ag·ing (āʹjĭng) n.
1. The process of growing old or maturing.
2. An artificial process for imparting the characteristics and properties of age.

* * *

Gradual change in an organism that leads to increased risk of weakness, disease, and death.

It takes place in a cell, an organ, or the total organism over the entire adult life span of any living thing. There is a decline in biological functions and in ability to adapt to metabolic stress. Changes in organs include the replacement of functional cardiovascular cells with fibrous tissue. Overall effects of aging include reduced immunity, loss of muscle strength, decline in memory and other aspects of cognition, and loss of colour in the hair and elasticity in the skin. In women, the process accelerates after menopause. See also gerontology and geriatrics.

* * *

▪ life process

      progressive physiological changes in an organism that lead to senescence, or a decline of biological functions and of the organism's ability to adapt to metabolic stress.

      Aging takes place in a cell, an organ, or the total organism with the passage of time. It is a process that goes on over the entire adult life span of any living thing. Gerontology (gerontology and geriatrics), the study of the aging process, is devoted to the understanding and control of all factors contributing to the finitude of individual life. It is not concerned exclusively with debility, which looms so large in human experience, but deals with a much wider range of phenomena. Every species has a life history in which the individual life span has an appropriate relationship to the reproductive life span and to the mechanism of reproduction and the course of development. How these relationships evolved is as germane to gerontology as it is to evolutionary biology. It is also important to distinguish between the purely physicochemical processes of aging and the accidental organismic processes of disease and injury that lead to death.

      Gerontology, therefore, can be defined as the science of the finitude of life as expressed in the three aspects of longevity (life span), aging, and death, examined in both evolutionary and individual (ontogenetic) perspective. Longevity is the span of life of an organism. Aging (human aging) is the sequential or progressive change in an organism that leads to an increased risk of debility, disease, and death; senescence consists of these manifestations of the aging process.

  The viability (survival ability) of a population is characterized in two actuarial functions: the survivorship curve (A in Figure 1—>) and the age-specific death rate, or Gompertz function (B in Figure 1—>). The relation of such factors as aging characteristics, constitutional vigour, physical factors, diet, and exposure to disease-causing organisms to the actuarial functions is complex; there is, nevertheless, no substitute for them as measures of the aging process and of the effect of environmental or genetic modifiers.

      The age-specific mortality rate is the most informative actuarial function for investigations of the aging process. It was first pointed out by an English actuary, Benjamin Gompertz, in 1825 that the mortality rate increases in geometric progression—i.e., by a constant ratio in successive equal age intervals. Hence, a straight line, known as the Gompertz function, results when death rates are plotted on a logarithmic (ratio) scale. The prevalence of many diseases and disabilities rises in the same geometrical manner as does the mortality rate, important exceptions being some infectious diseases and diseases arising from disturbances of the immunological system. Although the life tables of most species are remarkably similar in form, even closely related species can differ markedly in the relative incidence of the major causes of death.

George A. Sacher Nathan Wetherill Shock

Biological theories of aging
      Aging has many facets. Hence there are a number of theories, each of which many explain one or more aspects of aging; there is, however, no single theory that explains all of the phenomena of aging.

Genetic (gene) theories
      One theory of aging assumes that the life span of a cell or organism is genetically determined—that the genes of an animal contain a “program” that determines its life span just as eye colour is determined genetically. Although long life is recognized often as a familial characteristic, and short-lived strains of fruit flies, rats, and mice can be produced by selective breeding, other factors clearly can significantly alter the basic genetic program of aging.

      Another genetic theory of aging assumes that cell death is the result of “errors” introduced in the formation of key proteins, such as enzymes (enzyme). Slight differences induced in the transmission of information from the deoxyribonucleic acid (DNA) molecules of the chromosomes through ribonucleic (RNA) molecules (the “messenger” substance) to the proper assembly of the large and complex enzyme molecules could result in a molecule of the enzyme that would not “work” properly. These so-called error theories have not yet been firmly established, but studies are in progress.

      As cells grow and divide, a small proportion of them undergo mutation; (mutation) that is, they become “different” with a change in their chromosome structure that is then reproduced when they again divide. The “somatic mutation” theory of aging assumes that aging is due to the gradual accumulation of mutated cells that do not perform normally.

Non-genetic theories
      Other theories of aging focus attention on factors that can influence the expression of a genetically determined “program.” One of these is the “wear-and-tear” theory, which assumes that animals and cells, like machines, simply wear out. Animals, however, unlike machines, have some ability to repair themselves, so that this theory does not fit the facts of a biological system. A corollary to the wear-and-tear theory is the presumption that waste products accumulate within cells and interfere with function. The accumulation of highly insoluble particles, known as “age pigments,” has been observed in muscle cells in the heart and nerve cells of both human beings and other animals.

