2.7: Biological Aging Theories

Reasons for Theories of aging

The theories of aging are general statements proposed to summarize and explain some observations about aging. The theories are tested by additional research, after which they are modified to include the new information. While each theory may be valid for some observations about aging, none of them explain completely all aspects of aging. The theories are actually hypotheses in the scientific method of inquiry. As with all hypotheses, they are valuable in giving broad logical perspectives to diverse bits information; giving direction to additional research; and helping to develop practical applications of knowledge.

General Characteristics of the Theories

Developing good theories of aging is difficult for diverse reasons. Examples include the lack of agreement on a definition of aging; the multitude of possible causes of aging; the complexity of aging within one organism or species of organisms; the diverse ways aging reveals itself in different species; the interactions among aging processes, environmental influences and diseases (i.e., nature versus nurture); the limited information about aging processes; the diverse expertise or perspectives among people who develop the theories; and societal, cultural, and economic conditions. As a result, dozens of theories of aging have been proposed over the passed 100 years. Their diversity, complexity, and interconnections can be intimidating and confusing. While realizing this, we will look at some of them. First we will examine broad groups of theories, and then look at more specialized ones.

One group of theories, the evolutionary theories, attempts to explain evolutionary aspects of how and why aging exists in living things. Another group, the physiological theories, focuses on how and why aging occurs within present day animals. They explain structural and functional age changes in animal bodies. Physiological theories may concentrate on one aspect or one structural level of an animal. Examples include genes and genetic mechanisms (e.g., senescence genes); molecules and their chemical reactions (e.g., glycation); activities of cell organelles or entire cells (e.g., mitochondria, cell division); signaling among cells (e.g., interleukins); whole body regulatory and control systems (e.g., immune system, nervous system, endocrine system); or behavioral and psychological characteristics. Some physiological theories attempt to explain all age changes based on only one or a very few phenomena (e.g., free radical theory, cross-linkage theory). Others use a combination of factors (e.g., immuno-neuro-endocrine theory).

A dichotomy between the physiological theories separates programmed theories from stochastic theories. All programmed theories maintain that aging occurs because of intrinsic timing mechanisms and signals. Stochastic theories (i.e., probability theories) maintain that aging occurs by accidental chance events. Some theories include both aspects. For example, one theory proposes that aging occurs because timed programmed genetic signals make an organism more susceptible to accidental events. Another dichotomy between physiological theories separates universal theories of aging, which apply to all organisms, from theories that apply to only one type of organism (e.g., mammals, humans).

Theories of aging are difficult to categorize because many of them overlap. As examples, evolutionary theories may incorporate aspects of genetics and behavior; mitochondrial theories may incorporate aspects of free radicals, energy metabolism, membranes, and mitochondrial genetics. Scientists who focus on the interrelatedness of body structures and functions have proposed network theories, which combine physiological theories from the molecular to the system level of the body.

Here are some popular broad categories of aging theories. Some of them are discussed next. Genetic theories may emphasize nuclear gene mutations or damage; mtDNA mutations or damage; programmed aging genes; senescence genes; decreased DNA repair; error catastrophe; or dysdifferentiation. Altered molecule theories may emphasize damaged and abnormal proteins; cross-linkage; glycation; waste accumulation; or general molecular wear and tear. Free radical theories may emphasize free radical formation or free radical defense mechanisms. Cell and cell organelle theories may emphasize the cell membrane; mitochondria; telomeres; or heterochromatin. Signaling theories may emphasize intercellular signals or individual hormones. System theories may emphasize the nervous system, the endocrine system, the immune system, or combinations such as the immuno-neuro-endocrine theory.

Evolutionary Theories

Aging must have evolved because not all species and not all cells show aging. To understand evolutionary theories of aging, one must be familiar with the theory of evolution of living things. The theory of evolution states that early in the Earth's history there were no living things. Over millions of years and through chance chemical reactions, larger and more complex molecules were formed. Through continued chance events, some of these molecules grouped together into organized clusters that could reproduce. These were the first cells. Some of these cells developed cooperative interactions as they formed colonies. Over many generations, these multicellular colonies evolved into today's plants and animals.

