Human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases

Area of Science:

• Geroscience
• Computational Biology
• Pharmacology

Background:

• Extending human healthspan is a major geroscience goal.
• Current geroprotector discovery relies heavily on model organisms, with uncertain human efficacy.
• Identifying human-specific aging pathways is crucial for effective intervention discovery.

Purpose of the Study:

• To introduce and validate the Aging Network Based Drug Discovery (ANDRU) strategy for identifying human geroprotectors.
• To leverage human aging subnetworks and transcriptional data for drug discovery.
• To improve the identification of interventions targeting aging and age-related diseases.

Main Methods:

• Developed the ANDRU strategy to identify human aging subnetworks at the interface of aging and disease.
• Screened for pharmacological interventions to reverse age-associated transcriptional changes within these subnetworks.
• Applied ANDRU to human adipose gene expression data from the Genotype Tissue Expression (GTEx) project.

Main Results:

• ANDRU identified 31 potential compounds, with 19 showing evidence for improving metabolic traits or lifespan.
• Notable hits included type 2 diabetes drugs like pioglitazone.
• Refining aging genes to those with stronger disease links increased the identification of meaningful drug candidates.

Conclusions:

• ANDRU is a promising human data-driven strategy for accelerating the discovery of healthspan-extending interventions.
• The network-based approach improves the identification of geroprotective drug candidates compared to general screening.
• This method holds potential for discovering interventions against age-related diseases.