Comprehensive Bioinformatics Analysis Reveals Molecular Signatures and Potential Caloric Restriction Mimetics with...

Area of Science:

• Neuroscience
• Gerontology
• Bioinformatics

Background:

• Caloric restriction (CR) extends lifespan and ameliorates age-related diseases in preclinical models.
• Caloric restriction mimetics (CRMs) offer therapeutic potential for age-related conditions.
• Understanding CR's neuroprotective mechanisms is crucial for developing interventions.

Purpose of the Study:

• To investigate the neuroprotective effects of CR on the brain neocortex.
• To identify potential CRMs using integrative bioinformatics and systems biology.
• To explore CR-related signaling pathways and molecular mechanisms.

Main Methods:

• Analysis of brain neocortex gene expression data (GSE11291) under long-term CR.
• Integrative bioinformatics and systems biology approaches to identify CRMs.
• Machine learning models for classifying small molecules based on CNS activity and anti-inflammatory properties.
• In vitro validation using oxygen-glucose deprivation (OGD) model.

Main Results:

• Long-term CR enhances mitochondrial function, antioxidant capacity, and reduces inflammation, conferring neuroprotection.
• Key signaling pathways (PPAR, mTOR, FoxO, AMPK, Notch) are enriched, regulating metabolism, stress response, and longevity.
• Potential CRMs, including rapamycin, were identified, with top candidates showing ischemic neuroprotective effects in vitro.

Conclusions:

• Long-term CR activates protective mechanisms that preserve neuronal function.
• The study identifies key genes, regulatory molecules, and potential CRMs for neurological disorders.
• Findings provide a foundation for developing CR-based therapies for age-related neurological diseases.