Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans

Weijing Cai, Jaime Uribarri, Li Zhu, Xue Chen, Shobha Swamy, Zhengshan Zhao, Fabrizio Grosjean, Calogera Simonaro, George A. Kuchel, Michal Schnaider-Beeri, Mark Woodward, Gary E. Striker, Helen Vlassara

Research output: Contribution to journalArticle

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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 amodifiable 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.

Original languageEnglish
Pages (from-to)4940-4945
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number13
DOIs
Publication statusPublished - Apr 1 2014

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Glyoxal
Sirtuin 1
Dementia
Alzheimer Disease
Oxidants
Metabolic Brain Diseases
Nicotinamide Phosphoribosyltransferase
Diet
Peroxisome Proliferator-Activated Receptors
Advanced Glycosylation End Products
Gliosis
Amyloid Plaques
Energy Intake
Cognition
Insulin Resistance
Inflammation
Gene Expression
Food
Survival

Keywords

  • Caloric restriction
  • Insulin resistance
  • Neural
  • Nutrition
  • Obesity

ASJC Scopus subject areas

  • General

Cite this

Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans. / Cai, Weijing; Uribarri, Jaime; Zhu, Li; Chen, Xue; Swamy, Shobha; Zhao, Zhengshan; Grosjean, Fabrizio; Simonaro, Calogera; Kuchel, George A.; Schnaider-Beeri, Michal; Woodward, Mark; Striker, Gary E.; Vlassara, Helen.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 13, 01.04.2014, p. 4940-4945.

Research output: Contribution to journalArticle

Cai, W, Uribarri, J, Zhu, L, Chen, X, Swamy, S, Zhao, Z, Grosjean, F, Simonaro, C, Kuchel, GA, Schnaider-Beeri, M, Woodward, M, Striker, GE & Vlassara, H 2014, 'Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 13, pp. 4940-4945. https://doi.org/10.1073/pnas.1316013111
Cai, Weijing ; Uribarri, Jaime ; Zhu, Li ; Chen, Xue ; Swamy, Shobha ; Zhao, Zhengshan ; Grosjean, Fabrizio ; Simonaro, Calogera ; Kuchel, George A. ; Schnaider-Beeri, Michal ; Woodward, Mark ; Striker, Gary E. ; Vlassara, Helen. / Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 13. pp. 4940-4945.
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