03894nas a2200649 4500000000100000008004100001653001100042653001100053653000900064653000900073653001600082653001700098653003800115653002500153653006100178653003700239653001200276653004900288653002700337653002500364653004600389653004900435653007400484653002100558653002500579653004200604653002400646653005800670653000900728653002300737653005400760653003400814653002600848653007400874653003800948653005000986653004001036100001601076700001601092700001101108700001601119700001501135700001201150700001801162700001101180700001301191700001201204700001601216700001401232700002301246245010201269250001501371300001101386490000801397520178801405020005103193 2014 d 10 aFemale 10 aHumans 10 aAged 10 aMale 10 aMiddle Aged 10 aTime Factors 10 aADAM Proteins/genetics/metabolism 10 aAdministration, Oral 10 aAmyloid Precursor Protein Secretases/genetics/metabolism 10 aAmyloid beta-Peptides/metabolism 10 aAnimals 10 aBrain/drug effects/pathology/physiopathology 10 aCognition/drug effects 10 aCytokines/metabolism 10 aDementia/blood/ pathology/physiopathology 10 aGliosis/metabolism/pathology/physiopathology 10 aGlycosylation End Products, Advanced/administration & dosage/ adverse 10 aeffects/toxicity 10 aInsulin/pharmacology 10 aMembrane Proteins/genetics/metabolism 10 aMemory/drug effects 10 aMetabolic Syndrome X/blood/ pathology/physiopathology 10 aMice 10 aMice, Inbred C57BL 10 aNicotinamide Phosphoribosyltransferase/metabolism 10 aOxidative Stress/drug effects 10 aPPAR gamma/metabolism 10 aPyruvaldehyde/administration & dosage/ adverse effects/blood/toxicity 10 aReceptors, Immunologic/metabolism 10 aSirtuin 1/antagonists & inhibitors/metabolism 10 aTranscription, Genetic/drug effects 1 aVlassara H. 1 aUribarri J. 1 aCai W. 1 aGrosjean F. 1 aStriker G. 1 aChen X. 1 aWoodward Mark 1 aZhu L. 1 aSwamy S. 1 aZhao Z. 1 aSimonaro C. 1 aKuchel G. 1 aSchnaider-Beeri M. 00 aOral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans a2014/02/26 a4940-5 0 v111 3 a
Age-associated dementia and Alzheimer's disease (AD) are currently epidemic. Neither their cause nor connection to the metabolic syndrome (MS) is clear. Suppression of deacetylase survival factor sirtuin 1 (SIRT1), a key host defense, is a central feature of AD. Age-related MS and diabetes are also causally associated with suppressed SIRT1 partly due to oxidant glycotoxins [advanced glycation end products (AGEs)]. Changes in the modern diet include excessive nutrient-bound AGEs, such as neurotoxic methyl-glyoxal derivatives (MG). To determine whether dietary AGEs promote AD, we evaluated WT mice pair-fed three diets throughout life: low-AGE (MG(-)), MG-supplemented low-AGE (MG(+)), and regular (Reg) chow. Older MG(+)-fed mice, similar to old Reg controls, developed MS, increased brain amyloid-beta42, deposits of AGEs, gliosis, and cognitive deficits, accompanied by suppressed SIRT1, nicotinamide phosphoribosyltransferase, AGE receptor 1, and PPARgamma. These changes were not due to aging or caloric intake, as neither these changes nor the MS were present in age-matched, pair-fed MG(-) mice. The mouse data were enhanced by significant temporal correlations between high circulating AGEs and impaired cognition, as well as insulin sensitivity in older humans, in whom dietary and serum MG levels strongly and inversely associated with SIRT1 gene expression. The data identify a specific AGE (MG) as a modifiable risk factor for AD and MS, possibly acting via suppressed SIRT1 and other host defenses, to promote chronic oxidant stress and inflammation. Because SIRT1 deficiency in humans is both preventable and reversible by AGE reduction, a therapeutic strategy that includes AGE reduction may offer a new strategy to combat the epidemics of AD and MS.
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