As time passed, some molecules, cells, and organisms had characteristics making them better able to survive environmental problems and competition from others. They were able to produce more offspring with similar characteristics. The instructions to produce these characteristics were contained in their genes. These successful well-adapted offspring were able to produce the next generation, and so forth. Molecules, cells, and organisms with characteristics that made them less able to survive and reproduce became less common and, finally, extinct because their genes were not sustained through continuing generations. This is the process of natural selection.

During evolution by natural selection, environmental conditions and interactions among living things changed. At the same time, chance events caused alterations in genes such as mutations and recombinations. These alterations led to organisms with different characteristics. Natural selection allowed organisms with beneficial genetic changes to reproduce more successfully, so their genetic characteristics became more common. Genes in organisms that allowed less reproduction became less common but remained among the organisms because as generations passed, there were fewer of these organisms. Genes that allowed little or no reproduction gradually decreased and disappeared. These genes were not passed to future generations. Since these processes occurred in different environments (e.g., hot, cold; dry, wet; light, dark), different genes and types of organisms survived in different places.

Thus, chance events, genetic changes, and natural selection produced the great variety of living things present today. These processes are still happening. For example, selective breeding produces new varieties of plants and animals, and altering the environment causes extinction of species. Natural events and people are part of evolution by natural selection.

One evolutionary theory of aging is based on the disposable body theory. Once an organism has reproduced successful offspring that can eventually reproduce, its body is no longer needed, and it ages and dies. Here is why. Resources are limited. An organism must partition its resources between survival of its body and reproduction. Resources for survival are used for defense and repair activities, which would also slow or prevent detrimental aging. If an organism's genes allocate most of its resources toward its own survival, and thus limit or prevent aging, the organism could not allocate enough resources to reproduction. Its genes would not survive by natural selection. If an organism's genes allocate inadequate resources to survival, it would not live long enough to produce ample successful offspring. Its genes would not survive by natural selection. An organism whose genes allocate ample resources to survive long enough to produce many successful offspring would have its genes survive by natural selection. However, because genes limited the resources allocated to defense and repair mechanisms, these mechanisms begin to fail, aging occurs, and the organism dies. In this theory, genes do not cause aging, they just do not prevent it after successful reproduction.

A second evolutionary theory, the antagonistic pleiotropy theory, states that effects from certain genes may be beneficial early in life but detrimental later in life. These detrimental effects result in aging. For example, certain genes may promote rapid metabolism leading to rapid successful reproduction early in life. However, rapid metabolism may also cause damage to body molecules. The damaged molecules may accumulate. The continued accumulation of damaged molecules causes aging. According to this theory, genes actively cause aging.

A third evolutionary theory of aging, the accumulation of late-acting error theory, states that natural selection has permitted the evolution of genes that cause aging. During evolution, any genetic changes that caused detrimental changes prior to successful reproduction would be eliminated by natural selection. However, new detrimental genetic changes that do not cause harm until after adequate successful reproduction would not be eliminated by natural selection. Over evolutionary time, these late-acting genes have accumulated. The detrimental effects from these genes are what we know as aging. This theory also concludes that genes actively cause aging.

Other evolutionary theories of aging try to explain why not all species seem to have a maximum longevity, why there are such diverse maximum longevities among species within the same group (e.g., among mammals), and if aging is advantageous in any way.

Physiological Theories

Genetic Theories

Genetic theories suggest that aging is heavily influenced by or actually caused by genes (see Genes and Aging above). Finally, though certain genes that influence longevities and aging in research animals have been identified, no one has identified aging genes in humans (see Genes and Aging above).

Genetic Timers

One genetic theory of aging states that the genes are used in a specific sequence, much as a book would be read from the first sentence of the first chapter through the last sentence of the final chapter. Each section of this genetic biography would direct the body's activities during a specific stage of life including fetal development and maturation. The sections would also contain instructions on how to progress to the next stage. The sections for later stages in the individual's life would provide instructions on how to carry out the changes called biological aging. The person's life ends when aging limits adaptation enough that homeostasis cannot be maintained and death occurs. Another genetic biography theory, the antagonistic pleiotropy theory, was described with evolutionary theories of aging.

