| Theories of aging can be divided into two general categories: biological and chemical
|
| PROGERIAS - DISEASES OF ACCELERATED AGING CAUSED BY DEFECTS IN DNA REPAIR |
Certain genetic diseases are considered models of accelerated aging (progeria). These monogenic diseases display many, but never all, of the features of normal aging. Few progeric patients develop dementia or age-related pathologies, such as Alzheimer's disease. The progerias are sometimes described as caricatures of aging, but are useful models for understanding the aging process. Werner's and Bloom's syndromes are autosomal recessive diseases caused by mutation of distinct DNA helicase genes which are thought to have a role in replication and repair of damaged DNA. Patients with Werner's syndrome appear normal during childhood, but stop growing in their teens. They gradually show many symptoms of premature aging, including graying and loss of hair, thinning of skin, development of early cataracts, impaired glucose tolerance and diabetes, atherosclerosis and osteoporosis, and increased rates of cancer. Death usually occurs in the mid-40s from cardiovascular disease. Fibroblasts from Werner's patients divide only about 20 times in cell culture and have higher levels of protein-bound carbonyl groups, an indicator of increased oxidative stress. |
| Bloom's Syndrome is also characterized by increased frequency of chromosomal breaks, dwarfism, photosensitivity and increased frequency of cancer and leukemia; death occurs typically in the mid-20s. Ataxia-telangiectasia, or fragile chromosome syndrome, is associated with increased loss of telomeres with cell division and deficiency in repair of double-strand DNA breaks. It is caused by a defect in a protein kinase involved in signal transduction, cell cycle control and DNA repair. |
| Hutchinson-Gilford syndrome is a severe, pediatric form of progeria. Patients have many of the symptoms of Werner's syndrome, but the symptoms appear at an earlier age and death usually occurs by the mid-20s. This syndrome is caused by a defect in a gene for lamin, a component of the nuclear lamina, which together with nuclear membranes and pore complexes comprise the nuclear envelope. Hutchinson-Gilford is one of several distinct syndromes associated with lamin mutations. The progeric mutation appears to increase nuclear fragility and aberrant mRNA splicing; as in Werner's syndrome, cultured fibroblasts become prematurely senescent. These progeric diseases suggest that efficient repair of DNA is essential for prevention of cancer and for normal aging. |
 |
| Biological theories treat aging as a genetically controlled event, determined by the programmed expression or repression of genetic information. Aging and death are seen as the orchestrated end-stage of birth, growth, maturation and
reproduction. Apoptosis (programmed cell death) and thymic involution are examples of genetically programmed events at the level of cells and organs, and the decline in the immunological, neuroendocrine and reproductive systems may be seen, in a broader context, as evidence for action of a biological clock affecting the integrated functions of an organism. Biological theories attribute differences in lifespan to interspecies differences in genetics, but also provide an explanation for the observation that there is a genetic component to longevity within a species, e.g. in families with a history of longevity. Differences in lifespan among species are also closely correlated with the efficiency of DNA repair mechanisms. Longer-lived species have more efficient DNA repair processes (Fig. 42.3). Numerous diseases of accelerated aging (progeria) also illustrate the importance of genetics and maintenance of the integrity of the genome during aging.
|
| Figure 42.3 Relationship between DNA repair activity and longevity. Fibroblasts from various species were irradiated briefly, forming thymine dimers and thymine glycol (Chapter 30). The oxidized bases are removed and replaced by excision repair. DNA repair was assessed by the rate of incorporation of a [3H]thymidine tracer into DNA by autoradiography (adapted from Hart RW, Setlow RB: Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species. Proc Natl Acad Sci USA. 1974;71:2169-2173.) |
| page 601 | | | page 602 |
| Chemical theories of aging treat aging as a somatic process resulting from cumulative damage to biomolecules. At one extreme, the error-catastrophe theory proposes that aging is the result of cumulative errors in the machinery for replication, repair, transcription, and translation of genetic information. Eventually, errors in critical enzymes, such as DNA
and RNA polymerases or enzymes involved in the synthesis and turnover of proteins, gradually affect the fidelity of expression of genetic information and permit the accumulation of altered proteins. The propagation of errors and resultant accumulation of dysfunctional macromolecules leads eventually to the collapse of the system. Consistent with this theory, increasing amounts of immunologically detectable, but denatured or modified, functionally inactive, enzymes accumulate in cells as a function of age.
|
|
Table 42-2.
