Combining Life Extension Treatments: A Proposal for High-Throughput Testing in Rodents

Area of Science:

• Gerontology and aging research
• Experimental design and statistical modeling
• Pharmacology and drug discovery

Background:

• A significant backlog of potential life-extending treatments awaits mammalian testing.
• Existing therapies are rarely evaluated in combination, despite nonlinear dose-response and interaction effects.
• Optimized experimental designs are needed for high-throughput screening of complex interventions.

Purpose of the Study:

• To propose and evaluate two experimental designs for high-throughput screening of combined interventions.
• To maximize information gain for identifying synergistic treatments that extend lifespan.
• To develop cost-effective protocols for prioritizing promising therapeutic combinations.

Main Methods:

• Part I: Numerical simulations explored a protocol for single intervention dose-response assessment, maximizing information with unique dosages per animal.
• Part II: Simulations evaluated a protocol for testing interactions among multiple treatment combinations (focusing on triplets).
• Statistical inference using stepwise regression to identify individual treatment effects and pairwise interactions.

Main Results:

• Single intervention testing is most informative when each animal receives a distinct dosage.
• Testing combinations of three treatments offers a statistical sweet spot for detecting interactions.
• The proposed protocol can detect lifespan extension greater than 50% with 80% certainty, conserving resources by not detailing all survival curves.

Conclusions:

• The developed screening protocols can expedite the identification of potent life-extending treatment combinations.
• These methods enable efficient prioritization of interventions with the largest potential impact on lifespan.
• The designs balance statistical robustness with cost-effectiveness in preclinical aging research.