A modified version of the genetic biography theory, the genetic clock theory, suggests that some genes keep track of the body's progress and perhaps the passage of time or number of cell divisions. In this way, genes can control the age at which certain events occur. For example, when grown experimentally, some types of cells can reproduce only a certain number of times, after which they die. Furthermore, the number of times the cells can divide decreases as the age of the person from whom the cells were extracted increases.

Another modified version of the genetic biography theory, the death gene theory, states that the last chapter in the genetic instruction manual contains genes called death genes that tell the body to deteriorate and die. Some scientists consider genes that cause fatal age-related diseases to be death genes.

One way cells seem to keep track of their age is through shortening of their telomeres as they divide. The telomere theory states that shortening of the telomeres alters the expression of other genes, perhaps those closest to the telomeres. This might happen if heterochromatin near the telomere unwinds, allowing detrimental genes to become active. Different rates of aging could occur in different cells or parts of the body because the telomeres in some cells shorten faster than those in other cells. The heterochromatin loss theory suggests that unwinding of chromosomes happens at many areas in a cell. This activates detrimental genes that cause aging.

Limited Gene Usage

Other genetic theories of aging suggest that genes are used over and over during adult life rather than being used in a specific sequence. One of these theories, the limited gene usage theory, suggests that there is a limited number of times that the instructions in genes can be read. The reading somehow alters or damages the genes. After many years of being read and reread, some genes may become unreadable so that instructions are lost. Other genes may be read poorly, resulting in mistakes by the body. In either case, the results are the detrimental changes that are biological aging. A sufficient number of these changes weaken the body so much that it can no longer maintain itself, and death occurs.

There are two suggested explanations why genes can be read only a limited number of times. One explanation, the somatic mutation theory, proposes that harmful factors injure the genes. Possible environmental factors include radiation, toxic chemicals, and free radicals. Within the cell, genetic disruption can occur when movable parts of the genetic material, called transposable elements, shift positions. In humans and other organisms, transposable elements move between the mitochondrial DNA and the nuclear DNA. The other explanation for limited gene usage, the faulty DNA repair theory, states that though genes are being damaged throughout life, cells also have mechanisms to repair the damage as quickly as it occurs. At first, then, damage to the genes has little effect. After many years, though, the repair mechanisms begin to fail. With either of these explanations, the result is the same. The damage that accumulates over the years reduces the genes' ability to direct properly the body’s activities, and biological age changes begin to occur.

Error Catastrophe Theory

A related theory, the error catastrophe theory, states that the damage is not to the genes themselves but to the RNA and protein molecules that read the genes and carry out their instructions. These damaged molecules spread increasing numbers of mistakes throughout the cell and the body, causing biological age changes.

Rate of Living Theory

The rate of living theory of aging states that aging is determined by the rate of metabolism because metabolism causes damage. The higher the rate of metabolism, the faster the rate of aging and the shorter the mean and maximum longevity. The rate of metabolism in animals can be measured by the rate of oxygen use. This theory proposes that an animal can use only a certain amount of oxygen per unit of body mass in a lifetime. The animal can use the oxygen quickly and have rapid aging and a short life, or use it slowly and have slow aging and a long life.

Most animals follow this rule. Two major exceptions are mammals and birds, which have life spans longer than their rates of metabolism would predict. Proposed explanations for these discrepancies suggest that birds and mammals have more efficient metabolism resulting in less damage or that these animals have better repair mechanisms.

Free radical theory

In 1956, Harman proposed the free radical theory following research on how radiation causes damage to organisms. He used the research on free radicals from radiation to include other sources and effects of free radicals, including aging. The theory states that free radical damage is a main reason or the main reason for true aging and for age-related diseases. No one knows which, if any, of the many types of free radicals are more important in promoting aging.

This theory is now based on several observations. Main examples include positive correlations between the following; metabolic rate and free radical production; age and rate of free radical formation; age and amount of free radical damage; free radicals and many age-related diseases (e.g., atherosclerosis, heart attacks, strokes, Alzheimer's disease, parkinsonism, cataracts, renal failure, and certain cancers); and, sometimes, mean longevity and antioxidant supplements. Other examples supporting the free radical theory include negative correlations between longevity and free radical production; and between age and free radical defenses. Thus, the free radical theory of aging became the most likely explanation for the former rate of living theory.

