FOXO protects against age-progressive axonal degeneration

Inah Hwang, Hwanhee Oh, Evan Santo, Do Yeon Kim, John W. Chen, Roderick T. Bronson, Jason W. Locasale, Yoonmi Na, Jaclyn Lee, Stewart Reed, Miklos Toth, Wai H. Yu, Florian L. Muller, Jihye Paik

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


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.

Original languageEnglish
Article numbere12701
JournalAging Cell
Issue number1
StatePublished - Feb 2018

Bibliographical note

Publisher Copyright:
© 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.


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


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