Network analyses unveil ageing-associated pathways evolutionarily conserved from fungi to animals

Area of Science:

• Evolutionary biology
• Genetics
• Biochemistry

Background:

• The genetic underpinnings of aging and longevity vary significantly across species and are not fully understood.
• Existing knowledge of aging/longevity pathways is incomplete regarding their constituent genes, proteins, and molecular interactions.
• Limited overlap exists in aging/longevity genes among mammals, necessitating comparative analyses to find conserved pathways.

Purpose of the Study:

• To analyze protein interactions related to aging and longevity across different species using an evolutionary and systems biology approach.
• To identify evolutionarily conserved and central pathways associated with aging and longevity.
• To discover novel, evolutionarily conserved longevity/aging-associated proteins (LAPs) in humans and potential therapeutic targets.

Main Methods:

• Utilized a dual evolutionary and systems biology strategy to examine protein-protein interaction (PPI) networks in five Opisthokonta species.
• Ranked proteins and interactions based on evolutionary conservation and network centrality.
• Analyzed the emergence, conservation, and centrality of aging/longevity pathways across evolutionary lineages.

Main Results:

• Longevity/aging-associated proteins (LAPs) are highly central in current PPI networks, supporting the antagonistic pleiotropy theory.
• Identified key antagonistic regulators of aging/longevity, with 52 having human homologs.
• Discovered a significant transition in key aging/longevity pathway components within bilaterians.
• Predicted 487 novel evolutionarily conserved LAPs in humans, with 138 being druggable targets.

Conclusions:

• Protein interaction networks provide a systemic view of aging and longevity pathway evolution.
• Highly conserved LAPs exist, but functionally important components have shifted within bilaterians.
• Identified numerous novel, druggable, evolutionarily conserved LAPs in humans, offering promising avenues for anti-aging interventions.