      With increasing age, tendons, skin, and even blood vessels lose elasticity. This is due to the formation of cross-links between or within the molecules of collagen (a fibrous protein) that give elasticity to these tissues. The “cross-linking” theory of aging assumes that similar cross-links form in other biologically important molecules, such as enzymes. These cross-links could alter the structure and shape of the enzyme molecules so that they are unable to carry out their functions in the cell.

      Another theory of aging assumes that immune (autoimmunity) reactions, normally directed against disease-producing organisms as well as foreign proteins or tissue, begin to attack cells of the individual's own body. In other words, the system that produces antibodies loses its ability to distinguish between “self” and foreign proteins. This “autoimmune” theory of aging is based on clinical rather than on experimental evidence.

      These theories all attempt to explain aging in terms of cellular and molecular changes. Actually, age changes are much more marked in the overall performance of an individual than in cellular processes that can be measured. The age decrement in the ability to perform muscular work is much greater than any changes that can be detected in the enzyme activities of the muscles that perform the work. It is possible that aging in an individual is actually due to a breakdown in the control mechanisms that are required in a complex performance.

Nathan Wetherill Shock Ed.

Natural history of aging

Reproduction and aging
      Reproduction is an all-important function of an organism's life history, and all other vital processes, including senescence and death, are shaped to serve it. The distinction between semelparous and iteroparous modes of reproduction is important for an understanding of biological aging. Semelparous organisms reproduce by a single reproductive act. Annual and biennial plants are semelparous, as are many insects and a few vertebrates, notably salmon and eels. Iteroparous organisms, on the other hand, reproduce recurrently over a reproductive span that usually covers a major part of the total life span.

      In semelparous forms, reproduction takes place near the end of the life span, after which there ensues a rapid senescence that quickly leads to the death of the organism. In plants the senescent phase is usually an integral part of the reproductive process and essential for its completion. The dispersal of seeds, for example, is accomplished by processes—including ripening and fall (abscission) of fruits and drying of seed pods—that are inseparable from the overall senescence process. Moreover, the onset of plant senescence is invariably initiated by the changing levels of hormones (hormone), which are under systemic or environmental control. If, for example, the hormone auxin is prevented, by experimental means, from influencing the plant, the plant lives longer than normal and undergoes an atypical prolonged pattern of senescent change.

      Useful inferences can be drawn from the study of the aging processes of insects (insect) that display two distinct kinds of adaptive coloration: the procryptic (concealing coloration), in which the patterns and colours afford the insect concealment in its native habitat; and the aposematic (aposematic mechanism), in which the vivid markings serve as a warning that the insect is poisonous or bad tasting. The two adaptation patterns have different optimal species survival strategies: the procryptics die out as quickly as possible after completing reproduction, thus reducing the opportunity for predators to learn how to detect them; the aposematics have longer post-reproductive survival, thus increasing their opportunity to condition predators. Both adaptations are found in the family of saturniid moths, and it has been shown that the duration of their post-reproductive survival is governed by an enzyme system that controls the fraction of time spent in flight: procryptics fly more, exhaust themselves, and die quickly; aposematics fly less, conserve their energies, and live longer.

      These examples indicate that in semelparous forms, in which full vigour and function are required until virtually the end of life, senescence has an onset closely coupled with the completion of the reproductive process and is governed by relatively simple enzymatic mechanisms that can be modified by natural selection. Such specific, genetically controlled senescence processes are instances of programmed life termination (apoptosis).

      The iteroparous forms include most vertebrates, most of the longer-lived insects, crustaceans and spiders, cephalopod and gastropod mollusks, and perennial plants. In contrast to semelparous forms, iteroparous organisms need not survive to the end of their reproductive phase in order to reproduce successfully, and the average fraction of the reproductive span survived varies widely between groups: small rodents and birds in the wild survive on the average only 10 percent to 20 percent of their potential reproductive lifetimes; whales, elephants, apes, and other large mammals in the wild, on the other hand, live through 50 percent or more of their reproductive spans, and a few survive beyond reproductive age. In iteroparous forms the onset of senescence is gradual, with no evidence of specific systemic or environmental initiating mechanisms; senescence manifests itself early as a decline in reproductive performance. In species that grow to a fixed body size, decline of reproductive capacity begins quite early and accelerates with increasing age. In large egg-laying reptiles (reptile), which attain sexual maturity while relatively small in size and continue to grow during a long reproductive span, the number of eggs laid per year increases with age and body size but eventually levels off and declines. The reproductive span in such cases is shorter than the life span.

      These comparisons illustrate the influence exerted by factors of population dynamics on the evolution of reproductive and bodily (somatic) senescence. The proportional contribution of an individual to the rate of increase of the iteroparous population obviously diminishes as the number of his living progeny increases. In addition, his reproductive capacity diminishes with age. These facts imply that there is an optimum number of litters per lifetime. Whether or not these influences of population dynamics lead to the evolution of adaptive senescence patterns has long been debated by gerontologists but has not yet been investigated definitively.

