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AGE breaker update


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#1 marcus

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Posted 21 September 2006 - 07:55 PM


Alteon issued a press release today highlighting the further development of Alagebrium chrloride(formerly ALT 711). I haven't gotten a chance to review the paper, but the results reported in this press-release look promising. Alteon also issued 9 million more shares of stock and warrants for an additional 9 million shares yesterday through a private-placement. This raised a few million more bucks to help fund development. I'm not sure if Alteon will have enough money to make it all the way to market with Algaebrium, but it's good to see more money and research dollars spent on a type of therapy that has implications for SENS.

Alteon's alagebrium Indicates Protective Effect in Preclinical Diabetic Nephropathy Model
Wednesday September 20, 3:03 pm ET



-- Alagebrium appears to prevent, delay, and reverse kidney damage --
-- Study highlights biological marker associated with drug response --

PARSIPPANY, N.J., Sept. 20, 2006 (PRIMEZONE) -- Alteon Inc. (AMEX:ALT - News) announced today that the results of a preclinical study of alagebrium, a novel Advanced Glycosylation End-product (A.G.E.) breaker and Alteon's lead compound, expands existing evidence of the potential ability of alagebrium to reverse diabetic kidney disease. It also identifies a role for biomarkers that can be used to track drug effectiveness in anticipated clinical trials of alagebrium for diabetic nephropathy and diastolic heart failure. These results are published in the current issue of the American Journal of Nephrology (Am J Nephrol 2006;26:430-436).

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``This body of experiments performed by Peppa et al., attests to the potential of alagebrium to prevent, delay and reverse diabetic kidney disease, even when therapy is initiated late in the natural disease process,'' said Howard B. Haimes, Ph.D., Executive Director, Preclinical Sciences of Alteon. ``One of the major obstacles impeding the development of drugs in heart failure and diabetic nephropathy,'' continued Noah Berkowitz, M.D, Ph.D., Alteon President and CEO, ``is the lack of surrogate markers that can provide companies with early indications of their drug's efficacy. This study indicates that alagebrium can decrease the leakage of protein in the urine and markers of A.G.E.s in the blood. These markers may help us gain early recognition of the clinical effect of alagebrium in diabetic nephropathy and diastolic heart failure.''

Diabetic nephropathy, if unchecked, typically leads to organ failure, dialysis or organ transplantation. The study by Peppa et al., evaluated the effects of alagebrium on 3, 7 and 12 month old db/db mice. This strain of mice represents a model of human diabetes and is commonly used for drug evaluation. The authors made the following observations:


-- A.G.E.s can be important pathologic agents responsible for the
morphologic and functional deficits of diabetic nephropathy.

-- Alagebrium appears to protect kidney structure and function and
reverses A.G.E - mediated effects on the kidney.

-- As early as the 3rd week of treatment, alagebrium decreases the
serum concentration of eN-carboxymethyllysine (CML), a marker of
Advanced Glycation End-products (A.G.E.s), by 41%, concomitant
with increasing urinary excretion of CML by 138%.

-- By 3 months of treatment, alagebrium reduces serum, skin and
kidney levels of CML, while increasing their output in the urine.

-- A rise in the albumin/creatinine ratio and morphological and
structural changes associated with diabetic nephropathy can be
slowed or reversed by alagebrium.

Diabetic nephropathy is a major contributor to the overall morbidity of diabetes. The American Diabetes Association estimates that 20-30% of people with type 1 and type 2 diabetes will develop evidence of overt nephropathy, an advanced stage of the disease marked by proteinuria (the presence of proteins in the urine). After the onset of proteinuria, over 75% of type 1 diabetics and 20% of type 2 diabetics progress to ESRD (End-Stage Renal Disease) within 20 years. The discrepancy may be explained by the fact that patients with type 2 diabetes have a greater risk of dying from coronary artery disease than from kidney failure and therefore do not progress to ESRD. Nonetheless, because type 2 diabetes accounts for up to 95% of all diabetes cases, over half of the diabetic patients starting dialysis are type 2. After the start of dialysis, the mortality rate for people with diabetic nephropathy is approximately 38% within two years, and nearly 73% die within 5 years.

#2 John Schloendorn

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Posted 21 September 2006 - 08:59 PM

Hmm, so now we moved from breaking a hypothetical diketone crosslink in long-lived extracellular matrix to reduced soluble CML in serum... I wonder where else this is going. Do you have ideas how serum CML might get affected?

