Aims:Δ133p53α is a naturally occurring isoform of the human p53 protein that inhibits p53-mediated cellular senescence. We previously reported that transgenic expression of this senescence-inhibitory p53 isoform counteracts aging-associated pathological changes in progeria model mice (heterozygous Lmna G609G/+ ). The anti-aging effect of Δ133p53α was attributed in part to reduced levels of the proinflammatory cytokine IL-6. This study aims to comprehensively profile Δ133p53α-induced changes in cytokines and chemokines. Methods:A Luminex-based multiplex quantitative assay was performed using mouse serum samples from transgenic Δ133p53α-expressing Lmna G609G/+ mice and non-expressing controls. Quantitative RT-PCR and RNA in situ hybridization assays were used to assess Cxcl10 expression in mouse tissues. In addition, gene expression datasets from human tissues were analyzed. Results:We confirmed Δ133p53α-mediated repression of serum IL-6 levels. We also found that Δ133p53α reduced serum levels of CXCL1, IL-1α, and CXCL10. We further characterized CXCL10, which has not previously been associated with progeria in mice or humans. Consistent with reduced serum CXCL10 levels, both young (15-week-old) and old (10-month-old) Δ133p53α-expressing Lmna G609G/+ mice showed reduced Cxcl10 expression in the liver, spleen, and brain, major organs that produce CXCL10, compared with age-matched non-expressing controls. In naturally aged wild-type mice (2 years old), transgenic Δ133p53α expression also significantly repressed Cxcl10 expression in the spleen and brain. An inverse association between CXCL10 and Δ133p53α levels was observed in human spleen tissues, suggesting physiological relevance to human aging. Conclusion:CXCL10, a proinflammatory chemokine elevated in both accelerated and natural aging, is a potential target of the anti-inflammatory activity of Δ133p53α.

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.

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.

Δ133p53α is a naturally occurring isoform of the tumor suppressor protein p53. Δ133p53α functions as a physiological dominant-negative inhibitor of the full-length p53 protein (commonly referred to as p53). Δ133p53α preferentially inhibits p53-mediated cellular senescence, while it does not inhibit, or may even promote, p53-mediated DNA repair. Owing to this selective inhibitory activity that preserves genome stability, Δ133p53α represents a promising target for enhancement in the prevention and treatment of diseases associated with increased senescence of normal cells. These diseases include Alzheimer’s and other neurodegenerative diseases, premature aging diseases such as Hutchinson-Gilford progeria syndrome (HGPS), and idiopathic pulmonary fibrosis (IPF). Current cell-based therapies, which are limited by increased cellular senescence, may also benefit from Δ133p53α-mediated improvements. As an initial application of Δ133p53α in improving therapeutic cells, we here introduce Δ133p53α-armored chimeric antigen receptor (CAR)-T cells. Based on our previous and ongoing studies using various types of senescent human cells in vitro, we also discuss the importance of further exploring the therapeutic potentials of Δ133p53α, with particular focus on HGPS and IPF. The development of mouse models facilitates in vivo evaluation of the therapeutic effects of Δ133p53α, potentially leading to future clinical applications.

Non-neuronal glial cells in the brain, such as astrocytes, play essential roles in maintaining the functional integrity of neuronal cells. A growing body of evidence suggests that cellular senescence of astrocytes, characterized by loss of proliferative potential and secretion of neurotoxic cytokines, makes significant contribution to neurotoxicity in Alzheimer's disease and a wide range of other neurodegenerative diseases. This review discusses the beneficial effects of Δ133p53α, a natural p53 protein isoform that inhibits p53-mediated cellular senescence, thereby protecting astrocytes from senescence, highlights its potential as a therapeutic target, and underscores the need for continued research in this area. Both in senescent human astrocytes in culture, whether induced by replicative exhaustion, irradiation or exposure to amyloid-β, and in brain tissues with increased senescent astrocytes from patients with Alzheimer's disease, the expression levels of endogenous Δ133p53α protein were consistently and significantly reduced. The lentiviral vector-driven expression of Δ133p53α protected cultured human astrocytes from cellular senescence and neurotoxic secretory phenotype, leading to their cellular reprogramming to a neuroprotective state associated with neurotrophic growth factors. We thus propose that Δ133p53α is worth testing as a therapeutic target that can be enhanced in a wide range of neurodegenerative diseases with accumulated senescent astrocytes, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and chronic traumatic encephalopathy due to traumatic brain injury. We hypothesize that a Δ133p53α-mediated cellular reprogramming approach and a senolytic or senomorphic approach, both targeting non-neuronal cells, may be complementary with each other, and may cooperate with neuron-protecting or amyloid-β-targeting therapies currently in use.

