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Biology of Aging

Research on the biology of aging has led to a revolution in understanding the cellular and molecular changes that occur with aging. This new gerontology investigates the progressive biological and physiological changes that normally occur with advancing age and the abnormal changes that are risk factors for or accompany age-related disease states. Progress is being made in understanding the gradual changes in structure and function that occur in the brain and nerves, bone and muscle, heart and blood vessels, hormones, nutritional processes, immune responses, and other aspects of the body. Research has begun to reveal the biologic factors associated with extended longevity in humans and animal models. The ultimate goal of this effort is to develop interventions to reduce or delay age-related degenerative processes in humans.

Science Advances—Biology of Aging

Mitochondrial DNA Mutations Increase With Aging. One hypothesis of the cause of aging is the accumulation of mutations in mitochondrial DNA (mtDNA). Although earlier research has shown that a particular deletion mutation of mitochondrial DNA increases with age, it appeared that this mutation only occurred in less than 4 percent of mtDNA molecules. However the methods used to quantitate the level of this mutation would not have detected other deletions, so it was argued by some that the common deletion mutation represented the "tip of the iceberg" of mitochondrial mutations. Skeptics responded that this unproven hypothesis represented wishful thinking. By use of a sensitive method to look at point mutations in mitochondrial DNA, researchers found hard evidence that mtDNA point mutations increase with aging and mitochondria deteriorate as people age. These scientists show that one particular point mutation in the control region of the mtDNA occurs in a high proportion of the mtDNA molecules of more than 50% of people over the age of 65, but is absent in younger individuals. Because the mitochondria are the cellular sites for energy metabolism, deterioration of mitochondria could deprive cells of the energy they need to function and ultimately could lead to premature cell death.

Caloric Restriction Prevents Age-Associated Changes in Gene Expression. Most multicellular organisms exhibit a progressive and irreversible physiologic decline during the aging process. The only intervention known to slow the intrinsic rate of aging in mammals is caloric restriction. Given 30 to 40 percent fewer calories than in usual feeding schedules, but fed all the necessary nutrients, rodents and other nonprimate laboratory animals studied not only have lived far beyond their normal lifespans but have reduced rates of several diseases, especially cancers. In a new study, the gene expression profile of the aging process was analyzed in skeletal muscle of mice. Of the 6347 genes surveyed by new microarray techniques, only 58 (0.9%) displayed a greater than twofold decrease in expression. Thus, the aging process is unlikely to be due to large, widespread alterations in gene expression. The major effect of caloric restriction seems to be to heighten animals’ stress response in response to damage to proteins and other large molecules. Caloric restriction also completely or partially suppressed age-associated alterations in expression of a large proportion of genes. This is the first global assessment of the aging process in mammals at the molecular level. Potentially, gene expression profiles can be used to assess the biological age of mammalian tissues, providing a tool to evaluate experimental interventions.

Link Established Between Telomeres and Mammalian Aging. Telomeres are highly repetitive DNA sequences located at the end of chromosomes. They are essential for the stability of chromosomes and cell survival in a wide variety of organisms. In human cells grown in culture, telomere length shortens with each cell division and the progressive telomere shortening ultimately limits the ability of cells to divide. To test the possibility of a link between telomere shortening and aging of an organism, investigators have created genetically altered mice lacking telomerase, an enzyme that adds new telomeric DNA sequences to existing telomeres. In this transgenic model, telomeres progressively shortened throughout the lifespan, providing a unique opportunity to understand the cellular consequences and aging significance of telomere shortening in the living animal. Although loss of telomeres did not elicit a full spectrum of the classical symptoms of aging, age-dependent telomere shortening was associated with a shortened lifespan, reduced capacity to respond to physiological stress, slow wound healing, and an increased incidence of spontaneous cancers. As individuals age, aged organs show a markedly diminished capacity to cope with acute and chronic stress. The telomerase-deficient mouse provides a valuable model to study the role of telomere maintenance in cellular stress responses in the aging organism.