#3 Brainbox

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Posted 21 September 2006 - 09:25 PM

First of all, forgive me my ignorance regarding bioscience and pharmacy please... :)

Does this mean that a substance that has high potential of being a breakthrough in LE in general is going to be developed and marketed as a single-target-disease drug?
If correct, then it seems a shame to me that general LE does not have sufficient market potential as is?
Or is this a result of current limitations in research methodologies?
Or plain shortage of money (an acute form of the market potential issue)?

#4 John Schloendorn

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Posted 21 September 2006 - 09:33 PM

Brainbox,
Advanced glycation end-products (AGEs) are a form of aging that affects the material between cells. They can be classified are "junk" chemicals. Because the material between cells is fairly similar in all organs, a treatment that breaks them would definitely be a multi-target drug, with benefits in many diseases and frailty. There are many types of AGEs, each accumulating at a different rate.

The drug in question breaks an AGE that has not been demonstrated to occur in living organisms. This could be either because the methods of extracting AGEs are not good enough, or because it does not exist. It also has (slight) clinical benefits in multiple conditions or their animal models, but there is no direct evidence that this is due to AGE breakage.

#5 marcus

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Posted 21 September 2006 - 10:21 PM

John,

If alagebrium is indeed breaking the cross-links or at least inhibiting their formation at a rate that allows the equiibrium accumulation of AGE products to be lowered then it makes sense that serum CML levels would drop in the case of DN. It is theorized that AGE-induced oxidant stress might accelerate CML production in situ in the glomeruli. This is most likely due to the cellular response to AGE deposits through AGE-RAGE interactions which upregulate the production of various cytokines and growth factors such as TNF-á, PDGF, and VEGF. TNF-á and VEGF are known to increase vascular permeability and to diminish barrier properties which eventually leads to kidney dysfunction and higher CML levels. You take away the AGEs and the whole chain of events is broken up.

I'll try and find a couple of articles that can flesh this idea out in more detail and post them as I'm going on what I wrote down in my extra-cellular junk notebook awhile back when I was looking at AGE's.

Marcus

Edited by marcus, 21 September 2006 - 10:31 PM.


#6 DukeNukem

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Posted 21 September 2006 - 11:23 PM

Does this mean that a substance that has high potential of being a breakthrough in LE in general is going to be developed and marketed as a single-target-disease drug?

Brainbox, keep in mind that as soon as this is approved (or IF it's approved), there will be a ton of off-label use for it, especially by longevity doctors, just as they use hGH. Do not worry. ;-)

I've been using this chemical for about six months so far, at 1mg per kilogram. No noticeable effects, but then, I wouldn't expect any -- it would be very subtle -- perhaps a lowered blood pressure, but I haven't checked in months.

#7 eternaltraveler

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Posted 22 September 2006 - 02:12 AM

I've been using this chemical for about six months so far, at 1mg per kilogram. No noticeable effects, but then, I wouldn't expect any -- it would be very subtle -- perhaps a lowered blood pressure, but I haven't checked in months.


Do you really think it's wise to be using a not very well studied research chemical? If it might be expected for it to have dramatic positive effects it might be worth it, but it's effects certainly are not dramatically positive. The risk vs. return ratio just isn't worth it yet.

#8 John Schloendorn

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Posted 22 September 2006 - 02:14 AM

Hey Marcus, since you seem into the literature, may I throw a few more quick questions at you:

Has it been shown that RAGEs bind crosslinks? If so, how do they get access to them?

I imagine AGE crosslinks to link two protein fibers tightly together, which should impair access of other proteins to the crosslink. I think that this would be a major problem for enzymatic bioremediation of AGEs. Is my model wrong? How well is the AGE-RAGE interaction characterized for crosslinks?

#9 marcus

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Posted 24 September 2006 - 06:25 AM

John,

You would think that the crosslinks would impair access to other proteins, but it has been known for awhile that at least 1 class of AGE's binds to the RAGE cell surface receptor which initiates a cascade of events leading to advanced DN and many other pathologies. Actually, I think the name RAGE is short for Receptor for Advanced Glycation End products.

This is the original article from PNAS in'94
http://www.pubmedcen...x=1&artid=44695

I haven't read on this topic recently, but from what I remember and have in my notes there were some RAGE over-expression studies and transgenic/knock-out mice studies that left little doubt of the interaction and it's relationship with ND. I don't see why necessarily the fact that there is an interaction would rule out an enzymatic bio-remediation approach towards targeting AGE's. I don't think there would be any harm in any approach that reduces the level of AGE's below the pathological thresh hold. I've always felt that the small molecule approach could work quite well in this area considering there is likely to be no side effects to a drug that breaks something that is only harmful.

