Repurposing Regulatory Rodent Toxicology Safety Archives to Identify Candidate Hormetic Longevity Agents Highlights Emergent Mitochondrial Mechanisms.
5 affiliations
- 1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
- 2German Federal Institute for Risk Assessment (BfR), Berlin, Germany.
- 3Leipzig University, Leipzig, Germany.
- 4Department of Biosciences, Durham University, Durham, UK.
- 5Magnitude Biosciences Limited, NETPark Plexus, Durham, UK.
Abstract
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 (BfR) 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 (≥ 10%, p < 0.05). 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, complement conventional screening pipelines, align with 3Rs by maximising existing data, and supply high-quality datasets for AI-driven prioritisation of interventions for rigorous preclinical follow-up.
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BibTeX
@article{miwa2026repurposing,
title = {{Repurposing Regulatory Rodent Toxicology Safety Archives to Identify Candidate Hormetic Longevity Agents Highlights Emergent Mitochondrial Mechanisms.}},
author = {Satomi Miwa and Olena Kucheryavenko and Kristin Herrmann and Adelaide Raimundo and Feng Xue and Karthik Mohanraj and Christopher Saunter and Lars Niemann and David Weinkove and Thomas von Zglinicki},
journal = {Aging cell},
year = {2026},
month = nov,
doi = {10.1111/acel.70797},
url = {https://europepmc.org/article/MED/42967495},
note = {CC BY},
}
RIS
TY - JOUR
TI - Repurposing Regulatory Rodent Toxicology Safety Archives to Identify Candidate Hormetic Longevity Agents Highlights Emergent Mitochondrial Mechanisms.
AU - Satomi Miwa
AU - Olena Kucheryavenko
AU - Kristin Herrmann
AU - Adelaide Raimundo
AU - Feng Xue
AU - Karthik Mohanraj
AU - Christopher Saunter
AU - Lars Niemann
AU - David Weinkove
AU - Thomas von Zglinicki
PY - 2026
DA - 2026/11/01
JO - Aging cell
DO - 10.1111/acel.70797
UR - https://europepmc.org/article/MED/42967495
AB - 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 (BfR) 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 (≥ 10%, p < 0.05). 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, complement conventional screening pipelines, align with 3Rs by maximising existing data, and supply high-quality datasets for AI-driven prioritisation of interventions for rigorous preclinical follow-up.
SN - 1474-9718
SN - 1474-9726
ER -