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Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown. To test the idea that SnCs might play a causative role in OA, we used the p16-3MR transgenic mouse, which harbors a p16INK4a (Cdkn2a) promoter driving the expression of a fusion protein containing synthetic Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase (HSV-TK). This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.

Cellular senescence is defined as an irreversible growth arrest with the acquisition of a distinctive secretome. The growth arrest is a potent anticancer mechanism whereas the secretome facilitates wound healing, tissue repair, and development. The senescence response has also become increasingly recognized as an important contributor to aging and age-related diseases, including cancer. Although oncogenic mutations are capable of inducing a beneficial senescence response that prevents the growth of premalignant cells and promotes cancer immune-surveillance, the secretome of senescent cells also includes factors with pro-tumorigenic properties. On June 23rd and 24th, 2016, the Division of Cancer Biology of the National Cancer Institute sponsored a workshop to discuss the complex role of cellular senescence in tumorigenesis with the goal to define the major challenges and opportunities within this important field of cancer research. Additionally, it was noted how the development of novel tools and technologies are required to accelerate research into a mechanistic understanding of senescent cells in carcinogenesis in order to overcome the current limitations in this exciting, yet ill-defined area.

Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr-/-) mice, we show that these cells are detrimental throughout disease pathogenesis. We find that foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis, where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines. In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease production. Together, these results demonstrate that senescent cells are key drivers of atheroma formation and maturation and suggest that selective clearance of these cells by senolytic agents holds promise for the treatment of atherosclerosis.

Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations; increased chromosome missegregation; and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the [BUBR1.sup.L1012P] mutation in mice ([BubR1.sup.L1002P]) and combined it with 2 other MVA variants, [BUBR1.sup.X753] and [BUBR1.sup.H], generating a truncated protein and low amounts of wild-type protein, respectively. Whereas [BubR1.sup.X753/L1002P] and [BubR1.sup.H/X753] mice died prematurely, [BubR1.sup.H/L1002P] mice were viable and exhibited many MVA features, including cancer predisposition and various progeroid phenotypes, such as short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a reduction in total BUBR1 and spectrum of MVA phenotypes similar to that of [BubR1.sup.H/H] mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype complexity. Additionally, mice carrying monoallelic BubRI mutations were prone to select MVA-related pathologies later in life, with predisposition to sarcopenia correlating with mTORC1 hyperactivity. Together, these data demonstrate that BUBR1 allelic effects beyond protein level and aneuploidy contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations., Introduction Mosaic-variegated aneuploidy (MVA) syndrome is an autosomal recessive syndrome characterized by near-diploid aneuploidies involving multiple tissues and chromosomes (1-4). A wide variety of additional clinical features are associated with [...]

A homozygous truncating frameshift mutation in CEP57([CEP57.sup.T/T]) has been identified in a subset of mosaic- variegated aneuploidy (MVA) patients; however, the physiological roles of the centrosome- associated protein CEP57 that contribute to disease are unknown. To investigate these, we have generated a mouse model mimicking this disease mutation. [Cep57.sup.T/T] mice died within 24 hours after birth with short, curly tails and severely impaired vertebral ossification. Osteoblasts in lumbosacral vertebrae of [Cep57.sup.T/T] mice were deficient for Fgf2, a Cep57 binding partner implicated in diverse biological processes, including bone formation. Furthermore, a broad spectrum of tissues of [CEP57.sup.T/T] mice had severe aneuploidy at birth, consistent with the MVA patient phenotype. [Cep57.sup.T/T] mouse embryonic fibroblasts and patient-derived skin fibroblasts failed to undergo centrosome maturation in [G.sub.2] phase, causing premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high rates of chromosome missegregation. Mice heterozygous for the truncating frameshift mutation or a Cep57-null allele were overtly indistinguishable from WT mice despite reduced Cep57 protein levels, yet prone to aneuploidization and cancer, with tumors lacking evidence for loss of heterozygosity. This study identifies Cep57 as a haploinsufficient tumor suppressor with biologically diverse roles in centrosome maturation and Fgf2-mediated bone formation., Introduction Rare hereditary human syndromes characterized by extensive genetic and phenotypic heterogeneity are among the most difficult diseases to understand at a molecular mechanistic level, and research on such syndromes [...]

Cellular senescence, a major tumor-suppressive cell fate, has emerged from humble beginnings as an in vitro phenomenon into recognition as a fundamental mechanism of aging. In the process, senescent cells have attracted attention as a therapeutic target for age-related diseases, including cardiovascular disease (CVD), the leading cause of morbidity and mortality in the elderly. Given the aging global population and the inadequacy of current medical management, attenuating the health care burden of CVD would be transformative to clinical practice. Here, we review the evidence that cellular senescence drives CVD in a bimodal fashion by both priming the aged cardiovascular system for disease and driving established disease forward. Hence, the growing field of senotherapy (neutralizing senescent cells for therapeutic benefit) is poised to contribute to both prevention and treatment of CVD., Introduction During aging, the human mortality rate rises exponentially as a result of a loss of normal organ functions, including tissue maintenance and repair capacity. Stressors that young tissue may [...]

Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of [p16.sup.Ink4a] (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in [p16.sup.Ink4a]-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of [p16.sup.Ink4a]-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, [p16.sup.Ink4a]-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan., Cellular senescence is a well-established cancer defence mechanism that has also been proposed to have roles in ageing and age-associated diseases, presumably through the depletion of stem and progenitor cells, [...]