Marcus

#10 John Schloendorn

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Posted 24 September 2006 - 07:21 PM

Yes... my question wasn't if RAGEs bind AGEs, but if RAGEs bind crosslinks, which is an important difference. All the findings I am aware of are perfectly explicable by RAGEs binding to non-crosslink AGEs, such as CML, or soluble AGEs.

If RAGEs do bind xlinks in aged extracellular matrix, then I think a bioremediation enzyme will have a chance to get access to the xlinks as well. If they don't (because the xlinks are buried deep in protein secondary structures) then indeed one might consider focusing xlink remediation on small molecules, and solvent-exposed AGE remediation on enzymes.

#11 curious_sle

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Posted 24 September 2006 - 08:05 PM

[SIZE=1]First of all]
If correct, then it seems a shame to me that general LE does not have sufficient market potential as is?


Well, AFAIK you cannot get a "anti aging" medication approved as such by the FDA hence it has to be a "regular" drug.

Um, Duke Nukem... where do you get your alagebrium? Is there any reliable source that sells it caped etc? (PM is fine :-) )

#12 marcus

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Posted 25 September 2006 - 06:31 AM

John,

I don't see anything in the literature that fully characterizes what types of AGE's may be responsible for binding to RAGE. I agree there is nothing to rule out that it could be any of the soluble AGE's or possibly even some of the intermediates involved in forming the more highly stable cross links.

Overall, AGE's seem to be rather poorly studied and characterized due to the nature of trying to isolate them. This seems to be one of those strands of SENS that could definitely use more research attention. I know on the surface it doesn't seem as difficult a task to deal with extracellular "damage" to use Aubrey's term, but there is still a lot of work to be done in just characterizing exactly what types of AGE's are in what abundance in what tissues. Once you get that information you can go about more rationaly targeting them for remediation by whatever means.

I've always thought of the biggest hurdle to the enzyme approach to AGE's would be the lack of any kind of ATP coupling reaction which is going to be needed to break any of the more stable cross links.

Marcus

#13 John Schloendorn

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Posted 26 September 2006 - 02:32 AM

It seems that glucosepane and K2P both contain plenty of energy, and they are like 1000-fold more abundant than any other known crosslink, so this would postpone your ATP problem into the very far future. But in prinicple, it may be that there is a very high activation energy, which requires some energy source to initiate the breakdown (even though it would later release more energy), and only looking at the chemistry can answer this. For example, if you look at glucosepane, it is not absurd that the crosslink may be removed by an arginase-like reaction, which requires no ATP input in nature. But this is almost too speculative to consider. We simply need to culture and see what we get, if anything.

#14 marcus

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Posted 26 September 2006 - 03:17 AM

I suppose how far off in the future we will have to worry about the most stable cross-links that are low in relative abundance is dependent on what the threshold level of accumulation before pathology of the most stable cross-links is. I don't think we know enough about AGE's to rule out that the ones low in relative number don't contribute significantly to aging right now.

Getting a little more back on topic, I've been looking at the pre-clinical data for Alteon and I can't help but be convinced that they have a drug that does something very beneficial in regards to breaking or inhibiting an AGE product that has clinical relevance. Their clinical data has been marred poor choice in clinical end points, but maybe they are finally getting it right with the diabetes study starting up this quarter.

#15 Da55id

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Posted 26 September 2006 - 12:27 PM

Marcus - What do you think was the genesis of the poor end points decisions? Do you think that the difficulty of getting funding/FDA approval for general anti-aging treatments forced them into it? thoughts?

#16 marcus

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Posted 27 September 2006 - 04:33 AM

MM,

I believe Alteon management decided to test Algaebrium for hypertension due to the size of the market place for blood-pressure medications. An approved medication in that market has an instant customer base of 10's of millions. It turns out it was a bad decision as although their drug may be doing something very beneficial in terms of breaking a clinically relevant AGE, they failed to show that it could demonstrably help with hypertension. This was primarily due to a large placebo effect which I found out is common in hypertension trials. So many factors go into determining blood-pressure, that even though the drug maybe be helping restore elasticity in the circulatory system, it is hard to prove it's statistical relevance in regards to improving blood pressure. I'm hopeful they have chosen a better approach with their upcoming diabetes trials.

