BIOLOGY OF AGING

The phenomenon of aging means quite different things to different people. Most gerontologists would agree that aging is a process, or set of processes, of gradual development and then decline that characterize the life span of an organism. Beyond that, there is very little agreement, and indeed there are many who would argue with this description. In part this lack of agreement is the result of the fact that aging is a very complex phenomenon involving biological, behavioral, and social factors. These various and very varied realms interact to produce the life span trajectory of each single organism on the planet. Adding to this complexity are the cultural, political, and economic assumptions about aging that shape the ways individuals and their institutions think about the "problems of aging."

Biogerontology

The study of the biology of aging, or biogerontology, has as its primary objective understanding the basic processes that underlie aging and agerelated disease. For some this means increasing human life span, for others it means increasing human health-span. In either case, the ultimate objective is to reduce human suffering. Whether one wishes to extend human life span or alleviate age-related disease, understanding the underlying processes of aging is essential. Aging is not simply the result of the passage of time. Think of the life spans of guppies, dogs, horses, and humans. All age at a regular rate, but the rate of aging is vastly different from one species to another. Is aging different in each species, or does the same set of processes run at different speeds in different species? What do we actually mean by aging? The simplest definition is the loss of homeostatic ability with the passage of time. Homeostatic ability is the ability to maintain internal stability. That is, the ability of an organism to maintain a stable internal environment in the face of environmental challenges such as changes in temperature, humidity, air quality, and so on. At the most basic level, the loss of this ability is the primary deficit of aging.

What most of us think of as aging, however, is the loss of teeth, hair, muscle strength, memory, and reproductive ability, as well as the accumulation of wrinkles, joint pain, and what are commonly called the infirmities of old age. These changes are age related, but are not aging itself. They are not the inevitable consequence of aging, but rather the often-observed accompaniments of aging. The concept of "normal aging" is used to try to distinguish between aging as a process or set of processes, from aging as the result of the accumulation of damage from environmental insult, the ravages of disease, and the wear and tear of living. Normal aging is assumed to mean the age changes that result from basic biological processes. Whether normal aging actually can be studied is a matter of some controversy, although most gerontologists believe that the concept is meaningful.

The details of normal versus disease-related (or pathological) aging are the grist for biological theories of aging. These theories are attempts to explain the data we observe as we study aging organisms of many species and to construct frameworks that relate these explanations to a basic understanding of what aging means. Some of these theories assume that aging processes are not the same as wear and tear or the consequence of disease, while others assume that aging is essentially the result of these factors. The major biological theories of aging are described in a separate entry on theories.

Other approaches to the study of aging look at age-related diseases directly (geriatric medicine), at the aging of populations and incidence of age-related diseases in these populations (demography and epidemiology), and at the social and behavioral changes that characterize aging (social gerontology and gerontological psychology).

Research approaches

The areas of interest that fall within the purview of the biology of aging mirror the fascinating areas of biology today. Aging as a process, or set of processes, affects virtually all of our bodily organs and systems. At the most basic level, some portions of our aging patterns are set in our genes. The reliable differences in the life spans of various species are clear evidence of genetic "programs" that set the general boundaries of species life span. The environment modifies these boundaries, but guppies do not live eighty years, and humans often do. Genes are important in the differences in longevity between individual members of a single species (e.g., long- and short-lived humans), but environmental factors play a major role in these differences. Living in a toxic environment or making deleterious lifestyle choices can have a significant effect on individual longevity.

Genetic analyses

A major area of investigation in the biology of aging is the search for genes that influence life span and an understanding of how these genes exert their influence. Studies in lower organisms such as yeasts and fungi show that there are genes, called longevity assurance genes, that assure that cells function long enough for the organism to live out its normal life span. Cancer occurs when these longevity assurance functions go awry. Understanding the mechanisms by which a delicate balance between longevity assurance and disease are maintained is one of the very promising areas of biogerontology.

Knowing that a particular gene or set of genes have an effect on an aging parameter does not in and of itself tell us anything about how the genes produce that effect. Molecular biology and molecular genetics are the research areas devoted to seeking such explanations. These research programs look at molecular function in aging organisms from plants and small worms (Caenorhabditis elegans ) to fruit flies (Drosophila melanogaster ) to mammals and humans. Understanding the mechanisms by which genes turn molecular and cellular functions on and off at various times in the life span of organisms will eventually lead to the ability to modify those processes. This is the promise of molecular and genetic therapies, tailored to an individual's very specific genetic makeup, that is causing great excitement at the beginning of the twenty-first century.

Model systems

A basic assumption that underlies a great deal of this research is that the use of models for research on human aging is valid and informative. Models for research include a wide variety of organisms, including yeast, worms, rodents, and nonhuman primates. Many genes are common to the genomes of all of these organisms. Humans share genes even with yeasts. Thus it is assumed that phenomena observed in these model organisms provide relevant information about how aging occurs in the human species.

