Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans.
Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans.
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DOI：
10.1186/s12863-015-0167-2
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发表时间：
2015-02-03
期刊：
影响因子：
2.9
通讯作者：
Bradshaw PC
中科院分区：
文献类型：
--
作者：
Edwards C;Canfield J;Copes N;Brito A;Rehan M;Lipps D;Brunquell J;Westerheide SD;Bradshaw PC
关于氨基酸在细胞信号通路中的作用知之甚少，特别是当它涉及到调节衰老速率的通路时。然而，已经表明甲硫氨酸或色氨酸限制延长了高等真核生物的寿命，并且增加脯氨酸或色氨酸水平增加了C.优美的此外，亮氨酸强烈激活TOR信号传导通路，当抑制时会增加寿命。因此，将20种蛋白质氨基酸中的每一种单独补充到C。elegans和对寿命的影响进行了测定。除苯丙氨酸和天冬氨酸外，所有氨基酸在3种测试浓度中的一种或多种下至少在小程度上延长寿命，丝氨酸和脯氨酸显示出最大的效果。其中11种氨基酸在较高剂量下效力较低，而5种甚至会降低寿命。丝氨酸、脯氨酸或组氨酸介导的寿命延长在eat-2蠕虫（一种饮食限制模型）、daf-16/FOXO、sir-2.1、rsks-1（核糖体S6激酶）、gcn-2和aak-2（AMPK）长寿途径突变体以及bec-1自噬缺陷敲低蠕虫中受到极大抑制。测试的10种促进长寿的氨基酸中有8种激活了SKN-1/Nrf 2报告菌株，而丝氨酸和组氨酸是激活缺氧诱导因子（HIF-1）报告菌株的唯一氨基酸。补充脯氨酸或色氨酸可提高耐热性，而色氨酸介导的寿命延长不依赖于β-16/FOXO和SKN-1/Nrf 2信号传导，但色氨酸和几种相关的含吡啶化合物诱导线粒体未折叠蛋白反应和ER应激反应。高葡萄糖水平或影响电子传递链（ETC）功能的突变抑制了氨基酸介导的寿命延长，表明代谢起着重要作用。为C.秀丽线虫也增加了寿命，这表明三羧酸（TCA）循环底物的回补可能在寿命延长中起作用。补充了C.具有20种氨基酸中的18种的秀丽线虫延长了寿命，但寿命通常随着浓度的增加而减少，这表明了毒物兴奋效应。寿命延长似乎是由线粒体TCA循环代谢和呼吸底物利用的改变引起的，从而导致β-16/FOXO和SKN-1/Nrf 2应激反应途径的激活。本文的在线版本（doi：10.1186/s12863-015-0167-2）包含补充材料，可供授权用户使用。
Little is known about the role of amino acids in cellular signaling pathways, especially as it pertains to pathways that regulate the rate of aging. However, it has been shown that methionine or tryptophan restriction extends lifespan in higher eukaryotes and increased proline or tryptophan levels increase longevity in C. elegans. In addition, leucine strongly activates the TOR signaling pathway, which when inhibited increases lifespan. Therefore each of the 20 proteogenic amino acids was individually supplemented to C. elegans and the effects on lifespan were determined. All amino acids except phenylalanine and aspartate extended lifespan at least to a small extent at one or more of the 3 concentrations tested with serine and proline showing the largest effects. 11 of the amino acids were less potent at higher doses, while 5 even decreased lifespan. Serine, proline, or histidine-mediated lifespan extension was greatly inhibited in eat-2 worms, a model of dietary restriction, in daf-16/FOXO, sir-2.1, rsks-1 (ribosomal S6 kinase), gcn-2, and aak-2 (AMPK) longevity pathway mutants, and in bec-1 autophagy-defective knockdown worms. 8 of 10 longevity-promoting amino acids tested activated a SKN-1/Nrf2 reporter strain, while serine and histidine were the only amino acids from those to activate a hypoxia-inducible factor (HIF-1) reporter strain. Thermotolerance was increased by proline or tryptophan supplementation, while tryptophan-mediated lifespan extension was independent of DAF-16/FOXO and SKN-1/Nrf2 signaling, but tryptophan and several related pyridine-containing compounds induced the mitochondrial unfolded protein response and an ER stress response. High glucose levels or mutations affecting electron transport chain (ETC) function inhibited amino acid-mediated lifespan extension suggesting that metabolism plays an important role. Providing many other cellular metabolites to C. elegans also increased longevity suggesting that anaplerosis of tricarboxylic acid (TCA) cycle substrates likely plays a role in lifespan extension. Supplementation of C. elegans with 18 of the 20 individual amino acids extended lifespan, but lifespan often decreased with increasing concentration suggesting hormesis. Lifespan extension appears to be caused by altered mitochondrial TCA cycle metabolism and respiratory substrate utilization resulting in the activation of the DAF-16/FOXO and SKN-1/Nrf2 stress response pathways. The online version of this article (doi:10.1186/s12863-015-0167-2) contains supplementary material, which is available to authorized users.
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影响因子：
7.8
作者：
Alvers AL;Fishwick LK;Wood MS;Hu D;Chung HS;Dunn WA Jr;Aris JP
通讯作者：
Aris JP
影响因子：
3.7
作者：
Edwards CB;Copes N;Brito AG;Canfield J;Bradshaw PC
通讯作者：
Bradshaw PC
影响因子：
10.5
作者：
Hamilton, B;Doug, YQ;Lee, SS
通讯作者：
Lee, SS
影响因子：
5.4
作者：
Fuchs S;Bundy JG;Davies SK;Viney JM;Swire JS;Leroi AM
通讯作者：
Leroi AM
DOI：
10.1074/mcp.m113.027383
发表时间：
2013-12
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Depuydt G;Xie F;Petyuk VA;Shanmugam N;Smolders A;Dhondt I;Brewer HM;Camp DG 2nd;Smith RD;Braeckman BP
通讯作者：
Braeckman BP