The nuclear pore complex protein NUP88 is frequently elevated in aggressive human cancers and correlates with reduced patient survival; however, it is unclear whether and how NUP88 overexpression drives tumorigenesis. Here, we show that mice overexpressing NUP88 are cancer prone and form intestinal tumors. To determine whether overexpression of NUP88 drives tumorigenesis, we engineered transgenic mice with doxycycline-inducible expression of Nup88. Surprisingly, NUP88 overexpression did not alter global nuclear transport, but was a potent inducer of aneuploidy and chromosomal instability. We determined that NUP88 and the nuclear transport factors NUP98 and RAE1 comprise a regulatory network that inhibits premitotic activity of the anaphase-promoting complex/cyclosome (APC/C). When overexpressed, NUP88 sequesters NUP98-RAE1 away from [APC/C.sup.CDH1], triggering proteolysis of polo-like kinase 1 (PLK1), a tumor suppressor and multitasking mitotic kinase. Premitotic destruction of PLK1 disrupts centrosome separation, causing mitotic spindle asymmetry, merotelic microtubule-kinetochore attachments, lagging chromosomes, and aneuploidy. These effects were replicated by PLK1 insufficiency, indicating that PLK1 is responsible for the mitotic defects associated with NUP88 overexpression. These findings demonstrate that the NUP88-NUP98-RAE1-[APC/C.sup.CDH1] axis contributes to aneuploidy and suggest that it may be deregulated in the initiating stages of a broad spectrum of human cancers., Introduction Nuclear pore complexes (NPCs) are channels embedded in the nuclear envelope (NE) that facilitate trafficking of macromolecules into and out of the nucleus (1). The NPC consists of approximately [...]

Histone demethylase upregulation has been observed in human cancers, yet it is unknown whether this is a bystander event or a driver of tumorigenesis. We found that overexpression of lysine-specific demethylase 4A (KDM4A, also known as JMJD2A) was positively correlated with Gleason score and metastasis in human prostate tumors. Overexpression of JMJD2A resulted in the development of prostatic intraepithelial neoplasia in mice, demonstrating that JMJD2A can initiate prostate cancer development. Moreover, combined overexpression of JMJD2A and the ETS transcription factor ETV1, a JMJD2A-binding protein, resulted in prostate carcinoma formation in mice haplodeficient for the phosphatase and tensin homolog (Pten) tumor-suppressor gene. Additionally, JMJD2A cooperated with ETV1 to increase expression of yes associated protein 1 (YAP1), a Hippo pathway component that itself was associated with prostate tumor aggressiveness. ETV1 facilitated the recruitment of JMJD2A to the YAP1 promoter, leading to changes in histone lysine methylation in a human prostate cancer cell line. Further, YAP1 expression largely rescued the growth inhibitory effects of JMJD2A depletion in prostate cancer cells, indicating that YAP1 is a downstream effector of JMJD2A. Taken together, these data reveal a JMJD2A/ETV1/YAP1 axis that promotes prostate cancer initiation and that may be a suitable target for therapeutic inhibition., Introduction Prostate tumors are the most frequently diagnosed cancer in US men and a major health problem throughout the world. Apart from surgery and radiotherapy, androgen ablation is a standard [...]

Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related disease, and it is an attractive target for therapeutic exploitation. A wealth of information about senescence in cultured cells has been acquired over the past half century; however, senescence in living organisms is poorly understood, largely because of technical limitations relating to the identification and characterization of senescent cells in tissues and organs. Furthermore, newly recognized beneficial signaling functions of senescence suggest that indiscriminately targeting senescent cells or modulating their secretome for anti-aging therapy may have negative consequences. Here we discuss current progress and challenges in understanding the stressors that induce senescence in vivo, the cell types that are prone to senesce, and the autocrine and paracrine properties of senescent cells in the contexts of aging and age-related diseases as well as disease therapy., Aging is the progressive loss of tissue and organ function over time (1). The antagonistic pleiotropy theory of aging proposes that organismal fitness declines, at least in part, because natural [...]

Cellular senescence has recently been shown to have roles in complex biological processes other than protection against cancer, and to represent a series of progressive and diverse cellular states after initial growth arrest; better understanding of mechanisms underlying its progression and of acute and chronic senescent cells may lead to new therapeutic strategies for age-related pathologies. Cell senescence and the ageing process Relatively little is known about the basic biology of senescent cells, particularly in vivo, but mounting evidence that cell senescence plays a role in ageing and age-related disease has stimulated interest in the topic. Here Jan van Deursen reviews recent work on the role of senescent cells in ageing. New findings suggest that senescence is not a static cellular endpoint. Rather, it is a dynamic series of cellular states linked to tissue repair and cancer as well as to ageing. van Deursen goes on to discuss how the new information that is emerging could be exploited to clear detrimental senescent cell populations selectively to improve healthy lifespan. Cellular senescence has historically been viewed as an irreversible cell-cycle arrest mechanism that acts to protect against cancer, but recent discoveries have extended its known role to complex biological processes such as development, tissue repair, ageing and age-related disorders. New insights indicate that, unlike a static endpoint, senescence represents a series of progressive and phenotypically diverse cellular states acquired after the initial growth arrest. A deeper understanding of the molecular mechanisms underlying the multi-step progression of senescence and the development and function of acute versus chronic senescent cells may lead to new therapeutic strategies for age-related pathologies and extend healthy lifespan., Author(s): Jan M. van Deursen [sup.1] Author Affiliations: (1) Department of Pediatric and Adolescent Medicine and Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, USA Main [...]