TY - JOUR KW - Female KW - Humans KW - Aged KW - Male KW - Middle Aged KW - Time Factors KW - ADAM Proteins/genetics/metabolism KW - Administration, Oral KW - Amyloid Precursor Protein Secretases/genetics/metabolism KW - Amyloid beta-Peptides/metabolism KW - Animals KW - Brain/drug effects/pathology/physiopathology KW - Cognition/drug effects KW - Cytokines/metabolism KW - Dementia/blood/ pathology/physiopathology KW - Gliosis/metabolism/pathology/physiopathology KW - Glycosylation End Products, Advanced/administration & dosage/ adverse KW - effects/toxicity KW - Insulin/pharmacology KW - Membrane Proteins/genetics/metabolism KW - Memory/drug effects KW - Metabolic Syndrome X/blood/ pathology/physiopathology KW - Mice KW - Mice, Inbred C57BL KW - Nicotinamide Phosphoribosyltransferase/metabolism KW - Oxidative Stress/drug effects KW - PPAR gamma/metabolism KW - Pyruvaldehyde/administration & dosage/ adverse effects/blood/toxicity KW - Receptors, Immunologic/metabolism KW - Sirtuin 1/antagonists & inhibitors/metabolism KW - Transcription, Genetic/drug effects AU - Vlassara H. AU - Uribarri J. AU - Cai W. AU - Grosjean F. AU - Striker G. AU - Chen X. AU - Woodward Mark AU - Zhu L. AU - Swamy S. AU - Zhao Z. AU - Simonaro C. AU - Kuchel G. AU - Schnaider-Beeri M. AB -

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.

AD - Department of Geriatrics, Division of Experimental Diabetes, Medicine, Human Genetics, and Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY 10029. AN - 24567379 BT - Proceedings of the National Academy of Sciences of the United States of America C2 - PMC3977256 DP - NLM ET - 2014/02/26 LA - eng LB - PROF M1 - 13 N1 - 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
AG23188/AG/NIA NIH HHS/United States
M01-RR-00071/RR/NCRR NIH HHS/United States
R01 DK091231/DK/NIDDK NIH HHS/United States
R37 AG023188/AG/NIA NIH HHS/United States
Research Support, N.I.H., Extramural
United States
Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):4940-5. doi: 10.1073/pnas.1316013111. Epub 2014 Feb 24. N2 -

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.

PY - 2014 SN - 1091-6490 (Electronic)
0027-8424 (Linking) SP - 4940 EP - 5 T2 - Proceedings of the National Academy of Sciences of the United States of America TI - Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans VL - 111 ER -