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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, [...]

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 [...]

Cellular senescence, which is characterized by an irreversible cell-cycle arrest.sup.1 accompanied by a distinctive secretory phenotype.sup.2, can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16.sup.INK4A have been found to actively drive naturally occurring age-related tissue deterioration.sup.3,4 and contribute to several diseases associated with ageing, including atherosclerosis.sup.5 and osteoarthritis.sup.6. Various markers of senescence have been observed in patients with neurodegenerative diseases.sup.7-9; however, a role for senescent cells in the aetiology of these pathologies is unknown. Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the MAPT.sup.P301SPS19 mouse model of tau-dependent neurodegenerative disease.sup.10 accumulates p16.sup.INK4A-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation. Collectively, these results show that senescent cells have a role in the initiation and progression of tau-mediated disease, and suggest that targeting senescent cells may provide a therapeutic avenue for the treatment of these pathologies.In a mouse model of tau-dependent neurodegenerative disease, the clearance of senescent glial cells prevents the degeneration of cortical and hippocampal neurons and preserves cognitive function., Author(s): Tyler J. Bussian [sup.1] , Asef Aziz [sup.2] , Charlton F. Meyer [sup.2] , Barbara L. Swenson [sup.2] , Jan M. van Deursen [sup.1] [sup.2] , Darren J. Baker [...]

Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells (1,2). Senescent cells accumulate in various tissues and organs with ageing (3) and have been hypothesized to disrupt tissue structure and function because of the components they secrete (4,5). However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, [p16.sup.Ink4a], to design a novel transgene, INK-ATTAC, for inducible elimination of [p16.sup.Ink4a]-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes [p16.sup.Ink4a]-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye-in which [p16.sup.Ink4a] contributes to the acquisition of age-related pathologies, life-long removal of [p16.sup.Ink4a]-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan., To examine the role of cellular senescence in ageing and age-related pathologies, we designed a transgenic strategy for the clearance of senescent cells in mice. We based our approach on [...]

Author(s): Karthik B. Jeganathan [1]; Liviu Malureanu [1]; Jan M. van Deursen (corresponding author) [1] Cdc20 and Cdh1 are the activating subunits of the anaphase-promoting complex (APC), an E3 ubiquitin [...]

Author(s): Lawryn H. Kasper [1]; Fayçal Boussouar [1]; Paul A. Ney [1]; Carl W. Jackson [2]; Jerold Rehg [3]; Jan M. van Deursen [4]; Paul K. Brindle (corresponding author) [1] [...]

The signal transducer and activator of transcription 4 (Stat4) is essential for the activity, controlled by interleukin (IL) 12, of natural killers (NK) and T cells. Mice with an insertional mutation in the Stat4 gene produce no interferon-gamma and the activity of NK cells against its target cells is absent. The mutants show defects in IL-12 activated proliferation of lymphocytes and differentiation of Th1 helper T cells. However, the mice are viable and show normal spermatogenesis, haematopoiesis and serum levels of immunoglobulin isotypes.

Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16Ink4a, to design a novel transgene, INK-ATTAC, for inducible elimination of p16Ink4a-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16Ink4a-positive senescent cells upon drug treatment. In tissues-such as adipose tissue, skeletal muscle and eye-in which p16Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16Ink4a-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan. [ABSTRACT FROM AUTHOR]