Free radicals seem to contribute to aging and age-related diseases primarily by damaging DNA, proteins and lipids. The exact effects and the relative importance of effects from free radicals on DNA, proteins, and lipids are not known, though the general effects seem to be aging and an increase in certain age-related diseases. For example, damage to DNA slows DNA production for cell reproduction; adversely affects cell processes; and promotes cancer. Damage to proteins disturbs and distorts much bodily structure; reduces enzyme activity; makes proteins more susceptible to enzymatic destruction; promotes inflammation; and upsets signaling and control mechanism for homeostasis. Damage to lipids reduces the effectiveness of cellular membranes to regulate the movement of substances; reduces energy production by mitochondria; promotes atherosclerosis and blood clotting; and promotes additional free radical production.

In spite of all the body's efforts, free radical production and damage from *FRs occurs. Further, their rate of production, rate of causing damage, and amount of damage all increase with age. This free radical damage adversely affects a variety of essential bodily components and alter body functions. Many scientists believe that years of such damage are a main cause, if not the most important cause, of what we know as biological aging.

Mitochondrial theory

The mitochondrial theory was proposed by Ozawa and colleagues in 1989. This theory states that mitochondrial activities and damage to mitochondria cause aging. The theory developed from the free radical theory when scientists combined numerous discoveries. As examples, mitochondria are main sources of free radicals; mitochondria are severely damaged by free radicals; mitochondria are easily affected by harmful environmental agents (e.g., radiation, pollutants, medications); damaged mitochondria accumulate with aging; cells that do not divide (e.g., muscle, neurons) or that divide slowly (e.g., bone, liver) accumulate many damaged mitochondria; damaged mitochondria produce greater amounts of free radicals; mitochondria release substances that produce free radicals in other parts of the cell, other cells, and the blood; damaged mitochondria have less ability to regulate signaling substances (e.g., calcium); mitochondrial DNA (mtDNA) is much more susceptible to free radical damage than is nuclear DNA; mitochondria cannot repair their DNA; unlike nuclear DNA, cells use virtually all their mtDNA, so any mtDNA damage causes problems; mitochondrial transposable elements, including damaged mtDNA, move to the nucleus; and certain mitochondrial diseases promote specific age-related diseases (e.g., atherosclerosis, types of neuron degeneration).

Mitochondrial DNA theory

Scientists who focus more on genetic mechanisms of aging have also focused on the age-related changes in mtDNA to develop the mitochondrial DNA theory. According to this theory, mtDNA damage occurs much faster than does damage to nuclear DNA. mtDNA sustains damage 10 to 20 times faster than does nuclear DNA because mtDNA is not protected by proteins; it is attached to the inner mitochondrial membrane, where most free radicals are produced; and it cannot repair itself. Furthermore, damaged mtDNA accumulates in cells because damaged mitochondria replicate faster than undamaged mitochondria; mitochondria that replicate retain damaged mtDNA; mitochondria with damaged mtDNA are eliminated slower than normal mitochondria; and non-dividing cells or slowly dividing cells accumulate high percentages of damaged mitochondria. Some scientists believe that the XL for humans is approximately 130 years because by that age, all mtDNA in the body would have some type of damage from *FRs. Death would result soon after that from mitochondrial failure.

The damaged mtDNA leads to more age changes than does damage to nuclear DNA because each cell uses almost all its mtDNA genes while using only approximately 7 percent of its nuclear DNA genes. Thus, nearly any adverse change in mtDNA will have adverse effects on the mitochondria. These effects include less energy production; more free radical formation; reduced control of other cell processes; and accumulation of damaged harmful molecules. These changes lead to aging and certain age-related diseases.

Clinker theories

Potentially harmful substances are known to accumulate in the body over a period of years. Because these materials interfere with the body passively, theories that claim that they cause aging are called clinker theories. A material first proposed to cause aging is lipofuscin. It is a mixture of chemical waste products from normal cell activities, including those in mitochondria. As time passes, lipofuscin becomes more concentrated inside cells, such as those of the heart and the brain, because the cells cannot effectively eliminate it. When cells have accumulated a great deal of lipofuscin, they appear darker in color. Because of the gradual darkening, lipofuscin has been called age pigment. Though lipofuscin now seems unimportant in aging, some people believe that it contributes to aging by interfering with cell activities.