Δ133p53α, a human/primate-specific p53 protein isoform, delays or inhibits the induction of the cellular senescence and associated secretory phenotype (SASP) in various types of human cells, including astrocytes from neurodegenerative diseases, Hutchinson-Gilford progeria syndrome (HGPS) fibroblasts, and exhausted CD8+ T-cells. A major regulatory mechanism of Δ133p53α expression in these human cells is protein degradation via chaperone-assisted selective autophagy (CASA). In this study, we describe a novel cell-based quantitative high-throughput screening (qHTS) assay using fluorescently labeled Δ133p53α to screen large chemical libraries for the identification of compounds that upregulate the Δ133p53α protein level. qHTS enabled the comprehensive and reliable profiling of over 10,000 small-molecule compounds. It also provided an opportunity to repurpose compounds and gain new mechanistic insights into the pathways regulating Δ133p53α expression. We successfully identified two candidate compounds, AZD1981 and celastrol, which were shown to upregulate the fluorescently labeled Δ133p53α protein, as well as the endogenous Δ133p53α protein in primary human astrocytes and the normal lung fibroblasts MRC-5, leading to reduced induction of cellular senescence and SASP factor secretion. The identification of celastrol, an inducer of heat shock protein 70 (HSP70) chaperones, is consistent with the CASA-mediated regulation of Δ133p53α protein turnover. Together with our previous findings of Δ133p53α overexpression-induced restoration of cell proliferation and function in cells otherwise approaching senescence, we propose that these two compounds may have therapeutic potential in senescence- and aging-associated diseases. The qHTS assay developed in this study could be used to identify new therapies for these diseases.

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 p21WAF1, which mediates p53-induced senescence and is inhibited by Δ133p53α), senescence-associated β-galactosidase (SA-β-gal) staining, enzyme-linked immunosorbent assay (IL-6, which is a proinflammatory cytokine secreted from senescent cells), and qRT-PCR assays (p21WAF1 and IL-6). Results:Treatment with celastrol (0.1 μM for 24 h) or AZD1981 (10 μM for 24 h) reproducibly increased Δ133p53α expression and decreased p21WAF1 expression in two strains of fibroblasts derived from HGPS patients. These compounds reduced the percentage of SA-β-gal-positive senescent cells and the secretion of IL-6 into culture medium in both of these fibroblast strains, irrespective of their different basal levels of senescence and IL-6 secretion. These compounds had no effect on the level of progerin. 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.

Tyrosine kinase (TK) inhibitors improve clinical outcomes in non-small cell lung cancer (NSCLC) with targetable mutations. However, such NSCLC cases account for only about 50% in the western populations. Inhibition of the splicing factor SRSF3 has been reported to be tumor-suppressive in other cancer cell types. This study for the first time explores the tumor-suppressive activity of siRNA knockdown of SRSF3 in NSCLC cells. The cell lines used were A549 (no TK mutation; TP53 wild type), NCI-H1975 (EGFR L858R/T790M; TP53 R273H mutant), NCI-H322 (no TK mutation; TP53 R248L mutant), and NCI-H596 (no TK mutation; TP53 G245C mutant). In all these cell lines, SRSF3 knockdown increased cellular senescence, as indicated by increased senescence-associated β-galactosidase activity and reduced cell proliferation. In A549 cells, increased apoptotic cleavage of caspase-3 and poly(ADP-ribose) polymerase was also observed. A tumor-suppressive p53 isoform, p53β, was shown to be upregulated by SRSF3 knockdown. However, overexpression of p53β did not induce cellular senescence or apoptosis, suggesting that this p53 isoform is not a primary effector of SRSF3 knockdown in NSCLC cells. Gene expression analyses suggested that the SRSF3 knockdown-induced senescence in NSCLC cells may be mediated by the downregulation of TOP2A, UBE2C, or ASPM, which are known oncogenic factors associated with poor patient prognosis. We also generated SRSF3 siRNA-encapsulating lipid nanoparticles as a future therapeutic tool. This study proposes a therapeutic strategy for NSCLC that is independent of the mutation status of TP53 and TK-encoding genes.

