Cell Senescence and Death 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