Wide-scale comparative analysis of longevity genes and interventions

Area of Science:

• Genetics
• Evolutionary Biology
• Aging Research

Background:

• Hundreds of genes influence lifespan in model organisms, termed longevity-associated genes (LAGs).
• A key question is whether these LAGs are species-specific or act as universal aging regulators.
• Understanding conserved longevity mechanisms is crucial for aging research.

Purpose of the Study:

• To investigate the evolutionary conservation and functional roles of longevity-associated genes (LAGs) across diverse taxa.
• To determine if identified LAGs play universal roles in lifespan regulation or are model-specific.
• To explore conserved aging principles like antagonistic pleiotropy.

Main Methods:

• Comparative genomic analysis of 1805 known LAGs across 205 species.
• Ortholog identification and overrepresentation analysis in genomes and interactomes.
• Examination of lifespan effects from manipulating orthologous LAGs in different model organisms.

Main Results:

• LAG orthologs are significantly overrepresented across taxa, particularly essential LAGs.
• Manipulating orthologous LAGs yielded largely concordant lifespan effects despite evolutionary distances.
• LAGs conserved across many phyla are enriched in translational, metabolism, and DNA repair pathways.
• Taxa-specific LAGs are enriched in autophagy, G proteins, and neuroactive ligand-receptor interactions.

Conclusions:

• Longevity-associated genes exhibit significant evolutionary conservation, suggesting universal roles in aging.
• Antagonistic pleiotropy appears to be a conserved aging principle.
• Overexpression studies of LAGs hold promise for identifying longevity regulators.