Mutations effects on p53 isoforms' activities remain largely unknown, although they are mutated in 92% of TP53 mutant cancers. Therefore, exploring the effect of mutations on p53 isoforms activities is a critical, albeit unexplored area in the p53 field. In this article, we report for the first time a mutant Δ133p53α-specific pathway which increases IL4I1 and IDO1 expression and activates AHR, a tumor-promoting mechanism. Accordingly, mutant Δ133p53α R273H increases glioblastoma cancer cells proliferation and invasion while the WT does not. Furthermore, while WT Δ133p53α reduces apoptosis to promote DNA repair, the mutant also reduces apoptosis but fails to maintain genomic stability.Furthermore, both WT and mutant Δ133p53α reduce cellular senescence in a senescence inducer-dependent manner (temozolomide or radiation) because they regulate different senescence-associated target genes. Hence, WT Δ133p53α rescues temozolomide-induced but not radiation-induced senescence, while mutant Δ133p53α R273H rescues radiation-induced but not temozolomide-induced senescence. Lastly, using TCGA data, we determined that IL4I1, IDO1 and AHR are significantly higher in GBMs compared to LGGs. IL4I1 expression is increased in mutant TP53 LGGs and GBMs, although only significantly in LGG. Importantly, high expression of all three genes in LGG and IL4I1 in GBM is significantly associated with poorer patients' survival. These data show that, compared to WT Δ133p53α, R273H mutation reorientates its activities toward carcinogenesis and activates the oncogenic IL4I1/IDO1/AHR pathway, a potential prognostic marker and therapeutic target in GBM by combining drugs specifically modulating Δ133p53α expression and IDO1/Il4I1/AHR inhibitors.

Chimeric antigen receptor (CAR) T cell dysfunction is a major barrier to achieving lasting remission in hematologic cancers, especially in chronic lymphocytic leukemia (CLL). We have shown previously that Δ133p53α, an endogenous isoform of the human TP53 gene, decreases in expression with age in human T cells, and that reconstitution of Δ133p53α in poorly functional T cells can rescue proliferation [A. M. Mondal et al. , J. Clin. Invest. 123 , 5247–5257 (2013)]. Although Δ133p53α lacks a transactivation domain, it can form heterooligomers with full-length p53 and modulate the p53-mediated stress response [I. Horikawa et al. , Cell Death Differ. 24 , 1017–1028 (2017)]. Here, we show that constitutive expression of Δ133p53α potentiates the anti-tumor activity of CD19-directed CAR T cells and limits dysfunction under conditions of high tumor burden and metabolic stress. We demonstrate that Δ133p53α-expressing CAR T cells exhibit a robust metabolic phenotype, maintaining the ability to execute effector functions and continue proliferating under nutrient-limiting conditions, in part due to upregulation of critical biosynthetic processes and improved mitochondrial function. Importantly, we show that our strategy to constitutively express Δ133p53α improves the anti-tumor efficacy of CAR T cells generated from CLL patients that previously failed CAR T cell therapy. More broadly, our results point to the potential role of the p53-mediated stress response in limiting the prolonged antitumor functions required for complete tumor clearance in patients with high disease burden, suggesting that modulation of the p53 signaling network with Δ133p53α may represent a translationally viable strategy for improving CAR T cell therapy.

Supplementary Figure 1-12, Table 1 from Functional Diversity of Human Protection of Telomeres 1 Isoforms in Telomere Protection and Cellular Senescence

Supplementary Table 1 from Nutlin-3a Activates p53 to Both Down-regulate Inhibitor of Growth 2 and Up-regulate <i>mir-34a, mir-34b,</i> and <i>mir-34c</i> Expression, and Induce Senescence

Supplementary Figure 7 from Nutlin-3a Activates p53 to Both Down-regulate Inhibitor of Growth 2 and Up-regulate <i>mir-34a, mir-34b,</i> and <i>mir-34c</i> Expression, and Induce Senescence

Cellular senescence is an important contributor to aging and age-related diseases such as Alzheimer's disease (AD). Senescent cells are characterized by a durable cell proliferation arrest and the acquisition of a proinflammatory senescence-associated secretory phenotype (SASP), which participates in the progression of neurodegenerative disorders. Clearance of senescent glial cells in an AD mouse model prevented cognitive decline suggesting pharmacological agents targeting cellular senescence might provide novel therapeutic approaches for AD. Δ133p53α, a natural protein isoform of p53, was previously shown to be a negative regulator of cellular senescence in primary human astrocytes, with clinical implications from its diminished expression in brain tissues from AD patients. Here we show that treatment of proliferating human astrocytes in culture with amyloid-beta oligomers (Aβ), an endogenous pathogenic agent of AD, results in reduced expression of Δ133p53α, as well as induces the cells to become senescent and express proinflammatory SASP cytokines such as IL-6, IL-1β and TNFα. Our data suggest that Aβ-induced astrocyte cellular senescence is associated with accelerated DNA damage, and upregulation of full-length p53 and its senescence-inducing target gene p21WAF1. We also show that exogenously enhanced expression of Δ133p53α rescues human astrocytes from Aβ-induced cellular senescence and SASP through both protection from DNA damage and dominant-negative inhibition of full-length p53, leading to inhibition of Aβ-induced, astrocyte-mediated neurotoxicity. The results presented here demonstrate that Δ133p53α manipulation could modulate cellular senescence in the context of AD, possibly opening new therapeutic avenues.

