A recent review makes some valuable points about …

Fighting AGEs in Diabetic
Cardiovascular Disease

There are supplements and some drugs that can help

By Will Block


Figure 1. The crusts of most breads, such as these pretzels, are golden-brown due to Maillard browning, a chemical reaction between amino acids and reducing sugars that gives browned food its desirable flavor.
In human nutrition and biology, advanced glycation end products (known appropriately as AGEs), are factors in the development or worsening of many degenerative diseases, such as atherosclerosis, chronic renal failure, and Alzheimer’s disease. AGEs are also signaling proteins associated with several vascular and neurological complications in diabetes and diabetic cardiovascular disease. Glycation is a chemical bonding of reducing sugars—such as glucose—to lipids, nucleic acids, and proteins. This process plays an important role in aging and its diseases.

AGEs form and develop as a result of natural chemical processes from the formation of reversible Maillard products (the tasty brown stuff formed in high temperature cooking; see Fig. 1) to the eventual production of irreversible AGEs.

The detrimental role of AGEs has given rise to the development of pharmacological inhibitors. Clinical trials with anti-AGEs drugs have been developed, and a recent review summarized the most relevant reports.1


AGEs form and develop as a result of
natural chemical processes from the
formation of reversible
Maillard products.


Anti-AGE Drugs and Nutrients

While the review names a list of drugs, including aminoguanidine, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), statins, ALT-711 and thiazolidinediones, it also includes some nutrients such as pyridoxamine (a form of vitamin B6), benfotiamine (a form of vitamin B1), and thiamine. But the review does not include important nutrients such as carnosine, histidine, alpha lipoic acid, and rutin. These are almost always superior to the drugs, because they are often just as potent with far fewer adverse effects.


Carnosine was more effective in
preventing glycation of short-lived
proteins, a process that takes place
rapidly, whereas histidine and beta-
alanine provide protection over a
longer period of time.


Carnosine and Histidine

Durk Pearson & Sandy Shaw wrote about the anti-AGE aspects of carnosine and histidine along with other anti-AGEs (see “Reducing Glycation Reactions for Better Health and Longer Life” in the February 2008 issue). An abbreviated version follows:


Carnosine was highly protective
against glycation of human Cu, Zn-
superoxide dismutase and thus
protects the enzyme from
inactivation.


Carnosine is a dipeptide made up of two amino acids, beta-alanine and histidine. A lot has been written about the anti-glycation and other properties of carnosine, but much less about the anti-glycation effects of histidine.

Recent papers have reported that carnosine and its constituents (histidine and beta-alanine) inhibit the glycation of low-density lipoproteins (LDL) that promotes foam-cell formation in vitro.2 They do this by stimulating glycated-LDL uptake by macrophages, which then migrate into atherosclerotic plaques. In this study it was found that carnosine was more effective in preventing glycation of short-lived proteins, a process that takes place rapidly, whereas histidine and beta-alanine provide protection over a longer period of time, as happens in slower glycation reactions, such as those induced by glucose.

As the authors explain, “… histidine and beta-alanine have … a negligible carbonyl scavenging activity over a 5-hour period. However, over 24 hours, histidine (but not beta-alanine) afforded significant protection against modifications. Over even longer periods (2–17 days), all three compounds afforded significant protection against aldehyde-mediated protein cross-linking and loss of enzyme activity.”

Another study3 reported that carnosine was highly protective against glycation of human Cu, Zn-superoxide dismutase and thus protects the enzyme from inactivation.


AGE inhibitors such as carnosine
may show clinical promise for
diseases like Alzheimer’s.


Histidine was even more effective than carnosine in preventing glycation of the enzyme aspartate aminotransferase, a vitamin B6-dependent protein known to be glycated in vivo.4 Histidine was effective at suppressing cross-linking even at a 1:1 ratio, and the effect increased as the ratio of histidine to a glycating agent was increased to 10:1. A 10:1 ratio of carnosine to glyceraldehyde-3-phosphate is necessary to prevent protein cross-linking, suggesting that, “AGE inhibitors such as carnosine may show clinical promise for diseases like Alzheimer’s.”

Scientists5 found that histidine and carnosine delayed diabetic deterioration in mice by significantly decreasing plasma glucose and fibronectin levels and at 1-g/l of drinking water, either histidine or carnosine also significantly increased insulin levels.

