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Open Access Publications from the University of California

AMPK Functions to Modulate Tissue and Organismal Aging in a Cell Non-Autonomous Manner

  • Author(s): Ulgherait, Matthew John
  • Advisor(s): Walker, David W.
  • Guo, Feng
  • et al.

Understanding the biological mechanisms of aging represents an urgent biomedical challenge. AMP-activated protein kinase (AMPK) exhibits pro-longevity effects in diverse species. However, the tissue-specific mechanisms involved in AMPK regulation of aging are poorly understood. Here, we show that activation of AMPK in the adult Drosophila nervous system induces autophagy both in the brain and the intestinal epithelium. These cell autonomous and non-autonomous functions of AMPK are linked to improved intestinal homeostasis, muscle proteostasis and extended lifespan. Neuronal upregulation of the autophagy-specific protein kinase Atg1 is both necessary and sufficient to induce these inter-tissue effects during aging, resulting in prolonged lifespan. Furthermore, transgenic AMPK overexpression in neurons is sufficient to increase endogenous AMPK gene activity in distal tissues of the organism, including the intestine.

In a complementary approach, transgenic upregulation of AMPK specifically in the adult intestine induces autophagy both cell autonomously and non-autonomously in the brain, exhibiting slowed systemic aging and prolonged lifespan. Additionally, we show that the organism-wide response to tissue-specific AMPK/Atg1 activation is linked to suppressed Drosophila insulin-like peptide (DILP) signaling. Together, these results reveal that localized transgenic activation of AMPK can function to relay pro-longevity signals to distal tissues. AMPK may now represent part of a novel brain-to-gut and gut-to-brain signaling axis in Drosophila.

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