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Updated: Jun 21, 2026
A Screenable In Vivo Assay for Mitochondrial Modulators Using Transgenic Bioluminescent Caenorhabditis elegans
Published on: October 16, 2015
Cell-based screen identifies translation state modulators that extend lifespan in Drosophila melanogaster and
Binbin Wu1, Li-Jie Wang1, Adwait A Godbole1
1Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida, United States.
Abstract:
Aging is associated with declining mitochondrial function and translational regulation-processes modulated by interventions such as dietary restriction (DR) and cold-induced longevity (CHIL). Both DR and CHIL inhibit global protein synthesis but selectively enhance translation of proteins that support mitochondrial efficiency, stress resistance, and lifespan extension. These translational shifts are mediated, at least in part, by the 4E-BP/eIF4E pathway, which regulates translation according to mRNA 5'-untranslated region (5'-UTR) length and structure. To identify compounds that mimic the beneficial effects of DR/CHIL, we developed a cell-based phenotypic screen that reports on mRNA translation as a function of 5'-UTR length. A pilot screen identified compounds that preferentially increased the expression of mRNAs with short 5'-UTRs relative to those with long 5'-UTRs, and these hits were enriched for known lifespan-extending agents, such as curcumin and rapamycin. Among the novel candidates, fluspirilene significantly extended life in both Drosophila melanogaster and Caenorhabditis elegans, and mitigated age-related locomotor decline in female flies. Fluspirilene-mediated longevity in C. elegans required the DAF-16/FOXO and HLH-30/TFEB transcription factors and the autophagy gene, atg-18. Fluspirilene failed to extend lifespan in two other Caenorhabditis species, as well as in flies maintained on a high-yeast diet, indicating that its pro-longevity effects are constrained by evolutionary divergence and nutrient status. Together, our findings identify fluspirilene as a novel modulator of translation that extends life and preserves healthspan via an autophagy-dependent mechanism and support the promise of drug discovery efforts that modulate translation state as a therapeutic strategy for healthy aging.
Insights
Researchers discovered fluspirilene, a novel compound that extends lifespan and improves healthspan by modulating protein translation. This drug mimics beneficial aging interventions like dietary restriction, offering a new therapeutic strategy for healthy aging.
Area of Science:
- Gerontology and Molecular Biology
- Focuses on aging, mitochondrial function, and translational control.
Background:
- Aging involves decreased mitochondrial function and altered translational regulation.
- Dietary restriction (DR) and cold-induced longevity (CHIL) enhance mitochondrial efficiency and lifespan by selectively boosting specific protein synthesis.
- The 4E-BP/eIF4E pathway regulates translation based on mRNA 5'-untranslated region (5'-UTR) characteristics.
Purpose of the Study:
- To identify compounds that replicate the lifespan-extending effects of DR and CHIL by modulating mRNA translation.
- To investigate novel therapeutic strategies for healthy aging through translation state modulation.
Main Methods:
- Developed a cell-based phenotypic screen to identify compounds affecting mRNA translation based on 5'-UTR length.
- Tested identified compounds, including fluspirilene, for lifespan extension and healthspan benefits in model organisms (Drosophila melanogaster and Caenorhabditis elegans).
- Investigated the molecular mechanisms of fluspirilene's action, including genetic requirements (DAF-16/FOXO, HLH-30/TFEB, atg-18) and nutrient/evolutionary constraints.
Main Results:
- The screen identified compounds, including known agents like curcumin and rapamycin, that preferentially increase expression of short 5'-UTR mRNAs.
- Fluspirilene significantly extended lifespan and mitigated age-related locomotor decline in flies and worms.
- Fluspirilene's pro-longevity effects in C. elegans depend on DAF-16/FOXO, HLH-30/TFEB, and autophagy (atg-18), but are limited by species and diet.
Conclusions:
- Fluspirilene is a novel translation modulator that extends lifespan and preserves healthspan through an autophagy-dependent pathway.
- Targeting translational regulation represents a promising therapeutic avenue for promoting healthy aging.
- The efficacy of fluspirilene is influenced by evolutionary context and nutrient availability.
