Naturopathic Approach to Advanced Glycation End-products (AGEs)

Advanced glycation end-products (AGEs) are compounds that are generated under hyperglycemic conditions. They could be formed endogenously, or they could be consumed from our diet. Increased presence of AGEs in the human body is associated with diverse age-related and chronic conditions. Understanding the impact of AGEs on human health, how lifestyle factors contribute to the accumulation of AGEs, and which natural medicines modulate AGEs offers an opportunity to prevent the harmful effects of AGEs.

What you need to know about advanced glycation end-product

AGEs are the result of nonenzymatic reactions between carbonyl groups of reducing sugars and the free amino groups of proteins, lipids, or nucleic acids. Several AGEs have been identified and studied. Those include Nε‑carboxymethyllysine (CML), pentosidine, Nε‑carboxyethyllysine (CEL), methylglyoxal-derived hydroimidazolone‑1 (MG‑H1), and pyrraline.¹ AGEs accumulate intracellularly and extracellularly in body fluids and all tissues. AGEs have been implicated in the alteration of intracellular signalling, gene expression, production of reactive oxygen species, and activation of inflammatory pathways. Accumulation of AGEs has been associated with disease processes involved in diabetes,² chronic kidney disease,³ cardiovascular disease,⁴ osteoporosis,⁵ musculoskeletal disorders,⁶ ocular disease,⁷ cancer,^8,9 infertility,¹⁰ and neurodegenerative diseases including Alzheimer’s disease.^11,12

Consumed exogenous sources of AGEs are mostly found in foods that have been exposed to high, dry-heat cooking temperatures (i.e., grilling, broiling, roasting, searing, and frying) and extended cooking times. AGEs are particularly abundant in animal-derived foods (i.e., beef, higher-fat and aged cheeses). They are also present in higher concentrations in dry-heat–processed foods (i.e., crackers, chips, and cookies).¹³ Aqueous extracts of tobacco and tobacco smoke have also been identified as contributors to the increase of AGEs in vivo. Tobacco and tobacco smoke generate reactive species called glycotoxins, which are highly reactive glycation products that can rapidly induce AGE formation on proteins.¹⁴

Lifestyle modifications help reduce the accumulation of AGEs

Hyperglycaemic states encourage the formation of AGEs. Limiting the consumption of sugar-added foods and beverages, particularly of fructose,¹⁵ and the consumption of low-glycemic-index foods versus high-glycemic-index foods help to control glycaemia and reduce the endogenous production of AGEs.¹⁶

Adhering to a diet that reduces dietary AGEs intake has been shown to be an effective way of reducing circulating AGEs.¹⁷ This strategy includes limiting the consumption of animal products. Food preparation with brief heating time, at a lower temperature, with more moisture (i.e., boiling, poaching, stewing, and steaming), or with an acidic solution (marinade) of lemon juice and vinegar reduce the formation of AGEs. Opting for raw nuts and seeds instead of roasted nuts and seeds is also an effective way of reducing AGEs consumption.¹⁸

Exercise is another lifestyle strategy to decrease AGEs levels. In a 12‑week lifestyle modification program, seventeen nondiabetic middle-aged women exhibited significant positive correlation with decrease in CML and average number of steps in daily walking (p = 0.044).¹⁹ 

A clinical trial examining the impact of exercise on AGEs in patients living with the human immunodeficiency virus found that training for three months, consisting of sixty-minute sessions performed three times a week, decreased AGE levels (baseline: 0.93 ± 0.08 AU v. three-month follow-up: 0,59 ± 0,04 AU; p < 0.001) compared to control.²⁰

Eliminating exposure to tobacco products reduces circulating AGEs. In a cross-sectional study evaluating 8,905 individuals (current smokers, never smokers, and past smokers), skin autofluorescence, a biomarker for AGEs accumulation, was measured. Skin autofluorescence levels increased with active smoking and with increasing number of hours of being exposed to second-hand smoke. In addition, the study found that skin autofluorescence levels of former smokers approached levels of never smokers after around 15 years of smoking cessation.²¹

Natural Supplements Could Help to Reduce

Probiotics and Prebiotics: In a randomized, open-label, controlled trial, twenty patients undergoing peritoneal dialysis either continued their usual high-AGE diet or followed a one-month dietary AGE-restricted diet. The restriction of AGE consumption resulted in both the reduction of AGEs in serum and the alteration of bacterial gut microbiota.²² In another randomized, controlled clinical trial, sixty-five subjects with type 2 diabetes received either dextrin as a prebiotic or placebo. After eight weeks, supplementation with dextrin improved CML (−93.40 ng/ml, 26.30%) in the intervention group compared with the control group.²³

Benfotiamine: In a clinical trial, thirteen subjects with type 2 diabetes consumed high-AGE meals before and after a three-day therapy with benfotiamine (1,050 mg/d). Serum markers of endothelial dysfunction and oxidative stress, as well as AGEs, increased after the consumption of the high-AGE meal, and these effects were significantly reduced by benfotiamine. The authors concluded that benfotiamine can completely prevent micro- and macrovascular dysfunction induced by an AGE-rich test meal in patients with type 2 diabetes.²⁴

Carnosine: A systematic review of nineteen in vitro studies, fifteen animal studies, and two human studies investigating the role of carnosine on AGE-induced changes found that all but two indicated that carnosine can prevent the formation of AGEs. The review concluded that carnosine has antiglycating properties and may hinder the formation of protein carbonyls and the cross-links induced by reduced sugars.²⁵ A randomized, double-blind, placebo-controlled clinical trial involving fifty-four type 2 diabetic patients concluded that twelve weeks of l‑carnosine supplementation (1,000 mg/d) resulted in a significant reduction in the serum pentosidine levels compared with those at baseline (p < 0.05).²⁶

Quercetin: In a randomized, double-blinded, placebo-controlled, crossover trial, 160 mg/d of quercetin was found to decrease plasma methylglyoxal (the most potent precursor of AGEs) concentrations (95% CI: −73.6, −6.8 nmol/L; p = 0.019) compared to placebo.²⁷

Coenzyme Q10: In a randomized, double-blind, placebo-controlled clinical trial, fifty subjects with diabetic nephropathy were assigned to take the CoQ10 (100 mg/d) supplements or placebo for twelve weeks. In addition to demonstrating that CoQ10 supplementation for twelve weeks had favourable effects on glucose metabolism, this study found that CoQ10 supplementation significantly decreased AGEs (−316.4 ± 380.9 AU v. +318.6 ± 732.0 AU, p < 0.001) compared with the placebo.²⁸

Conclusion

Research surrounding advanced glycation end-products is continuing to evolve. As our understanding of how modern lifestyle factors contribute to the presence of AGEs, and as we continue to learn how AGEs behave in our bodies, we are presented with opportunities to effect changes in our personal AGEs status.