Theories of Biological Aging: Programmed Aging

In the past, many investigators tried to develop a unified theory of biological aging. Evidence that environmental factors can induce mutations and damage cells, and that repair processes are a normal part of cell function, led to development of error and damage theories of aging. According to these theories, accumulation of damage eventually outstrips the ability of the cells to repair themselves, leading to cell senescence and death. Other investigators felt that these theories focus attention on essentially random events, such as DNA damage induced by radiation, and do not provide a convincing explanation for vastly different longevity of different cell types within the same individual, or individuals from different species living in the same environment. Therefore they proposed a theory that aging is programmed (i.e., predetermined). The proposed mechanisms of programmed senescence included the existence of a life-span-determining clock or perhaps a system of tissue- or organ-specific clocks controlled by a master clock. A master clock would presumably control systems responsible for integration of various functions of the organism, such as the endocrine or the central nervous system.

Further refinement of the programmed senescence theory was developed by Bernard Strehler, who proposed that as cells differentiate to perform specific functions within the organism, they lose some of the ability to translate their genetic information, and that this eventually will lead to senescence. Although the specific mechanisms invoked by this and other theories of programmed aging are now of little more than historical interest, they served to establish some important concepts. The importance of the genetic endowment of an individual in aging and life expectancy has been proved beyond any doubt. Therefore, aging can be viewed as being genetically programmed. Furthermore, the concept that senescence is a price paid for development and differentiation is consistent with the life histories of different species. Early maturation and intensive, early reproductive effort are characteristic of short-lived species, whereas late puberty and low reproductive rate tend to be associated with delayed aging.

Recent research in gerontology focuses on the suspected mechanisms of aging. Theories of aging have been classified as organ, physiological, and genetic. Organ theories focus on the importance of age-related changes in the function of organ systems (e.g., neuroendocrine regulation or immune defenses). The physiological theories focus on a particular mechanism of aging, for example, the role of reactive oxygen species in damaging various components of the cell, as proposed by Denham Harman in his oxidative theory of aging. The genetic theory emphasizes the importance of somatic and mitochondrial mutations and the concept of programmed aging. The various aging theories are no longer viewed as mutually exclusive; instead, the multiplicity of mechanisms involved in senescence and regulation of longevity is appreciated. It is now understood that specific genes determine the ability of cells to deal with oxidative stress, and that oxidative damage to cells can lead to organ failure, senescence, and death. Thus, the program theory, physiological theory, and organ theory blend into one comprehensive picture.

Appreciation of the genetic control of aging can be viewed as a modern version of the program theory of aging. Convincing evidence for genetic programming of aging and life span was derived from the study of the effects of specific genes on longevity. Most of the available information on the genetics of aging came from the studies of three species widely used in biological experimentation: a microscopic worm, Caenorhabditis elegans; a fruit fly, Drosophila melanogaster; and a mouse, Mus musculus. In worms and flies, the life span can be greatly extended by experimental manipulation of the expression of specific genes. Overexpression of some of these genes by transgenic technology and the elimination or silencing others by targeted disruption (the so-called gene knockout) can delay aging and prolong life. The mechanisms involved in these effects remain to be fully elucidated but certainly include increased activity of enzymes which control oxidative damage by reducing the levels of reactive oxygen species. Other suspected mechanisms include alterations in energy metabolism, growth, and reproduction.

Results obtained in mice prove that genetic control of aging also applies to mammals. In hereditary dwarf mice, mutation of a single gene produces numerous alterations. These include changes in endocrine function, reduced growth and the characteristic dwarf phenotype, delayed aging, and extension of life span by approximately fifty percent (i.e., from two years to three years). In terms of human life, this would correspond to changing life expectancy from 80 to 120 years. The mechanisms responsible for this impressive extension of life span appear to include a long list of primary and secondary consequences of mutation of these particular genes. The list includes improved antioxidant defenses, increased responsiveness to insulin, reduced blood sugar levels, reduced adult body size, delayed sexual maturation, reduced body temperature, and altered level of expression of numerous genes. Most of these effects can readily be traced to the primary effects of the mutations involved (i.e., deficiency of three pituitary hormones: growth hormone, thyrotropin, and prolactin). The importance of reduced growth hormone action is strongly supported by recent evidence from mice with knockout of the growth hormone receptor gene. These mice are very small and live longer than normal mice. The concept that inhibition of growth and maturation, combined with hypothermia, hypoglycemia, and chronic alterations in blood hormone levels can program an individual for long life may seem surprising. However, these findings are entirely consistent with the overwhelming evidence that reducing food intake (caloric restriction), which causes similar alterations in growth, body temperature, and so on, can greatly prolong life in mice, rats, and apparently monkeys. There is also considerable but somewhat controversial evidence that shorter people live, on the average, longer than taller individuals.

Ongoing studies on humans, including studies of twins as well as exceptionally long-lived people and their relatives, should soon reveal to what extent human aging and life span are genetically programmed.