title: Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans.
abstract: 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-β42, deposits of AGEs, gliosis, and cognitive deficits, accompanied by suppressed SIRT1, nicotinamide phosphoribosyltransferase, AGE receptor 1, and PPARγ. 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.
authors.affiliation: Department of Geriatrics, Division of Experimental Diabetes, Medicine, Human Genetics, and Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Weijing
authors.initials: W
authors.lastname: Cai
authors.forename: Jaime
authors.initials: J
authors.lastname: Uribarri
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Xue
authors.initials: X
authors.lastname: Chen
authors.forename: Shobha
authors.initials: S
authors.lastname: Swamy
authors.forename: Zhengshan
authors.initials: Z
authors.lastname: Zhao
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Grosjean
authors.forename: Calogera
authors.initials: C
authors.lastname: Simonaro
authors.forename: George A
authors.initials: GA
authors.lastname: Kuchel
authors.forename: Michal
authors.initials: M
authors.lastname: Schnaider-Beeri
authors.forename: Mark
authors.initials: M
authors.lastname: Woodward
authors.forename: Gary E
authors.initials: GE
authors.lastname: Striker
authors.forename: Helen
authors.initials: H
authors.lastname: Vlassara
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein; D000284:Administration, Oral; D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003704:Dementia / Q000097:blood / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005911:Gliosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000008:administration & dosage / Q000009:adverse effects* / Q000633:toxicity; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008568:Memory / Q000187:drug effects; D024821:Metabolic Syndrome / Q000097:blood / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D011765:Pyruvaldehyde / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000633:toxicity; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D017127:Glycation End Products, Advanced; D007328:Insulin; D008565:Membrane Proteins; D047495:PPAR gamma; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011765:Pyruvaldehyde; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D056564:Sirtuin 1
keywords: caloric restriction; insulin resistance; neural; nutrition; obesity