The journals of gerontology. Series A, Biological sciences and medical sciencesJun 19, 2026

Cell-based screen finds protein-making regulators that may extend lifespan in fruit flies and worms

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 20, 2026

Abstract

Fluspirilene significantly extended life in both Drosophila melanogaster and Caenorhabditis elegans.

Aging is associated with declining mitochondrial function and translational regulation.
Dietary restriction and cold-induced longevity inhibit global protein synthesis but enhance the translation of specific proteins that improve mitochondrial efficiency and lifespan.
The 4E-BP/eIF4E pathway mediates translational shifts based on the length and structure of mRNA's 5'-untranslated region.
A cell-based screen identified compounds that increased the expression of mRNAs with short 5'-UTRs, including known lifespan-extending agents.
Fluspirilene's longevity effects require specific transcription factors and an autophagy gene.
Fluspirilene's ability to extend lifespan is limited by evolutionary differences and nutrient conditions.

Simplified

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.

Full Text

Full text is available at the source.

View Full Text ↗

Featured in

Longevity & AgingIssue #42

Blood proteins from 60,542 people suggest 1-in-4 are aging faster in at least one cell type

↗

Cell-based screen finds protein-making regulators that may extend lifespan in fruit flies and worms

Abstract

Full Text

Featured in

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief