65 replies to this topic

[Logic]

Bumpin this up. How would the potency of the various plants and extracts be quantified for ranking?

A very good question Luddist and part of the reason I have not done the summery.
The paper does seem to compare most extracts, very loosely, to aminoguanidine.
So the other part of the reason is laziness!

Edited by Logic, 13 July 2013 - 08:39 PM.

[Michael]

Hoo boy.

Almost all the putative AGE inhibitors in this thread (a) inhibit the early, easily-reversed first step (Schiff base formation) of classical Maillard glycation, (b) do so in vitro with zero evidence of in vivo efficacy, and © at concentrations that are physiologically unrealistic.

Of the three that Niner Solarfingers highlights (Green Tea Extract, Lipoic Acid, and L-Carnosine), the above three criticisms apply to carnosine (a recent study in humans finds that only 8 out of 25 subjects administered 60 mg/kg carnosine (4200 mg in a lean 70 kg adult male) exhibited a detectable increase in plasma carnosine, which was largely over in an hour in most subjects and totally gone by two), and there is a potential safety issue highlighted in people with carnosinemia (though it looks to me as if the rise of plasma and tissue carnosine has not yet been fingered as the actual mediator of neurological damage). Green tea extract "blocked tendon crosslinking ... fluorescent products at 385 and 440 nm (p = 0.052 and < 0.05, respectively) and tended to decrease skin pentosidine levels [at 10 months of age [in healthy C57BL/6 mice]"(1) and yet "glycoxidation [oxidatively-driven AGE] in tendon, aorta, and plasma was either worsened or not significantly improved by the vitamins and green tea. Glucosepane cross-links [the single greatest quantitative contributor to AGE crosslinking in human collagen yet identified] were increased by diabetes (P < 0.001), and green tea worsened total cross-linking. In conclusion, green tea and antioxidant vitamins improved several diabetes-related cellular dysfunctions but worsened matrix glycoxidation in selected tissues, suggesting that antioxidant treatment tilts the balance from oxidative to carbonyl stress in the extracellular compartment."(2)

Lipoic acid reduces aortic AGE (as measured by fluorescence at 370 nm and emission at 440 nm) in animals with metabolic syndrome induced by glucose feeding, but not in healthy ones(3) — an effect that I would expect to be generalizable to most AGE-prevention drugs or supplements, due if nothing else to stoichiometry.

References
1: Rutter K, Sell DR, Fraser N, Obrenovich M, Zito M, Starke-Reed P, Monnier VM. Green tea extract suppresses the age-related increase in collagen crosslinking and fluorescent products in C57BL/6 mice. Int J Vitam Nutr Res. 2003 Nov;73(6):453-60. PubMed PMID: 14743550; PubMed Central PMCID: PMC3561737.

2: Mustata GT, Rosca M, Biemel KM, Reihl O, Smith MA, Viswanathan A, Strauch C, Du Y, Tang J, Kern TS, Lederer MO, Brownlee M, Weiss MF, Monnier VM. Paradoxical effects of green tea (Camellia sinensis) and antioxidant vitamins in diabetic rats: improved retinopathy and renal mitochondrial defects but deterioration of collagen matrix glycoxidation and cross-linking. Diabetes. 2005 Feb;54(2):517-26. PubMed PMID: 15677510.

3: Midaoui AE, Elimadi A, Wu L, Haddad PS, de Champlain J. Lipoic acid prevents hypertension, hyperglycemia, and the increase in heart mitochondrial superoxide production. Am J Hypertens. 2003 Mar;16(3):173-9. PubMed PMID: 12620694.

Edited by niner, 04 October 2014 - 02:18 AM.

[blood]

Fisetin looks promising.

In this study, diabetic mice got 40 mg/kg/day fisetin; wild-type mice received 25 mg/kg/day. Doses like that (adjusting for body weight or surface area) would be doable in people.

Full text: http://www.plosone.o...al.pone.0021226

Fisetin Lowers Methylglyoxal Dependent Protein Glycation and Limits the Complications of Diabetes

Abstract

The elevated glycation of macromolecules by the reactive dicarbonyl and α-oxoaldehyde methylglyoxal (MG) has been associated with diabetes and its complications. We have identified a rare flavone, fisetin, which increases the level and activity of glyoxalase 1, the enzyme required for the removal of MG, as well as the synthesis of its essential co-factor, glutathione. It is shown that fisetin reduces two major complications of diabetes in Akita mice, a model of type 1 diabetes. Although fisetin had no effect on the elevation of blood sugar, it reduced kidney hypertrophy and albuminuria and maintained normal levels of locomotion in the open field test. This correlated with a reduction in proteins glycated by MG in the blood, kidney and brain of fisetin-treated animals along with an increase in glyoxalase 1 enzyme activity and an elevation in the expression of the rate-limiting enzyme for the synthesis of glutathione, a co-factor for glyoxalase 1. The expression of the receptor for advanced glycation end products (RAGE), serum amyloid A and serum C-reactive protein, markers of protein oxidation, glycation and inflammation, were also increased in diabetic Akita mice and reduced by fisetin. It is concluded that fisetin lowers the elevation of MG-protein glycation that is associated with diabetes and ameliorates multiple complications of the disease. Therefore, fisetin or a synthetic derivative may have potential therapeutic use for the treatment of diabetic complications.

Interview with the researchers from science daily.com:

http://www.scienceda...10627183932.htm

The study also defines a likely molecular mechanism underlying these effects. Researchers observed that blood and brain levels of sugars affixed to proteins known as advanced glycation end-products-or AGEs-were reduced in fisetin-treated compared to untreated Akita mice. These decreases were accompanied by increased activity of the enzyme glyoxalase 1, which promotes removal of toxic AGE precursors.

