Department of Biochemistry and Biophysics, Mission Bay Genentech Hall, 600 16th Street, Room S312D, University of California, San Francisco, San Francisco, CA 94158-2517, USA.
Cell Metab. 2013 Jan 8;17(1):85-100. doi: 10.1016/j.cmet.2012.12.013.
In long-lived C. elegans insulin/IGF-1 pathway mutants, the life-extending FOXO transcription factor DAF-16 is present throughout the animal, but we find that its activity in a single tissue can delay the aging of other tissues and extend the animal's life span. To better understand the topography of DAF-16 action among the tissues, we analyzed a collection of DAF-16-regulated genes. DAF-16 regulated most of these genes in a cell-autonomous fashion, often using tissue-specific GATA factors to direct their expression to specific tissues. DAF-16 could also act cell nonautonomously to influence gene expression. DAF-16 affected gene expression in other cells, at least in part, via the lipid-gene regulator MDT-15. DAF-16, and probably MDT-15, could act cell nonautonomously in the endoderm to ameliorate the paralysis caused by expressing Alzheimer's Aβ protein in muscles. These findings suggest that MDT-15-dependent intercellular signals, possibly lipid signals, can help to coordinate tissue physiology, enhance proteostasis, and extend life in response to DAF-16/FOXO activity.
在长寿的 C. elegans 胰岛素/IGF-1 信号通路突变体中，延长寿命的 FOXO 转录因子 DAF-16 存在于整个动物体内，但我们发现其在单个组织中的活性可以延缓其他组织的衰老并延长动物的寿命。为了更好地了解 DAF-16 在组织中的作用，我们分析了一组 DAF-16 调控的基因。DAF-16 以细胞自主的方式调控大多数这些基因，通常使用组织特异性 GATA 因子将其表达导向特定的组织。DAF-16 还可以通过细胞非自主的方式影响基因表达。DAF-16 通过脂质基因调节剂 MDT-15 影响其他细胞的基因表达，至少部分如此。DAF-16，可能还有 MDT-15，可以通过细胞非自主的方式在内胚层中发挥作用，以改善在肌肉中表达阿尔茨海默病 Aβ 蛋白引起的瘫痪。这些发现表明，MDT-15 依赖的细胞间信号，可能是脂质信号，可以帮助协调组织生理学、增强蛋白质稳态并延长寿命，以响应 DAF-16/FOXO 活性。
