Carnosine (beta-alanyl-L-histidine) is the dipeptide that is the most potent naturally occurring inhibitor of the advanced glycation end-product (AGE) formation — it is found in high concentrations in the skeletal muscle, the brain, the heart, and the other long-lived tissues, and it is one of the most important anti-glycation compounds in the human body. The glycation (also called the non-enzymatic glycosylation) is the spontaneous reaction between the reducing sugars (glucose, fructose) and the proteins, the lipids, and the DNA — and it is one of the primary mechanisms of the biological ageing and of the age-related diseases. The glycation produces the AGEs (advanced glycation end-products), which are the stable, irreversible adducts that cross-link the proteins, impair the protein function, activate the pro-inflammatory receptors (RAGE), and promote the oxidative stress and the cellular senescence. The carnosine inhibits the glycation through multiple mechanisms — it reacts with the carbonyl groups of the reactive carbonyl species (the dicarbonyls such as the methylglyoxal and the glyoxal that are formed during the glycolysis and during the lipid peroxidation), it scavenges the reactive carbonyl species before they can react with the proteins, and it protects the proteins from the oxidative damage that promotes the glycation. Without adequate carnosine and anti-glycation protection, the AGEs accumulate in the tissues, the protein function declines, the chronic inflammation increases, and the ageing accelerates — the hallmark of the carnosine deficiency and of the high-glycation diet. The typical dietary carnosine intake from the meat, the poultry, and the fish is 200-500mg daily, and the therapeutic doses for the anti-glycation effects are 500-1500mg of the carnosine supplement daily — making the carnosine supplementation one of the most evidence-based interventions for the prevention of the glycation and for the healthy ageing.
Carnosine and the Anti-Glycation Mechanisms
Carnosine inhibits the AGE formation primarily through the reaction with the dicarbonyl compounds (methylglyoxal, glyoxal, deoxyglucosones) — the highly reactive carbonyl species that are the primary drivers of the protein glycation and of the AGE formation. The carnosine acts as a carbonyl scavenger — it reacts with the dicarbonyls to form the carnosine-dicarbonyl adducts (the hydroimidazoles), which are stable and non-reactive and are excreted in the urine without causing the protein cross-linking or the receptor activation. This carbonyl-scavenging mechanism is one of the most important anti-glycation mechanisms in the body, because the dicarbonyls are the primary mediators of the intracellular glycation — they are formed in all cells during the glycolysis (as unavoidable by-products of the triose phosphate interconversion) and during the lipid peroxidation, and they are far more reactive than the glucose or the fructose in the glycation reactions. The carnosine also directly inhibits the glycation of the proteins by the glucose and the fructose — by binding to the protein amino groups (the epsilon-amino groups of the lysine residues and the N-terminal amino groups), the carnosine protects the proteins from the glycation by occupying the glycation sites that would otherwise be modified by the reducing sugars. The carnosine also acts as an antioxidant — it scavenges the hydroxyl radical, the superoxide anion, and the singlet oxygen, and it protects the proteins from the oxidative damage that accelerates the glycation (because the oxidative stress promotes the formation of the dicarbonyls and the cross-linking of the AGEs).
The clinical importance of the carnosine for the anti-glycation and the healthy ageing is underscored by the observation that the carnosine levels decline with age and that the carnosine supplementation improves the healthspan and the lifespan in multiple animal models. A study in 12-month-old mice found that the carnosine supplementation at 100mg/kg daily extended the median lifespan by 20% and improved the physical performance, the cognitive function, and the antioxidant status — demonstrating the potent anti-ageing effects of the carnosine in animals. The carnosine has also been shown to protect against the diabetic complications (the neuropathy, the retinopathy, the nephropathy), the neurodegenerative diseases (the Alzheimer’s disease, the Parkinson’s disease), and the cardiovascular disease (the atherosclerosis, the heart failure) — all of which are associated with the AGE accumulation and the chronic inflammation.
Practical Application
For general carnosine supplementation for the anti-glycation and anti-ageing support, the evidence-based approach is to supplement with 500-1500mg of carnosine daily (as the pure carnosine or as the carnosine annan, which is the stable form of the carnosine that is resistant to the enzymatic degradation). The carnosine should be taken in the morning and in the evening (in divided doses, to maintain the stable blood levels throughout the day). The carnosine is generally well-tolerated with no significant adverse effects at doses up to 3000mg daily. For comprehensive anti-glycation and longevity support, carnosine pairs well with the benfotiamine (which is a fat-soluble form of the thiamine that is a potent inhibitor of the AGE formation through the activation of the transketolase and the redirection of the glycolytic intermediates away from the glycation pathways), with the alpha-lipoic acid (which has complementary anti-glycation and antioxidant effects), with the pyridoxamine (which is an inhibitor of the AGE formation through the Schiff base and the Amadori product formation), and with the resveratrol (which activates the SIRT1 and which has complementary anti-inflammatory and anti-glycation effects).
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