The discovery of an AGE-antagonizing enzyme upregulated by fisetin is very intriguing, because substantial evidence implicates high blood AGE levels with many if not most diabetic complications. "We know that fisetin increases activity of the glyoxalase enzyme and may increase its expression," says Maher. "But what is important is that ours is the first report that any compound can enhance glyoxalase 1 activity."

Interestingly, excessively high AGE levels also correlate with inflammatory activity thought to promote some cancers. In fact, studies published by others confirm that fisetin decreases tumorigenicity of prostate cancer cells both in culture and in animal models, which if supported would represent a major added incentive to eat your strawberries.

To ingest fisetin levels equivalent to those fed Akita mice, Maher estimates that humans would have to eat 37 strawberries a day, assuming that strawberry fisetin is as readily metabolizable by humans as fisetin-spiked lab chow is by mice. Rather than through diet, Maher envisions that fisetin-like drugs could be taken as a supplement.

Schubert notes that fisetin is also effective in mouse models of Alzheimer's disease. "We and others have shown that diabetes may be a risk factor for Alzheimer's disease, making identification of a safe prophylactic like fisetin highly significant," he says.

Maher acknowledges that the public may be suffering from flavonoid-fatigue, given media coverage of the promises of these compounds. "Polyphenolics like fisetin and those in blueberry extracts are found in fruits and vegetables and are related to each other chemically," she says. "There is increasing evidence that they all work in multiple diseases. Hopefully some combination of these compounds will eventually get to the clinic."

Schubert concurs that their findings only reinforce what common sense and our mothers told us was a healthy lifestyle. "Eat a balanced diet and as much freshly prepared organic food as possible, get some exercise, keep socially and mentally active and avoid sodas with sugar and highly processed foods since they can contain high levels of AGEs," he advises.

But he also worries that hoops that must be jumped through to bring a natural product like fisetin, as opposed to a totally synthetic drug, to clinical trials are daunting because it is difficult to protect patents on natural products. "We will never know if a compound like fisetin works in humans until someone is willing to support a clinical trial."

Edited by blood, 06 November 2013 - 09:51 AM.

[blood]

ARBs appear to have anti-glycation or RAGE-antagonising properties independent of their bp lowering effects:

www.ncbi.nlm.nih.gov—19075484

Int Heart J. 2008 Nov;49(6):681-9.

Effects of 12-month valsartan therapy on glycation and oxidative stress markers in type 2 diabetic subjects with hypertension.

Komiya N, Hirose H, Saisho Y, Saito I, Itoh H.

Source
Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Abstract
Although it has been reported that angiotensin II receptor blockers inhibited the formation and accumulation of advanced glycation endproducts (AGEs) in vitro and in vivo, whether they can do so clinically is not clear. We investigated the effects of 12-month valsartan therapy on various markers of inflammation, glycation, and oxidation in type 2 diabetic subjects with hypertension. We started 40 mg/day valsartan treatment in 15 type 2 diabetic patients with hypertension. In 6 patients, the dose of valsartan was increased to 80 mg/day after 6 months and maintained until 12 months. Metabolic parameters including BMI and serum high molecular weight (HMW)-adiponectin, high-sensitivity C-reactive protein (hs-CRP) as an inflammation marker, AGEs, paraoxonase activity, platelet-activating factor (PAF)- acetylhydrolase activity, and urine 8-isoprostane levels were measured at baseline and after 6 and 12 months of treatment. Urine microalbumin level and carotid artery intima-media thickness (IMT) were also measured. Even after valsartan therapy, the blood pressure levels of the patients were not decreased significantly. Serum AGEs and urine 8-isoprostane levels decreased at both 6 and 12 months (P < 0.05 for both), although other metabolic and oxidative markers were unchanged. Though urine microalbumin levels tended to be decreased after 6 and 12 months of valsartan treatment, the changes were not significant. Mean IMT at 12 months was not changed from the baseline value. In conclusion, the findings suggest that treatment with valsartan, even at a low dose, may ameliorate some glycation and oxidative stress markers independently of an effect on blood pressure in hypertensive type 2 diabetic subjects.

PMID: 19075484 [PubMed - indexed for MEDLINE] Free full text

www.ncbi.nlm.nih.gov—17142134

Metabolism. 2006 Dec;55(12):1619-24.

Effects of valsartan therapy on protein glycoxidation.

Monacelli F, Poggi A, Storace D, Durante A, Traverso N, Viviani GL, Odetti P.

Source
Department of Internal Medicine and Medical Specialities, University of Genoa, 16132 Genova, Italy.

