Boosting proteolytic pathways as a treatment against glycation-derived damage in the brain?

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(definition)) 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. Glycation-derived damage in molecular aging and brain disease: Aging is a multifactorial biological phenomenon controlled by both genetic and environmental factors. The aging process is accompanied by gradual changes in multiple molecular and cellular processes whose malfunction leads to age-related diseases. Recent research on the biology of aging stresses diet as one the most profound environmental determinants for health, and a better understanding of the interactions between diet composition, physiology, biochemistry, and genetics is imperative for developing anti-aging interventions to prevent age-related disorders. Glycation is a non-enzymatic process that plays a pathogenic role in the progression of molecular and cellular aging. AGEs are toxic compounds formed during glycation, a chemical process in which reducing sugars react with different biomolecules, impacting their function, location, and/or solubility (Uchiki et al., 2012; Aragonès et al., 2020). Due to the age-related decline of different anti-AGEs defense mechanisms, glycated biomolecules accumulate during normal aging in our bodies in a tissue-dependent manner. Highly differentiated tissues with a low regenerative capacity, such as brain or ocular tissues, cannot dilute the AGEs-derived cellular damage through cellular division and are more susceptible to glycative-stress induced toxicity (Uchiki et al., 2012; Rowan et al., 2017; Bejarano and Taylor, 2019; Aragonès et al., 2020). Diabetes or consumption of high glycemia diets leads to increased blood glucose levels and triggers the aberrant production of AGEs and associated stress. Thus, hyperglycemia accelerates the age-associated accumulation of glycated proteins and exacerbates the detrimental consequences of AGE deposition on organ function. The deposition of extracellular and intracellular AGEs contributes to molecular aging and is a molecular mechanism underpinning age-related cellular and tissue deterioration. Extracellular AGEs trigger signaling pathways involved in inflammation, production of reactive oxygen species, changes in vasopermeability, and angiogenesis. Intracellular AGEs modify protein structure and induce conformational changes, leading to a loss of function. These changes include cross-linking of proteins, thereby decreasing their solubility, and accumulation of insoluble aggregates. Different age-related disorders are causally associated with AGEs production including ocular disorders such as cataract, diabetic retinopathy, and age-related macular degeneration (AMD), and neurodegenerative diseases (Semba et al., 2010; Rabbani and Thornalley, 2015; Bejarano and Taylor, 2019). Regarding brain function, glycation seems to play a role in the pathogenesis of central nervous system debilities such as peripheral diabetic polyneuropathies, Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis (Münch et al., 2012). AGEs are found in intracytoplasmic inclusions in Lewy bodies in subcortical neurons of Parkinson's patients, and it has been suggested that AGEs trigger Lewy body formation. Also, the AGEs content in plaques extracted from Alzheimer's disease patients is higher compared to age-matched control individuals (Münch et al., 2012). Accumulation of AGEs is thought to contribute to diabetes-associated cognitive decline by inducing neuronal differentiation defects in neural stem cells. Glycation is proposed to participate in the aggregation of different neuropathological proteins and also impacts on neurite regeneration. For example, recent literature highlights the ability of AGEs to cross-link neuropathological proteins such as α-synuclein, amyloid β, and tau, promoting aggregation and limiting the clearance of toxic oligomers. Multiple experiments in different cellular and animal models, including dopaminergic neurons, SHSY5Y cells, C. elegans and D. melanogaster, support the hypothesis that lowering AGEs accumulation is neuroprotective. The pathways by which AGEs