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Biology of the Aging Process
Posted on: June 28, 2005

Old age in most species is associated with impaired adaptive and homeostatic mechanisms leading to susceptibility to environmental or internal stresses with increasing rates of disease and death. A number of different theories of primary aging independent of disease have been put forward over the past 50 years; however, it has been also suggested that aging is simply the convergence of various diseases.
Without an underlying or "primary" aging process, the risk of death would remain constant or even decrease with old age as those individuals best able to avoid disease hazards survive. However, the risk of death does increase with chronological age, which is consistent with a progressive and independent aging process and forms the basis of the Gompertzian mortality curve. In centenarians, the mortality rate diminishes somewhat, suggesting survivor bias against the major mortal diseases. The aging phenotype is changing among successive birth cohorts because of variation in the spectrum of diseases and disease incidence with time. From the cellular perspective, there are several mechanisms that are considered to underlie the primary aging process and probably contribute to age-related changes in adaptive responses, including pharmacological responses. These include oxidative stress, mitochondrial dysfunction, telomere shortening, and various genetic mechanisms.

A. Oxidative Stress

Denman Harman first proposed the free radical theory of aging in the 1950s. There is now substantial evidence that supports that aging is associated with, if not the consequence of, free radical damage by various endogenous reactive oxygen species. This role of reactive oxygen species in aging is thought to explain the observation that animals with higher metabolic rates have shorter lifespans, the so-called "rate of living" hypothesis.
Reactive oxygen species include superoxide and hydroxyl radicals and other activated forms of oxygen such as hydrogen peroxide and singlet oxygen. In 1972 it was suggested that the primary sites of production of reactive oxygen species were the mitochondria, as a byproduct of oxidative metabolism. Other major sources of reactive oxygen species include phagocytic processes, prostaglandin synthesis, cytochrome P450 enzymes, nonenzymatic reactions of oxygen, and ionizing radiation. Enzymatic defenses that minimize oxidative injury include superoxide dismutase, catalase, glutathione peroxidase, glutathione transferases, peroxidases, and thiol-specific antioxidant enzymes. These, together with a host of low-molecular-weight compounds such as ascorbate, glutathione, β-carotene, α-tocopherol, uric acid, and bilirubin serve as free radical scavengers.
Aging is associated with evidence for deleterious changes to the molecular structure of DNA (deoxyguanosine derivatives), proteins (carbonyls), lipids (lipoperoxides, malondialdehydes), and prostaglandins (isoprostanes), all markers of oxidative stress. The "error catastrophe" theory of aging proposes that the accumulation of these molecular changes, particularly in proteins, constitutes the basis of cell aging and leads to death. More recently, it has been recognized that reactive oxygen species also play a role in normal signaling processes and that their generation is essential to maintain homeostasis and cellular responsiveness.

B. Mitochondria and Aging

Mitochondria are both producers and targets of oxidative stress; this fact forms the basis for the mitochondrial theory of aging. It has been proposed that accumulation of somatic mutations of mitochondrial DNA, induced by exposure to reactive oxygen species generated within mitochondria, leads to errors in the mitochondrial DNA-encoded polypeptides and subsequent defective electron transfer activity and oxidative phosphorylation. Such respiratory chain defects lead to increased reactive oxygen species production, thus establishing a "vicious cycle" with aging.
Declines have been reported with advancing age in the activity of the mitochondrial respiratory system and its constituent enzymes, notably cytochrome c oxidase, in a range of tissues including skeletal muscle, heart, and liver. Integrity of the mitochondrial DNA in these tissues gradually reduces with age, evidenced by the accumulation of deletions, duplications, and some point mutations in mitochondrial DNA. Direct evidence linking mitochondrial mutations and bioenergetic impairment has come from analysis of individual muscle cells, where a direct association between the amount of amplifiable mitochondrial DNA and the activity of cytochrome c oxidase has been demonstrated.

