14 replies to this topic

[niner]

Logic posted this paper in another thread, but I found it to be so interesting that I thought it deserved its own thread. The authors lay out a lot of evidence toward the premise that AGE blockers, like pyridoxamine and carnosine, and even AGE breakers like alagebrium/ALT-711 actually work through metal chelation and not via reactive carbonyl trapping like everyone thought.

Diabetes. 2012 Mar;61(3):549-59.
Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications.
Nagai R, Murray DB, Metz TO, Baynes JW.

Department of Food and Nutrition, Japan Women's University, Tokyo, Japan.

This article outlines evidence that advanced glycation end product (AGE) inhibitors and breakers act primarily as chelators, inhibiting metal-catalyzed oxidation reactions that catalyze AGE formation. We then present evidence that chelation is the most likely mechanism by which ACE inhibitors, angiotensin receptor blockers, and aldose reductase inhibitors inhibit AGE formation in diabetes. Finally, we note several recent studies demonstrating therapeutic benefits of chelators for diabetic cardiovascular and renal disease. We conclude that chronic, low-dose chelation therapy deserves serious consideration as a clinical tool for prevention and treatment of diabetes complications.

PMID: 22354928 Free Full Text

They implicate free (non-protein bound) iron and copper as bad actors. The chelation therapy that they suggest could be tricky, in that we need a combination of dose and potency that reduces the free levels significantly without depleting bound iron and copper stores.

[Kevnzworld]

I've taken LEF's MEO product with 1000 mg carnosine, 150 mg benfothiamine, 100 mg of P5P for at least 6 years. Two years ago I began taking 1000 mg of Metformin, and added an additional 500 mg of carnosine, and 150 mg of benfothiamine.
I just checked a blood test from 2008, my iron was 75Ug, ref range 40-155. I checked my most recent blood test in April..it was 82ug I don't know my copper number. So, as far as I can see, the AGE blockers I'm taking in the above amounts haven't reduced my iron. . My HBA1c did drop from 5.5 to 5.2.

[Dorian Grey]

If Iron and Copper are your target minerals, IP6 (Inositol Hexaphosphate) may be a kinder/gentler (and cheaper!) supp for you to look into.

I know IP6 chelates iron as I was donating blood as well as chelating with IP6 when I found my iron (ferritin) was high. They check my hemoglobin every time I make a deposit at the blood bank, and when I cycled off IP6 for a while as I neared my target level (Ferritin @ 20), my hemoglobin jumped up a bit during my regular blood donation once I had been off the IP6 for a couple of months. Back on IP6, my hemoglobin went back to middle range levels.

IP6 is supposed to strongly chelate excess copper too but I have no direct evidence of this.

IP6 and PPC (PhosChol) are my top two "Fountain of Youth" supplements! Have you read Bill Sardi's "Unifying Theory of Aging" (regarding over-mineralization and aging)?
http://www.longevine...of-aging-part1/

Edited by synesthesia, 07 August 2012 - 02:57 AM.

[maxwatt]

Aspirin chelates copper effectively.

But how would chelation affect pentosidine cross-links?

[Logic]

Thx Niner
I thought about starting a new thread after reading that, but thought better of it as I am not yet well known here and still learning/making stupid posts.

Synesthesia
are you the person who startad a thread about donating blood to decrease iron levels?

Question:
Copper is good for skin/collagen etc. So how does one balance copper intake for this purpose given the info here? Is it best applied topically?

[niner]

Question:
Copper is good for skin/collagen etc. So how does one balance copper intake for this purpose given the info here? Is it best applied topically?

Copper peptides are pretty useful as a topical. Balance is the fundamental problem here- How do you reduce free ions without impacting necessary stores of Cu and Fe? There is a test for bound vs free copper, but it's locked up with a patent and is quite expensive, as I recall. I don't worry about conventional agents like carnosine stripping out too many metals, but I wouldn't want to use a powerful chelator like EDTA (or even its more benign cousins) without some careful monitoring. Too bad, because EDTA and the like are a lot cheaper than carnosine.

[Dorian Grey]

"Synesthesia
are you the person who startad a thread about donating blood to decrease iron levels?"