Species differences in longevity and aging
      That there are large differences in life span between some species of animals has long been known, but only recently have the data become adequate for statistical analysis. Maximum life span provides an estimate of the potential longevity of mammalian and avian species because of the sharp upper limit of the survival curves in life tables. Also, it is superior to the average life span because the latter is influenced by environmental factors unrelated to aging (e.g., human protection).

      The taxonomic stratification of longevity can be seen among the mammals. Primates (primate), generally, are the longest lived group, although some small prosimians and New World monkeys have relatively short life spans. The murid (mouselike) rodents (rodent) are short-lived; the sciurid (squirrel-like) rodents, however, can reach ages two to three times longer than the murids. Three traits have independent correlations with life span: brain weight, body weight, and resting metabolic rate (basal metabolic rate). The dependence of life span on these traits can be expressed in the form of an equation: L = 5.5E 0.54S −0.34M −0.42. Mammalian life span (L) in months relates to brain weight (E ) and body weight (S ) in grams and to metabolic rate (M ) in calories per gram per hour. The positive exponent for E (0.54) indicates that longevity of mammals has a strong positive association with brain size, independent of body size or metabolic rate. The negative coefficient for metabolic rate implies that life span decreases as the rate of living increases, if brain and body weight are held constant. The negative partial coefficient for body weight indicates that the tendency for large animals to be longer lived results not from body size but rather from the high positive correlation of body weight with brain weight and its negative correlation with metabolic rate. The same kind of relation of L to E, S, and M holds for birds (bird), but there is a tendency for birds to be longer lived than mammals of comparable brain and body size despite their higher body temperatures and metabolic rates. The larger reptiles (reptile) have life spans exceeding those of mammals of comparable size, but their rates of metabolism are about ten times lower, so that their total lifetime energy expenditures are lower than those for mammals. The more highly cephalized animals (i.e., those with higher brain weight), especially the primates, have greater lifetime energy outputs; the total lifetime energy output per gram of tissue is about 1,200,000 calories for man and 400,000 calories for domestic animals such as cats and dogs.

      The above relations hold for the homeothermic mammals, those with nearly constant body temperature. The heterothermic mammals, which are able to enter daily torpor, or seasonal hibernation, thereby reduce their metabolic rates more than tenfold. The insectivorous bats (bat) of temperate latitudes are the most dramatic example; although they have life spans in excess of 20 years, almost 80 percent of that time is spent in deep torpor. As a result, their lifetime energy expenditures are no greater than are those of other small mammals.

      The longevities of arthropod species extend from a few days to several decades. The extremely short-lived insects have a brief single reproductive phase; the longer lived spiders and crustaceans are iteroparous, with annual reproductive cycles.

The inheritance of longevity (genetics)
      The inheritance of longevity in animal populations such as fruit flies and mice is determined by comparing the life tables of numerous inbred populations and some of their hybrids. The longevity of sample populations has been measured for more than 40 inbred strains of mice. Two experiments concur in finding that about 30 percent of longevity variation in female mice is genetically determined, whereas the heritability in male mice is about 20 percent. These values are comparable to the heritabilities of some physiological performances, such as lifetime egg or milk production, in domestic animals.

  The slope of the Gompertz function line indicates the rate of actuarial aging. The differences in longevity between species are the result primarily of differences in the rate of aging and are therefore expressed in differences in slope of the Gompertz function. Three species that vary in longevity, such as the opossum (seven years), rabbit (12 years), and cat (20 years), would have Gompertz functions like the three lines in B (see Figure 1—>), and they would have survival curves like the corresponding curves in 1A—>.

      Comparison of life tables between mouse strains of a single species indicates that the strain differences result primarily from differences in age-independent hardiness factors. If strains differ in hardiness, the less hardy have death rates higher by a constant multiple at all ages, as shown by the parallel Gompertz functions. It is frequently found that the first-generation (F1) hybrids of two inbred strains live longer than either parent. There has been no direct comparison of hybrid and inbred mice with regard to the rates of their biochemical aging processes, but life-table comparisons indicate that hybrid vigour (heterosis) is an increase of age-independent vigour and not a decrease in the rate of aging.

      Recent research indicates that much of the variation in survival time between mouse strains is attributable to differences in inherited susceptibility to specific diseases. An important task of gerontology is to determine the extent of such genetic influences on aging.

      The inheritance of longevity in humans is more difficult to investigate because length of life is influenced by socioeconomic and other environmental factors that generate spurious correlations between close relatives. A number of studies have been published, most of them pointing to some degree of heritability with regard to length of life or susceptibility to major diseases, such as cancer and heart disease. Although there is disagreement about the degree of heritability of longevity in man, the evidence for genetic transmission of susceptibility to coronary heart disease and related diseases is strong, as is the evidence that monozygotic (genetically identical) twins tend to have more similar life spans than do like sex dizygotic (genetically different, fraternal) twins.