Tau accumulation is a core component of Alzheimer's disease and other neurodegenerative tauopathies. While tau's impact on neurons is a major area of research, the effect of extracellular tau on astrocytes is largely unknown. This article summarizes our recent studies showing that astrocyte senescence plays a critical role in neurodegenerative diseases and integrates extracellular tau into the regulatory loop of senescent astrocyte-mediated neurotoxicity. Human astrocytes in vitro undergoing senescence were shown to acquire the inflammatory senescence-associated secretory phenotype (SASP) and toxicity to neurons, which may recapitulate aging- and disease-associated neurodegeneration. Here, we show that human astrocytes exposed to extracellular tau in vitro also undergo cellular senescence and acquire a neurotoxic SASP (e.g. IL-6 secretion), with oxidative stress response (indicated by upregulated NRF2 target genes) and a possible activation of inflammasome (indicated by upregulated ASC and IL-1β). These findings suggest that senescent astrocytes induced by various conditions and insults, including tau exposure, may represent a therapeutic target to inhibit or delay the progression of neurodegenerative diseases. We also discuss the pathological activity of extracellular tau in microglia and astrocytes, the disease relevance and diversity of tau forms, therapeutics targeting senescence in neurodegeneration, and the roles of p53 and its isoforms in astrocyte-mediated neurotoxicity and neuroprotection.

Background Chromosomal inversions involving anaplastic lymphoma kinase ( ALK ) and echinoderm microtubule associated protein like 4 ( EML4 ) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells. Methods Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes. Results The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16 INK4A and p21 WAF1 , and senescence-associated β-galactosidase (SA-β-gal) activity. In contrast, when EML4-ALK was expressed in normal human fibroblasts transduced with telomerase reverse transcriptase (hTERT), which is activated in the vast majority of NSCLC, the cells showed accelerated proliferation and acquired anchorage-independent growth ability in soft-agar medium, without accumulated DNA damage, chromosome aberration, nor p53 mutation. EML4-ALK induced the phosphorylation of STAT3 in both mortal and hTERT-transduced cells, but RNA sequencing analysis suggested that the different signaling pathways contributed to the different phenotypic outcomes in these cells. While EML4-ALK also induced anchorage-independent growth in hTERT-immortalized human bronchial epithelial cells in vitro, the expression of EML4-ALK alone did not cause detectable in vivo tumorigenicity in immunodeficient mice. Conclusions Our data indicate that the expression of hTERT is critical for EML4-ALK to manifest its in vitro transforming activity in human cells. This study provides the isogenic pairs of human cells with and without EML4-ALK expression.

The TP53 gene is a critical tumor suppressor and key determinant of cell fate which regulates numerous cellular functions including DNA repair, cell cycle arrest, cellular senescence, apoptosis, autophagy and metabolism. In the last 15 years, the p53 pathway has grown in complexity through the discovery that TP53 differentially expresses twelve p53 protein isoforms in human cells with both overlapping and unique biologic activities. Here, we summarize the current knowledge on the Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ), which are evolutionary derived and found only in human and higher order primates. All three isoforms lack both of the transactivation domains and the beginning of the DNA-binding domain. Despite the absence of these canonical domains, the Δ133p53 isoforms maintain critical functions in cancer, physiological and premature aging, neurodegenerative diseases, immunity and inflammation, and tissue repair. The ability of the Δ133p53 isoforms to modulate the p53 pathway functions underscores the need to include these p53 isoforms in our understanding of how the p53 pathway contributes to multiple physiological and pathological mechanisms. Critically, further characterization of p53 isoforms may identify novel regulatory modes of p53 pathway functions that contribute to disease progression and facilitate the development of new therapeutic strategies.