I do donate blood to dump excess iron and also take IP6!

I don't remember starting a post about it, but I do chime in with my thoughts on the evils of iron when I can.

My best effort was in a back and forth with Michael here:
http://www.longecity...n-accumulation/

[Logic]

I do donate blood to dump excess iron and also take IP6!

I don't remember starting a post about it, but I do chime in with my thoughts on the evils of iron when I can.

My best effort was in a back and forth with Michael here:
http://www.longecity...n-accumulation/

Ah yes; thats what I was thinking of. Thx

I must agree that this must be the cheepest way of dumping excess iron and benifiting someone else in the process.

Edited by Logic, 08 August 2012 - 02:24 PM.

[Dorian Grey]

I do donate blood to dump excess iron and also take IP6!

I don't remember starting a post about it, but I do chime in with my thoughts on the evils of iron when I can.

My best effort was in a back and forth with Michael here:
http://www.longecity...n-accumulation/

Ah yes; thats what I was thinking of. Thx

I must agree that this must be the cheepest way of dumping excess iron and benifiting someone else in the process.

Exactly! The argument regarding the health risks of high iron are debatable (though compelling), but perhaps the best argument for iron reduction is, there really is no "up-side" to carrying a 25 year reserve supply of stored iron around in your body.

Free/unbound iron is very toxic... There's no debating that. What most don't recognize is, stored iron like stored toxic waste CAN LEAK, and when it does it can cause problems. If ferritin and hemosiderin didn't leak, people with untreated hemochromatosis wouldn't get sick. Their properly stored iron shouldn't hurt them, but it does!

Why take the risk when there is no downside to dumping this stored toxic waste? Get thee to a blood bank!

Edited by synesthesia, 08 August 2012 - 03:04 PM.

[mikeinnaples]

Probably safest bet is to take chelators away from meals. For example, I take my IP6 right before bed.

[Logic]

Triethylenetetramine Pharmacology and Its Clinical Applications

Abstract
Triethylenetetramine (TETA), a CuII-selective chelator, is commonly used for the treatment of Wilson's disease. Recently, it has been shown that TETA can be used in the treatment of cancer because it possesses telomerase inhibiting and anti-angiogenesis properties. Although TETA has been used in the treatment of Wilson's disease for decades, a comprehensive review on TETA pharmacology does not exist. TETA is poorly absorbed with a bioavailability of 8 to 30%. It is widely distributed in tissues with relatively high concentrations measured in liver, heart, and kidney. It is mainly metabolized via acetylation, and two major acetylated metabolites exist in human serum and urine. It is mainly excreted in urine as the unchanged parent drug and two acetylated metabolites. It has a relatively short half-life (2 to 4 hours) in humans. The most recent discoveries in TETA pharmacology show that the major pharmacokinetic parameters are not associated with the acetylation phenotype of N-acetyltransferase 2, the traditionally regarded drug acetylation enzyme, and the TETA-metabolizing enzyme is actually spermidine/spermine acetyltransferase. This review also covers the current preclinical and clinical application of TETA. A much needed overview and up-to-date information on TETA pharmacology is provided for clinicians or cancer researchers who intend to embark on cancer clinical trials using TETA or its close structural analogs.

http://mct.aacrjourn...t/9/9/2458.full


The Metal Chelators, Trientine and Citrate, Inhibit the Development of Cardiac Pathology in the Zucker Diabetic Rat

Abstract.
Purpose. The objective of this study was to determine the efficacy of dietary supplementation with the metal chelators, trientine or citric acid, in preventing the development of cardiomyopathy in the Zucker diabetic rat. Hypothesis. We hypothesized that dietary chelators would attenuate metal-catalyzed oxidative stress and damage in tissues and protect against pathological changes in ventricular structure and function in type II diabetes. Methods. Animals (10 weeks old) included lean control (LC, fa/+), untreated Zucker diabetic fatty (ZDF, fa/fa), and ZDF rats treated with either trientine (triethylenetetramine) or citrate at 20 mg/d in drinking water, starting when rats were frankly diabetic. Cardiac functional assessment was determined using a Millar pressure/volume catheter placed in the left ventricle at 32 weeks of age. Results. End diastolic volume for the ZDF animals increased by 36% indicating LV dilatation (P < .05) and was accompanied by a 30% increase in the end diastolic pressure (P ≤ .05). Both trientine and citric acid prevented the increases in EDV and EDP (P < .05). Ejection fraction and myocardial relaxation were also significantly improved with chelator treatment. Conclusion. Dietary supplementation with trientine and citric acid significantly prevented structural and functional changes in the diabetic heart, supporting the merits of mild chelators for prevention of cardiovascular disease in diabetes.

