Screening compound libraries for effects on aging in short-lived species has grown to become a significant area of interest in the aging research community. As a general rule, discoveries are modest in effect size, and largely take the form of novel ways to influence the beneficial maintenance and repair activities (such as autophagy) triggered by calorie restriction, heat, cold, and other forms of stress. These responses have a much larger effect on life span in short-lived species than in long-lived species, so in the long run are not all that interesting. Nonetheless, considerable effort has been made to find ways to make this screening process more efficient and automated. Research equipment has been constructed to house tens of thousands of nematode worms and use machine learning analysis of imagery to report on measures of health. Many of the techniques involved have been attempted in mouse studies to at least some degree. Here find an example of the state of the art in this type of work.
We describe the development and implementation of an integrated, high-throughput platform to evaluate the effects of small molecules on longevity across yeast, nematodes, flies, killifish, and mice. By utilizing miniaturized, automated assays with longitudinal imaging and machine learning-based death detection, we screened over 400 compounds and evaluated thousands of drug-dose conditions. This effort represents a first-of-its-kind screening campaign of this magnitude, testing conditions at a scale comparable to the entire existing literature for several of these models.
In S. cerevisiae, a miniaturized PI/flow cytometry chronological lifespan assay enables scalable screening and identifies key assay confounders, while in C. elegans and D. melanogaster, compact imaging platforms coupled to object detection models provide a no-transfer, high-throughput survival scoring, and capture compound-, diet-, and sex-dependent effects. In killifish, we develop an in-house drug-pellet formulation for standardized oral delivery in large cohorts, and in mice we combine longitudinal lifespan studies with home-cage activity monitoring to assess late-life interventions.
Across five evolutionarily distant models, we observed that consistent lifespan extension across species was achieved for only a subset of compounds, reflecting the challenge of identifying truly conserved geroprotectors. This result supports prior observations that most reported interventions in aging literature are model-specific or context-dependent. Nevertheless, a substantial number of compounds, including baicalein, doxycycline, forskolin, metformin, resveratrol, and rifampicin, displayed significant positive effects in multiple species, suggesting a tractable space of conserved pharmacological regulators of longevity.
Link: https://doi.org/10.1016/j.celrep.2026.117897
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