PROJECT SUMMARY / ABSTRACT The age-related loss of muscle mass, strength, and function, known as sarcopenia, represents one of the five most common conditions in older adults. Of these five conditions, sarcopenia is the only one for which no FDA- approved treatment exists. To promote independence and prevent disability in our aging population, the identification of drug targets for sarcopenia is crucial. The accelerated sarcopenia seen in T2DM is an ideal model for this purpose, as it is possible to systematically interrogate those pathways that are normally altered somewhat by the aging process, but are extremely altered by T2DM. By examining these pathways, it may be possible to identify novel therapeutic targets for sarcopenia. One such pathway, upregulated by the hyperglycemic milieu of T2DM, is nonenzymatic protein glycosylation and the subsequent formation of AGE. This detrimental process is known to contribute to multiple disease states. While AGE concentration has previously been linked to muscle strength and function in cross-sectional studies, and blocking AGE accumulation in animal models improves muscle mass, the role of AGE in sarcopenia in humans has yet to be substantiated. We propose that AGE represents a potential mediator of sarcopenia in humans, but more evidence – specifically, evidence of muscle AGE responsiveness to existing treatment modalities – is required in humans prior to the conduct of specific clinical trials. To gather this evidence, the present study will examine subjects with T2DM and healthy older controls before and after 12 weeks of progressive resistance exercise training. Overall, we hypothesize that progressive resistance exercise training will reduce AGE concentrations in plasma and muscle, and that these reductions will be associated with improved sarcopenia outcomes – namely, muscle mass, strength, and function. Furthermore, we will test the hypothesis that progressive resistance exercise training can be used in patients with T2DM to normalize protein glycosylation and AGE accumulation, as compared to healthy older controls. Employing clinical, proteomic, biochemical methodologies, the present study will address this hypothesis through three Specific Aims: 1) identify and quantify glycated protein targets in aging human muscle and plasma from patients with and without T2DM, 2) identify the effects of progressive resistance exercise training on protein glycation, AGE concentration, and downstream effectors of AGE, and 3) determine whether AGE concentration is associated with baseline differences or intervention-induced changes in measures of muscle mass, strength, or function, and calculate the percent variation in these measures that is explained by AGE concentration. Determining the impact of progressive resistance exercise training on protein glycosylation and AGE accumulation will inform the search for novel therapeutic targets for sarcopenia, and assist in the formulation of future clinical trials.