FOXO protects against age-progressive axonal degeneration.

TitleFOXO protects against age-progressive axonal degeneration.
Publication TypeJournal Article
Year of Publication2018
AuthorsHwang I, Oh H, Santo E, Kim D-Y, Chen JW, Bronson RT, Locasale JW, Na Y, Lee J, Reed S, Toth M, Yu WH, Muller FL, Paik J
JournalAging Cell
Volume17
Issue1
Date Published2018 02
ISSN1474-9726
KeywordsAging, Animals, Axons, Forkhead Transcription Factors, Gene Expression Regulation, Mechanistic Target of Rapamycin Complex 1, Mice, Knockout, Protective Agents, Signal Transduction
Abstract

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.

DOI10.1111/acel.12701
Alternate JournalAging Cell
PubMed ID29178390
PubMed Central IDPMC5771393
Grant ListR01 CA193256 / CA / NCI NIH HHS / United States
R01 AG048284 / AG / NIA NIH HHS / United States
R56 AG048284 / AG / NIA NIH HHS / United States
R00 CA168997 / CA / NCI NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
S10 OD018164 / OD / NIH HHS / United States
Related Faculty: 
Ji-Hye Paik, Ph.D.

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