Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila.
Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila.
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DOI：
10.1371/journal.pgen.1009083
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发表时间：
2020-11
期刊：
影响因子：
4.5
通讯作者：
Partridge L
中科院分区：
文献类型：
--
作者：
Bjedov I;Cochemé HM;Foley A;Wieser D;Woodling NS;Castillo-Quan JI;Norvaisas P;Lujan C;Regan JC;Toivonen JM;Murphy MP;Thornton J;Kinghorn KJ;Neufeld TP;Cabreiro F;Partridge L
自噬导致的细胞降解增加是许多延缓衰老的干预措施的一个特点。我们在这里报告，增加自噬对于减少胰岛素样信号传导（IIS）以延长果蝇的寿命是必要的，并且其本身足以延长寿命。我们首先确定，通过下调必需的自噬基因 Atg5，可以完全消除与胰岛素受体底物 chico 缺失相关的寿命延长。接下来，我们通过过度表达主要自噬激酶 Atg1 直接诱导自噬，并发现自噬的轻微增加可以延长寿命。有趣的是，Atg1 的强烈上调不利于寿命。转录组学和代谢组学方法确定了果蝇中不同水平的自噬介导的特定特征。线粒体相关基因的转录上调是与 Atg1 轻度上调和延长寿命最相关的特征，而 Atg1 强烈过度表达的短命果蝇则表现出线粒体代谢减少和免疫系统途径上调。蛋白酶体活性增加和三酰甘油水平降低是 Atg1 中度和高过表达条件的共同特征。自噬对衰老和差异代谢特征的这些对比效应凸显了微调自噬水平以实现最佳健康寿命和疾病预防的重要性。患有与年龄相关疾病的人数不断增加，凸显了衰老研究对改善健康寿命的重要性。两种经过充分研究的延长寿命和改善健康的进化保守干预措施是饮食限制和营养感应途径的下调，例如胰岛素的葡萄糖感应和雷帕霉素靶标信号传导途径的氨基酸感应。这些抗衰老干预措施的一个共同特征是自噬的增加，自噬是一种细胞途径，可降解受损的蛋白质和细胞器以提供必需的构建模块和能量。为了帮助在自噬和健康衰老之间提供更直接的联系，我们微调了 Atg1 激酶（这对于自噬诱导至关重要）的过度表达，并测量了其对果蝇寿命的影响。有趣的是，我们观察到自噬的适度增加有利于延长健康寿命，而自噬的强烈上调则是有害的，会导致进行性脂质丢失和寿命缩短。 Atg1 中度和较强的过表达表现出相反的线粒体基因转录谱，在长寿的 Atg1 过表达动物中上调，在短命的 Atg1 过表达动物中下调。总体而言，我们详细描述了与体内不同程度的自噬上调相关的表型，证明自噬增强仅在适度应用时才能延缓衰老。
Increased cellular degradation by autophagy is a feature of many interventions that delay ageing. We report here that increased autophagy is necessary for reduced insulin-like signalling (IIS) to extend lifespan in Drosophila and is sufficient on its own to increase lifespan. We first established that the well-characterised lifespan extension associated with deletion of the insulin receptor substrate chico was completely abrogated by downregulation of the essential autophagy gene Atg5. We next directly induced autophagy by over-expressing the major autophagy kinase Atg1 and found that a mild increase in autophagy extended lifespan. Interestingly, strong Atg1 up-regulation was detrimental to lifespan. Transcriptomic and metabolomic approaches identified specific signatures mediated by varying levels of autophagy in flies. Transcriptional upregulation of mitochondrial-related genes was the signature most specifically associated with mild Atg1 upregulation and extended lifespan, whereas short-lived flies, possessing strong Atg1 overexpression, showed reduced mitochondrial metabolism and up-regulated immune system pathways. Increased proteasomal activity and reduced triacylglycerol levels were features shared by both moderate and high Atg1 overexpression conditions. These contrasting effects of autophagy on ageing and differential metabolic profiles highlight the importance of fine-tuning autophagy levels to achieve optimal healthspan and disease prevention. The increasing number of people living with age-related diseases underscores the importance of ageing research to improve healthspan. Two well-studied evolutionary conserved interventions that extend lifespan and improve health are dietary restriction and down-regulation of nutrient sensing pathways, such as glucose sensing by insulin and amino acid sensing by the target-of-rapamycin signalling pathway. One common characteristic of these anti-ageing interventions is an increase in autophagy, a cellular pathway that degrades damaged proteins and organelles to supply essential building blocks and energy. To help provide a more direct link between autophagy and healthy ageing, we fine-tuned overexpression of Atg1 kinase, which is critical for autophagy induction, and measured its effect on longevity in the fruit fly Drosophila. Interestingly, we observed that a moderate increase in autophagy is beneficial in extending healthy lifespan, whereas strong autophagy up-regulation is detrimental and leads to progressive lipid loss and decreased lifespan. Moderate and stronger Atg1 overexpression displayed opposing transcriptional profiles of mitochondrial genes, being upregulated in long-lived and down-regulated in short-lived Atg1 over-expressing animals. Overall, we provide a detailed description of the phenotypes associated with varying degrees of autophagy up-regulation in vivo, demonstrating that autophagy enhancement delays ageing only when applied in moderation.
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影响因子：
4.5
作者：
Chakrabarti S;Dudzic JP;Li X;Collas EJ;Boquete JP;Lemaitre B
通讯作者：
Lemaitre B
影响因子：
29
作者：
Cochemé HM;Quin C;McQuaker SJ;Cabreiro F;Logan A;Prime TA;Abakumova I;Patel JV;Fearnley IM;James AM;Porteous CM;Smith RA;Saeed S;Carré JE;Singer M;Gems D;Hartley RC;Partridge L;Murphy MP
通讯作者：
Murphy MP
影响因子：
64.5
作者：
de Cabo R;Carmona-Gutierrez D;Bernier M;Hall MN;Madeo F
通讯作者：
Madeo F
影响因子：
64.5
作者：
Böhni, R;Riesgo-Escovar, J;Hafen, E
通讯作者：
Hafen, E
影响因子：
3.9
作者：
Ford, Daniel;Hoe, Nicholas;Tower, John
通讯作者：
Tower, John