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On another newsgroup, I tried to point out to someone asking about "glycation" that this was a problem only if you have the wrong fatty acids in your body (and not enough antioxidant-rich foods). My first post was:
QUOTE:
Glycation is certainly a big problem, but remember that when it occurs
in your body, to vital biomolecules, you are in trouble once it passes
a certain threshold. What happens to the food before it gets into your
body may just make it undigestible, which is less of a problem. The
evidence suggests that it is the unsaturated fatty acids, especially
the omega 6, arachidonic acid, that causes a great deal of damage
(which is why I only consume trace amounts of polyunsaturated fatty
acids in my diet).
For example, see:
THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 271, No. 17, Issue of April
26, pp. 9982-9986, 1996
© 1996 by The American Society for Biochemistry and Molecular Biology,
Inc. Printed in U.S.A.
"The Advanced Glycation End Product, Ne-(Carboxymethyl)lysine, Is
a Product of both Lipid Peroxidation and Glycoxidation Reactions*"
QUOTE: "CML is also formed during
metal-catalyzed oxidation of polyunsaturated fatty
acids in the presence of protein... We also report that CML, heretofore
described as a gly-coxidation
product, is formed during peroxidation of polyunsat-urated
fatty acids (PUFA) in the presence of ribonuclease A (RNase), a protein
that contains neither enzymatically nor
nonenzymatically attached carbohydrate... oxidation of fatty acid is
clearly a more efficient source of CML, despite the fact that the
glucose is in solution throughout the course of the experiment,
while the PUFA are only progressively solubilized. Further,
after 6 days of incubation, a large fraction of the arachidonate
was oxidized based on its solubilization in the aqueous phase,
while 2% of the glucose is oxidized during this same time
period... The observations described above indicate that CML,
previ-ously
described as a glycoxidation product or AGE, may, in fact,
be derived from PUFA during lipid peroxidation reactions. UNQUOTE.
UNQUOTE.
After this followed several other responses, and basically they ignored my point and kept talking about issues unrelated to the role of fatty acids. I then posted the following:
QUOTE:
Seems like some of you are "seeing ghosts." It is the lipid peroxidation that is causing the glycation problems (in vivo). Here is yet another study that makes this point:
Diabetes, Obesity and Metabolism
Volume 7 Page 448 - July 2005
doi:10.1111/j.1463-1326.2004.00387.x
Volume 7 Issue 4
Short Report
High-fat diet enhances visceral advanced glycation end products, nuclear O-Glc-Nac modification, p38 mitogen-activated protein kinase activation and apoptosis
S.-Y. Li1, Y. Liu1, V. K. Sigmon1, A. McCort1 and J. Ren1*
High-fat diet intake often leads to obesity, insulin resistance and hypertension, which present a common and detrimental health problem. However, precise mechanism underlying tissue damage due to high-fat diet-induced obesity has not been carefully elucidated. The present study was designed to examine the effect of high-fat diet intake on visceral advanced glycation end products (AGEs) formation, nuclear O-Glc-NAc modification and apoptosis in heart, liver and kidney. Adult male Sprague-Dawley weight-matched rats were fed for 12 weeks with a high-fat diet (45% kcal from fat) or an isocaloric low-fat diet (10% kcal from fat). High-fat diet feeding significantly elevated body weight. Blood pressure and heart rate were comparable between the two rat groups. Competitive enzyme-linked immunosorbent assay showed significantly elevated serum AGE levels, visceral AGE formation, caspase-3 activation and cytoplasmic DNA fragmentation in heart and liver but not kidney samples of high-fat diet fed rats compared with those from low-fat diet fed group. Western blot analysis further revealed that high-fat diet feeding induced overt nuclear O-Glc-NAc modification and p38 mitogen-activated protein kinase activation in heart and liver although not in kidney samples of the high-fat diet-fed rats. Collectively, our results indicated that high-fat diet intake is associated with obesity accompanied by elevated serum and visceral AGEs, visceral post-translational nuclear O-Glc-NAcylated modification and apoptosis, which may contribute to high-fat diet-induced tissue damage.
Now, if they were more knowledgable they would do another experiment, this time using fresh coconut oil, and giving the animals a "high fat" diet. What they would find is that this diet is not a problem at all, but because they are assuming that "saturated fat is bad," they apparently don't even consider this possibility, and this is why much "science" today is unscientific. You must control for all possibly relevant factors in order to follow the scientific method.