George A. Sacher

Senescence in mammals

Changes in body composition, metabolism, and activity
      The lean body mass, consisting of the skeletal muscles and all other cellular tissues, decreases steadily after physical maturity until, in extreme old age, it may be reduced to two-thirds its value in young adults. Body weight, however, usually increases with age, because stored fat and body water increases in excess of the loss of lean body mass. The relative amount of extracellular fluid increases with age during adult life, after decreasing steadily throughout fetal and postnatal development. Despite appearances, therefore, all tissues, even the skin, become more laden with water as a consequence of aging. The steady loss of voluntary (striated) muscle tissue mass throughout adult life depends somewhat on the pattern of physical activity. Evidence indicates that a large part of the loss of muscle mass with age is the result of disuse and atrophy rather than loss of muscle fibres.

      The decrease of lean body mass is accompanied by a decrease in the level of overall metabolic activity. Basal metabolism is greatest during the period of most rapid mass growth; it then declines rapidly until physical maturity is reached and more slowly thereafter. In the rat the slow phase of decrease amounts to about 20 percent over a three-year period. The interior body temperature is maintained, despite lower heat production, by decreased blood flow through the skin with a consequent decrease of heat loss; the “cooling of the blood” with age, therefore, does not occur in the degree that might be inferred from the decrease in skin temperature. The amount of voluntary physical activity, such as running in an exercise wheel, typically decreases with age but varies considerably between individual animals.

Changes in structural tissues
      The structural integrity of the vertebrate organism depends on two kinds of fibrous protein molecules, collagen and elastin. Collagen, which constitutes almost one-third of the body protein, is found in skin, bone, and tendons. When first synthesized by cells called fibroblasts, collagen is in a fragile and soluble form (tropocollagen). In time this soluble collagen changes to a more stable, insoluble form that can persist in tissues for most of an animal's life. The rate of collagen synthesis is high in youth and declines throughout life, so that the ratio of insoluble to soluble collagen increases with age. Insoluble collagen then builds up with age as a result of synthesis exceeding removal, much like another fibrous tissue, the crystalline lens of the eye. With increasing age, the number of cross-linkages within and between collagen molecules increases, leading to crystallinity and rigidity, which are reflected in a general body stiffness. There is also a decrease in the relative amount of a mucopolysaccharide (i.e., the combination of a protein and a carbohydrate) ground substance; a measure of this, the hexosamine–collagen ratio, has been investigated as an index of individual differences in the rate of aging. An important consequence of these changes is decreased permeability of the tissues to dissolved nutrients, hormones, and antibody molecules.

      The rate of aging of collagen is related to the overall metabolic activity of the animal; rats kept on low calorie diets have more youthful collagen than fully nourished rats of the same age.

      Elastin is the molecule responsible for the elasticity of blood vessel walls. With age, progressive loss of elasticity of vessels occurs, presumably because of fragmentation of the elastin molecule.

      The cross-linkage of collagen is chemically similar to the cross-linkages that occur in skins when they are tanned to leather. This similarity has stimulated proposals that chemicals that inhibit cross-linkage in tanning will retard aging. Such compounds have been tried on animals, but the problems of toxicity have not yet been solved.

Tissue cell loss and replacement
      The tissues of the body fall into two groups, according to whether or not there is continuous renewal of tissue cells. At one extreme are nonrenewal tissues such as nerves and voluntary muscles, in which no new cells are formed (at least in mammals) after a certain stage of growth. In renewal tissues such as the intestinal epithelium and the blood, on the other hand, some cell types live only one or a few days and must be replaced hundreds of times in the life span of even a short-lived animal such as the rat. Between these limits lie many organs, such as liver, skin, and endocrine organs, that have cells that are replaced over periods ranging from a few weeks to several years in man.

      A peripheral nerve is a convenient object to study because the total number of fibres in the nerve trunk can be counted. This has been done for the cervical and thoracic spinal nerve roots of the rat, the cat, and man. In the ventral and dorsal spinal roots of man, the number of nerve fibres decreases about 20 percent from age 30 to age 90. In the cat, the rat, and the mouse, however, the data do not consistently indicate a decrease of number of spinal root fibres with age. In man the number of olfactory nerve fibres, which serve the sense of smell, decreases by age 90 to about 25 percent of the number present at birth, and the number of optic nerve fibres, serving vision, decreases at a nearly comparable rate.

      There is a striking decrease in the number of living cells in the cerebral cortex of the brain of humans with age. The cerebellar cortex of the rat and man is about as susceptible to age deterioration as is the cerebral cortex. Other parts of the brain are not so obviously marked by aging.

      There is, in short, a tendency for the higher and more recently evolved levels of the nervous system to undergo more severe aging loss than do other regions, such as the brain stem and spinal cord. It is not yet known how much of the loss of brain cells results from conditions within the brain itself and how much results from extrinsic causes, such as deterioration of the blood circulation. The nutrition and maintenance of nerve cells, or neurons, in the central nervous system depends to a considerable extent on neuroglia, small cells that surround the neurons. The absolute number of these cells apparently does not decrease with age, but some of the microscopic changes seen in the neurons of old persons are similar to the changes produced by starvation or physical exhaustion.

