Abstract: The worldwide adaptation of a Western lifestyle is associated with the increased consumption of high glycemia diets and an increased prevalence of obesity, metabolic syndrome, and diabetes. These diets increase the risk for a plethora of age-related diseases including cerebrovascular, cardiovascular, and eye-related disorders, which all share a common pathogenic factor: the accumulation of advanced glycation end-products (AGEs) (Semba et al., 2010; Aragno and Mastrocola, 2017). AGEs are a diverse group of pathogenic compounds formed via a non-enzymatic process called glycation in which dietary sugars, or reactive dicarbonyls formed during carbohydrate metabolism, are covalently attached to different biomolecules, inactivating them (Rabbani and Thornalley, 2015). A growing literature indicates that AGEs impact brain function and contribute to initiate and accelerate neurodegeneration and also interfere with the process of neuroregeneration (Li et al., 2012; Vicente Miranda et al., 2017; Fleitas et al., 2018; Bao et al., 2020). In order to avoid AGEs-derived toxicity, our cells have different anti-AGEs defense mechanisms including the clearance of these detrimental compounds through different proteolytic pathways. To date, the lysosomal system (autophagy) and the ubiquitin-proteasome system (UPS) have been identified as proteolytic routes able to degrade AGEs. Unfortunately, the proteolytic capacity declines with age, making tissues more vulnerable to AGEs-derived damage (Uchiki et al., 2012; Rowan et al., 2017; Aragonès et al., 2020). AGEs-modification also compromises the proteolytic machinery, leading to double jeopardy due to the higher glycemia diets or diabetes. Boosting proteolytic pathways might represent a therapeutic strategy to counteract the deposition of toxic, glycated, proteinaceous aggregates in the brain and other tissues with limited regeneration capacity, those most vulnerable to glycation-derived damage.