A multiparametric anti-aging CRISPR screen uncovers a role for BAF in protein synthesis regulation

Sophia Y. Breusegem, Jack Houghton, Raquel Romero-Bueno, Adrián Fragoso-Luna, Katherine A. Kentistou, Ken K. Ong, Anne F. J. Janssen, Nicholas A. Bright, Christian G. Riedel, John R. B. Perry, Peter Askjaer and Delphine Larrieu ()
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Sophia Y. Breusegem: Hills Road
Jack Houghton: Hills Road
Raquel Romero-Bueno: Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide-Junta de Andalucía
Adrián Fragoso-Luna: Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide-Junta de Andalucía
Katherine A. Kentistou: Institute of Metabolic Science
Ken K. Ong: Institute of Metabolic Science
Anne F. J. Janssen: Hills Road
Nicholas A. Bright: Hills Road
Christian G. Riedel: 141 57
John R. B. Perry: Institute of Metabolic Science
Peter Askjaer: Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide-Junta de Andalucía
Delphine Larrieu: Hills Road

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Progeria syndromes are very rare, incurable premature aging conditions recapitulating most aging features. Here, we report a whole genome, multiparametric CRISPR screen, identifying 43 genes that can rescue multiple cellular phenotypes associated with progeria. We implement the screen in fibroblasts from Néstor-Guillermo Progeria Syndrome male patients, carrying a homozygous A12T mutation in BAF. The hits are enriched for genes involved in protein synthesis, protein and RNA transport and osteoclast formation and are validated in a whole-organism Caenorhabditis elegans model. We further confirm that BAF A12T can disrupt protein synthesis rate and fidelity, which could contribute to premature aging in patients. This work highlights the power of multiparametric genome-wide suppressor screens to identify genes enhancing cellular resilience in premature aging and provide insights into the biology underlying progeria-associated cellular dysfunction.

Date: 2025
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DOI: 10.1038/s41467-025-56916-5

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