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The past century had witnessed vast advances in biomedical research, particularly in the fields of genomics and proteomics, yet the translation of these discoveries into clinical practice has been hindered by gaps in mechanistic understanding of variability governing disease susceptibility and pathogenesis. Among the greatest challenges are the dynamic nature of the proteome and the imperfect methodologies currently available to study it. Here, we review key recently developed proteomic techniques that have allowed for dynamic characterization of protein quality, as well as quantity, and discuss their potential applications in understanding aging and metabolic disorders including diabetes. These methodologies revealed that senescence is characterized, in part, by decreased rates of de novo protein synthesis and potentially also degradation, in addition to concomitantly increased levels of oxidative stress, ultimately resulting in excessive accumulation of damaged and dysfunctional proteins. Insulin may be a key mediator in these pathologies, as hyperinsulinemia has been shown to hinder protein degradation while transient insulin deficiency may accelerate oxidative damage. We also discuss two interventions that have been proposed to delay, and possibly reverse, senescence by augmenting protein degradation: chronic caloric restriction and aerobic exercise., (Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)