Abstract

Several lines of evidence suggest that both advanced glycation end products (AGEs) and oxidation processes play key roles in the physiology of aging and age-related pathologies, leading to irreversible proteins modifications in both tissues and the extracellular matrix. Such an accelerated accumulation of these modifications has been reported to be present in several age-related chronic diseases, such as atherosclerosis, diabetes, arthritis, and neurodegenerative diseases. The current literature reveals that the specific inhibition of AGEs may constitute an innovative therapeutic goal. In experimental animals, the use of sartans significantly reduces blood pressure and kidney pentosidine content, improving both histologic renal damage and proteinuria. In this study, 12 subjects who were affected by diabetes mellitus and hypertension were subjected to oral antihypertensive therapy with valsartan (class of sartans) with timed sampling of plasma and urine pentosidine, N(epsilon)-(carboxymethyl)lysine (CML), malondialdehyde, and isoprostanes levels, respectively, at baseline and after both 3 and 6 months, with parallel ongoing evaluation of glycemic control and blood pressure levels. Valsartan elicited a good antihypertensive effect with a 30% decrease in plasma pentosidine levels (P < .05) after 3 months of therapy, followed by a slight increase after 6 months. Urinary pentosidine concentrations exhibited a 40% decrease after 3 months (215 +/- 19 vs 129 +/- 23 nmol/24 h) and a further significant reduction after 6 months of therapy (105 +/- 24 nmol/24 h). Plasma CML levels showed a progressive decrease after 3 months (23.15 +/- 3.215 vs 19.88 +/- 1.684 micromol/mL) and achieved a further slight reduction after 6 months of therapy (19.48 +/- 1.339 micromol/mL); for urinary CML, a statistically significant reduction was gained after the sixth month of therapy (48.51 +/- 5.70 vs 30.30 +/- 2.77 micromol/24 h after 3 months and 27.02 +/- 4.13 micromol/24 h after 6 months; F = 7.62, P < .005). Plasma and urinary concentrations of malondialdehyde were slightly modified by valsartan treatment; the mean levels after both 3 and 6 months did not significantly differ from baseline. Urinary 15-F2t-isoprostanes (2.96 +/- 0.45 ng/24 h) levels displayed a progressive decrease after both 3 (2.27 +/- 0.31 ng/24 h) and 6 months (1.70 +/- 0.23 ng/24 h) with statistical significance achieved only at the end of the study (P < .05). The present data suggest interesting in vivo antiglycation and antioxidation effects of this angiotensin II receptor antagonist with reductions in plasma and urinary pentosidine, plasma CML, and urinary isoprostanes levels. The present study supports an antagonistic role of valsartan in the production of AGEs precursors through the chelation of transition metals and an antioxidant activity that scavenges reactive oxygen species. This property of valsartan may broaden the scope of newly developed pharmacologic inhibitors of advanced glycoxidation.

PMID: 17142134 [PubMed - indexed for MEDLINE]

Antagonising AGE receptors (RAGEs) ameliorates damage from AGEs:

www.ncbi.nlm.nih.gov—18855759

Protein Pept Lett. 2008;15(8):850-3.

Telmisartan inhibits advanced glycation end products (AGEs)-elicited endothelial cell injury by suppressing AGE receptor (RAGE) expression via peroxisome proliferator-activated receptor-gammaactivation.

Yamagishi S, Matsui T, Nakamura K, Takeuchi M, Inoue H.

Source
Department of Medicine, Kurume University School of Medicine, Kurume, Japan. shoichi@med.kurume-u.ac.jp

Abstract

Advanced glycation end products (AGEs)-their receptor (RAGE) axis plays a central role in the pathogenesis of diabetic microangiopathy. Since the pathophysiological crosstalk between the AGEs-RAGE system and angiotensin II has also been associated with diabetic microangiopathy, we examined here whether and how telmisartan, a unique angiotensin II type 1 receptor blocker (ARB) with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity, could inhibit the AGEs-elicited endothelial cell injury by suppressing RAGE expression in vitro. Telmisartan suppressed RAGE expression at both mRNA and protein levels in human cultured microvascular endothelial cells (ECs), which were prevented by GW9662, an inhibitor of PPAR-gamma. Further, telmisartan was found to inhibit up-regulation of mRNA levels for monocyte chemoattractant protein-1, intercellular adhesion molecule-1 and vascular endothelial growth factor in AGEs-exposed ECs. These results suggest that telmisartan inhibits the AGEs-elicited EC injury by down-regulating RAGE expression via PPAR-gamma activation. Our present study provides a unique beneficial aspect of telmisartan. Specifically, it could work as an anti-inflammatory agent against AGEs via PPAR-gamma activation and may play a protective role against diabetic microangiopathy.

PMID: 18855759 [PubMed - indexed for MEDLINE]

[Darryl]

The most recent good review appears to be:

Aldini, Giancarlo, et al. "Molecular strategies to prevent, inhibit and degrade advanced glycoxidation and advanced lipoxidation end products." Free radical research 0 (2013): 1-80.

Bad news: Benfotiamine trials are disappointing. Putative AGE-breakers (like ALT-711/alagebrium) don't actually break cross-links.

Recent clinical studies on patients suffering from diabetes (types 1 and 2), diabetic nephropathy, and peripheral nerve inflammation showed that benfotiamine does not result in significant reductions in plasma or urinary AGEs or plasma markers of endothelial dysfunction and nerve inflammation compared to placebo.

The beneficial effects of the so-called AGE breakers are unlikely to be the result of cleavage or reversal of preexisting AGE cross-links. It is more likely that AGE breakers may have more direct eff ects on the formation of AGEs through their antioxidant and chelating effects and their reaction mechanism with methylglyoxal and other dicarbonyl intermediates in the Maillard reaction.

Good news: aspirin, carnosine, ibuprofen, BHT, pyridoxamine (B6), lipoic acid, N-acetyl cysteine (NAC), selenium, and taurine receive favorable mentions, as well as a number of prescription drugs. Autophagy upregulation appears to be particularly important for removal of cross-linked proteins, though autophagy inducers are not discussed.

Numerous prescription drugs induce autophagy in vitro. Among food / supplement compounds, spermidine, parthenolide (feverfew), and the stilbenoids resveratrol & piceatannol appear most potent, though many (most?) polyphenols appear to have some activity.

Renna, Maurizio, et al. "Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative diseases." Journal of Biological Chemistry 285.15 (2010): 11061-11067.
Hundeshagen, Phillip, et al. "Concurrent detection of autolysosome formation and lysosomal degradation by flow cytometry in a high-content screen for inducers of autophagy." BMC biology 9.1 (2011): 38.
Eisenberg, Tobias, et al. "Induction of autophagy by spermidine promotes longevity." Nature cell biology 11.11 (2009): 1305-1314.
Pietrocola, Federico, et al. "Pro-autophagic polyphenols reduce the acetylation of cytoplasmic proteins." Cell Cycle 11.20 (2012): 3851-3860.

