What is a theory of aging?
Theories of aging can be divided into two categories: those that answer the question “Why do we age?” and those that address the question “How do we age?” Only a few broad, overarching theories attempt to explain why we and nearly all living organisms age. These theories compete with each other, making it unlikely that more than one of them could be true. Over time, some theories have fallen out of favor as others have become more widely accepted.
Other theories, more properly called hypotheses, are smaller in scope and address the question, “How do we age?” They attempt to explain the mechanisms that affect how we and other species age, and it is likely that a number of them are simultaneously true. Testing these hypotheses is the current pursuit of most aging research. Identification of the mechanisms that affect aging could lead to interventions to slow or alter aging. Recent research implies that there may be a limited number of these mechanisms, giving scientists hope that their efforts may one day lead to strategies that could help us lead longer, healthier lives.
Aging Theories Classification
The complexity of the aging process diminishes the probability that any one theory would satisfactorily explain aging. The concept that some age-related changes may be programmed, whereas others are stochastic and unpredictable, is now generally accepted. However, some theories include both kinds of changes and are impossible to classify as one or the other. In fact, experts probably would not even agree on a common list of aging theories, so the following list should not be regarded as definitive or exhaustive. A further complication is the need to distinguish between the aging process itself and the effects due to phenomena such as diseases.
Random damage theories
The most prominent random damage theory of aging was proposed by Denham Harman in 1955. This theory postulates that free radical reactions, primarily oxygen-free radicals, cause slowly accumulating damage to nucleic acids, proteins, and lipids that eventually leads to loss of their specific functions in the cell. This damage is caused primarily by the production of oxygen-free radicals as a by-product of normal metabolism in the mitochondria.
Thus, while this damage may be slow, it is continuous, and the well-accepted assumption is that the individual cells are unable to neutralize all of the free radicals generated by the mitochondria or to completely repair the damage that occurs. A small amount of free radicals may also be generated in nonmitochondrial biochemical reactions, and by external insults such as radiation. This general phenomenon is also referred to as oxidative stress, and the theory predicts either that the generation of free radicals increases with age, or that antioxidant defense systems decrease with age, or both.
Many scientific reports have attempted to prove this theory of aging. They document increased levels of oxidative damage with increasing age in a variety of animal model systems, but rarely has it been possible to implicate this increased damage as a cause of aging. Nevertheless, there is strong evidence that oxidative stress is a major factor in the damage occurring following a stroke or heart attack, two major age-related events leading to loss of organ function or death. It is also thought that oxidative stress is a factor in the age-related loss of neurons that accompanies a variety of neurodegenerative pathologies. Thus, any comprehensive theory of aging must include oxidative stress as a likely factor in the loss of biological function through human aging.
The free radical, or oxidative stress, theory of aging is a prototype for other, similar theories that suggest random damage occurs and that much, but not all, of it can be repaired. Complete repair is thought to be impossible, so damage slowly accumulates and eventually leads to dysfunction and overt pathology. These related theories include error catastrophe theory and DNA damage theory. The glycation theory of aging proposes that the nonenzymatic condensation of glucose with amino groups in proteins leads to dysfunction of those proteins, a process that is accelerated in diabetics because of their increased level of circulating glucose. This is well documented in hemoglobin, and for proteins in the eye lens, leading to premature cataract formation. Glycation also leads to protein cross-linking, which not only alters both the structure and function of these proteins, but also prevents their normal degradation. The rate of living theory proposes that aging rate is proportional to the rate of the organism’s metabolism, so that small mammals with high metabolic rates, like mice, will have much shorter life spans than large mammals, such as humans. This may generally be true for mammalian species, but birds live much longer than might be predicted by their high metabolic rates and high circulating glucose levels. The wear and tear theory of aging is a similar version of this class of theories.
Programmed aging theories
The other major group of theories postulates that genetically programmed changes that occur with increasing age are responsible for the deleterious changes that accompany aging. It is well known that development is genetically programmed, so logic dictates that aging changes might also be programmed. The principal systems implicated in this group of theories are the endocrine and immune systems. It has been easy to demonstrate that the immune system changes with age. The major function of the immune system is to recognize foreign biological entities (antigens) and destroy or inactivate them either by tagging them with very specific antibodies or by directly killing them. To do this, mammals produce circulating cells called lymphocytes in either the thymus (T-lymphocytes) or the bone marrow (B-lymphocytes). However, the thymus gradually disappears and is essentially gone by young adulthood. Thus, further production of T-lymphocytes depends upon cell proliferation and expansion of the existing pool of T-lymphocytes. The lymphocyte pool always consists of naive T-lymphocytes, which are not yet responsive to a specific antigen, and memory T-lymphocytes, which are programmed to respond to a particular antigen. As age increases, memory T-lymphocytes comprise an increasing percent of the T-lymphocyte pool, and the remaining T-lymphocytes are less able to respond to an immunologic challenge such as a bacterial infection.
The immune system is also able to distinguish between foreign antigens and nonforeign antigens. The immune system’s response to nonforeign antigens is called autoimmunity, and the frequency of autoimmune interactions increases with age. In fact, a number of age-related diseases are thought to be due to these inappropriate autoimmune responses; thus these apparently programmed changes could be important factors in aging.
It is also known that the levels of circulating hormones may change with age. This is particularly true for growth hormones, dehydroepiandrosterone (DHEA), and melatonin. It is not known whether the decreases observed are developmentally programmed to benefit the organism in some way, or whether they are simply another example of dysregulation with increasing age. A much clearer example is provided by estrogen. Estrogen declines rapidly after menopause in women, and menopause is programmed to occur at about age fifty. Besides the loss of reproductive capability, this decline in estrogen production greatly increases the risk of age-related diseases such as osteoporosis and cardiovascular disease. Thus, late-life programmed changes may produce a variety of effects, many of which are not beneficial.
It is clear that humans die for a variety of reasons. Usually one or more organ or system is more compromised than the others, so failure of that system is identified as the cause of death. Two examples are heart failure and stroke. Whereas the immediate cause of death in both cases is a blood clot that obstructs blood supply to critical cells (heart muscle cells or neurons, respectively), the aging-related cause is the gradual obstruction of arteries by protein and lipid deposits. Both genetic and environmental factors may contribute to this deposition, but it can hardly be considered programmed. A continuing controversy is whether there is such a thing as aging without such disease, or whether aging is simply the accumulated effects of wear and tear from disease and the various other life stresses.
Are there genes for aging?
While it is clear that longevity is genetically determined, it is widely believed that specific age-related changes cannot have evolved by natural selection, because most aspects of aging manifest themselves well after reproduction has ceased in humans. This does not mean that aging cannot be altered by genetic intervention. Work begun in the 1980s, and continued with great success in the 1990s, demonstrated clearly that life span in diverse invertebrate organisms can be dramatically extended by mutations in, or overexpression of, specific genes (e.g., antioxidant enzyme genes), often referred to as longevity assurance genes. These genes also code for a wide variety of proteins involved in processes such as signal transduction, hormone production, protein synthesis, and metabolic regulation. It has also been possible to isolate a long-lived strain of fruit flies by selecting for female flies that reproduce late in life, suggesting that certain gene combinations may be particularly beneficial in slowing aging. However, although it is clear that genes do control longevity and the rate of aging, this does not mean that aging is precisely genetically programmed in most organisms.
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