The increasing age of global populations highlights the urgent need to understand the biological underpinnings of ageing. To this end, inhibition of the insulin/insulin-like signalling (IIS) pathway can extend healthy lifespan in diverse animal species, but with trade-offs including delayed development. It is possible that distinct cell types underlie effects on development and ageing; cell-type-specific strategies could therefore potentially avoid negative trade-offs when targeting diseases of ageing, including prevalent neurodegenerative diseases. The highly conserved diversity of neuronal and non-neuronal (glial) cell types in the Drosophila nervous system makes it an attractive system to address this possibility. We have thus investigated whether IIS in distinct glial cell populations differentially modulates development and lifespan in Drosophila. We report here that glia-specific IIS inhibition, using several genetic means, delays development while extending healthy lifespan. The effects on lifespan can be recapitulated by adult-onset IIS inhibition, whereas developmental IIS inhibition is dispensable for modulation of lifespan. Notably, the effects we observe on both lifespan and development act through the PI3K branch of the IIS pathway and are dependent on the transcription factor FOXO. Finally, IIS inhibition in several glial subtypes can delay development without extending lifespan, whereas the same manipulations in astrocyte-like glia alone are sufficient to extend lifespan without altering developmental timing. These findings reveal a role for distinct glial subpopulations in the organism-wide modulation of development and lifespan, with IIS in astrocyte-like glia contributing to lifespan modulation but not to developmental timing. Our results enable a more complete picture of the cell-type-specific effects of the IIS network, a pathway whose evolutionary conservation in humans make it tractable for therapeutic interventions. Our findings therefore underscore the necessity for cell-type-specific strategies to optimise interventions for the diseases of ageing.

中文翻译：

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独立的神经胶质亚型可通过减少胰岛素-PI3K信号传导延迟发育并延长健康寿命。

全球人口年龄的增长凸显了迫切需要了解老龄化的生物学基础。为此，抑制胰岛素/类胰岛素信号传导（IIS）途径可以延长各种动物的健康寿命，但需要权衡取舍，包括延缓发育。发育和衰老可能是不同细胞类型的基础。因此，针对细胞类型的策略可以潜在地避免针对衰老疾病（包括普遍的神经退行性疾病）的负面权衡。果蝇神经系统中神经元和非神经元（神经胶质）细胞类型高度保守的多样性使其成为解决这种可能性的诱人系统。因此，我们研究了不同果胶质细胞群体中的IIS是否在果蝇中差异地调节发育和寿命。我们在这里报告，胶质细胞特异性IIS抑制，使用几种遗传手段，延缓了发育，同时延长了健康寿命。成年的IIS抑制作用可以概括对寿命的影响，而发育性IIS抑制作用对于调节寿命是必不可少的。值得注意的是，我们观察到的对寿命和发育的影响都是通过IIS途径的PI3K分支起作用的，并且取决于转录因子FOXO。最后，对几种神经胶质亚型的IIS抑制可以延迟发育而不会延长寿命，而仅在星形胶质样神经胶质中进行相同的操作就足以延长寿命而不会改变发育时间。这些发现揭示了不同的神经胶质亚群在整个生物体的发育和寿命调节中的作用，而星形胶质样神经胶质细胞中的IIS有助于寿命的调节，但对发育时间没有贡献。我们的研究结果使人们更完整地了解了IIS网络对细胞类型的特定作用，该途径在人体中的进化保守使其可用于治疗性干预。因此，我们的发现强调了针对细胞类型的策略以优化针对衰老疾病的干预措施的必要性。一种途径，其在人类中的进化保守性使其可用于治疗性干预。因此，我们的发现强调了针对细胞类型的策略以优化针对老年疾病的干预措施的必要性。一种途径，其在人类中的进化保守性使其可用于治疗性干预。因此，我们的发现强调了针对细胞类型的策略以优化针对老年疾病的干预措施的必要性。