UNQUOTE. |
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And here are some follow-up posts of mine:
More evidence to the point I've made in my posts above:
Diabetes 54:3103-3111, 2005
Glycation and Carboxymethyllysine Levels in Skin Collagen Predict the
Risk of Future 10-Year Progression of Diabetic Retinopathy and
Nephropathy in the Diabetes Control and Complications Trial and
Epidemiology of Diabetes Interventions and Complications Participants
With Type 1 Diabetes
Saul Genuth1, Wanjie Sun2, Patricia Cleary2, David R. Sell3, William
Dahms4, John Malone5, William Sivitz6, Vincent M. Monnier3,7, and for
the DCCT Skin Collagen Ancillary Study Group*
"...Although CML is in part a downstream product of furosine, thus
arising from hyperglycemia, CML is also a product of lipid peroxidation
and glycoxidation (30) and of metal and peroxynitrite catalyzed
oxidative stress (31); overproduction of reactive oxygen species in
mitochondria exposed to excessive cellular flux of glucose contributes
to CML formation..."
Online at:
http://diabetes.diabetesjournals.org/cgi/content/full/54/11/3103
Mainly, I have pointed out how experimental findings have been
misinterpreted. I present many of my conclusions at:
http://groups.msn.com/TheScientificDebateForum-
People like yourself, however, will not address obvious refutations,
which are the basis for "getting science right." For example, if rats
are fed a fat free diet, and live well and long, how can the claim of
"essential fatty acids" continue? And as I pointed out, this direct,
on point experiment was conducted in 1948 ! Yet people like MattLB do
not seem to understand that human reason and basic logic underly the
scientific method. People like him/her, instead, argue, implicitly or
explicity, that the textbook dogma must be correct, even though the
textbooks are filled with qualified statements. When on objectively
investigates the experiments upon which these claims are based, one
finds that they are hardly what one expects. I pointed this out to
him/her in may contexts, for example, I researched the literature on
"membranes," and the scientists make clear that their ideas are based
upon assumptions. One scientist who has conducted on point experiments
in this field is Gilbert Ling, who has also done excellent reviews of
the relevant literature. MattLB dismisses Ling's endeavors with a wave
of the proverbial hand.
Moreover, when asked, MattLB never cites, nor provides, a formal
hypothesis for any of his claims, something required of the scientific
method. I, on the other hand, have challenged him and others to do on
point experiments: the person who is wrong must pay for all expenses.
He has never shown any interest in such proposals. If MattLB thinks he
is so "scientific," why does he run from doing the actual experiments
that would determine who is correct? MattLB, please explain to the
readers why you speak loudly and carry such a small, fragile stick.
With regard to "essential fatty acids," "lipid bilayer membranes,"
"trans fat," and this "glycation" issue, the experiments would be
simple to do. One uses lab animals that have often been used in this
context in the past and one provides them with different diets to see
if there is a major difference. With glycation, if one claims that too
much sugar is the problem (or sugar in the presence of high protein
foods), then there is no problem doing the proper experients. However,
one must be willing to do the experiments so that the alternative ideas
are respresented. In this case, I would have a group of animals fed
the meat and sugar diet, but it would be prepared the way I would want
it to be. Then, another group would be fed this diet, but it would be
prepared differently, with the meat being fried in a highly unsaturated
oil. If the latter group was much less healthy and died at younger
ages, it would be clear that the lipid peroxidation was the problem,
not the sugar and protein food. Obviously, one could try several
different variations, but if one does not control for possibily
relevant factors, one is violating the scientific method. For some
reason, this simple point is unable to penetrate the mind of MattLB.
