori rearrangement), I think that it too should be
viewed as a transglycation agent, although perhaps it is merely sacrificially
attracting the glucose moiety to itself. In any case, its effect will be similar
with respect to glycation reduction. OTOH, pyridoxamine acts on the process at
the post Amadori stage to prevent the further reaction of cross linkage as I
understand it. This is why I always urge those who are taking ALT-711 to also
take pyridoxamine to inhibit relinkage after the crosslinks are broken. (At
least the ones that ALT-711 can break. It has recently become very clear that
the most important and plentiful crosslinks in many body tissues are not broken
by ALT-711.)

Readers who consult my and Kitty's regimens will know that we have both been
taking ALT-711, pyridoxamine, aminoguanidine, N-acetyl-cysteine, taurine and
carnosine for many years now. We do not take glutathione since it will generally
not survive the digestive process. We are looking into the availability of
penicillamine, cysteamine and anserine (of which I was aware). We have recently
added N-acetyl-L-carnosine (NALC) to our oral regimen because we think that by
effectively acting as a timed-release form of carnosine (as in its opthalmic
application), NALC may be an effective adjunct and/or more beneficial form of
carnosine. (Carnosine is rapidly broken into is constituent amino acids by the
body's enzyme carnosinase, but NALC is highly resistant to such metabolism until
it is deacetylated. Such deacetylation is a process which is done by the cells
of the body once the NALC has entered those cells. Thus once NALC gets into the
body it will get to the cells where it can have its beneficial effect before it
is broken down. For more detail on the positives and negatives regarding NALC
see my review page at: http://morelife.org/supplements/NALC.html --Paul]

[Update of our regimens is a bit "overdue", but will be done in the near future;
in the meantime, we are taking NALC in our powder mix "cocktail", 120mg by Paul
and 80mg by me, daily.
Some problems with our new Linux computers had us mostly system crippled for a
week until just 2 days ago, during which time though we made some real headway
with the cottage renovation task. We may let website updating go a bit longer so
that we can get the beam in place now that the large wall is down; then we can
stop living in a construction area. ;>)
Photos will make it online in the future to show off the completed job and give
everyone a peek at the in-progress work by a couple of 60+ year olds. Previous
pics of the planned project and early work done last year at this time can be
seen at http://morelife.org/personal/photos2005/photos_41.html **Kitty]