Targeting the FOXO4-p53 axis by retro-inverso peptide senolytic agents: a pharmacological strategy to mitigate brain...

Area of Science:

• Neuroscience
• Gerontology
• Cell Biology

Background:

• Cellular senescence, regulated by FOXO4-p53 interaction, is key in brain aging and neurodegeneration.
• Senescent cells accumulate with age, contributing to cognitive decline and neuroinflammatory conditions.
• The FOXO4-p53 axis is implicated in neuroinflammation, synaptic dysfunction, and impaired neurogenesis.

Purpose of the Study:

• To investigate the role of the FOXO4-p53 axis in brain aging and neurodegenerative diseases.
• To evaluate the therapeutic potential of senolytic peptide FOXO4-DRI in preclinical models.
• To explore FOXO4-axis modulators as a strategy for cognitive enhancement in aging.

Main Methods:

• Administration of senolytic peptide FOXO4-DRI in aged mammalian models.
• Assessment of senescent cell burden, cerebral blood flow, blood-brain barrier integrity, and cognitive function.
• Evaluation of amyloid-β and pathological tau levels in Alzheimer's disease and tauopathy models.
• Analysis of preliminary human data on FOXO4-axis modulators like fisetin.

Main Results:

• FOXO4-DRI reduced senescent cells, improved cerebral blood flow and BBB integrity, reversed atrophy, and enhanced cognition in aged models.
• In AD and tauopathy models, FOXO4-DRI cleared amyloid-β and tau, improving memory.
• Human studies showed fisetin reduced SASP and improved cognitive and physical measures in older adults.

Conclusions:

• The FOXO4-p53 axis is a viable pharmacological target for mitigating brain aging.
• Senolytic therapy, exemplified by FOXO4-DRI, shows promise in treating age-related cognitive decline and neurodegenerative diseases.
• Targeting FOXO4-dependent senescence may offer a novel strategy to counteract neuroinflammation and synaptic dysfunction in the aging brain.