Porth's Essentials of Pathophysiology, 4e

46

Cell and Tissue Function

U N I T 1

associated with aging. The most prominent example of the damage theory is the somatic mutation theory of aging, which states that the longevity and function of cells in various tissues of the body are determined by the double-stranded DNA molecule and its specific repair enzymes. Deoxyribonucleic acid undergoes continuous change in response to both exogenous agents and intrin- sic processes. It has been suggested that aging results from conditions that produce mutations in DNA or defi- cits in DNA repair mechanisms. The oxidative free radical explanation of aging is an error theory in which aging is thought to result partially from oxidative stress and the effects of free radical damage. The major by-products of oxidative metabolism include superoxides that react with DNA, ribonucleic acid, proteins, and lipids, leading to cellu- lar damage and aging. Blood glucose is another suspect in cellular deterioration. In a process called nonenzy- matic glycation , glucose molecules attach to proteins, setting in motion a chain of chemical reactions that ends with proteins binding together or cross-linking, thus altering their structure and function. Investigators hypothesize that glycation and oxidation are interde- pendent, since free radicals and cross-links seem to accelerate the formation of one another. Cross-links, also known as advanced glycation end products (AGEs), tend to stiffen tissues and cause some of the deterioration associated with aging. 2,35 For example, AGEs may help trap low-density cholesterol in arte- rial walls and thus contribute to atherosclerosis. They also have been linked to cataract formation, reduced kidney function, and neurologic disorders such as Alzheimer disease. Syndromes of Premature Aging The syndromes of premature aging, or progeria , rep- resent a range of phenotypes seen in usual aging, but with much earlier ages of onset and more rapid rates of progression. 1 Hutchinson-Gilford progeria syndrome is a rare fatal genetic disorder characterized by acceler- ated aging in children. 42 The disorder is caused by a mutation in the LMNA gene, which codes for a pre- cursor of lamin A—a scaffolding protein that lines the nucleus. The mutant gene leads to abnormal nuclear structure and altered gene regulation and DNA replica- tion. Although they are born looking healthy, children with the disorder begin to display many characteristics of accelerated aging at around 18 to 24 months of age. Progeria signs include growth failure, loss of body fat and hair, aged-looking skin, cataracts, and coronary artery disease and stroke (Fig. 2-11). Death occurs at an early age of atherosclerotic heart disease (average age 13 years). Other progeroid syndromes include Werner syn- drome, also known as adult progeria, which does not have an onset until the late teens, with a life span into the 40s and 50s. 1 The gene responsible for the disor- der has been localized to chromosome 8 and appears to code for an enzyme involved in unwinding DNA, a pro- cess that is necessary for DNA repair and replication.

FIGURE 2-11. A 5-year-girl with progeria. (From National Human Genome Research Institute, National Institutes of Health.)

SUMMARY CONCEPTS

■■ Cell injury can be caused by a number of agents, including physical agents, chemicals, biologic agents, and nutritional factors. ■■ Among the physical agents that generate cell injury are mechanical forces that produce tissue trauma, extremes of temperature, and electrical forces. Ionizing radiation can directly break chemical bonds, whereas nonionizing radiation exerts its harmful effects by causing vibration and rotation of atoms and molecules. Chemical agents can block enzymatic pathways, cause coagulation of tissues, or disrupt the osmotic or ionic balance of the cell. Biologic agents differ from other injurious agents in that they are able to replicate and continue to produce injury. Among the nutritional factors that contribute to cell injury are excesses and deficiencies of total energy, as well as individual nutrients. ■■ Injurious agents exert their effects largely through generation of reactive oxygen species (ROS)