I think the main reason they have had trouble attracting funding and partners is that they've got a little bit of a history of failure now and they still haven't proved that the drug works in humans or even exactly how the drug works(the precise chemistry involved). This has led to some doubt in their potential, but from everything I know about AGE's and the pre-clinical data I think it is very likely they have a great drug on their hands. I don't think Algaebrium being a potential anti-aging therapy has anything to do with their problems. They are looking at the drug as something that can help treat diseases associated with aging and not as an anti-aging treatment per se.

Marcus

Edited by marcus, 27 September 2006 - 04:43 AM.


#17 trh001

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Posted 25 August 2007 - 09:09 PM

Roughly 10-20% maximum life span difference in this "C57BL6 male mice" experiment that examined a low preformed AGE (reduced by 50% relative to control) diet.

Given Benfotiamine efficacy and availability, and combined with the approach (or better reduction in preformed AGE) below one wonders if we don't have some basis for being optimistic while we wait for access to safe age breakers (formally), and SENS in general.

Discussion snippet: "The mice exposed to a low-glycoxidant (RegAGE) diet had reduced levels of OS, less severe age-related metabolic and kidney changes, and a longer lifespan, relative to mice exposed to an isocaloric diet of standard AGE content (LowAGE). The findings suggest that avoidance of certain thermally induced oxidants in the standard diet, such as oxidant AGEs, may be beneficial. "

Am J Pathol. 2007 Jun;170(6):1893-902. Links
Reduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet: association with increased AGER1 expression.Cai W, He JC, Zhu L, Chen X, Wallenstein S, Striker GE, Vlassara H.
Mount Sinai School of Medicine, Box 1640, One Gustave Levy Place, New York, NY 10029, USA.

Aging is accompanied by increased oxidative stress (OS) and accumulation of advanced glycation end products (AGEs). AGE formation in food is temperature-regulated, and ingestion of nutrients prepared with excess heat promotes AGE formation, OS, and cardiovascular disease in mice. We hypothesized that sustained exposure to the high levels of pro-oxidant AGEs in normal diets (Reg(AGE)) contributes to aging via an increased AGE load, which causes AGER1 dysregulation and depletion of anti-oxidant capacity, and that an isocaloric, but AGE-restricted (by 50%) diet (Low(AGE)), would decrease these abnormalities. C57BL6 male mice with a life-long exposure to a Low(AGE) diet had higher than baseline levels of tissue AGER1 and glutathione/oxidized glutathione and reduced plasma 8-isoprostanes and tissue RAGE and p66(shc) levels compared with mice pair-fed the regular (Reg(AGE)) diet. This was associated with a reduction in systemic AGE accumulation and amelioration of insulin resistance, albuminuria, and glomerulosclerosis. Moreover, lifespan was extended in Low(AGE) mice, compared with Reg(AGE) mice. Thus, OS-dependent metabolic and end organ dysfunction of aging may result from life-long exposure to high levels of glycoxidants that exceed AGER1 and anti-oxidant reserve capacity. A reduced AGE diet preserved these innate defenses, resulting in decreased tissue damage and a longer lifespan in mice.

PMID: 17525257 [PubMed - indexed for MEDLINE]

#18 caston

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Posted 15 February 2009 - 04:29 PM

So what are sRAGE and esRAGE?

My take is that we may need to find or perhaps even engineer one or more wholefoods that have a number of different goodies each serving a different purpose e.g. cleave crosslinks, buffer against damage from AGEs, stop AGE's (re)forming.

that is I think a wholefood may be better in this context than a pure chemical.

#19 caston

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Posted 14 March 2009 - 04:52 AM

So I believe sRAGE is the serum soluble receptor and esRAGE is the endogenous secretory RAGE.

http://www.citeulike...article/3273701

http://www.pubmedcen...i?artid=1892766

Levels of sRAGE and esRAGE are associated with high inflammation. They connect to many ligands not just AGEs but "also certain members of the S100/calgranulin family, extracellular high-mobility group box 1, the integrin Mac-1, amyloid beta-peptide and fibrils".

http://www.citeulike...article/3273701

So inflammation is an immune response. I remember reading about why AGEs are so bad not only do they cause inflammation but DNA damage as well and modification of heat shock protein and chaperon function screwing up protein folding.

http://ouroboros.wor...gory/glycation/

But I wonder if just having a higher blood glucose is the only thing the makes AGEs form.

Is there a biological pathogen or pathogens involved?

I found this:

http://www.hubmed.or...i?uids=12057842

Edited by caston, 14 March 2009 - 08:32 PM.





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