Combining life extension treatments: A proposal for high-throughput testing in rodents

Josh Mitteldorf

An experimental design is proposed for high-throughput testing of combined interventions that might increase life expectancy in rodents. There is a growing backlog of promising treatments that have never been tested in mammals, and known treatments have not been tested in combination. The dose-response curve is often nonlinear, as are the interactions among different therapies. Herein are proposed two experimental designs optimized for detecting high-value combinations. In Part I, numerical simulation is used to explore a protocol for testing different dosages of a single intervention. With reasonable and general biological assumptions about the dose-response curve, information is maximized when each animal receives a different dosage. In Part II, numerical simulation is used to explore a protocol for testing interactions among many combinations of treatments, once their individual dosages have been established. Combinations of three are identified as a sweet spot for statistics. To conserve resources, the protocol is designed to identify those outliers that lead to life extension greater than 50%, but not to offer detailed survival curves for any treatments. Every combination of three treatments from a universe of 15 total treatments is represented, with just three mice replicating each combination. Stepwise regression is used to infer information about the effects of individual treatments and all their pairwise interactions. Results are not quite as robust as for the dosage protocol in Part I, but if there is a combination that extends lifespan by more than 50%, it will be detected with 80% certainty. These two screening protocols offer the possibility of expediting the identification of treatment combinations that are most likely to have the largest effect, while controlling costs overall.