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| [Glycation, glycoxidation and diabetes mellitus]. Boulanger, E., et al. QUOTE: Advanced glycation end-products (AGEs) result from a reaction between carbohydrates and the free amino groups of proteins, lipids, and DNA. Non enzymatic glycation, glycoxidation with glucose auto-oxidation and the polyol pathway are involved in glycated protein formation. AGEs also named glycotoxins are found in excess in pathological situations such as diabetes mellitus, renal failure, and aging or after absorption of food containing glycated products. Three major pathophysiological mechanisms are described to explain AGE toxicity, first AGEs can accumulate in the vessel wall and in collagen of different tissues; second in situ glycation is possible; third, AGEs bind to cell receptors inducing deleterious consequences. AGE receptor RAGE is a multiligand member of the immunoglobulin superfamily of cell surface molecules. AGE-receptor interaction can alter, macrophage, endothelial cell, mesangial and mesothelial cell functions and can induce inflammation. Oxidant stress, vascular hyperpermeability, vascular cell adhesion molecule-1 (VCAM-1) overexpression and monocytes chemotactic Protein-1 (MCP-1) production have been observed after cell activation by AGEs. AGEs appear to be involved in the genesis of diabetic macro but also microangiopathy such as retinopathy and glomerulosclerosis. New drugs are tested to prevent or break the AGE-protein cross-linkage, or to control the AGE-receptor interaction and their consequences. Dietary treatment, strict glycemic control and preservation of renal function remain the best approach for preventing AGE formation and limiting their deleterious effects. UNQUOTE. |
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Here's an example of how many if not most of today's researchers seek to change normal biochemistry, which may have deleterious effects (for instance, "side effects" from drugs meant to enhance or inhibit certain kinds of enzymatic activity), rather than just determining what people can do by themselves to avoid the problem:
QUOTE: Protein degradation and malfunction is a major cause of ageing and can be the result of attacks on proteins by other molecules.
One of these processes, called glycation, involves the spontaneous attack by sugars on proteins. If glycation gets out of hand many proteins are degraded or destroyed -- proteins which are important for the proper functioning of the body. Protection against glycation declines with age leading to increasing glycation damage with increasing age. A critical enzyme involved in protection against glycation is "Glyoxalase 1"...
"This work shows for the first time that this enzyme also protects proteins against damage by oxidation and nitration", says Professor Thornalley. The enzyme works by converting the damaging reactive products of glycation derived from glucose into harmless compounds. "This implies that glycation promotes multiple types of protein damage in ageing", says Prof Thornalley who will present his findings in the same session as plant scientist, Professor Dr Sudhir Sopory (International Center for Genetic Engineering and Biotechnology, New Delhi).
Professor Sopory has shown in tobacco and rice plants that increasing glyoxalase 1 enhances resistance to stress conditions, which demonstrates that the enzyme plays a similar role in both animal and plant systems in preventing protein damage. UNQUOTE.
Source: http://www.sciencedaily.com/releases/2007/04/070402102354.htm |
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QUOTE: ...The Warwick research team, led by Dr Antonio Ceriello, have now proven that the damage seems to be done in a process called glycation when early on in a period of high glucose levels glucose sugar molecules are able to bind to proteins in the mitochondria of cells (the parts of cells governing the production and regulation of energy). This persists even if glucose levels later fall to normal. This inhibits and distorts the mitochondria’s normal function and results in an overabundance of the production of free radicals (or Reactive Oxygen Species �?ROS) which cause oxidation and thus continued diabetic complications.
The Warwick Medical School researchers proved their hypothesis by taking tissue and exposing it to 2 weeks of high levels of glucose, followed by one week of normal glucose �?however for half the tissue they also applied several antioxidants at the end of the two weeks of high glucose. The tissue without antioxidants levels of glucose stress remained high but where antioxidants had been applied there was a dramatic fall in the incidence of free radicals and there was also a significant drop in 5 of the 6 key markers for high glucose stress... Dr Ceriello’s paper "Reactive oxygen species mediate a cellular ‘memory�?of high glucose stress signaling" has just been published in Diabetologia DOI 10.1007/s00125-007-0684-2. The second paper, about to be published in Diabetes Care, is entitled "Antioxidants and Free Radicals, Endothelial Dysfunction, Oxidative and Nitrosative Stress covers his work on the AT-1 receptor blocker Telmisartan. UNQUOTE.
Source: http://www.sciencedaily.com/releases/2007/06/070628162254.htm |
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A study titled "Glycated Hemoglobin Level Is Strongly Related
to the Prevalence of Carotid Artery Plaques With High Echogenicity in Nondiabetic Individuals" is important because arachidonic acid has been found to be an incredibly potent glycating agent, as is clear in the study cited in the fist message in this thread. Here is a key passage:
QUOTE: ...We conclude that increasing HbA1c [glycated hemoglobin] levels are related to an increased risk of carotid artery plaques and that the relationship depends on plaque echogenicity. Our results suggest that the degree of glycemia contributes to the development of hard echogenic plaques and that the process takes place already at modestly elevated levels of HbA1c. UNQUOTE.
