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FOXO protects against age-progressive axonal degeneration

Inah Hwang1, Hwanhee Oh1, Evan Santo1

  • 1Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.

Aging Cell
|November 28, 2017
PubMed

Insights

Forkhead Box O (FOXO) transcription factors protect neurons from aging-related degeneration. Inhibiting mTORC1 with rapamycin also prevents this decline, offering neuroprotection strategies for aging brains.

Area of Science:

  • Neuroscience
  • Genetics
  • Aging Research

Background:

  • Neurodegeneration, leading to cognitive and motor deficits, is a common aspect of aging.
  • The genetic factors regulating age-related neurodegeneration are not well understood.

Purpose of the Study:

  • To identify genetic regulators of age-related neurodegeneration.
  • To investigate the role of Forkhead Box O (FOXO) transcription factors in maintaining neuronal integrity during aging.

Main Methods:

  • Examined FOXO expression in aging human and mouse brains.
  • Generated mice with nervous system-specific deletion of Foxo transcription factors.
  • Assessed axonal degeneration, white matter gliosis, and mTORC1 activity.
  • Administered rapamycin to inhibit mTORC1 in knockout mice.

Main Results:

  • FOXO expression increased with age in mammalian brains.
  • Nervous system-specific Foxo deletion accelerated axonal degeneration and motor dysfunction in mice.
  • Accelerated degeneration in knockout mice showed increased astrogliosis and microgliosis.
  • Axonal degeneration was linked to elevated mTORC1 activity and reduced Sestrin3 expression.
  • Rapamycin treatment inhibited mTORC1, preventing axonal degeneration in knockout mice.

Conclusions:

  • FOXO transcription factors act as guardians of neuronal integrity, inhibiting age-progressive axonal degeneration.
  • FOXO-mediated neuroprotection during aging involves regulating mTORC1 activity and proteotoxic stress.
  • Targeting FOXO pathways or mTORC1 may offer therapeutic strategies for age-related neurodegeneration.
Keywords:
FOXOaccelerated agingagingcentral nervous systemmouse modelsneurodegenerationneuroinflammationoxidative stress

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