Edited by Darryl, 07 November 2013 - 05:29 PM.

[APBT]

I know we are getting off the topic of Astragolus and Telomeres but just to close the loop on my thinking, this looks like it might be an interesting read:
Natural inhibitors of advanced glycation end-products

I'm not quite ready to shell out $35.00 but it does look like an interesting article...

 

 

FULL TEXT: Natural inhibitors of advanced glycation end-products

[Logic]

Chelation: A Fundamental Mechanism of Action of AGE Inhibitors, AGE Breakers, and Other Inhibitors of Diabetes Complications
http://diabetes.diab...t/61/3/549.full

This is a very good and well referenced summary with many good leads to follow.

"...Citrate, at the same dose as triethylenetetramine (1 g/L in drinking water), provided comparable protection against cardiac structural and functional changes in the Zucker type 2 diabetic rat..."

"...Administration of triethylenetetramine for 6 months caused a significant ∼5% reversion of left ventricular mass toward normal in type 2 diabetic patients compared with an increase of 3% in left ventricular mass in untreated patients..."
 
"...The original AGE breaker, N-phenacylthiazolium bromide (PTB) (33), its dimethylthiazolium analog alagebrium (ALT)-711 (34), and recently described pyridinium analogs TRC4186 and TRC4149 (35,36) (Fig. 3) were designed to cleave AGE cross-links in tissue proteins. As support for their mechanism of action, these compounds 1) released AGE albumin from preformed AGE-albumin-collagen complexes, 2) released immunoglobulins bound to red cells of diabetic rats, and 3) reversed or decreased collagen cross-linking in diabetic rats..."

Edited by Logic, 16 June 2014 - 09:59 AM.

[Logic]

Chelating activity of advanced glycation end-product inhibitors.
http://www.ncbi.nlm....pubmed/11677237

"...All AGE inhibitors studied were chelators of copper, as measured by inhibition of metal-catalyzed autoxidation of ascorbate...."

Novel inhibitors of advanced glycation endproducts.
http://www.ncbi.nlm....pubmed/14568010

"...We have identified two new classes of aromatic compounds; aryl- (and heterocyclic) ureido and aryl (and heterocyclic) carboxamido phenoxyisobutyric acids, and benzoic acid derivatives and related compounds, as potential inhibitors of glycation and AGE formation..."

Effects of Chebulic Acid (from Haritaki) on Advanced Glycation Endproducts-induced Collagen Cross-links
https://www.jstage.j...-00034/_article

"...The chelating activities of CA, AG and ALT711 on copper-catalyzed oxidation of AA were compared, and in increasing order, ALT-711(IC50 of 1.92 ±0.20 mM) <CA (IC50 of 0.96 ± 0.07 mM ) <AG (0.47 ±0.05 mM)..."

 

 

The above info make one wonder if a course of chelation therapy combined with synergistic compounds already discussed may be the way to significantly reduce AGEs?

[Logic]

Not plant derived but interesting:
Blocking the receptors for the activin protein upregulates autophagy.
Follistatin blocks activin signalling.

This has all sorts of effects; from upregulating autophagy to growing a new pancreas if you can regulate the receptor blocking well enough!!

http://www.longecity...359#entry670359

[Trevor]

Mesima mushroom (phellinus linteus) has greater antiglycation properties than aminoguanidine.

 

Protein Glycation Inhibitors from the Fruiting Body of Phellinus linteus

→ source (external link)

 

 

At the last stage of glycation, compound 8 was found to be a potent inhibitor of the cross-linking of proteins, which was more effective than that of aminoguanidine, a well-known inhibitor for advanced glycation end products. Consequently, compound 8 showed the most potent inhibitory effects at each stage of protein glycation. This mechanism may help to provide a protective effect against hyperglycemia-mediated protein damage.

 

[Logic]

Linking nd old post by Health_Nutty to try and get all the info in one place.
http://www.longecity...ibit-glycation/

"... In the early stage of protein glycation,
luteolin, qucertin, and rutin
exhibited significant inhibitory activity ... more effective than that of aminoguanidine
For the middle stage,
luteolin and rutin developed more significant inhibitory effect on methylglyoxal-medicated protein modification, and the IC50's were 66.1 and 71.8 microM, respectively.
In the last stage.
luteolin was found to be potent inhibitors of both the AGEs formation and the subsequent cross-linking of proteins..."

[Tom Andre F. (ex shinobi)]

Effects of Chebulic Acid (from Haritaki) on Advanced Glycation Endproducts-induced Collagen Cross-links
https://www.jstage.j...-00034/_article

"...The chelating activities of CA, AG and ALT711 on copper-catalyzed oxidation of AA were compared, and in increasing order, ALT-711(IC50 of 1.92 ±0.20 mM) <CA (IC50 of 0.96 ± 0.07 mM ) <AG (0.47 ±0.05 mM)..."

 

 

The above info make one wonder if a course of chelation therapy combined with synergistic compounds already discussed may be the way to significantly reduce AGEs?

 

This can explain the telomere guard effect of Terminalia Chebula.

[YOLF]

So has anything been discussed that is able to degrade cross linked collagens? Or just prevent? Seems progress will be limited until the crosslinked stuff can be removed. Hopefully the FA! and SENS fundraiser will yield some good supplements.

[stefan_001]

I am wondering whether a way to test the removal of AGE is to create topical creams with some if the mentioned compounds. Reduction in wrinkles should indicate AGE removal or?

