Ulgherait Matthew, Rana Anil, Rera Michael, Graniel Jacqueline, Walker David W
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell Rep. 2014 Sep 25;8(6):1767-1780. doi: 10.1016/j.celrep.2014.08.006. Epub 2014 Sep 4.
AMPK exerts prolongevity effects in diverse species; however, the tissue-specific mechanisms involved are poorly understood. Here, we show that upregulation of AMPK in the adult Drosophila nervous system induces autophagy both in the brain and also in the intestinal epithelium. Induction of autophagy is linked to improved intestinal homeostasis during aging and extended lifespan. Neuronal upregulation of the autophagy-specific protein kinase Atg1 is both necessary and sufficient to induce these intertissue effects during aging and to prolong the lifespan. Furthermore, upregulation of AMPK in the adult intestine induces autophagy both cell autonomously and non-cell-autonomously in the brain, slows systemic aging, and prolongs the lifespan. We show that the organism-wide response to tissue-specific AMPK/Atg1 activation is linked to reduced insulin-like peptide levels in the brain and a systemic increase in 4E-BP expression. Together, these results reveal that localized activation of AMPK and/or Atg1 in key tissues can slow aging in a non-cell-autonomous manner.
AMPK在多种物种中发挥着延长寿命的作用；然而，其中涉及的组织特异性机制却知之甚少。在此，我们表明，成年果蝇神经系统中AMPK的上调会在大脑和肠道上皮中诱导自噬。自噬的诱导与衰老过程中肠道内环境稳定的改善以及寿命的延长有关。自噬特异性蛋白激酶Atg1在神经元中的上调对于衰老过程中诱导这些组织间效应并延长寿命而言，既是必要的也是充分的。此外，成年肠道中AMPK的上调会在大脑中细胞自主和非细胞自主地诱导自噬，减缓全身衰老，并延长寿命。我们表明，机体对组织特异性AMPK/Atg1激活的反应与大脑中胰岛素样肽水平的降低和4E-BP表达的全身增加有关。总之，这些结果表明，关键组织中AMPK和/或Atg1的局部激活可以以非细胞自主的方式减缓衰老。
