Pharmacologic activation of Δ133p53α reduces cellular senescence in progeria patients-derived cells.

Background: Patients with Hutchinson-Gilford progeria syndrome (HGPS) show accelerated aging phenotypes and have shortened lifespan, with implications in physiological aging processes as well. While therapeutic approaches targeting the disease-causing abnormal protein, progerin, have been developed, further efforts to explore mechanistically distinct and complementary strategies are still critical to better treatment regimens. We previously showed that lentiviral vector-driven expression of Δ133p53α, a natural inhibitory isoform of p53, rescued HGPS patients-derived fibroblasts from early entry into cellular senescence, which is a downstream event of progerin-induced DNA damage. We also performed a quantitative high-throughput screen (qHTS) of approved drug and investigational agent libraries, leading to the identification of celastrol and AZD1981 as compounds that upregulate Δ133p53α protein levels. Methods: To investigate whether celastrol and ADZ1981 upregulate endogenous Δ133p53α in HGPS-derived fibroblasts and reduce their senescence-associated phenotypes, we performed western blot assays (Δ133p53α, progerin, and p21 Results: Treatment with celastrol (0.1 μM for 24 h) or AZD1981 (10 μM for 24 h) reproducibly increased Δ133p53α expression and decreased p21 Conclusion: Celastrol and ADZ1981 upregulate endogenous Δ133p53α and, reproducing the effects of its vector-driven expression, inhibit cellular senescence and IL-6 secretion in HGPS-derived fibroblasts. Their progerin-independent action suggests that they may synergize with currently available progerin-targeting therapies. This study also warrants further investigation of these compounds for potential applications in other diseases and conditions in which Δ133p53α-regulated senescence plays a role.