ABSTRACT
The capacity to regenerate damaged or lost tissue varies widely along the animal kingdom and generally declines with aging of the organism. The gradual accumulation of senescent cells in tissues during aging has been causally involved in their reduced function at old age, and to be at the basis of age-related diseases. Recently, however, cellular senescence has been shown to play a positive role as a morphogenetic force modelling and promoting tissue development during embryogenesis, and to be responsible for tissue wound healing and repair. Work done on organismal models ranging from fish and amphibians, with extraordinary regenerative capacities, to mammals, with a more restricted regenerative potential, is shedding light on a novel and unexpected function of cellular senescence. In this review, we will analyze the senescence phenotype and how could it be contributing or restricting tissue regeneration.
Subject(s)
Aging/physiology , Cellular Senescence/physiology , Embryonic Development/physiology , Regeneration/physiology , Senescence-Associated Secretory Phenotype , Animals , Humans , Models, BiologicalABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions. Here we report the identification of Cardiac Glycosides (CGs) as a family of compounds with senolytic activity. CGs, by targeting the Na+/K+ATPase pump, cause a disbalanced electrochemical gradient within the cell causing depolarization and acidification. Senescent cells present a slightly depolarized plasma membrane and higher concentrations of H+, making them more susceptible to the action of CGs. These vulnerabilities can be exploited for therapeutic purposes as evidenced by the in vivo eradication of tumors xenografted in mice after treatment with the combination of a senogenic and a senolytic drug. The senolytic effect of CGs is also effective in the elimination of senescence-induced lung fibrosis. This experimental approach allows the identification of compounds with senolytic activity that could potentially be used to develop effective treatments against age-related diseases.
Subject(s)
Apoptosis/drug effects , Cardiac Glycosides/pharmacology , Cellular Senescence/drug effects , Chondrocytes/drug effects , Fibroblasts/drug effects , A549 Cells , Animals , Antibiotics, Antineoplastic/pharmacology , Bleomycin/pharmacology , Breast Neoplasms , Cell Line, Tumor , Cell Membrane/drug effects , Digoxin/pharmacology , Female , Humans , Hydrogen-Ion Concentration/drug effects , Mice , Osteoarthritis , Ouabain/pharmacology , Proscillaridin/pharmacology , Pulmonary Fibrosis , Xenograft Model Antitumor AssaysABSTRACT
Cellular senescence was traditionally considered a stress response that protected the organism by limiting the proliferation of damaged and unwanted cells. However, the recent identification of developmentally-programmed cellular senescence during embryo development has changed our view of the process. There are now a number of examples of developmental senescence in evolutionary distant organisms ranging from mammals to fish, showing senescence at various sites during specific time windows of development. Developmental senescence shares many features with stress-induced senescence but also present some specific characteristics. The different examples of developmental senescence provide evidence of the diverse functions contributed by senescence and represent an opportunity to learn more about this process. Also, the existence of senescence during embryogenesis opens the possibility of identifying human developmental syndromes caused by alterations in this response. Studying in more detail this process will expand our understanding of cellular senescence and could offer new insights into the cause of human pathologies.
Subject(s)
Cellular Senescence/physiology , Embryonic Development/physiology , Amphibians/embryology , Animals , Birds/embryology , Fishes/embryology , Humans , Phenotype , Phosphatidylinositol 3-Kinases/physiology , Smad Proteins/physiologyABSTRACT
Induction of pluripotency in somatic cells with defined genetic factors has been successfully used to investigate the mechanisms of disease initiation and progression. Cellular reprogramming and oncogenic transformation share common features; both involve undergoing a dramatic change in cell identity, and immortalization is a key step for cancer progression that enhances reprogramming. However, there are very few examples of complete successful reprogramming of tumor cells. Here we address the effect of expressing an active oncogene, RAS, on the process of reprogramming and found that, while combined expression with reprogramming factors enhanced dedifferentiation, expression within the context of neoplastic transformation impaired reprogramming. RAS induces expression changes that promote loss of cell identity and acquisition of stemness in a paracrine manner and these changes result in reprogramming when combined with reprogramming factors. When cells carry cooperating oncogenic defects, RAS drives cells into an incompatible cellular fate of malignancy.