Source: Circulation. 2004;110:466-470.
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Hans,
When my boyfriend and I asked Ray Peat a question he told us the following:
Question: What could a person with HIV do to help avoid or reverse some of the lipid problems usually seen in those on protease inhibitors?
Answer: ".... taking t3, and replacing all starches with Orange juice as your main source of carbohydrate".
Any idea why he might have said to avoid starches? |
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The following article is interesting showing the upregulation of matrix metalloproteases (MMPs), which break down the extracellular matrix (ECM), and decreased transcription of ECM components like collagen and fibronectin. These processes are also mediated by the LTB4 molecule AFAIK. I would like to know, whether they included some PUFAs in the reaction to prepare the AGE-ylated proteins. It's hard to belive that just mixing plain sugar with protein generates AGEs. I don't have access to the full text :-(
AGEs and the ECM
Advanced glycation endproducts (AGEs) are the result of nonenzymatic condensation reactions between sugars and proteins. AGEs accumulate in multiple tissues over the course of aging, and they have been implicated in a variety of age-related diseases. The data connecting them to aging isn’t terribly strong, in part because it’s hard to prevent them from forming and thereby observe aging and disease progression in their absence. Most of the evidence that they’re involved is circumstantial, derived from observations of diseases where they accumulate prematurely (e.g., diabetes, where the “sugar spikes�?that result from impaired glucose homeostasis cause increased AGE formation).
A mechanistic understanding of the effect of AGE on tissues and cells, then, would go a long way toward boosting the argument that these compounds are causative in aging, rather than merely a harmless epiphenomenon. To that end, Molinari et al. studied the effect of AGEs on gene expression in fibroblasts (mesenchymal cells that provide support and structure to tissues throughout the body, especially the skin):
Effect of advanced glycation endproducts on gene expression profiles of human dermal fibroblasts
The Maillard reaction and its end products, AGE-s (Advanced Glycation End products) are rightly considered as one of the important mechanisms of post-translational tissue modifications with aging. We studied the effect of two AGE-products prepared by the glycation of lysozyme and of BSA, on the expression profile of a large number of genes potentially involved in the above mentioned effects of AGE-s. The two AGE-products were added to human skin fibroblasts and gene expression profiles investigated using microarrays. Among the large number of genes monitored the expression of 16 genes was modified by each AGE-preparations, half of them only by both of them. Out of these 16 genes, 12 were more strongly affected, again not all the same for both preparations. Both of them upregulated MMP and serpin-expression and downregulated some of the collagen-chain coding genes, as well as the cadherin- and fibronectin genes. The BSA-AGE preparation downregulated 10 of the 12 genes strongly affected, only the serpin-1 and MMP-9 genes were upregulated. The lysozyme-AGE preparation upregulated selectively the genes coding for acid phosphatase (ACP), integrin chain α5 (ITGA5) and thrombospondin (THBS) which were unaffected by the BSA-AGE preparation. It was shown previously that the lysozyme-AGE strongly increased the rate of proliferation and also cell death, much more than the BSA-AGE preparation. These differences between these two AGE-preparations tested suggest the possibility of different receptor-mediated transmission pathways activated by these two preparations. Most of the gene-expression modifications are in agreement with biological effects of Maillard products, especially interference with normal tissue structure and increased tissue destruction.
The authors exposed fibroblasts to two types of AGE-modified (AGE-ylated?) proteins, which had overlapping but non-identical effects on gene expression. The common features of the response to the two proteins are most intriguing, however: increased transcription of matrix metalloproteases (MMPs), which break down the extracellular matrix (ECM), and decreased transcription of ECM components like collagen and fibronectin. Taken together, these effects would result in a net weakening of the ECM, which in turn would have profoundly negative effects on organ function, ranging from skin wrinkling to cardiomyopathy.
On another note: increased MMPs and ECM breakdown are hallmarks of fibroblast senescence, which is usually associated with DNA damage or telomere shortening �?could AGEs be stimulating premature senescence, either by damaging DNA or via some other pathway?
SOURCES:
http://www.springerlink.com/content/1g9w214567407np2/
http://ouroboros.wordpress.com/ |
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