Title: Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome Gabriel Balmus§1,2, Delphine Larrieu§*1,3, Ana C Barros1,2, Casey Collins2, Monica Abrudan2, Mukerrem Demir1, Nicola J Geisler1,2, Christopher J. Lelliott2, Jacqueline K. White2, Natasha A Karp2,4, James Atkinson5, Andrea Kirton2, Matt Jacobsen5, Dean Clift6, Sanger Mouse Genetics Project2, Raphael Rodriguez7,8,9, David J Adams2, Stephen P Jackson*1 § These authors contributed equally to the work 1. The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, CB2 1QN, United Kingdom. 2. The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom. 3. Current address: Cambridge Institute for Medical Research, Department of clinical biochemistry, University of Cambridge, CB2 0XY, United Kingdom. 4. Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, UK 5. Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge UK 6. Laboratory of Molecular Biology, Cambridge, CB2 OQH, United Kingdom. 7. Institut Curie, PSL Research University, Paris Cedex 05, France. 8. CNRS UMR3666, 75005 Paris, France. 9. INSERM U1143, 75005 Paris, France. 1 * Correspondence to
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[email protected] 2 Abstract Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence. Therapeutic approaches targeting farnesylation or aiming to reduce progerin levels have provided only partial health improvements.