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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK091231-09
Application #
8312657
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Leschek, Ellen W
Project Start
2003-12-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$564,140
Indirect Cost
$215,266
Name
Icahn School of Medicine at Mount Sinai
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Cai, Weijing; Uribarri, Jaime; Zhu, Li et al. (2014) Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans. Proc Natl Acad Sci U S A 111:4940-5
Migdalis, Ilias; Leslie, David; Papanas, Nikolaos et al. (2014) Diabetes mellitus. Int J Endocrinol 2014:108419
Schulman, Carl I; Uribarri, Jaime; Cai, Weijing et al. (2014) Increased circulating advanced glycation endproducts (AGEs) in acute trauma patients. Clin Chem Lab Med 52:103-8
Uribarri, Jaime; Cai, Weijing; Pyzik, Renata et al. (2014) Suppression of native defense mechanisms, SIRT1 and PPARýý, by dietary glycoxidants precedes disease in adult humans; relevance to lifestyle-engendered chronic diseases. Amino Acids 46:301-9
Vlassara, Helen; Uribarri, Jaime (2014) Advanced glycation end products (AGE) and diabetes: cause, effect, or both? Curr Diab Rep 14:453
Stirban, Alin; Kotsi, Paraskevi; Franke, Knut et al. (2013) Acute macrovascular dysfunction in patients with type 2 diabetes induced by ingestion of advanced glycated ?-lactoglobulins. Diabetes Care 36:1278-82
Lupia, Enrico; Zheng, Feng; Grosjean, Fabrizio et al. (2012) Pentosan polysulfate inhibits atherosclerosis in Watanabe heritable hyperlipidemic rabbits: differential modulation of metalloproteinase-2 and -9. Lab Invest 92:236-45
Vlassara, Helen; Uribarri, Jaime; Cai, Weijing et al. (2012) Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease. Clin J Am Soc Nephrol 7:934-42
Vlassara, Helen; Striker, Gary E (2011) AGE restriction in diabetes mellitus: a paradigm shift. Nat Rev Endocrinol 7:526-39