The impact of junk food on male fertility in mice: therapeutic interventions targeting advanced glycation end-products and oxidative stress

Abstract Frequent consumption of poor-quality diets “junk food” leads to the accumulation of sugar-derived advanced glycation end-products (AGEs), promoting inflammation and oxidative stress (i.e., diminished endogenous antioxidant defenses). This biology has been linked to reduced male fertility, but it is unclear whether reversing AGE damage or boosting antioxidant defenses can restore reproductive function. We used a mouse model to test two approaches: Alagebrium (ALT-711), an investigational drug which breaks AGE cross-links, and Fertilix®, an antioxidant micronutrient blend. Sixty-eight male C57BL/6 mice were fed either a standard or AGE-rich diet, then treated for 35 days and mated. The AGE-rich diet raised glycation and metabolic markers, increased oxidative stress, disrupted spermatogenesis, and produced poorer sperm (lower counts and motility, more DNA damage). These changes translated into fewer pregnancies, more miscarriages, and smaller litters. Both interventions corrected many redox-related sperm defects, but only Fertilix® restored reproductive outcomes to near normal levels in AGE-fed animals; ALT-711 improved some measures yet did not rescue fertility and in fact worsened pregnancy metrics in healthy controls. These findings implicate AGE-driven oxidative stress as a modifiable driver of diet-related male infertility and support targeted antioxidant repletion to restore fertility; confirmation in clinical trials, albeit challenging, is warranted.