Enhancing lifespan of budding yeast by pharmacological lowering of amino acid pools.
Enhancing lifespan of budding yeast by pharmacological lowering of amino acid pools.
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DOI：
10.18632/aging.202849
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发表时间：
2021-03-21
期刊：
影响因子：
--
通讯作者：
Dickson RC
中科院分区：
文献类型：
--
作者：
Hepowit NL;Macedo JKA;Young LEA;Liu K;Sun RC;MacGurn JA;Dickson RC
年龄相关疾病的日益流行以及由此产生的医疗不安全和情绪负担需要新的治疗方法。一些有希望的策略寻求限制营养和促进健康老龄化。不幸的是，人类对食物的渴望意味着这种策略对大多数人来说并不实用，但药理学方法可能是一种可行的选择。我们之前的研究表明，豆蔻素可以通过调节包括雷帕霉素复合物1 （TORC1）靶点在内的信号通路，从而损害鞘脂合成，延长酿酒酵母的寿命。由于TORC1感知细胞氨基酸，我们分析了氨基酸库，并鉴定出17个氨基酸库被肉豆蔻素处理后降低。研究蛋氨酸转运蛋白Mup1，我们发现新合成的Mup1可以运输到质膜上，并在几个小时内保持稳定，但在药物处理的细胞中不活跃。通过在培养基中添加鞘磷脂可以绕过药物抑制恢复活性，从而证实了鞘脂对Mup1活性的要求。重要的是，遗传分析揭示了肉豆蔻素诱导的长寿需要TORC1上游的Gtr1/2（哺乳动物Rags）和Vps34-Pib2氨基酸传感通路，这与氨基酸可用性降低的作用机制一致。这些研究证明了通过药物诱导类似氨基酸限制的状态来促进健康衰老的可行性。
The increasing prevalence of age-related diseases and resulting healthcare insecurity and emotional burden require novel treatment approaches. Several promising strategies seek to limit nutrients and promote healthy aging. Unfortunately, the human desire to consume food means this strategy is not practical for most people but pharmacological approaches might be a viable alternative. We previously showed that myriocin, which impairs sphingolipid synthesis, increases lifespan in Saccharomyces cerevisiae by modulating signaling pathways including the target of rapamycin complex 1 (TORC1). Since TORC1 senses cellular amino acids, we analyzed amino acid pools and identified 17 that are lowered by myriocin treatment. Studying the methionine transporter, Mup1, we found that newly synthesized Mup1 traffics to the plasma membrane and is stable for several hours but is inactive in drug-treated cells. Activity can be restored by adding phytosphingosine to culture medium thereby bypassing drug inhibition, thus confirming a sphingolipid requirement for Mup1 activity. Importantly, genetic analysis of myriocin-induced longevity revealed a requirement for the Gtr1/2 (mammalian Rags) and Vps34-Pib2 amino acid sensing pathways upstream of TORC1, consistent with a mechanism of action involving decreased amino acid availability. These studies demonstrate the feasibility of pharmacologically inducing a state resembling amino acid restriction to promote healthy aging.
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影响因子：
5.3
作者：
Cutler, Roy G.;Thompson, Kenneth W.;Camandola, Simonetta;Mack, Kendra T.;Mattson, Mark P.
通讯作者：
Mattson, Mark P.
影响因子：
64.5
作者：
Fontana L;Partridge L
通讯作者：
Partridge L
影响因子：
29
作者：
Brandhorst S;Choi IY;Wei M;Cheng CW;Sedrakyan S;Navarrete G;Dubeau L;Yap LP;Park R;Vinciguerra M;Di Biase S;Mirzaei H;Mirisola MG;Childress P;Ji L;Groshen S;Penna F;Odetti P;Perin L;Conti PS;Ikeno Y;Kennedy BK;Cohen P;Morgan TE;Dorff TB;Longo VD
通讯作者：
Longo VD
影响因子：
16
作者：
Binda, Matteo;Peli-Gulli, Marie-Pierre;De Virgilio, Claudio
通讯作者：
De Virgilio, Claudio
影响因子：
46.9
作者：
Fiehn, O;Kopka, J;Willmitzer, L
通讯作者：
Willmitzer, L