A transition to a raw or nearly raw diet and a permanent abstinence from all processed foods would be considered a radical diet change for most consumers. Moreover, a greater cost and an increase in food preparation time is likely to be incurred with this change in diet, so full compliance may be unrealistic. It must also be remembered that a complete elimination of exogenous AGEs is not possible just as eliminating all sugar from the diet is not possible. AGEs exist in nearly all of foods, albeit with dramatic differences in their concentration. Reassuringly, there are a number of AGE inhibitors that can potently decrease both exogenous and endogenous AGE levels. The compounds herein will feature different methods of anti-AGE activity including but not limited to: prevention of sugar autoxidation, antioxidant ability/reductions in oxidative stress (e.g. MPO/ myeloperoxidase activity), reactive carbonyl trapping, competition with AGEs for amino groups, RAGE (AGE receptor) blockage, upregulation of sRAGE (decoy for inflammatory AGE receptors), etc.
*The following list contains only natural AGE-inhibitors. Synthetic forms such as aminoguanidine (Pimagedine) have been met with minimal efficacy and potentially harmful side effects (e.g., gastrointestinal discomfort, alterations in liver function, and flu-like symptoms) in human trials, despite showing promise in animal studies. (1)
A promising anti-AGE supplemental regime need not only consist of supplements that directly block AGEs but those that inhibit oxidative stress and inflammation. The previous article (Glycation: Part I) mainly discussed oxidative stress and inflammation as effects of the glycation process and therefore reasons to minimize glycation, focusing on dietary sources, although oxidative stress and inflammation, including types that are independent of hyperglycemia-induced reactions, can precede and cause more glycation (2-6), increasing it endogenously.
And another reminder: ‘Anti-glycation’ supplements should be thought of as primarily preventative being that advanced glycation products (AGEs) are irreversible*. Once ingested, the negative impact of stable AGEs may only be mitigated through enhanced excretion and through the blockage or competition of AGE receptors. Therefore, the following compounds are not intended to fully replace a high-AGE diet. Listed and discussed below will include (for the most part) various inhibitors of early, intermediate, and late stage glycation. Some of the other compounds will feature abilities to attenuate the harmful responses from end-stage AGEs already entered into circulation. (More detail on varying MOAs listed in above in ‘Background’)
* Recent drugs referred to as ‘AGE-breakers’ can degrade AGEs by reversing cross-linking , however these drugs are still in the development and testing phase where safety and efficacy in human participants will be studied. Hence, these drugs are presently unavailable to the public.
Aged Garlic Extract: Multiple derivatives of garlic such as s-allylcysteine, diallyl disulfide, and s-ethylcysteine suppress glycation in vitro with s-allylcysteine (SAC) being the principal component. (112-113) Garlic and mainly SAC prevent the formation of AGEs in vitro (114), which at the very least is because it acts as a natural aldose reductase inhibitor. (115) Once again, aldose reductase is an enzyme that is responsible for development of AGEs. Garlic’s antioxidant properties which involve boosting catalase activity, superoxide dismutase activity, and increasing glutathione concentrations to guard against oxidation preceding AGE development and elevate the threshold for AGE-induced damage that is followed by reduced oxidative stress including markers of lipid peroxidaton and protein carbonyls (intermediate-stage glycation products) are other underlying mechanisms that support its antiglycative actions. (116 -118)
Evidence for an anti-glycation effect from garlic in humans is scant, though garlic was able to slightly reduce serum AGEs in one human study that supplemented diabetic patients with 3g of Kyolic®aged garlic extract daily for 3 months. (119) The modest reduction in serum AGEs should be seen in perspective with the relatively small dose of garlic given, among other factors. A previous study noted an increased antioxidant capacity (plus a decrease in the intermediate AGE product MDA) in volunteers with 10g of aqueous aged garlic extract after 4 months (120) while the study using 3g did not observe a difference in antioxidant status between the control group and the supplemented group. (119) This could mean a greater dose might result in a more profound AGE decline in serum. Another thing to consider is AGEs form over a period of time, accumulate mostly in tissue rather than in serum, and can be non-fluorescent ( the study in question utilized a fluorometric method to measure serum AGEs). Moreover, the same study reported a significant reduction of lipid hydroperoxide following 3g of garlic administration (119), and this is notable as it signifies both a decrease in glycation formation – by limiting the formation of early form lipid peroxide products – and an improvement in disease symptoms.
