Systematic Druggable Genome-Wide Analysis Identifies Therapeutic Targets for Aging: A Mendelian Randomization Study

Area of Science:

• Genetics and Bioinformatics
• Pharmacology
• Aging Research

Background:

• No effective drug treatments currently exist for aging.
• Mendelian randomization (MR) is a powerful tool for drug repurposing and identifying therapeutic targets.
• Aging presents a significant unmet medical need, driving the search for novel interventions.

Purpose of the Study:

• To identify druggable genes associated with aging.
• To evaluate potential adverse effects of targeting these genes.
• To explore underlying mechanisms and identify actionable drugs for aging.

Main Methods:

• Integrated druggable genome, cis-expression quantitative trait loci (eQTL), and genome-wide association study (GWAS) data.
• Employed two-sample Mendelian randomization (MR) to analyze gene-aging relationships.
• Conducted sensitivity analyses, Bayesian colocalization, phenome-wide MR (Phe-MR), and mediation MR for validation and mechanistic insights.

Main Results:

• Identified five key druggable genes linked to aging: ATP1B3, VKORC1, SLC5A11, HNRNPA1, and SMN2.
• Phenome-wide MR (Phe-MR) indicated no significant adverse effects associated with targeting these genes.
• Mediation MR revealed ten plasma proteins involved in the gene-aging pathway, and identified cardiac glycosides, Bisacodyl, Olsalazine, and Tegoprazan as potential therapeutics targeting ATP1B3.

Conclusions:

• ATP1B3, VKORC1, SLC5A11, HNRNPA1, and SMN2 represent promising targets for anti-aging drug development.
• These findings provide a foundation for prioritizing therapeutic strategies against aging.
• The study highlights potential drug repurposing opportunities for existing medications.