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1 CHAPTER 4 ANSWERS A4.1 population doublings 10 20 30 40 50 relative number of cells cell line phase III phase II phase I (primary culture) 0 2 4 6 8 10 12 14 16 18 months Biology of Aging | boa04-10 Roger McDonald | 978-0-8153-4213-7 www.blink.biz © www.garlandscience.com Phase I: a period ofredesign slow by cell division in which the cells are adapting to their new environment; phase II: a period of rapid cell division; phase III: a period in which cell replication slows and the majority of cells begin to die. Cell cultures have a finite life span. Cell lines have an infinite life span. Phase II has the highest fitness, because this is the time when the most cells are replicating. A4.2 Morphological alterations Enlarged cells Multinucleated cells Breakdown of extracellular matrix Cell function alterations Decrease in proteins associated with DNA replication Decrease in RNA synthesis and associated proteins Decrease in overall rate of protein synthesis Arrest in cell division Lengthening of cell cycle Molecular brakes at G1-S phase Cells remain responsive to extracellular mitogenic signals Immunity-associated function Increase in cellular “junk”—remnants of nonfunctional proteins Decrease in the general function of the cellular catabolic machinery Increase in secretion of pro-inflammatory cytokines A4.3 No, not all cells have lost their mitotic capacity when the population of cultured cells has failed to double within four weeks. Like whole organisms, cells show variation in the rate of aging and replicative senescence. Some individual cells in a populations undergoing replicative senescence continue to have robust division capacity. 2 A4.4 All matter in the universe is subject to the second law of thermodynamics, which states that in any reaction requiring energy, some of the energy will become unusable, leading to an increase in entropy and disorder of the system. Increasing entropy decreases the molecular fidelity (and thus functionality) of biologically active molecules. Because the proteins involved in degrading cellular molecules that are damaged or have lowered molecular fidelity are also subject to the second law, removal of damaged molecules from the cell declines. Thus, damaged proteins can accumulate, leading to the effects often observed in cell senescence. A4.5 Oxygen is the final electron acceptor in the ETS pathway. Due to oxygen’s orbital structure, it must be reduced one electron at a time. In the process, the superoxide radical (•O2−) is generated. The superoxide ion is highly reactive and can damage other molecules. Under normal aerobic conditions, damage to proteins and other molecules is prevented by the quick enzymatic reduction of •O2− to hydrogen peroxide (H2O2). However, about 1–2% of superoxide ions escape this reduction and have the potential to cause damage. A4.6 The structure of a protein, its amino acid sequence and its folding configuration (tertiary structure), determines its biological activity. Alterations in the optimal structure of the protein lessen or eliminate its biological activity. ROS change the structure of a protein, rendering it less functional. This leads to a decrease in cell function and can increase the rate of cellular aging. A4.7 The hydroxyl radical (•OH), once formed, can react quickly with the lipids in cell membranes. Alterations in the lipids caused by the hydroxyl radical lead to changes in the membrane’s structure and fluidity. Chemical reactions in the cell that depend on separation between the extracellular and intracellular compartments can be affected, leading to changes observed in aging. Two general mechanisms have evolved to protect membrane lipids from hydroxyl radicals. First, intracellular antioxidant enzymes, such as glutathione peroxidase, have a high affinity for •OH and reduce it to water before it reacts with the cell membrane. Second, vitamin E is positioned in the cell membrane and has a higher affinity for •OH than do the membrane lipids. Vitamin E is oxidized in preference to oxidation of the membrane lipids, thereby preventing formation of the lipid peroxide radical. A4.8 False. Reactive oxygen species are used by some cells and molecules of the immune system to degrade bacteria and toxic molecules that can cause damage to tissues. It also seems that the generation of ROS stimulates the expression of antioxidant enzymes, which, in turn, reduce ROS to water. A4.9 DNA replication takes place in both directions from the replication origin. However, DNA polymerase moves only in the 5'→3' direction. As a result, DNA polymerase must move backward on the lagging strand template, generating small fragments (Okazaki fragments) of newly synthesized DNA that are then backstitched together. The backward movement of DNA polymerase means that an RNA primer must be made for each Okazaki fragment. When DNA polymerase comes to the end of the chromosome, there is not enough DNA to use as template for the RNA primer. If there is no mechanism for generating RNA primers, DNA polymerase will use coding sections for generating the primers, and important DNA sequences will be lost—this is the end-replication problem. Mitotic cells have solved this problem by adding telomeres, repetitive, noncoded base-pair sequences, at the end of chromosome to be used as templates for primers. A4.10 Due to the backstitching mechanism on the lagging strand, a portion of a telomere is lost with each cell division. When enough of the telomeres has been lost, mitotic cells will transition to the G0 phase permanently—that is, enter replicative senescence. The telomeres serve as a clock that informs the cell when to stop replicating. Replicative senescence results in age-related changes to the cell. The argument against this mitotic clock theory is that the overwhelming majority of cells in a whole organism are non-mitotic, so it is unclear how a cellular aging theory based on replicative senescence, or lack of mitosis, predicts aging in a non-mitotic organism.