All forms of garlic have a very good safety profile, though aged garlic extract has an even higher safety profile with fewer adverse effects more commonly associated with other forms of garlic such as garlic odor, gastric irritation, and a reduced risk of bleeding problems with the blood-thinner warfarin. (121) Amounts as high as 7.2g (7200mg) of aged garlic extract were given daily for an extended period (6 months) without any adverse side effects. (122) Based on such data, reasonably high amounts can be taken with high tolerability.
Astaxanthin: The carotenoid has lately reached a revered status for its broad-protection in cancer prevention, heart, brain, immune, vision, and skin health. (272) Now, it should be recognized for its activity against glycation. In accordance with its ability to strongly inhibit oxidative stress, astaxanthin protects against endogenous AGE formation. (273) Moreover, damage mediated by exogenous AGEs are allayed by the carotenoid. (274) In diabetic retinopathy, astaxanthin protects eye health by diminishing the damage by growth factors (e.g., VEGF/vascular endothelial growth factor) and enzymes (e.g., MMP-2/matrix metalloproteinases) that are secreted throughout the disease process. (275) Treatment with astaxanthin in vivo lowers progression of diabetic nephropathy and its symptoms by lessening albumin excretion caused by AGEs. (276-277) Since albuminuria from poor AGE control also precedes kidney damage (276), a preventative role is also implied. Yet another rodent study proved that astaxanthin protects diabetic livers by lowering hepatic AGE content and other metabolic dysfunction that precedes and proceeds the glycation process (e.g., oxidative stress, lipid peroxidation, inflammation). (278)
Through rutin, drenching meals in tomato sauce (an acidic solution) inhibits AGE formation during heat preparation.( Tomato paste fraction inhibiting the formation of advanced glycation end-products.) (Amino Acids in Human Nutrition and Health)
Adding chlorella to the diet will serve as a healthful source of astaxanthin and lutein. (Astaxanthin is responsible for antiglycoxidative properties of microalga Chlorella zofingiensis.)( Accumulation of astaxanthin and lutein in Chlorella zofingiensis (Chlorophyta).)
Unlike other dietary antioxidants that could become prooxidants, even in their natural form, when dosed significantly over normal amounts (279), astaxanthin is notoriously safe based on several human trials. (280-283) Dosages as low as 2mg and 8mg markedly decreased DNA damage according to plasma 8-OHdG and lowered subclinical inflammation as measured by plasma CRP (C-reactive protein) in young healthy females. (281) Similarly, another study featuring very low dosages of astaxanthin (1.8, 3.6,14.4 and 21.6 mg per day) found a reduced rate of LDL oxidation in volunteers in comparison to the control group, and the protective effect was noted to be dose-dependent. (284) The highest amounts of astaxanthin administered to human subjects were 40mg and 100mg with increased bioavailability in lipid-based forms and no reported negative side effects. (282-283)(285)
Diabetics and those exposed to increased stress – environmental or internal – expectedly will require larger doses than what a healthy person may require. Fortunately, astaxanthin’s antioxidant potency surpasses that of other vitamins and carotenoids (e.g., alpha-tocopherol, lycopene beta-carotene, alpha-carotene, lutein, etc.) (286), which means higher anti-glycation activity will occur without the inconvenience of mega-doses.