Other materials that accumulate and seem to get in the way include a protein called amyloid. It is found between cells within the heart, the brain, and other organs. In some disease conditions, called amyloidosis, it becomes excessive and severely interferes with the operation of these organs. For example, amyloid is found in great abundance between the nerve cells in the brains of people with with Alzheimer's disease. Accumulation of glucose has also been implicated as causing age changes. It binds to molecules (e.g., collagen, hemoglobin), causing them to stick closer together, restricting their movements, and altering their functions. Collagen with many glucose cross-links also becomes darker and contributes to age pigments.

Cross-linkage theories

The fact that collagen molecules and other chemicals in the body become linked together as time passes has led to another group of theories of aging, the cross-linkage theories. Free radicals, glucose, and even light seem to promote the formation of bonds between molecules. The cross-linkage theories maintain that such bonding reduces the movement of molecules for chemical reactions, the movement of materials through the body, and the movement of body parts. The result is malfunctioning and aging. In addition, when glucose cross-links proteins by glycation, free radicals are produced. These free radicals may also contribute to aging. The glycation theory proposes that most aging is caused by glycation and the resulting free radicals.

Hormone theories

Some research provides evidence that aging is caused by hormones. Hormones are chemical messengers produced in the body by structures called endocrine glands. Hormones are carried by the blood and give instructions to almost all body cells.

Some hormone theories attribute human aging to only one hormone. An example is the insulin theory. It proposes that when cells are subjected to high levels of insulin, they become less sensitive to insulin. Also, elevated levels of insulin reduce the production of growth hormone (GH) from the pituitary gland. Combining the proposed effects of high insulin and low GH resulted in the insulin/growth factor imbalance theory. It proposes that aging results from excess stimulation of growth by insulin and other growth-promoting substances including GH and glucocorticoids. The results are faster cell reproduction, larger cell size, larger body size, and the decline in physiological reserve that marks aging. This theory is reflected in the disposable body theory.

The glucocorticoid theory focuses on glucocorticoid hormones, which are secreted by the adrenal glands. It states that if glucocorticoid levels are slightly elevated frequently or steadily, aging is inhibited because such levels keep the body's adaptive mechanisms at peak performance. The slightly elevated levels of glucocorticoids also prevent damage from excess inflammatory responses or immune responses. Aging results from improper levels of glucocorticoids. When levels are low, adaptive mechanisms become inadequate. When levels are high, damage results from excess suppression of defense mechanisms (e.g., inflammation, immune function) and stimulation of high blood glucose levels. In addition, high levels of glucocorticoids cause damage to certain areas in the brain. Since mild stress promotes slightly elevated levels of glucocorticoids, proponents of this theory suggest that life expectancy and perhaps quality of life are maximized in people with mildly stressful lives. In other words, having realistic challenges throughout life is beneficial.

Another hormone theory, the reproductive hormone theory, states that aging results when reproductive hormone levels decline after reproductive years. With lower sex hormones, genes receive inadequate or detrimental signals. The result is declining production of desirable proteins and excess production of deleterious proteins, leading to aging.

More complex hormone theories combine interactions and effects from insulin, GH, glucocorticoids, melatonin, and other hormones.

Calcium theory

Some scientists have used portions of several theories to develop the calcium theory. This theory states that abnormal concentrations and movements of calcium occur from several factors including free radical damage to membranes in cells; inadequate energy supply from damaged mitochondria; accumulations of amyloid protein; and elevated levels of glucocorticoids. Since many of the body's regulatory mechanisms rely on calcium as a signaling substance, abnormal levels of calcium lead to cell malfunctions and inadequate regulation of adaptive mechanisms. Examples include the functions of many enzymes, muscle cells, nerve cells, and blood vessels. The result is aging.

