Senescence-inhibitory Δ133p53α Counteracts Accelerated Ageing and Mortality

Research on progeria not only contributes to treatments for the disease but also enhances our understanding of physiological ageing1. Mouse models of progeria recapitulate pathological ageing phenotypes seen in patients, including cardiovascular defects, increased cellular senescence, systemic inflammation, DNA damage accumulation, and shortened lifespan2. In cultured cells from Hutchinson-Gilford progeria syndrome (HGPS) patients, the human p53 isoform Δ133p53α was previously shown to inhibit p53-mediated cellular senescence, proinflammatory IL-6 production, and DNA damage accumulation, and to extend cellular replicative lifespan3. Here we show that, in a heterozygous HGPS mouse model4, transgenic expression of Δ133p53α reproduces these in vitro-observed effects across multiple organs in vivo and extends median lifespan by 11% (387 versus 349 days, P = 0.0379). In the aorta and skin, Δ133p53α abrogates progeria-characteristic pathological changes and preserves tissue integrity. Our data further suggest that Δ133p53α may promote a broad spectrum of ageing-counteracting mechanisms, including bone homeostasis, metabolic fitness, antioxidant defense, youthful epigenome, and tissue stemness. Together with the anti-inflammatory and tissue-preserving effects of Δ133p53α in naturally aged mice and its age-associated downregulation in human tissues, this study suggests that Δ133p53α-based therapeutic strategies may be applicable not only to HGPS but also as broader interventions for preventing or delaying ageing.