Cell Senescence and Death - Biology Notes PDF

Video 44: Cell Senescence and Death Slide 3: Senescent cells no longer divide; however, they are still metabolically active. These cells also have an immunogenic phenotype (can induce an immune response) and express senescence-associated beta-galactosidase (SABG). Typically, senescent cells are lar...

Video 44: Cell Senescence and Death Slide 3: Senescent cells no longer divide; however, they are still metabolically active. These cells also have an immunogenic phenotype (can induce an immune response) and express senescence-associated beta-galactosidase (SABG). Typically, senescent cells are larger and have a characteristic flattened appearance. Their nuclei have senescence-associated heterochromatin foci (SAHF). Changes in gene expression are observed. There is a senescence- associated secretory phenotype; thus, some senescent cells express inflammatory cytokines. Slide 4: Fibroblasts in culture become senescent after ~ 50 divisions. This is called also a “replicative senescence” and is known as the Hayflick limit. Replicative senescence results from the telomere shortening of the chromosomes and the consequent DNA damage responses. Senescence can also occur independently of telomere shortening as a result of oxidative damage, oncogene activation, or cell fusion. The number of senescent cells increases with age. Cell senescence may have evolved as an anti-cancer mechanism. However, whereas the cellular senescence in younger organisms is anti-tumorigenic, it may become pro-tumorigenic in older organisms. The senescence-associated secretory phenotype (SESP) is associated with age- related diseases. Senolytic therapy is an anti-aging approach: it kills and eliminates senescent cells to improve the health of older organisms. In mice, the removal of senescent cells improves health and extends the lifespan. Slide 5: Apoptosis is programmed cell death, and the process is highly regulated and orderly. Molecular/biochemical events of apoptosis lead to cell blebbing, shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, mRNA decay. Normally, billions of human cells undergo apoptosis every day. Therefore, apoptosis is a part of the normal homeostasis of tissues. However, apoptosis can be deregulated in disease; therefore, too much apoptosis or too little apoptosis is damaging. There are two pathways of apoptosis: intrinsic (when the cell senses stress) and extrinsic (when the cell responds to outside signals that induce apoptosis). Both pathways activate specific proteases called caspases. Initiator caspases start the “caspase cascade” and executioner caspases perform the terminal steps in the process. There is also caspase-independent apoptosis (with an apoptosis-inducing factor or AIF). Slide 6: The apoptotic pathways include: Intrinsic pathway: - Mediated through mitochondria - Steps include deactivation of proteins that inhibit apoptosis (IAPs) - Cytochrome c is released from the mitochondria and binds to factors to form an apoptosome - Caspase 9 is activated and in turn, it activates the executioner caspase 3 Extrinsic pathway: - TNF-induced or Fas-Fas ligand-mediated - Factors such as TNF-alpha or Fas bind to receptors, forming death-inducing signaling complexes with factors such as TRADD and FADD - Activation of caspase 8 (and other caspases) begin the cascade Slide 7: The caspase cascade of apoptosis includes a series of caspases, leading to the final downstream effects of programmed cell death. Initiating and executioner caspases for the intrinsic and extrinsic pathways are shown in the diagram (please, know these!). The initiating caspases activate the executioner caspases. The executioner caspases are responsible for the degradation of cellular macromolecules that cause cell death. Slide 8: This slide shows some steps of the apoptotic disassembly resulting from caspase action. Included are membrane blebbing, nuclear fragmentation, protrusions, and cell fragmentation. Slide 9: The Bcl-2 family of factors affects/modulates apoptosis. They are either pro-apoptotic or anti-apoptotic types (see diagram at left) and contain Bcl-2 homology (BH) domains that are critical for the function. The Bcl-2 factors are localized to the outer mitochondrial membrane of animal cells and typically exert their effects through mitochondria-mediated apoptotic steps. Slide 10: Deregulation of apoptosis can cause disease. For example, too little apoptosis can promote cancer (e.g., the loss of the p53 tumor suppressor protein can cause reduced apoptosis), inflammatory diseases, autoimmune syndromes, and infections. Too much apoptosis can cause neurodegenerative diseases (loss of neurons). Therapeutics can be aimed at promoting or suppressing apoptosis as needed. Slide 11: What is necrosis? It is, typically, non-apoptotic cell death (but can occur after apoptosis). Generally, it is caused by external factors: infection, toxins, trauma to the cell. Can involve receptor activation, followed by the loss of cell membrane integrity. Typically, the DNA is degraded, the nucleus shrinks, there is fragmentation and dispersal of the nucleus. Necrosis is almost always harmful to the organism, can be the result of an inflammatory response, or damage to surrounding tissue (e.g., gangrene), etc. Slide 12: Fundamental points. Senescence, apoptosis, and necrosis all stop the replicative life of the cell, but do so in different ways, with varying consequences to the cell and organism. Senescence can be replicative or induced, senescent cells do not divide but are metabolically active and have a distinct phenotype. Apoptosis is a tightly controlled cell death process that can be via the intrinsic or extrinsic pathways. BCL-2 proteins are important modulators of apoptosis. Necrosis is typically a detrimental non-apoptotic cell death resulting from cell stress. Apoptosis is a normal part of tissue homeostasis but can become deregulated in disease.