Cell senescence

Cellular functions are basic life processes throughout the life span of any organism. In most tissues in the body, cells must reproduce themselves (replicate) on a regular basis in order for the tissue, and thus the organism, to survive. The study of cell replication, and the changes that occur with aging (cell senescence ), is an important branch of biogerontology.

The seminal observations of Leonard Hayflick on the senescence of cells in culture are at the core of this research. Hayflick showed that cells in culture appear to senesce (grow old) and cease dividing after about fifty population doublings. When one cell splits into two, that is one population doubling. When those two cells become four that is the next doubling, and so on. This observation, made in 1965, puzzled gerontologists for decades as no mechanism could be found to explain how cells in culture could count the number of times they divided. Research on telomeres and the phenomenon of telomere shortening has provided at least one workable mechanism. Telomeres are chains of DNA at the ends of each chromosome that get shorter at each cell division in most tissues. The role of telomeres and the enzyme telomerase (telomerase controls telomere shortening) in aging and in cancer is a very promising and exciting area of research.

Hormonal changes

The endocrine system controls the production and distribution of hormones throughout the body. Many hormones decline with advancing age. Decline in the levels of reproductive hormones (e.g., testosterone and estrogen) could contribute to loss of function in older individuals. The degree to which such decline is responsible for loss of function, and what can safely be done about it, are important research questions.

Replacing reproductive hormones, or their precursors, could be dangerous since these hormones also play a role in the development of cancers of the reproductive organs. Hormone replacement therapy for postmenopausal women is often desirable, but its desirability depends upon a number of factors, such as family history, personal history, lifestyle, and risk tolerance. Hormone replacement therapy for male reproductive hormones and for growth hormones in both genders is much more controversial. The ready availability of hormone precursors in the form of dietary supplements poses a significant public health problem. Large numbers of people are taking substances that might cause harm without an understanding of the risks.

Nutrition

Nutrition is another area of biogerontologic research that intersects with the dietary and diet supplement industry. The study of the nutritional requirements of older people includes understanding their eating habits, their ability to absorb nutrients, their ability to metabolize those nutrients, and the role of over or under nutrition on health and longevity. A particularly interesting branch of this research is the study of the effects of restricting calorie intake. Caloric restriction, with adequate nutrition, is the only experimental manipulation currently known to extend life span. Understanding how caloric restriction produces extended longevity could provide valuable clues to basic aging processes as well as suggest new therapies for age-related diseases.

Life span alteration

The study of life span extension includes genetic, hormonal, and nutritional components that are part of the subject matter of biogerontology. The impact of success in achieving life span extension is of great interest to social and psychological gerontology, to practitioners of geriatric medicine, and to policy makers in virtually every nation in the world.

The other side of the life span coin is exemplified by the diseases that mimic accelerated aging. Research on these human progeroid syndromes such as progeria and Werner's Syndrome, is being conducted in order to try to cure or prevent the diseases. Understanding how the genes responsible for these diseases produce their life-shortening effects is another approach to finding the key aging processes needed to ensure "normal" life spans.

Neural aging

Research on the aging of the brain, nervous system, and neuroendocrine systems constitutes a major portion of biogerontology. Brain cells do not usually replicate and thus must last for most of the life span of the organism. Neurodegenerative diseases that destroy the functionality of neurons and other neuronal tissues, such as in Alzheimer's disease, are a major source of disability in the last third of human life span. Here again, understanding what goes wrong may provide valuable information about normal function as well as lead to effective therapies to combat these terrible diseases.

From this brief summary of the subject matter of the biology of aging it is obvious that aging affects virtually every aspect of our lives. The tremendous strides in this understanding that have resulted from the application of molecular techniques to aging research are described, and the promise that ongoing research holds for better understanding and even better therapies provides positive examples of the benefits of biological research for all of us.

Richard L. Sprott

See also Aging; Epidemiology; Geriatric Medicine; Physiological Changes; Theories of Biological Aging.

BIBLIOGRAPHY

Austad, S. N. Why We Age. New York: John Wiley & Sons, 1997.

Kirkwood, T. Time of Our Lives. New York: Oxford University Press, 1999.

Schneider, E. L., and Rowe, J. W., eds. Handbook of the Biology of Aging. New York: Academic Press, 1996.

Sprott, R. L., and Pereira-Smith, O., eds. The Genetics of Aging. Generations 24 no. 1 (2000): 1–85.

Aging, Biology of

Human life span, or longevity, has two components: mean longevity (also called life expectancy) and maximum longevity. Mean longevity is the average age at death of all members of a population. Throughout history, human life expectancy has increased. For example, life expectancy in the United States in the late eighteenth century was thirty-five years. By the last quarter of the twentieth century, it had increased to seventy-two years. The second component of life span, maximum longevity, is the age at which the most long-lived individuals of a population will die. This is difficult to determine in humans but is generally accepted to fall between 110 and 120 years.

The trend for life expectancy to get closer to maximum longevity has been attributed to improvements in nutrition, sanitation, and medical care. Maximum longevity, in actuality, appears to be independent of these environmental factors and is an absolute limit, probably determined by the action of genes. The genes that determine maximum longevity are believed to be responsible for repairing errors in the genetic information, repairing mistakes in the process of protein synthesis, and determining the time of death.