Carnitine: Dysfunctional carnitine regulation occurs in diabetes, and resultantly, type I and type II diabetes reveal decreased amounts of the amino acid. (92-93) Carnitine is an in vitro and in vivo inhibitor of protein glycation and its deficiency directly correlates with tissue accumulation of AGEs in humans. (94-95) Administration of 900mg of carnitine daily in patients with hemodialysis (another condition exhibiting poorer carnitine retention) significantly decreased skin AGEs in 6 month. (96) Expectedly, this strong inhibitor of AGE formation also ameliorated endothelial function and cardiac health in hemodialysis patients in a separate study. (101) Additionally, supplementary carnitine reduced fructose-induced glycation and also resulted in the betterment insulin sensitivity. (97)
Carnitine is classified as a nonessential acid, meaning it can be synthesized by the body and is not required by diet; however, its precursor amino acids are needed from the diet (98), so other than those experiencing disease-induced carnitine deficiency, non-diabetic vegetarians would most likely benefit from carnitine to reduce AGE content. Furthermore, carnitine demand increases with aging, obesity, and other kids of metabolic stress that does not depend on diabetes as a necessity for sufficient carnitine depletion. (99) Considering the high-fat, high-sugar, and highly glycated modern diet, supplementary carnitine would probably be of use to most. Despite marketing claims, acetyl carnitine or ALCAR does not appear to offer any benefit in absorption over L-carnitine; in fact, it may be an inferior form. (100)
Carnosine: Abundant in meat, but also in poultry, fish, and eggs, this amino acid is a naturally-occurring nontoxic alternative to synthetic AGE-inhibitors with comparable clinically efficacy. Despite the dearth of studies with carnosine and its value as an modulator of diabetic complications in humans, it has been demonstrated to delay cataract development in diabetic rats as well as protect against diabetic nephropathy and diabetes-induced atherosclerosis in vitro and in vivo through delaying the ‘AGE-ing’ process. (7-10) Carnosine’s prominence as an anti-glycation substance is in part due to its free radical scavenging abilities (11), a natural ACE inhibiting property (12), metal chelation (13), prevent protein carbonyl group formation (14) and modulate their reactivity (e.g., inactivating pre-formed AGE products) (15), and based on that mechanism, possibly facilitate the excretion of pre-formed AGEs out of cells (16) … ultimately resulting in the inhibition of the formation of AGEs including ‘ALEs’ (advanced lipoxidation products) and their damaging effects.
Carnosine is the chief reason why omnivores were reported to have significantly lower markers of AGEs (fluorescent AGEs, CML) than vegetarians despite their higher consumption of exogenous AGEs (high temperature cooked foods). (17) The vegetarians in that study had more endogenously-derived AGEs due to increased consumption of high-fructose fruits and honey that was not able to be mitigated due to the absence of sufficient carnosine. With carnosine’s broad AGE-inhibiting abilities and the fact that diabetic animals along with humans have revealed lower carnosine levels in plasma and in erythrocytes respectively (18-19), both type I and type II diabetes are likely to benefit profoundly from supplementation. The vastly superior safety profile of carnosine will allow supplementation up to doses to three times more than those used – and poorly received – with aminoguanidine (~600mg). (20)
