Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans
Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans
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DOI：
10.1073/pnas.1316013111
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发表时间：
2014-04-01
影响因子：
11.1
通讯作者：
Vlassara, Helen
中科院分区：
文献类型：
--
作者：
Cai, Weijing;Uribarri, Jaime;Vlassara, Helen
阿尔茨海默病（Alzheimer's disease，AD）是一种常见的老年痴呆症。它们的原因和与代谢综合征（MS）的联系都不清楚。去乙酰化酶生存因子sirtuin 1（SIRT 1），一个关键的宿主防御的抑制，是AD的一个中心特征。糖尿病相关的MS和糖尿病也与SIRT 1抑制有因果关系，部分原因是氧化糖毒素[晚期糖基化终产物（AGEs）]。现代饮食的变化包括过量的营养素结合的AGEs，如神经毒性的甲基乙二醛衍生物（MG）。为了确定饮食AGEs是否促进AD，我们评估了WT小鼠一生中成对喂养三种饮食：低AGE（MG（-）），MG补充的低AGE（MG（+））和常规（Reg）食物。与老年Reg对照组相似，老年MG（+）喂养小鼠发生MS，脑淀粉样蛋白β（42）增加，AGEs沉积，神经胶质增生和认知缺陷，伴有SIRT 1，烟酰胺磷酸核糖基转移酶，AGE受体1和PPAR γ抑制。这些变化不是由于衰老或热量摄入，因为这些变化和MS都不存在于年龄匹配的配对喂养的MG（-）小鼠中。高循环AGEs与认知受损以及老年人胰岛素敏感性之间的显著时间相关性增强了小鼠数据，其中饮食和血清MG水平与SIRT 1基因表达强烈负相关。这些数据确定了一种特定的AGE（MG）作为AD和MS的可改变的风险因素，可能通过抑制SIRT 1和其他宿主防御作用，促进慢性氧化应激和炎症。由于SIRT 1缺陷在人类中是可预防的和可逆的AGE减少，治疗策略，包括AGE减少可能提供一个新的战略，以打击AD和MS的流行。
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-beta(42), deposits of AGEs, gliosis, and cognitive deficits, accompanied by suppressed SIRT1, nicotinamide phosphoribosyltransferase, AGE receptor 1, and PPAR gamma. 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.