      It has been shown that after an attack of measles, the virus remains in the host's body for the remainder of life and infrequently gives rise to a rapidly progressing degeneration of the cerebral cortex. This virus or other inapparent viruses may also be responsible for the individual differences in onset of senility in man.

      The renewal tissues are typically made up of a population of proliferative cells, which retain the capability for division, and a population of mature cells, produced by the proliferative cells and with limited life spans. The production of cells must balance the steady loss and also compensate quickly for unusual losses caused by injury or disease, so each renewal tissue has one or more channels of feedback control to adjust production to demand. Aging of renewal tissues is expressed in several ways, including decrease in the number of proliferative cells (cell), decrease in the rate of cell division, and decrease in responsiveness to feedback signals. Changes of these factors in the blood-forming tissues of the mouse are small, yet the blood-forming tissues do suffer an aging deficit, for the ability to respond to extreme or repeated demand is significantly reduced in older mice.

      The intact skin has a cell turnover time of several weeks, with the capability, shared by all renewal tissues, of temporarily increasing the rate of cell production by a large factor in response to injury. The rate of wound healing decreases with age, rapidly at first and more slowly as age increases.

      One of the most regular and striking aging processes is the decrease in the ability to focus on both close and distant objects. This loss in visual (eye disease) accommodation is the result in part of a weakening of the ciliary muscle of the eye and of a decrease in the flexibility of the lens. A further contributing factor, however, is that the lens continues to grow throughout life at a rate that diminishes with age. This growth is the result of continuous division of epithelial cells near an imaginary midline of the lens, giving rise to fresh cells that differentiate into the precisely aligned lens fibres. Once formed, the fibres remain permanently in place.

      An important feature of the renewal mechanism is the stem cell. These cells, which may normally continue to divide at a low rate throughout life, under conditions of increased demand enter a compensatory proliferative phase during which they divide rapidly. Blood-forming tissue has a stem-cell population that responds to injury readily in youth, but its capacity diminishes with age. The increased incidence of anemia in old age and the reduced capacity to respond to blood loss have been attributed to depletion of the blood-forming stem cells. Stem-cell populations have not been identified with certainty in other proliferative tissues. The intestinal mucosa, in particular, has a high cell-division rate without any clear indication of a reserve population of stem cells.

Mammalian cell cultures
      Dividing cells from various mammalian tissues can be grown in vitro (outside the body) under careful laboratory control. Various lines of cancer cells have been grown in continuous culture for many decades. In the early period of tissue-culture (tissue culture) technology it was claimed that certain chicken cells (fibroblasts) had been maintained in culture for 20 years. This led to the belief that dividing cells were potentially immortal and focussed interest on nondividing cells as the seat of the aging process. This view has lost standing in recent years. It has now been established that a population ( clone) of fibroblasts has a finite life history in culture. It has a period of healthy growth, during which it can be transferred, or “split,” several dozen times, indicating that the cells have undergone more than that number of generations. The cultures, however, go into a senescent phase and die out, usually before the 50th transfer. Occasionally, the chromosomes in a cell in the culture undergo a mutation (change) that results in a loss of a growth-limiting factor, leading to the establishment of a subclone capable of indefinite growth. This happens fairly often in cultures of mouse cell strains but only rarely in cultures of human cells. Such mutations usually involve chromosomal rearrangements or changes in the number of chromosomes.

      The present view, therefore, is that dividing mammalian cells with a normal chromosomal complement have a limited growth potential and that the capacity for indefinite growth shown by cancer cells and transformed cells is the result of the loss of a growth-limiting factor. The number of transfers that cell strains can undergo decreases as the age of the donor increases, in a way reminiscent of the decreased turnover rate of fibroblasts in living chickens and of the decreased rate of wound healing with age.

Changes in tissue and cell morphology
      There are numerous instances of tissue changes with age. The atrophy of tissues of moderate degree is usual. The shrinkage of the thymus is especially striking and important in view of its role in immunological defense. The diminution of cellular tissue and replacement by fatty or connective tissue is prominent in marrow and skin. In the kidney, entire secretory structures (nephrons) are lost. The secretory cells of the pancreas, thyroid, and similar organs decrease in numbers.

      An important age change is the accumulation of pigments and inert—possibly deleterious—materials within and between cells. The pigment lipofuscin accumulates within heart muscle cells; it is not detectable at ten years of age but rises to almost 3 percent of the cell volume by age 90. Amyloid substance, a protein–carbohydrate complex, increases in tissues in middle age; it is presumably a product of autoimmune reactions, immune reactions misdirected against the organism itself. In an extreme case of a rare autoimmune disease, amyloid disease, particular organs are virtually choked with amyloid substance. Trace metals also accumulate in various tissues with age, and although the amounts are very small, certain metals can poison enzyme systems, stimulate mutations, or cause cancer.

