title: Suppression of native defense mechanisms, SIRT1 and PPARγ, by dietary glycoxidants precedes disease in adult humans; relevance to lifestyle-engendered chronic diseases.
abstract: SIRT1 and PPARγ, host defenses regulating inflammation and metabolic functions, are suppressed under chronic high oxidant stress and inflammation (OS/Infl) conditions. In diabetes, dietary advanced glycation end products (dAGEs) cause OS/Infl and suppress SIRT1. Herein, we ask whether dAGEs also suppress host defense in adults without diabetes. The relationships between dAGEs and basal SIRT1 mRNA, PPARγ protein levels in mononuclear cells (MNC) and circulating inflammatory/metabolic markers were examined in 67 healthy adults aged >60 years and in 18 subjects, before and after random assignment to either a standard diet (regular >15 AGE Eq/day) or an isocaloric AGE-restricted diet (<10 AGE Eq/day) for 4 months. Also, the interactions of AGEs and anti-AGE receptor-1 (AGER1) with SIRT1 and PPARγ were assessed in wild type (WT) and AGER1-transduced (AGER1(+)) MNC-like THP-1 cells. We found that dAGE, but not caloric intake, correlated negatively with MNC SIRT1 mRNA levels and positively with circulating AGEs (sAGEs), OS/infl, MNC TNFα and RAGE. Basal MNC PPARγ protein was also lower in consumers of regular vs. AGE-restricted diet. AGE restriction restored MNC SIRT1 and PPARγ, and significantly decreased sAGEs, 8-isoprostanes, VCAM-1, MNC TNFα and RAGE. Model AGEs suppressed SIRT1 protein and activity, and PPARγ protein in WT, but not in AGER1(+) cells in vitro. In conclusion, chronic consumption of high-AGE diets depletes defenses such as SIRT1 and PPARγ, independent of calories, predisposing to OS/Infl and chronic metabolic disease. Restricted entry of oral AGEs may offer a disease-prevention alternative for healthy adults.
authors: Department of Medicine, The Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY, 10029, USA, jaime.uribarri@mssm.edu.
authors: Jaime
authors: J
authors: Uribarri
authors: Weijing
authors: W
authors: Cai
authors: Renata
authors: R
authors: Pyzik
authors: Susan
authors: S
authors: Goodman
authors: Xue
authors: X
authors: Chen
authors: Li
authors: L
authors: Zhu
authors: Maya
authors: M
authors: Ramdas
authors: Gary E
authors: GE
authors: Striker
authors: Helen
authors: H
authors: Vlassara
mesh_terms: D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D002908:Chronic Disease; D003296:Cooking; D005247:Feeding Behavior; D015870:Gene Expression; D020868:Gene Silencing; D017127:Glycation End Products, Advanced / Q000009:adverse effects / Q000097:blood; D008019:Life Style; D008239:Lysine / Q000031:analogs & derivatives / Q000097:blood; D018384:Oxidative Stress; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017127:Glycation End Products, Advanced; D008239:Lysine; C048496:N(6)-carboxymethyllysine; D047495:PPAR gamma; C447939:SIRT1 protein, human; D056564:Sirtuin 1
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