Histidine and carnosine significantly increased catalase activity and dose-dependently reduced levels of malondialdehyde (a lipid peroxidation product). Glutathione peroxidase activity in mouse kidney and liver increased at 1-g/l (drinking water) histidine and carnosine treatments, whereas 1-g/l histidine and carnosine significantly reduced elevated levels of tumor necrosis factor-alpha (TNF-alpha), an important inflammatory cytokine. Interestingly, “Histidine supplementation alone effectively increased carnosine content in organs, and supplementing carnosine alone also increased histidine content in organs.”


1-g/l of drinking water, either
histidine or carnosine also
significantly increased insulin levels.


A separate experiment involved 15 healthy human male subjects, aged 21–28. Researchers found that histidine and carnosine supplements effectively protected human LDL derived from these subjects against glucose-induced oxidation and glycation. The histidine and carnosine concentrations in the human LDL experiments were 1 and 2 μM, and these concentrations were lower than the concentrations found in the organs of the histidine- and carnosine-supplemented mice. “These results also suggest that these agents might provide effective protection for humans against diabetic development or deterioration.”


Histidine and carnosine
supplements effectively protected
human LDL derived from these
subjects against glucose-induced
oxidation and glycation.


Alpha-Lipoic Acid

Among many other beneficial effects, alpha-lipoic acid prevents glycation of serum albumin, increases intracellular glutathione levels, quenches reactive oxygen species, and chelates heavy metals.6 Interestingly, the reduced form of alpha-lipoic acid—dihydrolipoic acid—participates in the regeneration of ascorbate and vitamin E.6

The authors6 explain, “Because of their localization and function … endothelial cells seem to be a primary target for AGEs and AGE-mediated late diabetic complications. This view is emphasized by the existence of specific receptors for AGEs (e.g., RAGE) on the endothelial surface.”

The study reported that alpha-lipoic acid successfully reduced AGE-albumin-dependent activation of NF-kappaB in cultured bovine aortic endothelial cells (BAECs). The BAECs were incubated with AGE albumin for 30 minutes before cellular glutathione was determined. Compared with cells not treated with AGE albumin, there was a 64% reduction of cellular glutathione levels. However, preincubation of the BAECs with alpha-lipoic acid restored glutathione in a dose-dependent manner, from 0.1 mM up to the most effective dose, 2 mM alpha-lipoic acid.

The protection of the cells by alpha-lipoic acid against AGE-albumin-dependent activation of NF-kappaB may be very important because “Activation of NF-kappaB has been identified as a central mediator in many life-threatening diseases, such as HIV infection, septicemia, atherosclerosis, and Alzheimer’s disease …”


The histamine and carnosine
results also suggest that
these agents might provide effective
protection for humans against
diabetic development or
deterioration.


Alpha-Lipoic Acid Protects Against AGEs

Another paper7 reports on the protective effects of alpha-lipoic acid against AGE products. AGEs have been identified as relevant mediators of late diabetic complications such as atherosclerotic disease.

One of the first steps in atherogenesis is the expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), which increase monocytes (such as macrophage foam cells, which take up glycated-LDL) binding to endothelium. NF-kappaB, activated by exposure to AGEs, induces the expression of VCAM-1.

Human umbilical vein endothelial cells (HUVECs) were treated with alpha-lipoic acid at various concentrations and for different periods of time to test whether it could reduce the NF-kappaB-related expression of VCAM-1 after stimulation with AGE albumin.

Pretreatment of HUVECs with 10-mM alpha-lipoic acid suppressed VCAM-1 expression to baseline levels no matter how long the treatment lasted, whereas a concentration of 5 mM was required to suppress VCAM-1 when alpha-lipoic acid was administered for 24 hours. The lowest concentration of alpha-lipoic acid (0.05 mM) did not affect VCAM-1, whereas 2 to 24 hours of preincubation with alpha-lipoic acid at 0.5 mM attenuated VCAM-1 response to AGE albumin.


“Activation of NF-kappaB
has been identified as a
central mediator in many
life-threatening diseases,
such as HIV infection,
septicemia, atherosclerosis, and
Alzheimer’s disease …”


Rutin

Rutin, a flavonoid found in fruits and vegetables, modulates the formation of AGEs.8,9 “Advanced glycation end products accumulate on long-lived proteins such as collagen, altering structural, biochemical, and physical properties. The concentration of AGE-modified collagen increases in tissues with increasing age and may contribute to the reduction in elasticity of artery, heart, and lung tissues that occurs as organisms age … . Additional clinical conditions possibly accelerated by AGEs include neuropathy, nephropathy [kidney dysfunction], retinopathy, joint stiffness, senile cataracts, Alzheimer’s disease, and cardiovascular disease.”