Aging at the molecular and cellular levels

Aging of genetic information systems
      The physical basis of aging is either the cumulative loss and disorganization of important large molecules (e.g., proteins and nucleic acids) of the body or the accumulation of abnormal products in cells or tissues. A major effort in aging research has been focussed on two objectives: to characterize the molecular disruptions of aging and to determine if one particular kind is primarily responsible for the observed rate and course of senescence; and to identify the chemical or physical reactions responsible for the age-related degradation of large molecules that have either informational or structural roles. The working molecules of the body, such as enzymes and contractile proteins, which have short turnover times, are not thought to be sites of primary aging damage. The deoxyribonucleic acid ( DNA) molecules of the chromosomes appear to be potential sites of primary damage, because damage to DNA corrupts the genetic message on which the development and function of the organism depend. Damage at a single point in the DNA molecule can be followed by the synthesis of an incorrect protein molecule, which may result in the malfunction or death of the host cell or even of the entire organism. Attention therefore has been given to the somatic mutation hypothesis, which asserts that aging is the result of an accumulation of mutations in the DNA of somatic (body) cells. Aneuploidy, the occurrence of cells with more or less than the correct (euploid) complement of chromosomes, is especially common. The frequency of aneuploid cells in human females increases from 3 percent at age 10 to 13 percent at age 70. Each DNA molecule consists of two complementary strands coiled around each other in a double helix configuration. Evidence indicates that breaks of the individual strands occur with a higher frequency than was once suspected and that virtually all such breaks are repaired by an enzymatic mechanism that destroys the damaged region and then resynthesizes the excised portion, using the corresponding segment of the complementary strand as a model. The mutation rate for a species is therefore governed more by the competence of its repair mechanism than by the rate at which breaks occur. This may help to explain why the mutation rates of different species are roughly proportional to their generation times and justifies research to determine whether the enzymatic mechanisms involved are accessible to control. It remains to be seen whether a reduction of mutation rates will retard the onset of generalized aging or of a specific disease process.

      There are, however, serious objections to the somatic mutation theory. The wasp Habrobracon is an insect that reproduces parthenogenetically (i.e., without the need of sperm to fertilize the egg). It is possible to obtain individuals with either a diploid, or paired, set of chromosomes, as in most higher organisms, or a haploid, single, set. Any gene mutation in a haploid cell at an essential position would result in loss of a vital process and impairment or death of the cell; in a diploid cell a serious mutation is often compensated for by the complementary gene and the cell can carry on its vital functions. Experiments have shown that haploid wasps live about as long as diploids, implying either that mutations are not a quantitatively important factor in aging or that parthenogenetic species have compensated for the vulnerability of their haploids by developing an increased effectiveness of DNA repair.

      Chromosomes can be separated into DNA and protein molecules, but with increasing difficulty in older cells. The isolated DNA of old animals, however, does not differ from that of the young. Although most of the DNA in a given cell at a given time is repressed (i.e., blocked from functioning), it is more repressed in old animals; it is not yet known whether this is a primary age change or a consequence of reduced cell metabolism arising from other causes.

Aging of the immunological system (immune system)
      Another important molecular information system of the body is the immunological system, part of which, the thymus-dependent subsystem, is specialized for defense against invading micro-organisms and for the as yet poorly understood role of detecting and removing body cells that have changed in such ways that they are no longer recognized by the body as part of its own substance, leading to the autoimmune reactions mentioned above. The immunological system has been implicated in the body's defenses against cancer. Cancerous growths (neoplasms) are thought to arise from single cells that undergo a drastic transformation as a result of either a genetic mutation or the activation of a latent (hidden) virus that may have been transmitted genetically from parent to offspring. The control of cancer susceptibility by genetically governed defense mechanisms has been indicated by the breeding of high and low cancer susceptibility in mice. There is a growing body of evidence that the thymus-dependent immunological system is instrumental in repressing the development of cancer.

      One piece of evidence is that the immunosuppressive procedures of organ transplantation are often followed by a greatly increased incidence of neoplasms. The thymus-dependent system can itself, however, give rise to age-related autoimmune disease, in which the immunological system perceives normal body tissue as foreign and attacks it with antibodies. The initial step in these diseases is considered to be a somatic mutation in a single cell of the immunological system. Such considerations are the basis of several immunological theories of aging, which seek to explain the phenomena of senescence in terms of mutations in the immunological system.

Aging of neural and endocrine systems
      The loss of psychological and neurophysiological capacities with age is undoubtedly the result, in large part, of the loss of neurons, but deficiencies in the metabolic processes of the surviving cells are demonstrably involved. The ability of the eye to dark-adapt (i.e., increase its sensitivity at low light levels) decreases with age, but part of that decrease can be restored by breathing pure oxygen. Various mental processes in old people are also found to be improved by breathing oxygen. The establishment of a memory trace (connections in the brain that are associated with memory) involves the synthesis of protein; any slowed induction of protein synthesis, as from lower oxygen intake, with age could be a factor in the deficits of learning and memory of old people.

