Brain molecular aging, promotion of neurological disease and modulation by sirtuin 5 longevity gene polymorphism.
Brain molecular aging, promotion of neurological disease and modulation by sirtuin 5 longevity gene polymorphism.
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DOI：
10.1016/j.nbd.2010.09.016
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发表时间：
2011-02
影响因子：
6.1
通讯作者：
Sibille, Etienne
中科院分区：
文献类型：
--
作者：
Glorioso, Christin;Oh, Sunghee;Douillard, Gaelle Guilloux;Sibille, Etienne
确定神经系统疾病特征性发病年龄的机制在很大程度上是未知的。正常的脑老化与稳健的和进行性的转录组变化（“分子老化”）有关，但与疾病途径的交叉点大多未被表征。在这里，使用四个人类大脑区域的跨队列微阵列分析，我们表明，神经系统疾病的途径在很大程度上与分子衰老重叠，并且在推定的长寿基因（Sirtuin 5; SIRT 5 prom 2）中携带新特征的低表达多态性的受试者具有较老的大脑分子年龄。具体来说，分子老化在整个队列和大脑区域中非常保守，包括许多发育和转录调节基因。神经系统疾病相关基因在年龄相关基因中的比例过高，并且几乎一致地朝着疾病的方向变化，这表明衰老的潜在遗传“程序”逐渐促进疾病。为了开始测试这一假定的途径，我们开发并使用了年龄生物特征来评估与分子衰老率相关的五个候选长寿基因多态性。最强有力的是，携带SIRT 5启动子多态性的受试者的扣带核而不是杏仁核中的衰老加速（+9岁，p=0.004），与扣带核特异性SIRT 5表达降低一致。这种效应是由一组核心转录物（+24岁，p=0.0004）驱动的，其中许多是线粒体，包括帕金森病基因，PINK 1和DJ 1/PARK 7，因此表明SIRT 5 prom 2可能代表线粒体功能障碍相关疾病的风险因素，包括帕金森病，通过加速疾病相关基因的分子老化。基于这些结果，我们推测，一个“共同的机制”可能是几种神经系统疾病发病年龄的基础。阐明这一途径及其通过常见遗传变异的调控将为预测、延迟和治疗神经系统疾病提供新的策略。
Mechanisms determining characteristic age of onset for neurological diseases are largely unknown. Normal brain aging associates with robust and progressive transcriptome changes (“molecular aging”), but the intersection with disease pathways is mostly uncharacterized. Here, using cross-cohort microarray analysis of four human brain areas, we show that neurological disease pathways largely overlap with molecular aging and that subjects carrying a newly-characterized low-expressing polymorphism in a putative longevity gene (Sirtuin5; SIRT5prom2) have older brain molecular ages. Specifically, molecular aging was remarkably conserved across cohorts and brain areas, and included numerous developmental and transcription-regulator genes. Neurological disease-associated genes were highly overrepresented within age-related genes and changed almost unanimously in pro-disease directions, together suggesting an underlying genetic “program” of aging that progressively promotes disease. To begin testing this putative pathway, we developed and used an age-biosignature to assess five candidate longevity gene polymorphisms association with molecular aging rates. Most robustly, aging was accelerated in cingulate, but not amygdala, of subjects carrying a SIRT5 promoter polymorphism (+9yrs, p=0.004), in concordance with cingulate-specific decreased SIRT5 expression. This effect was driven by a set of core transcripts (+24 yrs, p=0.0004), many of which were mitochondrial, including Parkinson’s disease genes, PINK1 and DJ1/PARK7, hence suggesting that SIRT5prom2 may represent a risk factor for mitochondrial dysfunction-related diseases, including Parkinson s, through accelerated molecular aging of disease-related genes. Based on these results we speculate that a “common mechanism” may underlie age of onset across several neurological diseases. Confirming this pathway and its regulation by common genetic variants would provide new strategies for predicting, delaying, and treating neurological diseases.
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DOI：
10.1126/science.1173635
发表时间：
2009-07-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Colman RJ;Anderson RM;Johnson SC;Kastman EK;Kosmatka KJ;Beasley TM;Allison DB;Cruzen C;Simmons HA;Kemnitz JW;Weindruch R
通讯作者：
Weindruch R
影响因子：
3.1
作者：
Colantuoni, Carlo;Hyde, Thomas M.;Kleinman, Joel E.
通讯作者：
Kleinman, Joel E.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
64.5
作者：
Kawahara TL;Michishita E;Adler AS;Damian M;Berber E;Lin M;McCord RA;Ongaigui KC;Boxer LD;Chang HY;Chua KF
通讯作者：
Chua KF
影响因子：
2.1
作者：
Feher, Agnes;Anna Juhasz;Janka, Zoltan
通讯作者：
Janka, Zoltan