[Logic]

More than genes and cells: drug discovery in the ECM.

 

Alas, AGE formation is purely chemical, and so cannot be blocked by an enzyme inhibitor or a mouse knock-out. AGE formation could be blocked by agents that trap the -dicarbonyl intermediates on the path to AGE. Aminoguanidine and pyridoxamine have been tested as AGE blockers19. Results have not been that impressive in man, however, possibly in part because you have to take the compounds continuously for 10 years to block the accumulation of AGEs in a protein with a 10-year half-life. It is likely that one of the benefits of calorie restriction (among many others) is reduced blood sugar levels and hence reduced glycation, but this is an even harder regime to adhere to.

 

A better route would be to clear glucosepane from the body, but here again we are stymied for lack of an enzyme or, until very recently, even a good supply of authentic glucosepane to test enzymes on. However one compound – Alagebrium (ALT711 – see Figure 2) – has been developed as a chemical AGE-breaker. It was designed to be a reagent that catalytically breaks - dicarbonyls, which (at the time) were seen as a major form of cross-link in vivo20. Early trials showed a beneficial effect in man, but a larger follow- up trial showed no benefit20-22. There is also controversy over the drug’s mode of action. Recent research has confirmed that Alagebrium does catalytically cleave dicarbonyls23, resolving doubt about this in the past, but it is now believed that dicarbonyls are quantitatively trivial compared to the chemically stable AGE cross-links16. So the trials of Alagebrium have generated a drug that does something in rats24, may do something in man, but it is as yet not clear what or how.

Torrent Pharmaceuticals is taking the compound TRC4186 into clinical trials as an AGE-breaker. Its chemical mode of action is obscure; the compound was identified by randomly reacting highly AGEd serum albumin (made by incubating BSA with 1.67M glucose for 16 weeks) with collagen, a chemistry that bears little relationship to AGE cross-links in vivo, and then searching for compounds that released the BSA. TRC4186 appears beneficial in animal hypertension models25 but no human efficacy data has been released26...

 

...It is now understood that the quality of the ECM in vivo can also be decisive in determining how well cells function to repair tissue after damage. Several studies have suggested that the failure of older tissue to repair itself as well as young tissue is due at least as much to the ‘old’ ECM as to the cells themselves being old. For example, the replicative and differentiation potential of mesenchymal stem cells from old mice could be ‘rescued’ by growing them on ECM generated by young stem cells31. Kang and Lightman tracked regenerating peripheral nerves in the mouse and showed that the poorer regeneration in old mice over young ones was due to the lack of ability of the growing axon tips to clear debris from damaged nerves from their path. In the absence of debris, they grew and innervated muscle as well as nerves from young animals32. Loss of functional fibroblasts in the dermis of the skin, and hence loss of skin strength, elasticity and thickness with ‘normal’ ageing is primarily driven by degradation of the collagen matrix to which the cells attach, including glycation33. Thus ECM repair is likely to be a key component of either of the regenerative medicine strategies34.

The structural proteins of the body, especially collagen, have traditionally been viewed as nonstarters as drug discovery targets, because they are not obviously active as catalysts or signal transduction molecules. The recent work summarised above shows that this is not necessarily a good argument for ignoring the ECM. As an alternative route to identifying the role of every gene in every cell in a complex disease such as chronic inflammation or in cancer, targeting damage to the ECM may prove a valuable approach to new treatments for a range of diseases and disabilities of old age.

 

http://www.ddw-onlin...-winter-13.html

I think we need to track down Dr William Bains and his articles!

 

Edited by Logic, 05 March 2016 - 12:16 PM.

[Logic]

From the above:

"...Early trials showed a beneficial effect in man, but a larger follow- up trial showed no benefit..."

"...aminoguanidine made me feel better and helped biologically, as I'd taken it over 5 years..."

http://www.longecity...ndpost&p=202763

 

"...I've looked at the three human trials studies of Alagebrium, and there was very encouraging improvement in such things as blood pressure and skin elasticity..."

http://www.longecity...ndpost&p=202795

 

n one study, aminoguanidine was administered to diabetic rats. Those rats which received aminoguanidine had a significantly superior survival rate than those who remained untreated.

 

Aminoguanidine corrected approximately 86% of the nerve conduction velocity deficits in about 4 weeks. Fifty percent of the maximal effect was experienced in 6 days.

 

en randomly assigned to treatment with aminoguanidine or placebo for four years...he aminoguanidine group evinced a significant (<0.05) reduction in doubling of serum creatinine concentration in those who had proteinuria >2g/24h. There was a nonsignificant “trend” toward slowing the creatinine rise in the entire group. Simultaneously, protection against diabetic retinopathy and a decrease in hyperlipidemia was noted in the treated group. Side effects in the aminoguanidine group included a transient flu-like syndrome, worsening anemia, and development of antinuclear autoantibodies (ANA).

A similar study in 599 subjects with Type 2 diabetes enrolled in 84 centers in Canada and the U.S. was interrupted because of liver function abnormalities in the aminoguanidine treated group. Other adverse effects of aminoguanidine treatment included myocardial infarction, congestive heart failure, atrial fibrillation, anemia, ANA titre conversion, and upper GI symptoms.

{What went wrong with this study, when hundreds of studies had been conducted prior? Aminoguanidine has been around for over 65 years as a food additive}..."

http://www.longecity...ndpost&p=202958

 

Is it just me, or are others also beginning to wonder if they don't to smell a rat when it comes to promising anti AGE substances?

 

 

 

[YOLF]

More than genes and cells: drug discovery in the ECM.