      A general characteristic of aging of the endocrine system (endocrine system, human) is that the cells that once responded vigorously to hormones become less responsive. A normal chemical in cells, cyclic adenosine monophosphate (AMP), is thought to be a transmitter of hormonal information across cell membrane; it may be possible to identify the specific sites in the membrane or the cell interior at which communication breaks down.

Internal and external causes of aging

External environmental agents
Ionizing radiations (ionizing radiation injury)
      The shortening of life caused by ionizing radiations (e.g., X rays) has been determined for many species, including mice, rats, hamsters, guinea pigs, and dogs. The occurrence of some diseases, such as leukemia, may increase disproportionately after irradiation, with the degree of increase influenced by age and sex.

      The permanent nature of radiation damage is shown by the comparison of life spans of irradiated and control populations. An irradiated population dies out like a chronologically older unirradiated population. Members of a population given a single dose of X rays or gamma rays in early adult life die of the same diseases that afflict the unirradiated control population, but they die months or even years earlier.

      Continuous irradiation throughout life at low dose rates (daily doses from one-thousandth to one-tenth the dose that would kill immediately) speeds the mortality process. It is not yet clear if the molecular damage produced by such irradiation is the same as the molecular changes that accompany natural aging. Studies of animals and of cells grown in culture suggest that large doses of radiation kill by producing deleterious rearrangements of chromosomes in the proliferative cell population. Such aberrations also increase with age, but they seem to be less important in the natural aging process. At low radiation doses, chromosome aberrations become relatively less important than other effects, and the primary radiation damage in these conditions may bear a closer relation to the aging lesion. Under conditions of low-dose irradiation, however, the only definite effect is slightly increased cancer incidence; a generalized aging effect has not yet been observed.

      Natural radioactivity (radiation) in the body, arising mostly from radioactive potassium and radium, and natural background irradiation, from the Earth and from cosmic rays, are not major contributors to the aging process, even in the long-lived human species. They are responsible, however, for a small percentage of cancer incidence. Although the dose to the body from medical radiations is a fraction of the background level and the radiation from nuclear weapon test fallout is less than 1 percent of the background, both sources contribute to cancer induction in proportion to their amounts.

      Flour beetles, fruit flies, fishes, and other poikilothermic (temperature-variable) organisms live longer at the lower range of environmental temperature. These observations led to the rate-of-living hypothesis, which, simply stated, holds that an organism's life span is dependent on some critical substance that is exhausted more rapidly at higher temperature. Careful analysis of the data on temperature–longevity relations shows, however, that the rate-of-living hypothesis is inadequate in its original form. The most telling evidence comes from experiments in which fruit flies were kept at one temperature for part of their lives and at another temperature for the remainder. The results are not consistent with the rate-of-living hypothesis, but no satisfactory theory has appeared as yet to take its place. An important factor that has not yet been adequately taken into account is the relation of metabolic efficiency to temperature. The energy cost of the biosynthetic processes studied has been discovered to be minimal at an intermediate temperature in the range to which the species is adapted and to increase at higher or lower temperatures. A related phenomenon holds for longevity; the number of calories expended by fruit flies per lifetime is maximal at an intermediate temperature, so the rate of aging per calorie is minimal at that temperature.

      There is a question of the degree to which aging occurs as a result of heat destruction (thermal denaturation) of proteins. Thermal denaturation is predominately a disruption of the folding of molecules, which requires the breaking of numbers of low-energy bonds. It seems not to be a strong contributing factor to aging. There is still the possibility that rare events, such as mutations, may arise to a significant degree from thermal denaturation.

Physical wear of nonrenewable structures
      One of an animal's most important assets is its chewing apparatus, including jaws and teeth. Adaptation to tooth rate of wear is especially important for animals that consume large quantities of grass and herbage. Such adaptations include higher tooth crowns (hypsodonty), larger grinding area, and longer tooth growth period. Tooth wear may be limiting for survival in adverse environments, but, on the whole, it is not an important life-limiting characteristic. The same can be said for other external organs subject to physical wear.

Infectious disease and nutrition
      The populations in poor environments, characterized by high rates of infectious disease and poor nutrition (nutrition, human), have higher death rates than populations in good environments at all ages, yet there is no positive evidence that disadvantaged populations experience a higher rate of aging.

      Rats kept on diets restricted in calories live longer and have lower cancer incidence than do rats that are allowed to eat at will; maximum longevity, however, is achieved at a nutritional level that keeps the animal sexually immature and below normal weight.

Internal environment: consequences of metabolism
      The metabolic activities of organisms produce highly reactive chemicals, including strong oxidizing agents. The internal structure of the cell, however, minimizes the harmful effects of such agents; the critical reactions take place within enclosed structures such as ribosomes, membranes, or mitochondria, and counteractive enzymes such as peroxidases are present in abundance. It is nevertheless likely that low concentrations of these reactive substances can reach vital molecules and contribute to the characteristic rate of aging injury. Experiments in which mice are fed low levels of antioxidants such as butylated hydroxytoluene (BHT) have been encouraging but are still somewhat equivocal.

