A DUAL MTOR/NAD+ ACTING GEROTHERAPY.

Area of Science:

• Gerontology and disease research
• Molecular biology and metabolic pathways
• Neurodegenerative and liver disease research

Background:

• The geroscience hypothesis posits that targeting aging processes can prevent multiple age-related diseases.
• The mechanistic target of rapamycin (mTOR)/insulin and nicotinamide adenine dinucleotide (NAD+) pathways are key validated aging pathways, but their interaction in aging remains unclear.
• Non-alcoholic steatohepatitis (NASH) and amyotrophic lateral sclerosis (ALS) are debilitating diseases lacking effective treatments and convenient biomarkers.

Approach:

• Utilized genome-wide CRISPRa screening to identify novel compounds, leading to the discovery of N-O-Methyl-propanamide-containing compounds named BIOIO-1001.
• Identified lipid metabolism, specifically involving SIRT3, as a convergence point for mTOR/insulin and NAD+ pathways.
• Conducted in vivo testing of BIOIO-1001 in diet-induced NASH models and both sporadic and familial ALS models.

Key Points:

• BIOIO-1001 demonstrated efficacy in reducing metabolic derangements, inflammation, and fibrosis characteristic of NASH.
• The compound exhibited protective effects in both sporadic and familial models of ALS, suggesting broad therapeutic potential.
• Plasma triglycerides were identified as a potentially convenient biomarker for monitoring patient response to BIOIO-1001 therapy.

Conclusions:

• BIOIO-1001 represents a novel therapeutic approach aligning with the geroscience hypothesis by targeting multiple core aging pathways.
• This compound shows potential for alleviating multiple age-related conditions, including NASH and ALS, after onset.
• The modulation of plasma triglycerides offers a practical biomarker for patient stratification and therapeutic monitoring.