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Aging Cell. 2018 Feb;17(1). doi: 10.1111/acel.12701. Epub 2017 Nov 26.

FOXO protects against age-progressive axonal degeneration.

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Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu, Korea.
Center for Systems Biology and the Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.


Neurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age-progressive axonal degeneration in mammals. FOXO expression progressively increased in aging human and mouse brains. The nervous system-specific deletion of Foxo transcription factors in mice accelerates aging-related axonal tract degeneration, which is followed by motor dysfunction. This accelerated neurodegeneration is accompanied by levels of white matter astrogliosis and microgliosis in middle-aged Foxo knockout mice that are typically only observed in very old wild-type mice and other aged mammals, including humans. Mechanistically, axonal degeneration in nerve-specific Foxo knockout mice is associated with elevated mTORC1 activity and accompanying proteotoxic stress due to decreased Sestrin3 expression. Inhibition of mTORC1 by rapamycin treatment mimics FOXO action and prevented axonal degeneration in Foxo knockout mice with accelerated nervous system aging. Defining this central role for FOXO in neuroprotection during mammalian aging offers an invaluable window into the aging process itself.


FOXO ; accelerated aging; aging; central nervous system; mouse models; neurodegeneration; neuroinflammation; oxidative stress

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