 

Alas, AGE formation is purely chemical, and so cannot be blocked by an enzyme inhibitor or a mouse knock-out. AGE formation could be blocked by agents that trap the -dicarbonyl intermediates on the path to AGE. Aminoguanidine and pyridoxamine have been tested as AGE blockers19. Results have not been that impressive in man, however, possibly in part because you have to take the compounds continuously for 10 years to block the accumulation of AGEs in a protein with a 10-year half-life. It is likely that one of the benefits of calorie restriction (among many others) is reduced blood sugar levels and hence reduced glycation, but this is an even harder regime to adhere to.

 

A better route would be to clear glucosepane from the body, but here again we are stymied for lack of an enzyme or, until very recently, even a good supply of authentic glucosepane to test enzymes on. However one compound – Alagebrium (ALT711 – see Figure 2) – has been developed as a chemical AGE-breaker. It was designed to be a reagent that catalytically breaks - dicarbonyls, which (at the time) were seen as a major form of cross-link in vivo20. Early trials showed a beneficial effect in man, but a larger follow- up trial showed no benefit20-22. There is also controversy over the drug’s mode of action. Recent research has confirmed that Alagebrium does catalytically cleave dicarbonyls23, resolving doubt about this in the past, but it is now believed that dicarbonyls are quantitatively trivial compared to the chemically stable AGE cross-links16. So the trials of Alagebrium have generated a drug that does something in rats24, may do something in man, but it is as yet not clear what or how.

Torrent Pharmaceuticals is taking the compound TRC4186 into clinical trials as an AGE-breaker. Its chemical mode of action is obscure; the compound was identified by randomly reacting highly AGEd serum albumin (made by incubating BSA with 1.67M glucose for 16 weeks) with collagen, a chemistry that bears little relationship to AGE cross-links in vivo, and then searching for compounds that released the BSA. TRC4186 appears beneficial in animal hypertension models25 but no human efficacy data has been released26...

 

...It is now understood that the quality of the ECM in vivo can also be decisive in determining how well cells function to repair tissue after damage. Several studies have suggested that the failure of older tissue to repair itself as well as young tissue is due at least as much to the ‘old’ ECM as to the cells themselves being old. For example, the replicative and differentiation potential of mesenchymal stem cells from old mice could be ‘rescued’ by growing them on ECM generated by young stem cells31. Kang and Lightman tracked regenerating peripheral nerves in the mouse and showed that the poorer regeneration in old mice over young ones was due to the lack of ability of the growing axon tips to clear debris from damaged nerves from their path. In the absence of debris, they grew and innervated muscle as well as nerves from young animals32. Loss of functional fibroblasts in the dermis of the skin, and hence loss of skin strength, elasticity and thickness with ‘normal’ ageing is primarily driven by degradation of the collagen matrix to which the cells attach, including glycation33. Thus ECM repair is likely to be a key component of either of the regenerative medicine strategies34.

The structural proteins of the body, especially collagen, have traditionally been viewed as nonstarters as drug discovery targets, because they are not obviously active as catalysts or signal transduction molecules. The recent work summarised above shows that this is not necessarily a good argument for ignoring the ECM. As an alternative route to identifying the role of every gene in every cell in a complex disease such as chronic inflammation or in cancer, targeting damage to the ECM may prove a valuable approach to new treatments for a range of diseases and disabilities of old age.

 

http://www.ddw-onlin...-winter-13.html

I think we need to track down Dr William Bains and his articles!

Well there are AHAs, a few that can be taken orally are coming to mind.

 

Was pyridoxamine the one that was removed from store shelves by the FDA citing safety concerns? How dangerous was it? Is there a prophylaxis for the damage it causes?

[Logic]

Was pyridoxamine the one that was removed from store shelves by the FDA citing safety concerns? How dangerous was it? Is there a prophylaxis for the damage it causes?

 

 

Not dangerous at all.

The smell of rat is strong in this case!

 

Pyridoxamine was marketed as a dietary supplement, often as the hydrochloride salt, pyridoxamine dihydrochloride. However, in the United States, the FDA ruled in January 2009 that pyridoxamine must be regulated as a pharmaceutical drug because it is the active ingredient in Pyridorin, a drug designed by Biostratum, Inc., to prevent the progression of diabetic nephropathy.[9][10][11][12]

Pyridorin had success in early clinical trials, found to be effective in slowing the progression of diabetic neuropathy in a phase II trial on 224 patients.[10] However, in 2005 Biostratum ran out of money and so was unable to begin a Phase III trial.[10] Investors in Biostratum had realized that because Biostratum had no patent on pyridoxamine itself, and that pyridoxamine was commonly available for purchase as a dietary supplement, the company would be unable to charge enough money for the treatment (should it be approved as a prescription drug by the FDA) for the investors to get a reasonable return on the investment they had already made (about $100M) much less on the additional investment a Phase III trial would require.[10] To solve this problem, Biostratum submitted a Citizen Petition to the FDA on July 29, 2005, seeking to disallow sales of pyridoxamine-containing supplements on the grounds that pyridoxamine, as the subject of an Investigational New Drug Application with the FDA, is a drug and not a dietary supplement.[10] This petition was opposed by the Council for Responsible Nutrition, a trade association of the dietary supplement industry.[10]

On January 12, 2009, the FDA ruled that products containing pyridoxamine are excluded from the definition of dietary supplements as defined by the Dietary Supplement Health and Education Act of 1994.[11] The FDA stated that the status of Pyridorin as an investigational new drug, as a result of an application filed by BioStratum in July 1999 and effective on September 1, 1999, meant that "the marketing of pyridoxamine in a dietary supplement is essentially equivalent to the marketing of an investigational new drug as a dietary supplement" because there was an "absence of independent, verifiable evidence that the substance was marketed as a food or a dietary supplement prior to its authorization for investigation as a new drug."[13]

https://en.wikipedia...ki/Pyridoxamine

[YOLF]

Some things have been drugs for a long time and are still sold as supps... but this one gets it just cuz they asked? I don't understand that...

