Giannakou Maria E, Goss Martin, Jacobson Jake, Vinti Giovanna, Leevers Sally J, Partridge Linda
Centre for Research on Ageing, Department of Biology, University College London, London, UK.
Aging Cell. 2007 Aug;6(4):429-38. doi: 10.1111/j.1474-9726.2007.00290.x. Epub 2007 Apr 26.
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.
胰岛素/胰岛素样生长因子（IGF）信号传导（IIS）通路在调控秀丽隐杆线虫、果蝇和小鼠的寿命方面具有保守作用。在秀丽隐杆线虫中，已表明通过降低IIS来延长寿命需要关键的IIS靶点——叉头框O类（FOXO）转录因子DAF - 16。果蝇的DAF - 16同源物dFOXO也是一个IIS靶点，其在成年脂肪体中的过表达可延长寿命。在秀丽隐杆线虫中，IIS仅在成年期起作用以决定成年后的存活率。我们在此使用诱导性过表达系统表明，在果蝇中，成年脂肪体中持续的dFOXO过表达可降低整个成年期的死亡率。我们在果蝇不同的成年年龄改变其IIS状态，并研究这些改变对dFOXO表达和死亡率的影响。在所有检测的年龄，诱导性表达系统均可上调或下调dFOXO蛋白水平。如果在成年早期逆转IIS状态，类似于另一种降低果蝇成年死亡率的干预措施——饮食限制（DR）的效果，随后的死亡率会完全转变为长期处于新IIS状态的果蝇的死亡率。在这个年龄，IIS因此会急性地决定死亡风险。成年后长达4周，死亡率持续对IIS状态的改变做出反应，但之后则不再有反应。然而，与DR不同的是，随着IIS状态在越来越晚的年龄被改变，死亡率显示出不完全的转变，且反应变化越来越小。这些发现表明，随着年龄增长，dFOXO表达水平的改变对IIS状态的影响可能会下降，可能存在某种过程阻止或减轻对IIS状态改变的生理反应，或者与DR不同，该通路调节与衰老相关的损伤。过表达dFOXO的果蝇死亡率降低和寿命延长与对雌性繁殖力的任何影响以及大脑中果蝇胰岛素样肽的表达水平无关。