C. Telomeres and Cellular Senescence

In culture, diploid cells exhibit a limited proliferative potential. After a finite number of divisions, primary cell cultures enter a state of replicative senescence with arrest in cellular propagation, refractory to further mitogenic stimuli. This number of divisions, known as the Hayflick limit, has been postulated to determine the maximum lifespan of an organism. One explanation for cells reaching this limit arises from telomeres, the repetitive DNA sequences at the end of linear DNA. Telomeres shorten slightly each time the cell divides (about 50-200 base pairs per cell division). Depletion of telomeric DNA prohibits further cell division.
In tests of this hypothesis, it has been demonstrated that the maximal number of times that human fibroblast can divide in culture decreases with the age of the donor and that the maximal number of fibroblast divisions is related to the maximal lifespan of different species. Furthermore, in several premature aging conditions such as Werner's syndrome, tissues of a particular chronological age contain cells much closer to their programmed cell division limit than those from similarly aged normal individuals.
Cells of the germ line contain an enzyme called telomerase that replaces telomeric DNA lost during cell division. The possibility of reversing cellular senescence by switching on a copy of the gene encoding the telomerase catalytic subunit into normal cells, thus turning on telomerase activity has been considered. This strategy may also increase the risk that cells become immortalized.
The cellular senescence theory of aging has limitations. Organs, such as the brain, that consist mostly of nondividing cells still age. The link between donor age and cell division potential is more tenuous if fetal tissue is excluded from the analysis. Moreover, there are multigenerational telomere knockout mice and cell lines that are immortalized without telomerase.

D. Apoptosis

Aging is associated with dysregulation of apoptosis, and overall, it has been suggested that aging is mostly associated with up-regulation of apoptosis. For example, brain apoptosis has been demonstrated in age-related neurodegenerative diseases and with aging. It is not clear whether age-related dysregulation of apoptosis is the result of genetic programming or stochastic aging processes such as oxidative stress.

E. Genetic Mechanisms for Aging

In the past, the accumulation of somatic mutations secondary to unrepaired damage to DNA was postulated as a cause of tissue dysfunction in aging, but this is no longer considered to be likely.
The role of genetically programmed aging is still controversial. Evidence for a primary role for genetic programming includes the observations that the lifespan of a given species is relatively fixed and human aging has a hereditary component. In addition, single mutations in humans can produce premature aging syndromes, and altered expression of single genes may increase maximum lifespan in lower organisms. However, a cogent evolutionary principle makes the possibility of genetic determination of aging less plausible. In the past, most organisms have not lived long enough because of trauma, predation, and disease for older members of most species to exert genetic pressure toward a programmed aging or antiaging process.
A Scandinavian twin study calculated that the heritability of life expectancy is limited to 20 to 30%, which has been interpreted to indicate that longevity is primarily related to individual health-related behavior rather than genes. Even so, some genes do influence longevity ("gerontogenes"), probably by influencing the response to the underlying aging processes or disease susceptibility. In humans, genetic variations associated with longevity are essentially those associated with disease susceptibility, in particular, the apolipoprotein E4 allele, rather than genes that appear to be associated with an intrinsic aging process. Family studies of centenarians are suggestive of a familial component to extreme longevity, although the specific genes involved remain unknown. In human progeroid syndromes, a number of genes have been identified that appear causative, and these are mostly involved with DNA metabolism. For example, Werner's syndrome has been found to be caused by variation in the wrn gene, which is a DNA helicase.
Aging is associated with altered gene expression, an observation that has been established by the use of microarray DNA chip technology. However, as yet, DNA microarray studies have not identified any unexpected changes in old age. For example, in the aging brain there are changes in the expression of genes involved with inflammation, oxidative stress, and neurotrophic support. In drosophila, aging is associated with altered expression of genes involved with oxidative stress, carbohydrate metabolism, detoxification, and heat shock responses. Patterns of gene expression are different between aging and progeria, and patterns of gene expression seen in aging in drosophila cannot be reproduced by oxidative stress.

F. Caloric Restriction

Caloric restriction refers to a diet in which calories are limited by 30 to 40% compared with organisms fed without restriction. Caloric restriction extends lifespan in yeast, drosophila, worms, rodents, and probably primates. Despite extensive work demonstrating the effectiveness of calorific restriction, the mechanism by which caloric restriction extends lifespan is unclear.
One hypothesis is that caloric restriction slows metabolism and hence the production of reactive oxygen species. However, this relationship can be overcome by genetic factors. This is evident both within species (e.g., drosophila live longer after the single methuselah gene mutation without reduction in the metabolic rate) as well as between species (bats have a similar metabolic rate to mice but live 10 times longer).

Source: Allan J. Mc Lean and David G. Le Couteur; Aging Biology and Geriatric Clinical Pharmacology; Pharmacol. Rev. Vol. 56 Nr. 2:163-184, 2004
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