Aging Changes that Occur in Humans

Some of the most easily observed age-related changes in humans are found in the skin and its derivatives. These include a loss of pigment in the hair, wrinkling of the skin, an increase in pigment in the skin, and thickening of the nails. Other observable changes are a decrease in size, due to loss of muscle and bone mass; a decrease in muscle strength; a decrease in mobility in the joints; and a variety of neurological changes, including diminished sensory function (vision, hearing, smell, and taste), increased response time, and diminished capacity for learning and memory. The latter have been attributed to a loss in brain mass, due at least in part to a loss of brain cells.

Less easily observed changes include a decrease in metabolic rate; diminished function of the kidneys, lungs, and pancreas; cardiovascular disease; diminished immune function; increased susceptibility to cancer; and a decrease (in males) or termination (in females) of reproductive function. All of these changes have been attributed to cellular events and processes that are described by various theories of aging.

Theories of Aging

It is widely accepted that the process of aging cannot be traced to a single cause. A number of theories have been proposed to explain the changes observed during aging. In order to be a valid candidate for an explanation of the aging process, the changes proposed by the theory must meet the following criteria: (1) they will commonly occur in all or most humans; (2) as an individual ages, these changes will become more pronounced; and (3) the changes will lead to cellular or organ dysfunction that ultimately cause failure of the organ or system. The following explanations are the most commonly accepted ones for the aging process.

Free Radicals. Free radicals are chemical particles that contain an unpaired electron and are extremely reactive. They are produced by aerobic metabolism and by radiation and other environmental agents. Their effects are widespread. They alter or break down the structure of many other molecules in the cell and thus impair their functions. Free radicals react with proteins, which have enzymatic , structural, and control functions. They cause breaks in deoxyribonucleic acid (DNA) and thus alter the information necessary for synthesizing proteins. They cause lipids to stick together, which causes cell membranes to break down.

Their effects on carbohydrates are less well documented. Free radicals are most abundant in the cellular organelles called mitochondria , where oxidative reactions occur. Mitochondrial damage, including damage to mitochondrial DNA, has been proposed as a contributing factor to the aging process. The effects of free radicals are diminished by certain enzymes (superoxide dismutase and catalase) that interrupt the cycle of reactions that cause their damage. Antioxidants such as vitamins C and E also protect against free radical damage by quenching the reactions.

Crosslinkage of Proteins. In addition to the effects of free radicals, proteins can be altered by the spontaneous and uncontrolled joining of protein molecules to one another by glucose . The cumulative effect of this glycosylation is to cause the proteins to stick together. For example, the fibrous extracellular protein collagen, found in connective tissue , becomes stiff via this process, which contributes to the wrinkling of the skin and the loss of joint mobility.

Events Affecting the Genetic Material. Mutations, or changes in the DNA, are common and can lead to changes in the structure and function of proteins. There are a number of mechanisms that can repair these changes, but it is possible that these mechanisms diminish in their effectiveness with age, since they are carried out by enzymatic proteins, which are themselves damaged by the aging process. Another suggestion is that there are specific genes responsible for the death of individual cells.

Also, it is known that cells in tissue culture will undergo only a certain number of cell divisions. In human cells, this limit is approximately fifty cell divisions. This so-called Hayflick limit (after the scientist who first described it) has been tentatively explained by the progressive shortening of the telomere, the section of each DNA molecule that is responsible for initiating replication of DNA. As the telomere becomes too short, an increasing number of mistakes occur in the replicated DNA.

The Effects of Hormones. These chemical messengers normally have well-regulated effects on body tissues. Abnormally high levels of some hormones (which may be caused by other changes described here) can change the sensitivity of tissues to the hormones, as well as stimulate the secretion of other hormones whose uncontrolled effects could be deleterious. Insulin, growth hormone, glucocorticoid hormones, and reproductive hormones have been suggested as candidates in this mechanism.

Changes in the Immune System. This major defense system of the body may experience two kinds of change, either one of which could contribute to the aging process. First, the immune system may gradually lose its ability to distinguish cells of the body from foreign cells, resulting in immune attack on the body itself. Second, the immune system appears to be less able to respond to microbes or foreign molecules, thus rendering the cells of the body more susceptible to the effects of these noxious agents.

see also Autoimmune Disease; Life Cycle, Human; Mitochondrion; Peroxisomes

Steven N. Trautwein

Bibliography

Christiansen, James L., and John M. Grzybowski. Biology of Aging: An Introduction to the Biomedical Aspects of Aging. New York: McGraw-Hill, 1999.

Clark, William R. A Means to an End: The Biological Basis of Aging and Death. New York: Oxford University Press, 1999.

DiGiovanna, Augustine Gaspar. Human Aging: Biological Perspectives, 2nd ed. Boston: McGraw-Hill, 2000.

Spence, Alexander P. Biology of Human Aging, 2nd ed. Englewood Cliffs, NJ: Prentice Hall, 1995.