      Membranes (membrane) are the site of much of the metabolic activity of cells; they provide the barriers that keep incompatible reactions separated. Certain membrane structures, called lysosomes, contain enzymes capable of digesting the cell if released; the stability of cells and organisms is therefore very much bound up with the stability of membranes. A number of drugs, including corticosteroids, salicylates, and antihistamines, act by stabilizing cell membranes against inflammatory stimuli. Some of them are found to prolong life in fruit flies and to prolong survival of cells (cell) in vitro. The mode of action of these drugs is connected to substances called prostaglandins, which can alter specific membrane characteristics.

George A. Sacher

Additional Reading
General considerations are addressed by John A. Behnke, Caleb B. Finch, and Gairdner B. Moment (eds.), The Biology of Aging (1978), a collection of articles covering many aspects of the subject, including aging in cells and molecules, aging in plants and animals, and evolutionary considerations; Michael R. Rose, Evolutionary Biology of Aging (1991), a provocative treatise that proposes an explanatory theory of aging grounded in evolutionary biology, of value to gerontologists, population geneticists, and other interested readers; Robert R. Kohn, Principles of Mammalian Aging, 2nd ed. (1978), with emphasis on the role of interstitial tissue changes in the aging process; Bernard L. Strehler, Time, Cells, and Aging, 2nd ed. (1977), an examination of cellular and molecular mechanisms and theories of aging; Brian Charlesworth, Evolution in Age-Structured Populations, 2nd ed. (1994), a theoretical consideration of the consequences of age-structure and age-specific differences in reproduction and mortality, which also considers the broader issue of life-history evolution and hence treats senescence as a part of the continuum of development; Caleb E. Finch, Longevity, Senescence, and the Genome (1990), an encyclopaedic treatment of the theories of aging, the statistical methods for evaluating aging, and the full range of empirical methods used to study the aging process for all levels of biological organization, ranging from molecules to populations, with tables and summaries of observed maximum life spans and mortality rates; and Robert E. Ricklefs and Caleb E. Finch, Aging: A Natural History (1995).

* * *

Universalium. 2010.

Игры ⚽ Поможем написать курсовую

Look at other dictionaries:

  • aging — aging; an·ti·aging; pho·to·aging; …   English syllables

  • Aging — 〈[ɛıdʒıŋ] n. 15; unz.〉 1. das Reifen (best. Tabaksorten) 2. 〈allg.〉 das Älterwerden [amerikan. engl. (engl. Schreibweise auch ageing), „Altern, Älterwerden“] * * * Aging   [ eɪdʒɪȖ, englisch »Alterung«] das, die Reifung bestimmter Tabaksorten… …   Universal-Lexikon

  • Aging — [ e:dʒiŋ] das; s, s <aus engl. aging »Alterung« zu age »Alter«, dies über altfr. aage, eage u. vulgärlat. aetaticum aus lat. aetas, Gen. aetatis »Leben(szeit)«> die Reifung bestimmter Tabaksorten durch ein bis zwei Jahre dauernde Lagerung… …   Das große Fremdwörterbuch

  • Aging — Ag ing, n. the process by which objects or materials acquire desirable qualities by being left undisturbed for some time under specific conditions. It is used mostly for foods snd beverages, but also for other materials. [Also spelled {ageing}.]… …   The Collaborative International Dictionary of English

  • Aging — Aging. См. Старение. (Источник: «Металлы и сплавы. Справочник.» Под редакцией Ю.П. Солнцева; НПО Профессионал , НПО Мир и семья ; Санкт Петербург, 2003 г.) …   Словарь металлургических терминов

  • aging — [n] becoming older crumbling, declining, developing, fading, fermenting, getting along*, getting on*, maturing, mellowing, senescent, slumping, stale, waning, wearing out*; concept 701 …   New thesaurus

  • aging — ag|ing1 [ eıdʒıŋ ] adjective an aging person is becoming old: a town with an aging population a. an aging machine, vehicle, or building is too old and no longer useful aging ag|ing 2 [ eıdʒıŋ ] noun uncount the process of becoming old: a way to… …   Usage of the words and phrases in modern English

  • Aging — The process of becoming older, a process that is genetically determined and environmentally modulated. Research into aging: To sum up the state of research into aging is well beyond the confines of this space (and this writer s talents). However …   Medical dictionary

  • aging — A report or schedule of all outstanding accounts payable or accounts receivable that lists all account debtors or creditors by name, shows the total amount due to each debtor, and shows how much of the amount due to each debtor is due within… …   Financial and business terms

  • Aging — Age Age, v. i. [imp. & p. p. {Aged}; p. pr. & vb. n. {Aging}.] To grow aged; to become old; to show marks of age; as, he grew fat as he aged. [1913 Webster] They live one hundred and thirty years, and never age for all that. Holland. [1913… …   The Collaborative International Dictionary of English

Share the article and excerpts

Direct link
Do a right-click on the link above
and select “Copy Link”