Age-dependent chemical changes in biomolecules. |
| Body_ID: None |
| Chemistry and aging |
| Body_ID: T042002.50 |
| Protein modification | DNA modification and mutation | Other |
| Body_ID: T042002.100 |
| crosslinking | oxidation | lipofuscin |
| Body_ID: T042002.150 |
| oxidation | depurination | inactive enzymes |
| Body_ID: T042002.200 |
| deamidation | substitutions | |
| Body_ID: T042002.250 |
| D-aspartate | insertions and deletions | |
| Body_ID: T042002.300 |
| protein carbonyls | inversions and transpositions | |
| Body_ID: T042002.350 |
| glycoxidation | | |
| Body_ID: T042002.400 |
| lipoxidation | | |
| Body_ID: T042002.450 |
|
| Body_ID: T042002.500 |
Long-lived proteins, such as lens crystallins and tissue collagens accumulate damage with age. Modification and crosslinking of proteins occurs as a result of non-oxidative (deamidation, racemization) or oxidative (protein carbonyls) mechanisms or by reactions of proteins with products of carbohydrate or lipid peroxidation (glycoxidation, lipoxidation). Damage to DNA is often silent, i.e. modified forms of nucleotides may not accumulate, but the damage increases in the form of mutations resulting from errors in repair.
|
|
| Figure 42.4 Changes in lens protein and costal cartilage with age. Browning is a characteristic feature of the aging of proteins, not just in the lens, which is exposed to sunlight, but also in tissue collagens throughout the body. Crosslinking of proteins also increases with browning. Crosslinking contributes to the gradual insolubilization of lens protein with age. Aggregates of lens protein disperse light, contributing to the development of 'senile' cataracts. Crosslinking of articular and vascular collagens decreases the resilience of vertebral disks and compliance of the vascular wall with age. These changes in extracellular proteins, shown here for costal collagen, are similar to changes induced by reaction of carbohydrates and lipids with protein during the cooking of foods, a process known as the Maillard or browning reaction. At one level, humans have been described as low temperature ovens, operating at 37°C, with long cooking cycles (∼75 years). Many of the Maillard reaction products detected in the crust of bread and pretzels have been identified in human crystallins and collagens, and increase with age. (See also discussion of diabetic complications in Chapter 20.) |
| page 602 | | | page 603 |
| More general chemical theories treat aging as the result of chronic, cumulative chemical (non-enzymatic) modification, insults, or damage to all biomolecules (Table 42.2). Like rust, erosion, or corrosion, the accumulation of damage with age gradually affects function. This damage is most apparent in long-lived tissue proteins, such as lens crystallins and extracellular collagens, which accumulate chemical modifications with age. A brown color commonly results from formation of a wide range of conjugated compounds with absorbance in the yellow-red region of the spectrum (Fig. 42.4). Chemical damage to the integrity of the genome also occurs, but is more difficult to quantify because of the efficiency of repair processes that excise and repair modified nucleotides. As noted in Table 42.2, there are a number of silent consequences of DNA damage. This damage is primarily
endogenous, but is enhanced by xenobiotic and environmental agents.
|
| Organ system theories of aging incorporate various aspects of the above theories. These theories attribute aging to the failure of integrative systems, such as the immunological, neurological, endocrine, or circulatory system. While they do not assign a specific cause, these theories integrate biological and chemical theories, acknowledging both genetic and environmental contributions to aging.
|
|