Streptozotocin-induced diabetic rats had increased skin-collagen fluorescence, indicative of glycation.8 Aminoguanidine (an antiglycation compound) or rutin protected against the formation of these fluorescent adducts. Certain natural metabolites of rutin, including quercetin, also provided protection.

The authors calculated that since the blood glucose concentration of normal humans is about 5 μM, and since the ratio of rutin metabolite to monosaccharide examined in the study was 0.001, only micromolar levels of rutin may be necessary for rutin efficacy in vivo.


Rutin, a flavonoid found in fruits and
vegetables, has been reported to
modulate the formation of AGEs.


The amount of active metabolites would need to be about 5 μM, and the authors say that such concentrations could be reached in the human volunteers when 50 mg of rutin were used in their diets.

In Reference 9, rutin had a significant inhibitory effect on glycation of hemoglobin, and it was more effective than aminoguanidine. Testing for glycated hemoglobin is a good way to keep track of long-term glycation.

Benfotiamine

Benfotiamine is a lipid-soluble form of thiamine (vitamin B1). While thiamine also has anti-glycation effects, it is a water-soluble form of the vitamin that cannot enter fatty tissues. Benfotiamine is more bioavailable than thiamine.10

Benfotiamine blocks three major pathways of hyperglycemic damage in bovine aortic endothelial cells and prevents diabetic retinopathy in rats.10 Three pathways blocked by benfotiamine are all involved in hyperglycemia-induced vascular damage (which promotes atherosclerosis); they are the hexosamine pathway, the AGE-formation pathway, and the diacylglycerol (DAG)-protein kinase C pathway. Benfotiamine also inhibits hyperglycemia-associated NF-kappaB activation (an important inflammatory signaling molecule). It also normalized AGE levels in the retinas of long-term diabetic rats.


Benfotiamine is a lipid-soluble form
of thiamine (vitamin B1).
While thiamine also has antiglycation
effects, it is a water-soluble form of
the vitamin that
cannot enter fatty tissues.


AGEs Drugs

The most recent promising anti-AGEs drugs are statins, alagebrium (aka ALT-711), and thiazolidinediones. The role of AGEs in disease and new compounds interfering with their effects are currently under investigation in preclinical setting. These newer anti-AGEs drugs may undergo clinical evaluation in the next years. Compounds with anti-AGEs activity—but still not available for clinical scenarios—are ALT-946, OPB-9195, tenilsetam, LR-90, TM2002, sRAGE and PEDF.

Statins

As we know, statins have a lot of side effects, some of which are severe. Although the association between type 2 diabetes and cardiovascular diseases is well-documented, the increased prevalence of atherosclerosis in DM is incomplete. AGEs may play an important role in the development of atherosclerosis in diabetic patients.

In 2007, researchers11 examined the effect of the HMG-CoA reductase inhibitor (HMGRI) cerivastatin on serum concentration of AGE-CML in patients with elevated fasting glucose, impaired glucose tolerance or DM.


Benfotiamine is more
bioavailable than thiamine.


The study was a multicenter, double-blind, randomized, parallel-group comparison of cerivastatin at 0.4 mg daily for 12 weeks (n=34) and placebo (n=35). Patients were characterized by combined hyperlipoproteinemia and the preponderance of dense LDL.

Primary objective of the study was the effect of cerivastatin on the concentration of dense LDL subfractions. After 12 weeks of treatment cerivastatin reduced cholesterol, apolipoprotein B, LDL cholesterol and the concentration of dense LDL.

Furthermore, cerivastatin significantly lowered the concentration of AGE-CML by 21%. In addition to the lipid-lowering effects of HMGRI, the reduction of AGE-CML observed may entail an improvement of the cardiovascular prognosis in patients with chronic hyperglycemia.

During postmarketing surveillance, 52 deaths were reported in patients using cerivastatin, mainly from rhabdomyolysis and its resultant renal failure. This statin was withdrawn from the market.

There have been at least 5 other clinical studies, showing AGE benefits using atorvastatin and simvastatin. As with most other statins, these have both major and minor side effects. Myopathy with elevation of creatinine kinase and rhabdomyolysis are the most serious side effects.

ALT-711

Despite extensive investigation in clinical trials, few data in clinical trials of ALT-711 have been published, and some of these studies were terminated early due to financial constraints and adverse effects. ALT-711 is an AGE-breaking drug (it breaks carbon-carbon bonds between carbonyls) that has been around for nearly forever but may never get FDA approval. It actually breaks previously formed “irreversible” AGEs. It was the first drug candidate to be clinically tested for the purpose of breaking the crosslinks caused by AGEs, thereby reversing one of the main mechanisms of aging. However, with a price tag for FDA approval estimated to be over $1 Billion. It may never see the light of day.

