A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome.
A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome.
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DOI：
10.1016/j.cmet.2014.10.005
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发表时间：
2014-11-04
期刊：
影响因子：
29
通讯作者：
Bohr VA
中科院分区：
文献类型：
--
作者：
Scheibye-Knudsen M;Mitchell SJ;Fang EF;Iyama T;Ward T;Wang J;Dunn CA;Singh N;Veith S;Hasan-Olive MM;Mangerich A;Wilson MA;Mattson MP;Bergersen LH;Cogger VC;Warren A;Le Couteur DG;Moaddel R;Wilson DM 3rd;Croteau DL;de Cabo R;Bohr VA
柯凯因综合征（Cockayne syndrome， CS）是一种以编码DNA修复蛋白CSA或CSB的基因突变引起的进行性神经变性为特征的加速衰老疾病。给Csbm/m小鼠高脂肪、限热量或添加白藜芦醇的饮食。高脂肪饮食在代谢、转录组学和行为水平上挽救了Csbm/m小鼠的表型。进一步的分析表明，CS小鼠、线虫和人类细胞的早衰是由于DNA修复缺陷导致SIRT1活性降低和线粒体功能障碍导致PARP激活异常所致。值得注意的是，高脂肪饮食增加了β-羟基丁酸水平；β-羟基丁酸、PARP抑制或NAD+补充可以激活SIRT1并挽救cs相关表型。从机制上讲，CSB能够从受损DNA中取代活化的PARP1，从而限制其活性。本研究通过去乙酰化酶SIRT1将两种新兴的长寿代谢物β-羟基丁酸盐和NAD+联系起来，并提出了可能的CS干预措施。
Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in the genes encoding the DNA repair proteins CSA or CSB. Csbm/m mice were given a high fat, caloric restricted or resveratrol supplemented diet. The high fat diet rescued the phenotype of Csbm/m mice at the metabolic, transcriptomic and behavioral levels. Additional analysis suggests that the premature aging seen in CS mice, nematodes and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, β-hydroxybutyrate levels are increased by the high fat diet; and β-hydroxybutyrate, PARP inhibition, or NAD+ supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB is able to displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, β-hydroxybutyrate and NAD+, through the deacetylase SIRT1 and suggests possible interventions for CS.
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DOI：
10.1126/science.1227166
发表时间：
2013-01-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Shimazu T;Hirschey MD;Newman J;He W;Shirakawa K;Le Moan N;Grueter CA;Lim H;Saunders LR;Stevens RD;Newgard CB;Farese RV Jr;de Cabo R;Ulrich S;Akassoglou K;Verdin E
通讯作者：
Verdin E
DOI：
10.1083/jcb.201205149
发表时间：
2012-12-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Menoni H;Hoeijmakers JH;Vermeulen W
通讯作者：
Vermeulen W
影响因子：
64.5
作者：
Puigserver, P;Wu, ZD;Spiegelman, BM
通讯作者：
Spiegelman, BM
影响因子：
5.3
作者：
Jeong, Eun Ae;Jeon, Byeong Tak;Roh, Gu Seob
通讯作者：
Roh, Gu Seob
影响因子：
82.9
作者：
Jucker, Mathias
通讯作者：
Jucker, Mathias