Abstract Accumulating results of clinical trials lead targeted therapies to be the first choice for unresectable or recurrent lung cancer with driver mutations. Echinoderm Microtubule Associated Protein Like 4 (EML4) - Anaplastic lymphoma kinase (ALK) fusion is known as such a driver mutation. It presents in 3-6% of non-small cell lung carcinoma (NSCLC). EML4-ALK fusion protein generate the constitutive ALK kinase activity in NSCLC. The basic understanding of EML4-ALK remains insufficient due to the lack of functional studies using normal human cells. We investigated the role of EML4-ALK in mortal and immortalized normal human cells. The expression of EML4-ALK in normal, mortal human fibroblasts caused accumulated DNA damage, telomere shortening and the early induction of cellular senescence with senescence-associated beta-galactosidase activity and upregulation of p16INK4A and p21WAF1. In contrast, when EML4-ALK was expressed in telomerase reverse transcriptase (hTERT)-immortalized normal human fibroblasts and bronchial epithelial cells, the cells showed accelerated proliferation in vitro and anchorage-independent growth in soft agar, revealing its transformation activity. No chromosome aberrations, no mutations or loss of p53, nor impairment of the p16INK4A response was associated with this in vitro transformation, likely reflecting certain clinical features of EML4-ALK-positive NSCLC. In both mortal and immortalized cells, EML4-ALK induced the phosphorylation of STAT3, which is involved in both cellular senescence and transformation. Our data validate that EML4-ALK functions as an oncogene, although an additional oncogenic event(s) seems to be required for full tumorigenicity in vivo. This study also suggests that telomerase-mediated immortalization manifests the oncogenic activity of EML4-ALK, switching from its senescence-inducing activity. The RNA-seq analysis showed that the STAT3-induced cytokine/interferon signaling pathways were most significantly upregulated by EML4-ALK in mortal fibroblasts, consistent with accumulated DNA damage and senescence induction. The blood coagulation pathway activated by EML4-ALK in hTERT-immortalized cells may contribute to increased risk of disseminated intravenous coagulation in patients with EML4-ALK-positive cancer. These results suggest that EML4-ALK regulates the different signaling pathways in mortal versus immortalized normal human cells to induce the different cellular outcomes. Citation Format: Masaru Matsumoto, Akihiko Miyanaga, Jessica Beck, Izumi Horikawa, Mohammed Khan, Delphine Lissa, Masahiro Seike, Akihiko Gemma, Hiroyuki Mano, Curtis Harris. An ALK fusion gene regulates different signaling pathways in mortal versus immortalized normal human cells for cellular senescence and transformation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4900.

Cellular senescence and the associated secretory phenotype (SASP) promote disease in the aged population. Targeting senescent cells by means of removal, modulation of SASP or through cellular reprogramming represents a novel therapeutic avenue for treating cancer- and age-related diseases such as neurodegeneration, pulmonary fibrosis and renal disease. Cellular senescence is partly regulated by the TP53 gene, a critical tumor suppressor gene which encodes 12 or more p53 protein isoforms. This review marks a significant milestone of 40 years of Carcinogenesis publication history and p53 research and 15 years of p53 isoform research. The p53 isoforms are produced through initiation at alternative transcriptional and translational start sites and alternative mRNA splicing. These truncated p53 isoform proteins are endogenously expressed in normal human cells and maintain important functional roles, including modulation of full-length p53-mediated cellular senescence, apoptosis and DNA repair. In this review, we discuss the mechanisms and functions of cellular senescence and SASP in health and disease, the regulation of cellular senescence by p53 isoforms, and the therapeutic potential of targeting cellular senescence to treat cancer- and age-associated diseases.

Cellular senescence is a cell cycle arrest in damaged or aged cells. Although this represents a critical mechanism of tumor suppression, persistence of senescent cells during aging induces chronic inflammation and tissue dysfunction through the adoption of the senescence-associated secretory phenotype (SASP). This has been shown to promote the progression of age-associated diseases such as Alzheimer's disease, pulmonary fibrosis, and atherosclerosis. As the global population ages, the role of cellular senescence in disease is becoming a more critical area of research. In this review, mechanisms, biomarkers, and pathology of cellular senescence and SASP are described with a brief discussion of literature supporting a role for cellular senescence in veterinary diseases. Cell culture and mouse models used in senescence studies are also reviewed including the senescence-accelerated mouse-prone (SAMP), senescence pathway knockout mice (p53, p21 [CDKN1A], and p16 [CDKN2A]), and the more recently developed senolysis mice, which allow for direct visualization and elimination (or lysis) of senescent cells in live mice (p16-3MR and INK-ATTAC). These and other mouse models have demonstrated the importance of cellular senescence in embryogenesis and wound healing but have also identified a therapeutic benefit for targeting persistent senescent cells in age-associated diseases including neurodegeneration, diabetes, and cardiac fibrosis.