Identifying Hormetic Agents that Modestly Slow Aging from Mouse Toxicology Study Data
Regulatory systems in wealthier parts of the world ensure that a great many different compounds at different doses are entered into long-term toxicology studies primarily conducted in mice. Researchers here report on the results of looking through that data in search of compounds that improved health and extended life. Hormesis is the name given to the benefits to health and longevity resulting from mild exposure to stress, whether toxicity, heat, cold, lack of nutrients, and so forth. Cells have evolved to react with increased maintenance and defenses when placed under stress, and if the stress is mild and transient, then the overall outcome is a net benefit to cell and tissue function. It is thus reasonable to think in advance of checking that some toxicology studies incorporated doses that improved health rather than damaged it.
Efforts to extend longevity and healthspan have benefited from the use of in vitro systems, short-lived model organisms and computational approaches, but translation to humans depends on demonstrating efficacy and safety in mammalian in vivo models. However, rigorously controlled rodent lifespan studies are slow, costly, and low-throughput. Hormesis, the induction of adaptive stress response pathways by low-level toxic or metabolic challenges, provides a mechanistic means for improved resilience, but testing hormetic dose-response relationships in mammals is logistically challenging.
Regulatory long-term toxicity studies, mandated for chemical authorisation, routinely generate lifespan and chronic toxicity data from large cohorts across multiple dose groups and therefore represent an underused resource for detecting unexpected survival benefits. We mined a random subset of the German Federal Institute for Risk Assessment electronic archive for long-term rodent pesticide studies in ≥ 50 animals per dose and sex. From qualifying studies with 154 substances, we identified 27 substances (18% of entries) that significantly increased survival at study termination.
Fifteen publicly disclosable substances were examined further; roughly half perturbed mitochondrial oxygen consumption rates in mammalian cells, and bromoxynil acted as a mitochondrial uncoupler. Back-translation to Caenorhabditis elegans showed bromoxynil improved multiple healthspan indicators without compromising organismal health. Regulatory toxicity archives can thus be repurposed to identify candidate compounds, targets, and mechanisms for mammalian healthy ageing research, and complement conventional screening pipelines.