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Hutchinson-Gilford Progeria Syndrome (HGPS), characterised by accelerated ageing, causes cardiovascular defects resembling aspects of cardiovascular ageing. We used human left ventricle cardiomyocytes (CMs) derived from HGPS-induced pluripotent stem cells (iPSCs), and their isogenic-corrected controls, to investigate HGPS-CM dysfunction and identify potential therapies.1 2 Our results revealed that HGPS-iPSC-CMs exhibit greater maturity resulting in elevated oxidative stress compared to controls, which they cannot contend with, leading to cellular senescence.Increased senescence was also observed in cardiac tissue from mouse and human physiologically-aged and HGPS individuals. Functionally, HGPS-iPSC-CMs showed dysregulated mitochondrial respiration and calcium handling. Amongst the six drugs tested, rapamycin and lonafarnib were the most effective against HGPS-cardiac phenotypes. Although lonafarnib raised safety concerns, it partially reverted the cardiac senescent phenotype by inducing cellular autophagy and decreasing progerin expression in progeroid mice. Our study supports the use of HGPS-iPSC-derived cardiomyocytes as a platform for identifying novel biomarkers and therapeutic strategies for HGPS, with potential relevance to physiological cardiac ageing as well.Reference bioRxiv 2025.06.27.661680; doi: https://doi.org/10.1101/2025.06.27.661680 Dark N, et al. Generation of left ventricle-like cardiomyocytes with improved structural, functional, and metabolic maturity from human pluripotent stem cells. Cell Rep Methods 2023;3(4):100456.