Catechins: Flavonoids consisting of catechin, epicatechin, epigallocatechin, epicatechin gallate, and epigallocatechin gallate (EGCG) are extremely valuable anti-glycating compounds. In a study quantifying AGE inhibitory capacity, catechin performed better than all other impressive inhibitory agents in the experiment including caffeic acid, ferulic acid, syringic acid by scavenging reactive carbonyls and was attributed as the main metabolite responsible for the effective in vivo AGE inhibitory effect of lotus speedpod oligomeric procyanidins . (258) Epicatechin was identified as a novel AGE-breaker on account of its startling ability to break already formed AGEs – in this case, glycated human serum albumin isolated from diabetics. In addition, epicatechin proved to be successful in the vivo part of the study by dose-dependently reversing the accumulation of exogenously-injected AGEs in the retina of rats, maintaining retinal vascular function. (259) Epigallocatechin in vitro produced the highest inhibition of methylglyoxal compared to other epicatechins. (260) Epicatechin gallate has also showed methylglyoxal trapping ability and its prevention of lipid peroxidation is comparable to that of the flavonoid queretin. (261-262) Epigallocatechin gallate (EGCG) is a lipid peroxidation inhibitor as well (263), and more pertinently, a trapper of methylglyoxal. (264)
Green tea contains a mix of catechins (epicatechin/EC, epicatechin gallate/ECG, epigallocatechin/EGC, and epigallocatechin gallate/EGCG ) with the most potent ones being EGCG and EGC. (265) The mixture of catechins in the form of green tea extract decreased AGE concentration in rats based on reduced collagen linked fluorescence. (266) A separate rat study examining green tea extract also confirmed an attenuated degree of AGE production with an increased antioxidant capacity and a reduction in lipid peroxides (pre-AGES) in the treated diabetic rats. (267) Rich sources of epicatechin include cocoa and apple with lesser but significant amounts in blueberries and blackberries. (268-269) Besides diet, cocoa extracts can be a viable route for supplementary epicatechin. In general, catechins are found mostly within fruit but are also available in nuts, seeds, and spices. (270-271)
Cinnamic Acid and Derivatives: As the name suggests, cinnamic acid is obtained primarily from cinnamon whereas its derivatives (e.g., ferulic acid, p-coumaric acid, eugenol, chlorogenic acid, and caﬀeic acid) can be found in varied sources. In vitro research has shown cinnamic acid to prevent protein glycation as noted from the reduction of pre-AGEs (fructosamine), markers of glycaton-associated protein oxidation and aggregation (carbonylation, amyloid cross β-structure), thiol oxidation, and AGE products (CML) by as high as 63.4%. (174) In this in vitro experiment, cinnamic acid actually inhibited pre-AGE Amadori product fructosamine to a greater degree than anti-AGE drug aminoguanine. By acting as an antioxidant, AGE formation is ultimately suppressed by the reduction of oxidative stress and its generation of early glycation products. Cinnamon’s proven effectiveness against diabetic nephropathy and neuropathy and anti-atherosclerotic activity (175-176) in vivo appears to be derived from its ability to decrease the glycation response. Granted, these beneficial effects are at least partially attributable to its other antiglycative components – manganese and proanthocyadins; however, cinnamic acid would have an undeniable role in potentiating the anti-AGE effect as another prominent component in cinnamon.
Ceylon cinnamon would need to be used for ameliorative purposes over cassia (Chinese cinnamon) to avoid toxicity at therapeutic dosages (177), and although Ceylon cinnamon was not a successful hypoglycemic agent in humans (178), its prime role as a medicinal spice may in fact be as an anti-glycative natural product, which, theoretically, could reduce glucose over the long-term with control of AGE generation.
