conceptual context of gerontology
gerontology is the scientific study of the processes and problems of aging from all aspects—biologic, clinical, psychologic, sociologic, legal, economic, and political. geriatrics is the branch of medicine that deals with the diagnosis, management, and prevention of medical problems associated with senility and senescence.
although the terms “aging” and “senescence” are sometimes used synonymously, they are often differentiated by biologists. for example, leopold (1978), a plant biologist, said that aging consists of “the processes associated with the accrual of maturity in time, whereas senescence may be defined as the deteriorative processes which are natural causes of death.” the implication is that aging begins at birth.
most gerontologists, however, are concerned primarily with age-related alterations in structure and function that occur after maturation. maturation is usually defined as the achievement of sexual maturity and the adult stage of morphology and physiology. in addition, most gerontologists would not regard phenomena that were strictly coupled to chronologic time as fundamental, intrinsic aging processes. for example, changes (racemization) in amino acids in the ocular lens reveal how old an animal is, but do not differentiate between the rate of aging of a short-lived mammal, such as a mouse, and that of a long-lived mammal, such as a human.
no one denies that developmental events before maturation are immensely important in setting the stage for the patterns of post maturational aging. thus, it is conceivable that perturbation of a particular aspect of development (e.g., the modification of some stem-cell pools by environmental agents) would have drastic effects on some aging processes decades later. for example, a depletion of the precursors of neurons of the substantia nigra could increase the probability of an early onset of parkinson's disease. a change in the apparent thresholds for a great many other pathophysiological phenomena that accompany aging might have, in part, such an etiology.
the genetic concepts of genotype and phenotype require definition. johannsen (1909) originally defined the genotype, now commonly referred to as the genome, as the sum of the genetic information carried in the chromosomes of an organism. we now know of non chromosomal inheritance (e.g., via mitochondrial dna), and the term “genotype” is used to include all possible forms of genetic information that define a cell or organism and to refer to the particular form (allele) of a single gene or small group of genes. until the advent of recombinant-dna technology, the genotype of an organism was deduced, in large part, from mating experiments. one can now directly isolate, clonally amplify, and analyze a particular segment of dna.
johannsen (1909) defined the phenotype as the sum of the observable properties (structural, biochemical, and physiological) of an organism or cell. one can refer to the senescence phenotype (or the aging phenotype) as the collection of attributes that are generally believed to
characterize senescence (or aging). gerontologists disagree about the extent to which
age-related diseases should be considered integral features of that phenotype. one view is that each age-related degenerative or proliferative disorder has a pathogenesis that does not necessarily include an underlying component of intrinsic aging.
theories of aging
theories of aging can be grouped generally into two broad categories: those that invoke deterministic, or “programed,” alterations in gene expression or gene structure, and those that invoke a variety of stochastic, or “random,” alterations in the structure and function of macromolecules, cells, and organ systems.
there are limitations to this distinction, however, because stochastic alterations in individual cells can lead to predictable phenomena in the large population of cells. an example of the blurring of the deterministic and stochastic categorization is the use of terminal differentiation to explain the limited replicative life span of somatic cells (bell et al., 1978; martin et al., 1974)—that is, populations of cells cease dividing because they have differentiated into more specialized cells. for each individual cell, this differentiation is a random event. however, when viewed at the level of a population of many cells, the process appears deterministic.
although primarily applied to the cell-culture model of cell aging (hayflick and moorhead, 1961), the idea of terminal differentiation might be applied to cohorts of stem cells in vivo (martin, 1979). if the idea is valid, any environmental agent, such as retinoic acids (strickland and sawey, 1980), that depletes subsets of cells or alters states of differentiation might prove to be an important modulator of aging. terminal differentiation would also have a large impact on cells undergoing rapid amplification, such as stem cells during early development.
the relative contributions of both classes of mechanisms are likely to be coupled to the reproductive strategy of the organism. programed aging is characteristic of species with single massive episodes of reproduction (e.g., periodical cicadas). placental mammals have ample opportunity for a variety of stochastic processes to take place during their long reproductive and post reproductive phases. the associated patterns of structural and functional decline can vary substantially both qualitatively and quantitatively and both among and within species.
deterministic theories
developmental switches in gene expression
senescence does not appear to be programmed in the same way as development—that is, regulated by a series of linked gene actions, whose primary result is to produce a limited life span. only under special conditions in organisms that have a single episode of reproduction in their lifetime (semelparous organisms) can senescence be seen to be directly “programed.” senescence does not seem to be driven by the sequential, systematic turning on and off of new genes; indeed, there is little change in the transcripts that are made throughout the organism's adult life (rothstein, 1982).
this does not mean that modulation of transcriptional activity or gradual loss of tight control of gene transcription plays no role in senescence, and detailed investigation of environmental agents that alter gene expression in a way that suggests an impact on specific aspects of the aging phenotype might be warranted. no examples are yet known, although such agents as amanitin, which perturbs transcription, and cycloheximide, which perturbs translation, have potential utility.
neuroendocrine-cascade theories
finch and landfield (1985) reviewed a group of theories that can be classified as neuroendocrine-cascade theories. an excellent example is the glucocorticoid-cascade hypothesis of aging proposed by sapolsky et al. (1986b).
the basis of the hypothesis is the finding in rats that basal plasma corticosterone concentrations increase with age, and that although the increase in plasma corticosterone in response to stress does not change with age, the return to basal concentrations after the removal of stress is markedly delayed with age. the reason for the age-related changes is a gradual impairment in negative feedback control of plasma glucocorticoid concentration themselves (sapolsky et al., 1986a). the loss in sensitivity is related initially to a loss of corticosterone receptors in some hippocampal neurons and ultimately to a loss of hippocampal neurons themselves (sapolsky et al., 1983a). moreover, it is the cumulative exposure to glucocorticoids that is responsible for the decrease in glucocorticoid receptors and for the loss of the hippocampal neurons themselves (sapolsky et al., 1986b).
stochastic theories
intrinsic mutagenesis theory
burnet (1974) summarized arguments that cumulative damage to the genetic material causes aging in mammals. according to this proposition, short-lived mammals are more prone to develop somatic-cell mutations than long-lived mammals. that could occur, for example, if the dna polymerases of short-lived species were comparatively error-prone or if their various dna repair mechanisms were comparatively inefficient. support for the theory comes from observations of a positive correlation between species longevity and the efficiency of the cellular repair of dna damage induced by ultraviolet light (francis et al., 1981; hart and setlow, 1974).
genomic instability could also result from mechanisms not associated with classical forms of somatic-cell mutation. by definition, the latter involve alterations in the primary structure of the genetic material (including various rearrangements), as well as changes in the amount of the genetic material. stochastic changes in gene expression, for example, might be attributable to perturbations of chromatin configuration or of the patterns of dna methylation. this theory has obvious implications for categories of environmental agents (physical, chemical, and viral mutagens) that could accelerate the aging processes.