[Logic]

Some things have been drugs for a long time and are still sold as supps... but this one gets it just cuz they asked? I don't understand that...

 

Money!?

By that  I mean the money made treating the 'diseases of old age/AGEs...

ie:  IMHO AGE accumulation is the main reason for aging.

 

The other sources of aging/inflammation/NF-kB/TNF-alpha etc are:

• A gut that becomes old (and leaky and more 'dis-biotic') faster than other organs.
• Chronic low level infections.

IMHO...

(NB that the gut has... 'the highest' cell turnover in the body. = short telomeres etc.

And its cells and stem/progenitor cells, etc have (almost) direct contact/access to the supps we take. Like astragalus or other stem cell activators, etc.
So perhaps you just think you are better all over from say, Astragalus, when in fact its the decrease in NF-kb etc everywhere else, due to a 'younger' gut that's actually 'healing' us the most..??

 

This is a post/blog entry I am working on with more references than Jesus. )

 

[niner]

So whatever happened to Torrent Pharmaceuticals' alleged AGE breaker TRC4186?   It looks like Torrent's product line is strictly generic versions of very popular off-patent drugs.  I guess we don't know if TRC4186 breaks glucosepane, pentosidine, or what.  It's probably not glucosepane.  I saw an IUPAC name for 4186, so the structure has been disclosed.

[Logic]

So whatever happened to Torrent Pharmaceuticals' alleged AGE breaker TRC4186?   It looks like Torrent's product line is strictly generic versions of very popular off-patent drugs.  I guess we don't know if TRC4186 breaks glucosepane, pentosidine, or what.  It's probably not glucosepane.  I saw an IUPAC name for 4186, so the structure has been disclosed.

 

The research on these breakers all seem to fizzle out Niner.
I guess that when they go looking for partners with big pharma the maths is:
"If we sell this to the public we make X dollars , but we lose X+100 000 000 on all the other stuff we normally sell that they won't need anymore.

Perhaps its just me being a conspiracy theorist, but we seldom even have Vit C with Aspirin...

The only way around this that I can think of, off hand is the MMTP and getting this stuff into mice and rats.
http://www.majormouse.org/

 

Maybe I should start a new thread with all the info on these 'forgotten' breakers gathered in one place and see if we can drum up enough interest for another crowdfund to get these in the program?

I'll invite SteveH to this thread.
 

[Kirito]

Eugenol looks pretty interesting...

 

http://www.nature.co...icles/srep18798

[cuprous]

Eugenol looks pretty interesting...

 

http://www.nature.co...icles/srep18798

 

Which is basically clove oil.  Any guesses as to what sort of dose a human would have to take to get a similar effect?

[Daniel Cooper]

Notice that Benfotiamine and L-Carnosine are both Inhibitors and Breakers with low risk. PABA has low to moderate risk factor. I like it when I find supplements that do double duty as does L-Carnosine. Carnosine has also been demonstrated to extend cellular life through it's ability to rejuvenate cells approaching senescence. This is what I call more bang for the buck. Is there any question we all should be taking L-Carnosine if we are taking this business seriously?

 

 

I know that Benfotiamine and L-Carnosine and AGE inhibitors, but is there really evidence that they are AGE breakers as well?

[Logic]

...Autophagy upregulation appears to be particularly important for removal of cross-linked proteins, though autophagy inducers are not discussed...

 

http://www.longecity...e-3#entry766445

[Logic]

 

Notice that Benfotiamine and L-Carnosine are both Inhibitors and Breakers with low risk. PABA has low to moderate risk factor. I like it when I find supplements that do double duty as does L-Carnosine. Carnosine has also been demonstrated to extend cellular life through it's ability to rejuvenate cells approaching senescence. This is what I call more bang for the buck. Is there any question we all should be taking L-Carnosine if we are taking this business seriously?

 

 

I know that Benfotiamine and L-Carnosine and AGE inhibitors, but is there really evidence that they are AGE breakers as well?

 

 

There are conflicting reports and the whole subject is in need of some research with the latest studies taken into account. 

Then one has to look at who sponsored the studies as this particular field of research seems to 'smell  of rat!' quite badly!?

 

Speaking of rats; they only live 2 years while the collagen, with its cross links, in the ECM has a turnover of around 10 years.

This means that breakers that do so slowly (the same rate as their buildup?) are difficult to study in rats...

 

NB:

"... Collagen is turned over very slowly: some measures of ECM turnover in tendons and bone suggest protein half-lives of years to decades in man...

 

...A more exciting application of ECM-modulating therapeutics is in Regenerative Medicine. Regenerative Medicine seeks to repair disease- or age-related damage through one of two broad strategies: stimulating endogenous repair mechanisms that have been damaged or down-regulated, or providing exogenous cells or tissues. It is now well-known that cells grown in tissue culture mimic in vivo cell behaviour better if the cells are grown in a 3D matrix mimicking the ECM, rather than on flat glass or plastic surfaces, and that, far from being inert, many components of the ECM have powerful signalling effects on cells2. Even cell growth that is dependent on growth factors such as TGF- is in fact also dependent on the mechanical properties of the ECM in vivo, because TGF- is stored in the ECM as bound complexes, and released by cell-specific proteases or mechanical tension30..."

http://www.ddw-onlin...-winter-13.html

Carnosine is broken down by carnosinase pretty quickly.  There is new research on 

non-hydrolized carnosine or carcinine or anserine

that seems to overcome this problem.