Ferulic acid, found in differing concentrations in nuts, fruits, vegetables, and spices, seems to be among the most powerful of AGE-inhibiting cinnamic acid derivatives. In vitro studies have uncovered its quenching abilities of hydroxyl radicals, peroxynitrite, and oxLDL (179), reducing a proglycation environment. An unrelated study reported an attenuation of CML formation and fluorescent AGEs by almost 90% plus a lesser, but measurable inhibition of early-formed glycation products (e.g. the binding of free amino groups to sugars). (180) A marked decrease in protein glycation and oxidative damage in an in vitro BSA (bovine serum albumin) model using glucose, fructose, and ribose was observed and accompanied by a reduction in both fluorescent and nonfluorescent AGEs. A decrease in fructosamine was also reported in this study and together with reduced AGEs, was associated with a prevention of protein carbonyl content. (182) It is speculated that most of ferulic acid’s anti-glycation activity derives from its antioxidant (radical scavenging) ability, amino acid binding, abating sugar autoxidation, and preventing degradation of early glycation products. (180) Another apparent advantage of ferulic acid is the special ability to form complexes with HSA (human serum albumin) to protect against glycation of this vulnerable protein. (181)
Despite the absence of human studies assessing ferulic acid’s effects on diabetes-mediated pathologies, diabetic rodent studies substantiate the findings in in vitro models as revealed by increased defense against the progression of diabetic nephropathy, enhanced cardiovascular protection with its sodium salt (sodium ferulate), and improved wound healing. (183-185) Possibly the most relevant information includes a reduction in the formation of AGEs CML(Nε-(carboxymethyl)lysine) and CEL (Nε-(carboxyethyl)lysine) in cake when ferulic acid was added to the mixture during the pre-baking preparation. (186)
Chlorogenic acid is another potent cinnamic acid derivative that inhibits AGE formation and the cross-linking of proteins and does so more effectively than aminoguanine in vitro. It is able to do this by acting as an antioxidant and it interacting with highly reactive carbonyl species (e.g., methylglyoxal) as carbonyl trappers … scavenging intermediate glycation products. (187) Chlorogenic acid displays preventative effects in vitro on lens opacity in rats and also is protective against glycation-induced cytotoxicity in human lens epithelial cells, which signifies cataract protection. (188) It also offers strong defense against beta-amyloid neural toxicity that is enhanced by glycation. (189-190)
Chlorogenic is a major contributor in the inverse relationship between coffee consumption in Alzheimer’s and diabetes. Chlorogenic acid is heat sensitive, but it is incorrect to presume traditionally roasted coffees are a poor source of this polyphenolic acid. Despite inevitable degradation during roasting (191), chlorogenic acid is present in roasted coffee in 2 to 5 grams out of 100g and this is evident as recorded by its detection in the serum of consumers of conventional coffee drinks. (192) Adding roasted coffee or continuing consumption as a dietary source of chlorogenic acid over fresh food sources such as apples, blueberries, pears, peaches, and plumes for example is nonetheless discouraged in the already diabetic. Even though coffee is a very rich source of chlorogenic acid, the roasting process also makes the popular beverage a source of glycation products. Roasted coffee contains both intermediate glycation products (e.g., 5-hydroxymethylfurfural/HMF) and AGEs (e.g., CML) that are both known to react with AGE receptors to generate oxidative stress and inflammation. (193-195) A diet high in Maillard reaction products (i.e. a ‘brown diet’), despite being high in polyphenols including chlorogenic acid, does not improve antioxidant response in healthy individuals. (196) At best, the effect of chlorogenic acid from roasted coffee in diabetics will have a net neutral effect on total glycative activity considering the presence of its very own glycation products coexisting.
For an ideal source of chlorogenic acid, it may be best to consume it as a supplement, as part of an extract, or acquire it from other dietary sources to receive the most anti-glycation potential.
Coenzyme Q10: The vital antioxidant, found in plenty in the healthy, is considerably decreased in diabetics and those with diseases who chronically suffer from high oxidative stress. (310-312) When administered to a rat diabetic model, multiple diabetes-related parameters were improved, including glycation-related markers malondialdehyde/MDA (intermediate glycation product), fructosamine (early stage glycation product), sRAGE, glycated hemoglobin/HbA1c (early-intermediate glycation product), and a “subtle, yet significant” effect on serum glucose, probably due to the restriction of glycation activity. (313-314) At least part of the decrease in AGE production can be attributed a unique mode of action in which coenzyme Q10 down-regulates MPO (myeloperoxidase ) activity. (313) Although measuring possible changes in AGE accumulation as a result of coenzyme Q10 supplementation has not yet been assessed in diabetic human trials, the antioxidant was studied for its effect on HbA1c on human subjects, which at the very least is an estimate for glycemia-induced AGE formation (315) and a rough approximate for total AGEs. In terms of HbA1c, the study noted a significant decrease in the coenzyme Q10 group, and of course, a meaningful decrease in fasting plasma glucose as well since HbA1c measures longer-term glucose control. (316)
The dose in human diabetics that resulted in clinically relevant changes was 150mg. (317) However, much higher amounts (1200mg-3600mg daily) have been well-tolerated in healthy adults. (318) General aging alone causes an incremental falling in coenzyme Q10 levels, so even the generally healthy might consider a typical daily dosage of 30 to 90mg a day as the absolute minimum. (319) Other non-diabetic manifestations of a coenzyme Q10 deficiency or insufficiency could result from intense exercise (e.g., athletes), a vegetarian diet (e.g., lack of oily fish, organ meats), other nutrient deficiencies (e.g., selenium, vitamin B6, magnesium, etc), nutrient overdoses (e.g., vitamin E), use of statins, etc. (320) In these cases greater intakes of 500mg and above may be demanded to saturate whole body stores. (319) The nutrient is more bioavailable as ubiquinol, its naturally reduced form, over the oxidized variant known as ubiquinone (321-322), and being fat-soluble, it is best absorbed with a meal containing fat.