http://www.ncbi.nlm....les/PMC2669293/


Citric acid inhibits development of cataracts, proteinuria and ketosis in streptozotocin (type1) diabetic rats

Abstract.
Although many fruits such as lemon and orange contain citric acid, little is known about beneficial effects of citric acid on health. Here we measured the effect of citric acid on the pathogenesis of diabetic complications in streptozotocin-induced diabetic rats. Although oral administration of citric acid to diabetic rats did not affect blood glucose concentration, it delayed the development of cataracts, inhibited accumulation of advanced glycation end products (AGEs) such as Nε-(carboxyethyl)lysine (CEL) and Nε-(carboxymethyl)lysine (CML) in lens proteins, and protected against albuminuria and ketosis . We also show that incubation of protein with acetol, a metabolite formed from acetone by acetone monooxygenase, generate CEL, suggesting that inhibition of ketosis by citric acid may lead to the decrease in CEL in lens proteins. These results demonstrate that the oral administration of citric acid ameliorates ketosis and protects against the development of diabetic complications in an animal model of type 1 diabetes.

http://www.ncbi.nlm....les/PMC2917331/


Chelators in the Treatment of Iron Accumulation in Parkinson's Disease

"...Iron chelators, therefore, may be required to remove iron in a highly selective manner whilst stabilising iron levels elsewhere even within the same cell. Initial clinical trials [65] demonstrate that doses of deferiprone are well tolerated over the long term (6 months) with no stated propagation of a challenge to systemic iron homeostasis. The early successes of these patient studies demonstrate that this issue may not be as pertinent in PD as in FA. Furthermore, deferiprone itself has been shown to be highly selective when used at low concentrations in FA patients?relocating iron from areas of accumulation in the brain to ferritin, thereby preventing deprivation in other tissues..."

http://www.hindawi.c...cb/2012/983245/


Novel molecular targets of the neuroprotective/neurorescue multimodal iron chelating drug M30 in the mouse brain.

The Novel multifunctional brain permeable iron, chelator M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In the present study, we demonstrate that systemic chronic administration of M30 resulted in up-regulation of hypoxia-inducible factor (HIF)-1? protein levels in various brain regions (e.g. cortex, striatum, and hippocampus) and spinal cord of adult mice. Real-time RT-PCR revealed that M30 differentially induced HIF-1?-dependent target genes, including vascular endothelial growth factor (VEGF), erythropoietin (EPO), enolase-1, transferrin receptor (TfR), heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), and glucose transporter (GLUT)-1. In addition, mRNA expression levels of the growth factors, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) and three antioxidant enzymes (catalase, superoxide dismutase (SOD)-1, and glutathione peroxidase (GPx)) were up-regulated by M30 treatment in a brain-region-dependent manner. Signal transduction immunoblotting studies revealed that M30 induced a differential enhanced phosphorylation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK)/ERK kinase (MEK), protein kinase B (PKB/Akt), and glycogen synthase kinase-3? (GSK-3?). Together, these results suggest that the multifunctional iron chelator M30 can up-regulate a number of neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain that might function as important therapeutic targets for the drug in the context of neurodegenerative disease therapy.

http://www.ncbi.nlm....pubmed/21570450


Neuroprotection by the multitarget iron chelator M30 on age-related alterations in mice.

Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelating compound, M30, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we report that a chronic systemic treatment of aged mice with M30 (1 and 5mg/kg; 4 times weekly for 6 months), had a significant positive impact on neuropsychiatry functions and cognitive age-related impairment. M30 significantly reduced cerebral iron accumulation as demonstrated by Perl's staining, accompanied by a marked decrease in cerebral ?-amyloid plaques. In addition, our results demonstrate that M30 caused a significant inhibition of both MAO-A and -B activities in the cerebellum of aged mice, compared with vehicle-treated aged control mice. In summary, the present study indicates that the novel MAO inhibitor/iron chelating drug, M30, acting against multiple brain targets could reverse age-associated memory impairment and provide a potential treatment against the progression of neurodegeneration in ageing.

http://www.ncbi.nlm....rations in mice

[xks201]

Aspirin chelates copper effectively.

But how would chelation affect pentosidine cross-links?

Does aspirin chelate anything else? I read there is a lot of aluminum in aspirin pills. 

Well if they break metal crosslinks it is not hard for me to believe that they could chelate metal. I'm presently quite curious in the potential for methylene blue as a chelator. 

[Logic]

n-phenacylthiazolium bromide (PTB) is very similar to ALT-711 ad reduces AGE content in bone:
http://www.longecity...reaker-in-bone/

Its mentioned in this study:
Chelating activity of advanced glycation end-product inhibitors.
http://www.ncbi.nlm....pubmed/11677237

[Logic]

LR-90 a new advanced glycation endproduct inhibitor prevents progression of diabetic nephropathy in streptozotocin-diabetic rats

LR-90 inhibited the increase in albumin and creatinine concentrations, and concentrations of circulating AGE in diabetic rats without any effect on glycaemic control. LR-90 treated-rats also showed higher body weights than untreated diabetic rats. LR-90 prevented glomerulosclerosis, tubular degeneration and collagen deposition in the kidney. AGE-induced cross-linking and fluorescence of tail collagen were reduced by LR-90 treatment. LR-90 also decreased AGE accumulation in kidney glomeruli and nitrotyrosine deposition in the renal cortex. In vitro, LR-90 was capable of reacting with reactive carbonyl compounds and was a more potent metal chelator than pyridoxamine and aminoguanidine.
LR-90 reduces in vivo AGE accumulation, AGE-protein cross-linking and protein oxidation, and could be beneficial in preventing the progression of diabetic nephropathy. The AGE inhibitory and therapeutic effects of LR-90 could be attributed, at least in part, to its ability to react with reactive carbonyl species and/or potent metal chelating activity that inhibits glycoxidative-AGE formation.

https://www.research...n-diabetic_rats

 

Ninety Percent Reduction in Cancer Mortality after Chelation Therapy With EDTA

http://www.longecity...rapy-with-edta/

 

Seven compounds are here reported to be active in breaking AGE-protein cross-links. These compounds are:

1,4-benzene-bis[4-methyleneaminophenoxyisobutyric acid] (LR102);

4-[(3,5-dichlorophenylureidophenoxyisobutyryl]-4-aminobenzoic acid (LR99);

L-bis-[4-(4-chlorobenzamidophenoxyisobutyryl)cystine] (LR20);

4-(3,5-dichlorophenylureido)phenoxyisobutyryl-1-amidocyclohexane-1-carboxylic acid (LR23);

methylene bis [4,4′-(2-chlorophenylureidophenoxyisobutyric acid)] (LR90);

5-aminosalicylic acid (5-ASA);

and metformin.

http://www.freepaten...om/6787566.html

 

 

Novel inhibitors of advanced glycation endproducts (AGEs): a review

https://www.research...s_AGEs_a_review

Edited by Logic, 07 March 2016 - 09:30 PM.

[Nate-2004]

Rather than start a new thread I thought I'd ask: Are EDTA and Carnosine equal in potency. Also, is EDTA more potent by IV or oral use?

 

As always, Quackwatch blasts Chelation and I'm skeptical about it too, to some degree, but have been taking Carnosine for a year now despite this. Stephen Barrett also hasn't taken a single look at the glycation angle and is unlikely to, given his cynical bias, typical of skeptic bloggers.

Edited by Nate-2004, 10 April 2017 - 09:35 PM.