Other theories of aging focus on the immune system. The immune system consists of cells found in many parts of the body. Some of the cells are grouped in structures like the lymph nodes. The lymph nodes may become noticeable when an ill person has “swollen glands.” Other immune system cells are concentrated in the outer layer (i.e., epidermis) of the skin. Many immune system cells are carried from place to place in the body by the blood and the lymphatic fluid. Most of these mobilized cells are lymphocytes.

The immune system is one of the major defense systems in the body. This system operates by identifying many large molecules and all cells in the body. Those identified as normal parts of the body are left undisturbed. However, anything identified as not belonging in the body is attacked and destroyed by the immune cells.

One immune theory of aging is like the error catastrophe theory in that it focuses on making mistakes. This immune theory states that as a person gets older, the ability of the immune system to distinguish normal from foreign materials weakens. The immune cells begin to attack and destroy important bodily components, thereby causing changes associated with aging. An example of such changes would be inflammation of the joints (i.e., arthritis). Because the body's immune system is attacking the body itself, this theory is called the autoimmune theory.

Other types of immune theories are the immune deficiency theories. One version resembles the disposable body theory. It states that an immune system with indefinite capabilities never evolved because such ability is not needed for reproductive success. The other version resembles the limited gene usage theory. It states that the immune system becomes weaker as it is used. With either theory, after many years the immune system is not able to defend the body against foreign molecules and microbes. These noxious agents are allowed to injure the cells of the body and to disrupt their functioning. Detrimental age changes are the result.

Both types of immune theories have been combined into a more unified immune dysregulation theory. It states that both changes in the immune system occur and cause aging because regulating signals among immune system functions become disproportionate. Additional age changes occur because of imbalanced signals sent by the immune system to other cells.

Wear and tear theory

The wear and tear theory suggests that aging is nothing more than the accumulation of injuries and damage to parts of the body. Use, accidents, disease, radiation, toxins, and other detrimental factors adversely affect parts of the body randomly. The result of years of such abuse is aging. This theory was once quite popular, but it has fallen into disrepute. A major reason for its demise is it cannot account for the rather regular and universal nature of biological age changes in humans. However, as shown above, more focused forms of this theory have appeared in stochastic theories, such as the somatic mutation theory, the free radical theory, and the cross-linkage theory.

Network theories

Many scientists believe that aging results from combinations of phenomena like those in the above theories. Scientists who believe that there are interactions among these phenomena have developed network theories. Sometimes, these interactions seem to interact in a positive feedback fashion, producing an expanding spiral of damage and leading to aging. For example, free radicals from mitochondria damage the mitochondria, cause somatic mutations, cause leakage of calcium from the mitochondria, and promote glycation. These changes reduce the production and effectiveness of enzymes that remove free radicals and that repair molecules damaged by free radicals. Also, glycation increases free radical production. With more free radicals and less free radical defenses, the rate of damage to mitochondria increases, leading to faster free radical production, and so forth. A network theory for human aging may include all these phenomena plus their effects on the immune, nervous, and endocrine systems. Damage to these systems leads to disruption in regulatory and defense systems needed for homeostasis. Some theories of human aging may also include social and cultural factors. Aging is a result of degeneration or breakdown in proper integration and regulation among all these levels.

In conclusion, the number and diversity of theories attempting to explain biological aging can be confusing. Each theory is supported by some evidence, and each can explain certain aspects of biological aging. However, none tells the complete story. This may be because aging results from a combination of causes. Some causes may be more important than others, and some may act at different times. Others may affect different parts of the body or may be effects rather than causes. It is also possible that none of the theories are correct.

However, it is still important to formulate, test, and revise theories if the cause or causes of aging are to be discovered. Once they are known, influencing the processes in biological aging might be possible. It might also be possible to identify undesirable but not inevitable changes that frequently occur along with aging and to direct more attention to them. Much progress has already been made in this direction. Many diseases that are not part of aging but that are associated with aging provide excellent examples. Some of the more common ones include heart attack, stroke, osteoporosis, emphysema, and cancer. Numerous others will be mentioned in the following chapters. Through good nutrition, exercise, timely health care, and avoidance of the risk factors for these diseases, many cases can be prevented, improved, or at least have their progress slowed.

We now turn to a detailed examination of biological aging in humans. We will start on the outside of the body and examine the integumentary system.