Curcumin and Turmeric: The spice and its bioactive compound, curcumin, are ascribed antioxidant, inflammatory, antimicrobrial, anticancer, memory-enhancing, life-extending, and finally, antidiabetic properties. Curcumin uniquely protects against AGE-induced diabetic complications ultimately by inhibiting AGE/RAGE (receptor for AGES) interaction, which is achieved through upregulating PPARγ activity and stimulating glutathione synthesis. With RAGE pathways inhibited, AGEs cannot exert their harmful effects. Through this mechanism, the status of hepatic fibrosis in type II diabetes is improved. (21) With the genetic expression of RAGE inhibited, this leaves strong implications for curcumin preventing or lessening the impact of all other glycation-induced complications as well.
Other than altering the activity that pre-existing AGEs exert in the body, curcumin can also prevent AGE formation. When compared with ferulic acid, only curcumin was able to prevent AGE formation by means of trapping AGE precursor methylgloxal. (25) A rat study revealed that curcumin is capable of decreasing the undue AGE accumulation in diabetes including their cross-linking reactions, which are known to precede diabetic vascular stiffening and myocardial dysfunction. (22-24)
If supplementing with curcumin, formulations with piperline, nanoparticles, liposomes, and phospholipid complexes are important for increasing the bioavailability of the compound . (26) The metabolism, however, is still rapid, so it is advised that curcumin is taken in multiple doses through the day, rather than as a single large dose.
While curcumin does appear to possess the primary role in attenuating the consequences of diabetes (27), turmerin – an antioxidant in turmeric – is a potent antioxidant with hypoglyclemic effects. Specifically, turmerin inhibits important enzymes in diabetes including alpha-glucosidase and α-amylase activity. (28) Inhibition of these enzymes delays carbohydrate digestion time/glucose release, lowering postprandial (after meal) glucose. (29-30) This mechanism can indirectly restrict the production of endogenous AGEs by reducing available glucose.
With the added anti-diabetic properties of turmeric-specific antoxidant turmerin plus the additional benefits curcumin-free turmeric components have shown to offer (31), it would be propitious to consider supplementing curcumin and turmeric together. Whole turmeric is an option, though curcumin is stronger in invoking anti-diabetic changes in similar concentrations. Therefore, separate supplementation may be best as to not sacrifice the full extent of curcumin’s effects while benefiting from other components of turmeric.
Turmeric is water-soluble, but the fact remains that the 3-4% of curcumin remains to be fat-soluble, and thus the powder would need to be dissolved in a fat if the full utilization from curcumin in turmeric is desired. Curcumin or turmeric powder may be craftily included in sauce recipes or taken alone with olive oil, palm oil, coconut oil, or even ghee as it is consumed with in South Asia. Importantly, curcumin elicits gallbladder contractions, so curcumin-containing supplements are contraindicated in gallstones or bile duct obstructions. (32)
(References on Part III of III)