The studies showing AGE breaking are all by the same patent holders, so...???

 

"...The finding that already-formed AGE cross-links can be pharmacologically severed and attendant pathology thereby reversed by non-hydrolized carnosine or carcinine in patented oral formulations thereof has broad implications for the skin beautification and therapeutics of the complications of diabetes and skin diseases associated with aging..."

http://www.ncbi.nlm....pubmed/21756141

 

"...therapeutic interventions utilizing the specific oral formulation (Can-C Plus), timing dosing and pharmaco-nutritional boost of imidazolecontaining dipeptides can maintain health, enhance physical exercise performance and prevent aging. The patented therapeutic concept protects the existence of the interesting physiological major activities, better controls and therapeutic treatments for aging/age-related disorders (including age-related loss of muscle mass and muscle function) using carnosine dipeptide for cellular rejuvenation and manipulating telomeres and enzyme telomerase activity that may reduce some of the physiological declines that accompany aging..."

http://benthamscienc...issue/1/page/1/

 

Antiviral = less NF-kB.  See Telomeres above.

"...These data are consistent with the hypothesis that natural products, such as chicken soup and chicken breast extracts rich in carnosine and its derivative anserine (beta-alanyl-1-methyl-l-histidine) could contribute to the pathogenesis and prevention of influenza virus infections and cold but have a limitation due to susceptibility to enzymatic hydrolysis of dipeptides with serum carnosinase and urine excretion after oral ingestion of a commercial chicken extract..."

http://journals.lww....0&article=00014

 

This one isnt:

"...Recently, we have discovered the potential use of telomere-restorative imidazole-containing dipeptide (non-hydrolized carnosine, carcinine) based therapy for better survival of smokers. We conclude that a better therapeutic or nutritional maintenance of TL may confer healthy aging in smokers and exceptional longevity in regularly ROS-exposed human survivors..."

http://www.livelonge...g.com/research/

 

My thx to Tom Andre F. (ex shinobi) for the above 'lead'.

[Logic]

As supps are known to contain high levels of heavy metals (amongst many other sources) and heavy metals catalyse the formation of AGEs:

Is Black Sesame seed/powder the best 'filler' for supps I wonder?

 

Efficient Binding of Heavy Metals by Black Sesame Pigment: Toward Innovative Dietary Strategies To Prevent Bioaccumulation

Black sesame pigment (BSP) was shown to bind lead, cadmium, and mercury at pH 7.0 and to a lower extent at pH 2.0. BSP at 0.05 mg/mL removed the metals at 15 μM to a significant extent (>65% for cadmium and >90% for mercury and lead), with no changes following simulated digestion. The maximum binding capacities at pH 7.0 were 626.0 mg/g (lead), 42.2 mg/g (cadmium), and 69.3 mg/g (mercury). In the presence of essential metals, such as iron, calcium, and zinc, BSP retained high selectivity toward heavy metals. Model pigments from caffeic acid, ferulic acid, and coniferyl alcohol showed lower or comparable binding ability, suggesting that the marked properties of BSP may result from cooperativity of different sites likely carboxy groups and o-diphenol and guaiacyl functionalities. Direct evidence for the presence of such units was obtained by structural analysis of BSP by solid-state Fourier transform infrared spectroscopy and 13C nuclear magnetic resonance spectroscopy...

 

In conclusion, in the present study, we have shown the high binding capacity of the pigment from black sesame seeds toward heavy metals, such as lead, cadmium, and mercury, that are commonly found in food. The highest activity is associated with neutral pH values simulating the intestinal environment compared to the acidic pH values peculiar of the gastric compartments. Even at low concentrations (0.05 mg/mL), the pigment proved able to remove the metals to a significant extent (>65% for cadmium and >90% for mercury and lead). At such doses, the pigment is able to remove the metals completely at the highest levels that have been reported in contaminated food. A good chelating ability against lead and to a lower extent cadmium is retained by BSP, even with the metal at concentrations up to 200μM. The binding activity is not lost following digestion as simulated using a model of the gastrointestinal transit, and on the basis of competition experiments, it should not interfere with the absorption of essential metals, a drawback exhibited by several dietary supplements, such as cereal fibers.In combination with our previous observations indicating the marked antioxidant properties of BSP, these results highlight the potential of this low-cost, easily accessible material from plant sources as an ingredient of functional food or as a food supplement.

 

http://sci-hub.io/10...cs.jafc.5b05191

(this site gives paywalled papers FOC)

 

[Logic]

C16, a novel advanced glycation endproduct breaker, restores cardio-vascular dysfunction in experimental diabetic rats

...treatment for 4 weeks resulted in a dose-dependent and significant increase in cardiac output, a reduction of total periph-eral resistance, and an increase in systemic arterial compliance when comparedwith vehicle-treated diabetic rats.  Biochemical studies showed that C16 treatmentalso resulted in a significant decrease in immunoglobulin G-red blood cell surfacecrosslink content and an increase in collagen solubility.  Morphological and im-munohistochemical examinations indicated that C16 was able to prevent increasesof the collagen type III/I ratio in the aorta and decrease the accumulation of AGEin the aorta.  Conclusion: C16 has the ability to reduce AGE accumulation intissues in vivo, and can restore diabetes-associated cardiovascular disorders inrats.  This provides a potential therapeutic approach for cardiovascular diseaseassociated with diabetes and aging in humans...

 

Sci-hub =no paywall:

https://www.facebook.com/sci.hub.org/

 

The above paper:

http://sci-hub.bz/10...54.2005.00240.x

 

[normalizing]

thanks for keeping updates to this thread logic, i really wish your natural autophagy thread is going strong though :(

Edited by normalizing, 10 June 2016 - 02:35 AM.