Porth's Essentials of Pathophysiology, 4e

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Cellular Responses to Stress, Injury, and Aging

C h a p t e r 2

maintained by an enzyme called telomerase , which is present in low levels in stem cells, but is usually absent in most adult cells. Therefore, as cells age, their telo- meres become shorter and they lose their ability to rep- licate and replace damaged or senescent cells. Moreover, oxidative stress induces single-stranded damage to telomeric DNA, and this defect cannot be repaired in telomeres. In theory, such mechanisms could also pro- vide a safeguard against uncontrolled cell proliferation of abnormal cells. It has been shown that telomerase is reactivated and telomeres are not shortened in immortal cancer cells, suggesting that telomere elongation may be important in tumor formation. Genetic Influences There is ongoing interest in genes that determine longev- ity. Longevity genes have been found in fruit flies and roundworms, organisms that have attracted consider- able attention from scientists because of their short life span and their well-characterized genomes. One exam- ple is the mutation of the Indy (I’m Not Dead Yet) gene in the fruit fly, which can double the length of its life. 35 Scientists have also found genetic clues to the aging pro- cess in the tiny roundworm, Caenorhabditis elegans . By altering one of its daf-2 genes, which codes for a pro- tein that is similar to insulin and insulin growth factor (IGF)-1 receptors found in humans, researchers can substantially extend the longevity of these worms. 1,35 Pathways related to the daf-2 gene, for example, may be responsible for relationships between caloric restriction and prolonged life span in rodents and other animals. Whether human counterparts of genes found in these laboratory organisms exist and whether they have simi- lar effects remain an ongoing area of inquiry. However, many genes that are associated with human life span are not intrinsically “longevity genes,” per se. For example, because mutations in the tumor- suppressor genes BRAC1 and BRAC2 increase mortal- ity associated with breast and ovarian cancer, they are rare among long-lived women. 40 Conversely, genes that reduce the risk of atherosclerosis may be more common in long-lived individuals. Genetic studies of biologic aging have also explored the involvement of variants of genes encoding apolipoproteins (proteins that bind lip- ids for transport in the circulatory system), in particular, the APOE gene encoding the synthesis of apolipoprotein E. The presence of the variant apoE4 is associated with an increased incidence of cardiovascular and neurode- generative diseases, thereby shortening life span. 37,41

infection involving a limb. Hyperbaric oxygen therapy has been used, but clinical data supporting its efficacy has not been rigorously assessed.

Cellular Aging Aging is a complex natural process in which there are physiologic and structural alterations in almost all organ systems. 1,2,34–38 Even in the absence of disease, beginning in the fourth decade of life, there is a progressive decline in muscle strength, cardiac reserve, vital capacity, nerve conduction time, and glomerular filtration rate. Although the biologic basis of aging is poorly understood, there is general consensus that its elucidation should be sought at the cellular level. Many cell functions decline with age. Oxidative phosphorylation by the mitochondria is reduced, as is synthesis of nucleic acids and transcription factors, cell receptors, and cell proteins. A number of theories have been proposed to explain the cause of aging. The main theories are based on sci- entific observations at the molecular, cellular, organ, and system levels. In general, these theories can be divided into either programmed or error theories. The programmed theories propose that the changes that occur with aging are genetically programmed, whereas the damage or error theories maintain that the changes result from an accumulation of random events or envi- ronmental agents or influences that are associated with DNA damage. 35–39 Evidence suggests that the process of aging and longevity is multifaceted, with both genetic and environmental factors playing a role. In animal studies, genetics accounted for less than 35% of the effects of aging, whereas environmental influences accounted for over 65%. 36 In humans, long life appears to have a stronger genetic basis, which explains why centenarians and near centenarians tend to cluster in families. 40 Replicative Senescence Replicative senescence implies that cells have a limited capacity for replication. At the cellular level, Hayflick and Moorhead observed more than 40 years ago that cultured human fibroblasts have a limited ability to rep- licate (approximately 50 population doublings) and then die. 41 Before achieving this maximum, they slow their rate of division and manifest identifiable and predictable morphologic changes characteristic of senescent cells. One explanation of replicative senescence is related to the length of the outermost regions of each chro- mosome, called telomeres, that contain short repeat sequences of DNA bases. 1,2,35 During mitosis, the molec- ular machinery that replicates DNA cannot copy the extreme ends of the chromosome. Thus, with each cell division, a small segment of telomeric DNA is lost. Over time, it is theorized that as the telomeres become pro- gressively shorter, the DNA at the ends of the chromo- somes cannot be protected, resulting in inhibition of cell replication. The lengths of the telomeres are normally

Accumulation of Environmental and Genetic Damage

In addition to the importance of timing and a genetic clock, cellular life span may be determined by a balance between cellular damage resulting frommetabolic events occurring within the cell and molecular responses that repair the damage. The damage eventually accumulates to a level sufficient to result in the physiologic decline