The MetSyn is associated with elevated oxidative stress (OS) and inflammation. High OS, inflammation and cell injury are promoted by advanced glycation endproducts (AGEs). The completed objectives of the initial award period showed that: a). most AGEs are derived from the common diet, contrary to previous beliefs that AGEs are mainly endogenously derived. Hence, both young and old Healthy persons consuming AGE-rich foods have abnormally high AGE and OS levels;b). Restriction of dietary AGE intake reduces OS and inflammation in healthy older and young age subjects and the effects of the intervention were independent of age, c). restriction of dietary AGE intake resulted in similar reductions in OS and inflammation in a pilot study of patients with chronic kidney disease. d). these effects are regulated by AGER1, a cell-surface anti-AGE receptor, with potent anti-OS properties. A pilot study in patients with T2D (n=20) showed that AGE restriction can reduce hyper-insulinemia, OS and inflammation in a 4-month period. Based on these data, we hypothesize that the addition of AGE-restriction to standard care will improve the MetSyn. In this event, the intervention could help suppress progression to T2D and CVD. New preliminary data suggest that AGEs impair molecular pathways related to insulin action and inflammation, via Sirt-1. They also introduce the first evidence of a coordinate positive regulation of AGER1 and Sirt-1 and its functions in animals and humans, substantially strengthening the mechanistic basis of the proposed intervention. While expression of AGER1, a first-line cellular anti-AGE defense becomes deficient under chronic OS, it can be restored to normal levels by AGE restriction, an event also associated with enhanced Sirt-1. Therefore, under the current pro-oxidant (food) environment, depletion of AGER1 may be linked to Sirt-1 suppression and thus, to metabolic and anti- inflammatory deregulation. The MetSyn is an appropriate choice for study, since the prevention of T2D and CVD is a high priority. Thus, if the MetSyn can be reversed, or progression to T2D is avoided by AGE restriction, this would represent a major clinical advance. This strategy represents a novel concept, there are no major life-style limitations, it is cost-effective, and is marked by a high level of compliance. In this revised application, the Experimental Design was revised and a clinical trial/epidemiological expert was added to the study team. The power of the proposed AGE-Restriction intervention was increased by including a larger population sample of subjects with the MetSyn, and the scope of the mechanistic studies was expanded.
The Specific Aims are:
Aim 1 : Interventional Study: Determine the Effects of AGE Restriction on the MetSyn in Aging;
Aim 2 : Assessment of Mononuclear Cell (PMNC) AGER1 in the MetSyn of Aging;
and Aim 3 : Assessment of the Impact of Exogenous AGEs and AGER1 on Sirt-1, Insulin Resistance and Inflammation in vitro. Several additional methodological comments and suggestions by the reviewers of the previous submission were also addressed.
The Metabolic Syndrome (MetSyn) is a forerunner of diabetes, obesity and cardio vascular disease, three major "epidemics" of aging. MetSyn is associated with elevated oxidative stress (OS) and inflammation, and we have shown that dietary oxidants (AGEs) can cause these changes;further, our pilot data suggests that by restricting oxidants in the diet, we can reduce these changes, even when AGE levels are excessively high. Thus, our proposed research seeks to extend these findings into a larger group of "pre-diabetic" adults, and to demonstrate that this safe, practical and economical intervention can arrest the progression to diabetes and vascular disease associated with the metabolic syndrome;this simple intervention could have significant health and economic implications.
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