Aminoguanidine

Aminoguanidine—mentioned above in the rutin section as inferior to rutin—is an AGE inhibitor. It is still considered an experimental drug due to side effects which flagged it in a study. Aminoguanidine has undesirable side effects in patients with diabetes.


During postmarketing surveillance,
52 deaths were reported in
patients using cerivastatin,
mainly from rhabdomyolysis and its
resultant renal failure. This statin was
withdrawn from the market.


Thiazolidinediones

Thiazolidinediones, anti-diabetic drugs proved to have a role in anti-AGE treatment because of their PPARγ-agonist activity. PPARγ-agonist activity determines an increase in sRAGE expression, which is inversely associated with atherosclerosis. These drugs have serious side effects, including increasing the incidence of hepatitis and inducing potential liver failure. A 2013 meta-analysis concluded that use of pioglitazone (one of the thiazolidinediones) is associated with a slightly higher risk of bladder cancer compared to the general population.12

Conclusion

AGEs are serious business. One has to wonder why the review was written. If all of the drugs proffered for control of advanced glycemic endproducts have adverse effects, some quite serious, what was to be gained by this this review, except to rub off by association the benefits of adverse effect-free nutrients.

As we know, many researchers view drugs to be the only solution to any biomedical problem. By the way, where was the Conflict of Interest paragraph at the end of the study? It wasn’t there.

References

  1. Nenna A, Nappi F, Avtaar Singh SS, Sutherland FW, Di Domenico F, Chello M, Spadaccio C. Pharmacologic Approaches against advanced glycation end products (ages) in diabetic cardiovascular disease. Res Cardiovasc Med. 2015 May 23;4(2):e26949. doi: 10.5812/cardiovascmed.4(2)2015.26949. eCollection 2015 May. Review. PubMed PMID: 26393232; PubMed Central PMCID: PMC4571620.
  2. Rashid I, van Reyk DM, Davies MJ. Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro. FEBS Lett. 2007 Mar 6;581(5):1067-70.
  3. Ukeda H, Hasegawa Y, Harada Y, Sawamura M. Effect of carnosine and related compounds on the inactivation of human Cu,Zn-superoxide dismutase by modification of fructose and glycolaldehyde. Biosci Biotechnol Biochem. 2002 Jan;66(1):36-43.
  4. Hobart LJ, Seibel I, Yeargans GS, Seidler NW. Anti-crosslinking properties of carnosine: significance of histidine. Life Sci. 2004 Jul 30;75(11):1379-89.
  5. Lee YT, Hsu CC, Lin MH, Liu KS, Yin MC. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J Pharmacol. 2005 Apr 18;513(1-2):145-50.
  6. Bierhaus A, Chevion S, Chevion M, Hofmann M, Quehenberger P, Illmer T, Luther T, Berentshtein E, Tritschler H, Müller M, Wahl P, Ziegler R, Nawroth PP. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes. 1997 Sep;46(9):1481-90.
  7. Kunt T, Forst T, Wilhelm A, Tritschler H, Pfuetzner A, Harzer O, Engelbach M, Zschaebitz A, Stofft E, Beyer J. Alpha-lipoic acid reduces expression of vascular cell adhesion molecule-1 and endothelial adhesion of human monocytes after stimulation with advanced glycation end products. Clin Sci. (Lond). 1999 Jan;96(1):75-82.
  8. Cervantes-Laurean D, Schramm DD, Jacobson EL, Halaweish I, Bruckner GG, Boissonneault GA. Inhibition of advanced glycation end product formation on collagen by rutin and its metabolites. J Nutr Biochem. 2006 Aug;17(8):531-40.
  9. Wu CH, Yen GC. Inhibitory effect of naturally occurring flavonoids on the formation of advanced glycation endproducts. J Agric Food Chem. 2005 Apr 20;53(8):3167-73.
  10. Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med. 2003 Mar;9(3):294-9.
  11. Scharnagl H, Stojakovic T, Winkler K, Rosinger S, März W, Boehm BO. The HMG-CoA reductase inhibitor cerivastatin lowers advanced glycation end products in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes. 2007 Jun;115(6):372-5.
  12. Ferwana M, Firwana B, Hasan R, Al-Mallah MH, Kim S, Montori VM, Murad MH. Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies. Diabet Med. 2013 Sep;30(9):1026-32.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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