https://research.vu.nl/ws/files/104498064/Cellular_Senescence_Defining_a_Path_Forward.pdf

Cellular Senescence: Defining a Path Forward

Cellular senescence is a stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stimuli, as well as developmental signals Senescence is considered to be a highly dynamic, multi-step process, during which the properties of senescent cells continuously evolve and diversify in a context dependent manner It is associated with multiple cellular and molecular changes and distinct phenotypic alterations, including a stable proliferation arrest unresponsive to mitogenic stimuli Senescent cells remain viable, have alterations in metabolic activity and undergo dramatic changes in gene expression and develop a complex senescence-associated secretory phenotype Cellular senescence can compromise tissue repair and regeneration, thereby contributing toward aging Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span Senescence can also act as a potent anti-tumor mechanism, by preventing proliferation of potentially cancerous cells It is a cellular program which acts as a double-edged sword, with both beneficial and detrimental effects on the health of the organism, and considered to be an example of evolutionary antagonistic pleiotropy Activation of the p53/p21WAF1/CIP1 and p16INK4A/pRB tumor suppressor pathways play a central role in regulating senescence Several other pathways have recently been implicated in mediating senescence and the senescent phenotype Herein we review the molecular mechanisms that underlie cellular senescence and the senescence associated growth arrest with a particular focus on why cells stop dividing, the stability of the growth arrest, the hypersecretory phenotype and how the different pathways are all integrated

/pdf/mechanisms-of-cellular-senescence-cell-cycle-arrest-and-36fgzpfvg2.pdf

Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype

Parkinson's disease (PD) is a disabling neurodegenerative disease that manifests with resting tremor, bradykinesia, rigidity and postural instability. Since the discovery of microRNAs (miRNAs) in 1993, miRNAs have been shown to be important biological molecules involved in diverse processes to maintain normal cellular functions. Over the past decade, many studies have reported dysregulation of miRNA expressions in PD. Here, we identified 15 miRNAs from 34 reported screening studies that demonstrated dysregulation in the brain and/or neuronal models, cerebrospinal fluid (CSF) and blood. Specific miRNAs-of-interest that have been implicated in PD pathogenesis include miR-30, miR-29, let-7, miR-485 and miR-26. However, there are several challenges and limitations in drawing definitive conclusions due to the small sample size in clinical studies, varied laboratory techniques and methodologies and their incomplete penetrance of the blood-brain barrier. Developing an optimal delivery system and unravelling druggable targets of miRNAs in both experimental and human models and clinical validation of the results may pave way for novel therapeutics in PD.

/pdf/role-of-micrornas-in-parkinson-s-disease-as2tql83vd.pdf

Role of MicroRNAs in Parkinson's Disease

The bright and dark side of extracellular vesicles in the senescence-associated secretory phenotype

Introduction Aging is a normal, inevitable, irreversible, and progressive process which is driven by internal and external factors. Oxidative stress, that is the imbalance between prooxidant and antioxidant molecules favoring the first, plays a key role in the pathophysiology of aging and comprises one of the molecular mechanisms underlying age-related diseases. However, the oxidative stress theory of aging has not been successfully proven in all animal models studying lifespan, meaning that altering oxidative stress/antioxidant defense systems did not always lead to a prolonged lifespan, as expected. On the other hand, animal models of age-related pathological phenotypes showed a well-correlated relationship with the levels of prooxidant molecules. Therefore, it seems that oxidative stress plays a more complicated role than the one once believed and this role might be affected by the environment of each organism. Environmental factors such as UV radiation, air pollution, and an unbalanced diet, have also been implicated in the pathophysiology of aging and seem to initiate this process more rapidly and even at younger ages. Aim The purpose of this review is to elucidate the role of oxidative stress in the physiology of aging and the effect of certain environmental factors in initiating and sustaining this process. Understanding the pathophysiology of aging will contribute to the development of strategies to postpone this phenomenon. In addition, recent studies investigating ways to alter the antioxidant defense mechanisms in order to prevent aging will be presented. Conclusions Careful exposure to harmful environmental factors and the use of antioxidant supplements could potentially affect the biological processes driving aging and slow down the development of age-related diseases. Maybe a prolonged lifespan could not be achieved by this strategy alone, but a longer healthspan could also be a favorable target.

/pdf/a-comprehensive-overview-of-the-complex-role-of-oxidative-13ucz1t2.pdf

A Comprehensive Overview of the Complex Role of Oxidative Stress in Aging, The Contributing Environmental Stressors and Emerging Antioxidant Therapeutic Interventions

Aging is a multifactorial process characterized by the progressive deterioration of physiological functions. Among the multiple molecular mechanisms, microRNAs (miRNAs) have increasingly been implicated in the regulation of Aging process. However, the contribution of miRNAs to physiological Aging and the underlying mechanisms remain elusive. We herein performed high-throughput analysis using miRNA and mRNA microarray in the physiological Aging mouse, attempted to deepen into the understanding of the effects of miRNAs on Aging process at the "network" level. The data showed that various p53 responsive miRNAs, including miR-124, miR-34a and miR-29a/b/c, were up-regulated in Aging mouse compared with that in Young mouse. Further investigation unraveled that similar as miR-34a and miR-29, miR-124 significantly promoted cellular senescence. As expected, mRNA microarray and gene co-expression network analysis unveiled that the most down-regulated mRNAs were enriched in the regulatory pathways of cell proliferation. Fascinatingly, among these down-regulated mRNAs, Ccna2 stood out as a common target of several p53 responsive miRNAs (miR-124 and miR-29), which functioned as the antagonist of p21 in cell cycle regulation. Silencing of Ccna2 remarkably triggered the cellular senescence, while Ccna2 overexpression delayed cellular senescence and significantly reversed the senescence-induction effect of miR-124 and miR-29. Moreover, these p53 responsive miRNAs were significantly up-regulated during the senescence process of p21-deficient cells; overexpression of p53 responsive miRNAs or knockdown of Ccna2 evidently accelerated the cellular senescence in the absence of p21. Taken together, our data suggested that the p53/miRNAs/Ccna2 pathway might serve as a novel senescence modulator independent of p53/p21 pathway.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/acel.12918

The p53/miRNAs/Ccna2 pathway serves as a novel regulator of cellular senescence: Complement of the canonical p53/p21 pathway.

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The p53/miRNAs/Ccna2 pathway serves as a novel regulator of cellular senescence: Complement of the canonical p53/p21 pathway.