Mechanistically linking age-related diseases and dietary carbohydrate via autophagy and the ubiquitin proteolytic systems

Abstract

Epidemiological data indicate that consuming diets that deliver sugar to the blood rapidly (called high glycemic index, GI) is associated with enhanced risk for age-related diseases such as cardiovascular disease, type 2 diabetes, cataract and age-related macular degeneration (AMD). These debilities are associated with accumulation of toxic protein aggregates as observed in other protein precipitation or amyloid diseases including Alzheimer, Parkinson and Huntington diseases and encephalopathies. Barriers to recommending lower-GI diets to promote health include the absence of established intracellular biochemical mechanisms that link high-GI diets to compromised homeostasis. The data herein corroborate the epidemiological findings and provide platforms to elucidate additional mechanistic aspects of salutary effects of consuming diets of different GIs. They are also useful for testing drugs, including autophagy enhancers, glycemia regulators, or nutraceuticals, which can be exploited to extend health.

Figure 1. This scheme proposes that under normal homeostatic conditions, the UPS and LPS, functioning independently or in concert, maintain the proteome (top). Protein editing is unperturbed, and AGEs and ubiquitin conjugates do not accumulate. However, upon chronic glycative stress and ⁄or aging, proteolytic capacities are insufficient to maintain the proteome and may themselves be diminished (bottom). Sugar metabolites promote protein modification resulting in accumulation of ubiquitin conjugates, aggregation and cross-linking. Amino acid residues that encode susceptibility for the degradation of substrates may be blocked. Glycated ubiquitin may be incorporated into conjugates, rendering them less susceptible to degradation. This situation is exacerbated by the accumulation of damaged proteins, which may diminish proteolytic efficacy or render it insufficient, and induce oxidative stress, setting up a vicious cycle that results in additional stress and limited cellular function. The stress may also alter the interaction between the UPS or LPS as one or both pathways are attenuated and proteopoise (the balance of protein synthesis, modification and degradation) is perturbed.