title: AMPK modulates tissue and organismal aging in a non-cell-autonomous manner.
abstract: 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.
authors.affiliation: 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.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ulgherait
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Rana
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rera
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Graniel
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: davidwalker@ucla.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Walker
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000375:Aging; D000818:Animals; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D001921:Brain / Q000378:metabolism; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010448:Peptide Initiation Factors; C410006:Thor protein, Drosophila; C518074:Atg1 protein, Drosophila; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases