Glycation‐altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age‐related disease (in nondiabetics)

Abstract

Summary Epidemiologic studies indicate that the risks for major age-related debilities including CHD, diabetes, and age-related macular degeneration (AMD) are diminished in people who consume lower glycemic index (GI) diets but lack of a unifying physiobiochemical mechanism that explains the salutary effect is a barrier to implementing dietary practices that capture the benefits of consuming lower GI diets. We established a simple murine model of age-related retinal lesions that precede AMD (hereafter called AMD-like lesions). We found that consuming a higher GI diet promotes these AMD-like lesions. However, mice that consumed the lower vs. higher GI diet had significantly reduced frequency (p<0.02) and severity (p<0.05) of hallmark age-related retinal lesions such as basal deposits. Consuming higher GI diets was associated with >3 fold higher accumulation of advanced glycation end products (AGEs) in retina, lens, liver and brain in the age-matched mice, suggesting diet-induced systemic glycative stress that is etiologic for lesions. Data from live cell and cell free systems show that the ubiquitin-proteasome system (UPS) and lysosome/autophagy pathway (LPS) are involved in the degradation of AGEs. Glycatively-modified substrates were degraded significantly slower than unmodified substrates by the UPS. Compounding the detriments of glycative stress, AGE-modification of ubiquitin and ubiquitin conjugating enzymes impaired UPS activities. Furthermore, ubiquitin conjugates and AGEs accumulate and are found in lysosomes when cells are glycatively stressed or the UPS or LPS/autophagy are inhibited indicating that the UPS and LPS interact with one another to degrade AGEs. Together these data explain why AGEs accumulate as glycative stress increases.

Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract

“…1D, panels 1-4, and Fig. S1E, panels [5][6][7][8]. By overlapping the F-actin and intermediate filament images, a distinct perturbation of cytoskeletal structure in K6W-Ub lenses is revealed (Fig.…”

“…It appears that an inability to clear Cx43 conjugates that incorporate K6W-Ub results in their accumulation, a backup of this UPS, and, thus, stabilization of the parent protein as well. This mechanism additionally suggests that expression of K6W-Ub may also compromise and saturate the other UPSs, and it provides further rationale as to why cells in which K6W-Ub is expressed have limited capacity to withstand various stresses, particularly proteotoxicity (8,13). Please see SI Text for discussion of relations between monoubiquitination and calpain function and for possible other proteolytic or nonproteolytic mechanisms regulating Cx43, Cx46.…”

“…Crystallins, the major gene products of the lens, are very long-lived proteins, with half-lives of decades, and their aberrant synthesis or modification results in aggregation, insolubilization, and cataract (6). Common age-related stresses that confront proteins in the lens and other tissues during aging include oxidation, glycation, and methylation, as well as their sequels (3,(6)(7)(8)(9). Effective stress-reducing systems including antioxidants, antioxidant and repair enzymes, and chaperone and proteolytic capacities help limit damage and maintain solubility and function in younger tissues (3).…”

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

“…Increased levels of advanced glycation end products (AGEs), i.e., covalent posttranslational oxidative and nonoxidative modifications of proteins by sugar-derived metabolites, were observed in the mice fed a high-glycemia (HG) diet (hereafter, "HG mice") (10,11). AGEs are cytotoxic (12), and this cytotoxicity is corroborated by the accumulation of AGEs in AMD.…”

Review of nutrient actions on age-related macular degeneration

“…Similarly, a significant synergistic interaction was described with regard to omega-3 fatty acids and dietary glycemic index; higher intake of omega-3 fatty acids (DHA and EPA) and low dietary glycemic index were associated with an even lower risk for advanced AMD compared to either of the two dietary factors alone [78]. In addition, recent studies on murine models also support these results [22,88].…”