Senescence-inhibitory Δ133p53α Mitigates Accelerated Ageing in Mice

Abstract Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder caused by a de novo LMNA G608G mutation, is characterized by the accumulation of DNA damage and persistent inflammation, which drive accelerated aging and lead to severe clinical manifestations, including skin atrophy, alopecia, and progressive deterioration of the aortic wall due to loss of vascular smooth muscle cells, resulting in severely shortened lifespan. Mouse models of HGPS recapitulate these pathological aging phenotypes, including cardiovascular defects, increased cellular senescence, DNA damage accumulation, systemic inflammation, and shortened lifespan.The human p53 isoform Δ133p53α, which lacks the N-terminal 133 amino acids, is a naturally occurring truncated variant with distinct biological functions. In HGPS patient-derived fibroblasts, Δ133p53α suppresses cellular senescence, reduces pro-inflammatory IL-6 production, limits DNA-damage accumulation, and extends replicative lifespan. These findings suggest that Δ133p53α selectively attenuates p53-mediated cell-cycle arrest and senescence while preserving DNA-repair functions.Here, in a heterozygous HGPS mouse model, we show that transgenic expression of Δ133p53α reproduces these in vitro-observed effects across multiple organs in vivo and extends median lifespan by approximately 10% (387 vs. 358 days, P = 0.0235). In the aorta and skin, Δ133p53α mitigates progeria-associated pathological changes and preserves tissue integrity. Δ133p53α also mitigates spinal kyphosis characteristic of the HGPS mouse phenotype. RNA-sequencing analysis suggests that Δ133p53α promotes mitochondrial function and metabolic fitness. The effects of Δ133p53α in naturally aging mice are under investigation. Our human expression database analysis shows an age-associated downregulation of Δ133p53α in multiple human tissues, including aorta and skin.This study suggests not only a Δ133p53α-based therapeutic approach for HGPS but also broader interventions for preventing or delaying aging. Citation Format: Leo Yamada, Huaitian Liu, Natalia Von Muhlinen, Curtis C. Harris, Izumi Horikawa, . Senescence-inhibitory Δ133p53α mitigates accelerated ageing in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6001.