FOXO protects against age-progressive axonal degeneration

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.