Dynamics of the action of dFOXO on adult mortality in Drosophila
Dynamics of the action of dFOXO on adult mortality in Drosophila
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DOI：
10.1111/j.1474-9726.2007.00290.x
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发表时间：
2007-08-01
期刊：
影响因子：
7.8
通讯作者：
Partridge, Linda
中科院分区：
文献类型：
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作者：
Giannakou, Maria E.;Goss, Martin;Partridge, Linda
胰岛素/胰岛素生长因子（IGF）样信号（IIS）通路在秀丽隐杆线虫、果蝇和小鼠的寿命调节中具有保守作用。在秀丽隐杆线虫中，通过减少IIS来延长寿命需要关键的IIS靶标，叉头盒O类（FOXO）转录因子DAF-16。dFOXO，果蝇DAF-16同源基因，也是IIS的靶点，其在成人脂肪体中的过表达可延长寿命。在秀丽隐杆线虫中，IIS仅在成虫期起作用，决定成虫的存活率。通过诱导过表达系统，我们发现在果蝇成年脂肪体中持续的dFOXO过表达降低了整个成年期的死亡率。我们改变了不同成年年龄果蝇的IIS状态，并检测了这些开关对dFOXO表达和死亡率的影响。通过诱导表达系统，dFOXO蛋白水平在各年龄阶段均可上调或下调。如果IIS状态在成年早期被逆转，类似于另一种降低果蝇成年死亡率的干预措施，即饮食限制（DR），那么随后的死亡率就会完全转变为长期暴露于新的IIS状态的果蝇的死亡率。因此，在这个年龄，IIS对确定死亡风险起着重要作用。直到成年后4周，死亡率仍然对IIS状态的转换有反应，但此后没有反应。然而，与DR不同的是，随着IIS状态在逐渐变晚的年龄发生改变，死亡率表现为不完全转换，并以逐渐变小的变化作出反应。这些发现表明，dFOXO表达水平的改变对IIS状态的影响可能随着年龄的增长而下降，可能存在一些过程阻止或减少IIS状态切换的生理反应，或者与DR不同，该途径调节与衰老相关的损伤。dFOXO过表达果蝇的死亡率降低和寿命增加与雌性繁殖力的影响以及果蝇大脑中胰岛素样肽的表达水平无关。
The insulin/insulin growth factor (IGF)-like signaling (IIS) pathway has a conserved role in regulating lifespan in Caenorhabditis elegans, Drosophila and mice. Extension of lifespan by reduced IIS has been shown in C. elegans to require the key IIS target, forkhead box class O (FOXO) transcription factor, DAF-16. dFOXO, the Drosophila DAF-16 orthologue, is also an IIS target, and its overexpression in adult fat body increases lifespan. In C. elegans, IIS acts exclusively during adulthood to determine adult survival. We show here, using an inducible overexpression system, that in Drosophila continuous dFOXO overexpression in adult fat body reduces mortality rate throughout adulthood. We switched the IIS status of the flies at different adult ages and examined the effects of these switches on dFOXO expression and mortality rates. dFOXO protein levels were switched up or down by the inducible expression system at all ages examined. If IIS status is reversed early in adulthood, similar to the effects of another intervention that reduces adult mortality in Drosophila, dietary restriction (DR), there is a complete switch of subsequent mortality rate to that of flies chronically exposed to the new IIS regime. At this age, IIS thus acts acutely to determine risk of death. Mortality rates continued to respond to a switch in IIS status up to 4 weeks of adult age, but not thereafter. However, unlike DR, as IIS status was altered at progressively later ages, mortality rates showed incomplete switching and responded with progressively smaller changes. These findings indicate that alteration of expression levels of dFOXO may have declining effects on IIS status with age, that there could be some process that prevents or lessens the physiological response to a switch in IIS status or that, unlike DR, this pathway regulates aging-related damage. The decreased mortality and increased lifespan of dFOXO overexpressing flies was uncoupled from any effect on female fecundity and from expression levels of Drosophila insulin-like peptides in the brain.