Cardiovascular disease remains the leading cause of mortality worldwide and is markedly accelerated by both diabetes mellitus and aging, conditions that converge on common pathways of vascular dysfunction, including arterial stiffening and endothelial dysfunction. Methylglyoxal, a reactive glycolytic byproduct that accumulates with both hyperglycemia and aging, has emerged as a potential shared contributor to these pathways. As current measures of disease management alone are insufficient to prevent vascular damage, methylglyoxal represents a promising therapeutic target shared across age-related metabolic conditions.

Mechanistically, methylglyoxal reacts with proteins, lipids and DNA to form advanced glycation end-products, driving oxidative stress, inflammation and endothelial dysfunction. Rather than targeting a single point in this pathway, we designed a novel, multi-compound therapy combining pyridoxamine, which directly scavenges methylglyoxal, with resveratrol and hesperidin, which enhances its enzymatic breakdown via glyoxalase 1. This combined approach simultaneously quenches reactive methylglyoxal and enhances its degradation.

In a mouse model of type 1 diabetes, this combined treatment prevented the diabetes-associated increase in plasma methylglyoxal levels, improved endothelial function and increased aortic distensibility, protecting vascular health beyond glycemic control. These findings support methylglyoxal metabolism as a promising therapeutic target for diabetes-associated vascular dysfunction and vascular aging.