Sunday 7 March 2004
Cellular aging is the result of a progressive decline in the proliferative capacity and life span of cells and the effects of continuous exposure to exogenous influences that result in the progressive accumulation of cellular and molecular damage.
Structural and Biochemical Changes with Cellular Aging
A number of cell functions decline progressively with age.
Oxidative phosphorylation by mitochondria is reduced, as is synthesis of nucleic acids and structural and enzymatic proteins, cell receptors, and transcription factors.
Senescent cells have a decreased capacity for uptake of nutrients and for repair of chromosomal damage. The morphologic alterations in aging cells include irregular and abnormally lobed nuclei, pleomorphic vacuolated mitochondria, decreased endoplasmic reticulum, and distorted Golgi apparatus.
Concomitantly, there is a steady accumulation of the pigment lipofuscin, which, as we have seen, represents a product of lipid peroxidation and evidence of oxidative damage; advanced glycation end products, which result from nonenzymatic glycosylation and are capable of cross-linking adjacent proteins; and the accumulation of abnormally folded proteins.
Advanced glycation end products are important in the pathogenesis of diabetes mellitus, but they may also participate in aging.
- For example, age-related glycosylation of lens proteins may underlie senile cataracts. The nature of abnormally folded proteins was discussed earlier in the chapter.
The concept that cells have a limited capacity for replication was developed from a simple experimental model for aging. Normal human fibroblasts, when placed in tissue culture, have limited division potential.
Cells from children undergo more rounds of replication than cells from older people. In contrast, cells from patients with Werner syndrome, a rare disease characterized by premature aging, have a markedly reduced in vitro life span. After a fixed number of divisions, all cells become arrested in a terminally nondividing state, known as cellular senescence.
Many changes in gene expression occur during cellular aging, but a key question is which of these are causes and which are effects of cellular senescence.83 For example, some of the proteins that inhibit progression of the cell growth cycle (as detailed in Chapter 7)-such as the products of the cyclin-dependent kinase inhibitor genes (e.g., p21)-are overexpressed in senescent cells.
How dividing cells can count their divisions is under intensive investigation. One likely mechanism is that with each cell division, there is incomplete replication of chromosome ends (telomere shortening), which ultimately results in cell cycle arrest.
Telomeres are short repeated sequences of DNA (TTAGGG) present at the linear ends of chromosomes that are important for ensuring the complete replication of chromosome ends and protecting chromosomal termini from fusion and degradation.
When somatic cells replicate, a small section of the telomere is not duplicated, and telomeres become progressively shortened. As the telomeres become shorter, the ends of chromosomes cannot be protected and are seen as broken DNA, which signals cell cycle arrest.
The lengths of the telomeres are normally maintained by nucleotide addition mediated by an enzyme called telomerase. Telomerase is a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes.
The activity of telomerase is repressed by regulatory proteins, which restrict telomere elongation, thus providing a length sensing mechanism. Telomerase activity is expressed in germ cells and is present at low levels in stem cells, but it is usually absent in most somatic tissues.
Therefore, as cells age, their telomeres become shorter, and they exit the cell cycle, resulting in an inability to generate new cells to replace damaged ones.
Conversely, in immortal cancer cells, telomerase is reactivated, and telomeres are not shortened, suggesting that telomere elongation might be an important-possibly essential-step in tumor formation.
Despite such alluring observations, however, the relationship of telomerase activity and telomeric length to aging and cancer still needs to be fully established.
Genes That Influence the Aging Process
Studies in Drosophila, C. elegans, and mice are leading to the discovery of genes that influence the aging process.87 One interesting set of genes involves the insulin/insulin growth factor-1 pathway.
Decreased signaling through the IGF-1 receptor as a result of decreased caloric intake, or mutations in the receptor, result in prolonged life span in C. elegans.
The signals downstream of the IGF-1 receptor involve a number of kinases and may lead to the silencing of particular genes, thus promoting aging. Analyses of humans with premature aging are also establishing the fundamental concept that aging is not a random process but is regulated by specific genes, receptors, and signals.
Accumulation of Metabolic and Genetic Damage
In addition to the importance of timing and a genetic clock, cellular life span may also be determined by the balance between cellular damage resulting from metabolic events occurring within the cell and counteracting molecular responses that can repair the damage. Smaller animals have generally shorter life spans and faster metabolic rates, suggesting that the life span of a species is limited by fixed total metabolic consumption over a lifetime.
One group of products of normal metabolism are reactive oxygen species. As we have seen, these byproducts of oxidative phosphorylation cause covalent modifications of proteins, lipids, and nucleic acids.
The amount of oxidative damage, which increases as an organism ages, may be an important component of senescence, and the accumulation of lipofuscin in aging cells is seen as the telltale sign of such damage.
Consistent with this proposal are the following observations: (1) variation in longevity among different species is inversely correlated with the rates of mitochondrial generation of superoxide anion radical, and (2) overexpression of the antioxidative enzymes superoxide dismutase (SOD) and catalase extends life span in transgenic forms of Drosophila.
Thus, part of the mechanism that times aging may be the cumulative damage that is generated by toxic byproducts of metabolism, such as oxygen radicals.
Increased oxidative damage could result from repeated environmental exposure to such influences as ionizing radiation, progressive reduction of antioxidant defense mechanisms (e.g., vitamin E, glutathione peroxidase), or both.
A number of protective responses counterbalance progressive damage in cells, and an important one is the recognition and repair of damaged DNA.
Although most DNA damage is repaired by endogenous DNA repair enzymes, some persists and accumulates as cells age. Several lines of evidence point to the importance of DNA repair in the aging process.
Patients with Werner syndrome show premature aging, and the defective gene product is a DNA helicase - a protein involved in DNA replication and repair and other functions requiring DNA unwinding.
A defect in this enzyme causes rapid accumulation of chromosomal damage that mimics the injury that normally accumulates during cellular aging. Genetic instability in somatic cells is also characteristic of other disorders in which patients display some of the manifestations of aging at an increased rate, such as ataxia-telangiectasia, in which the mutated gene encodes a protein involved in repairing double strand breaks in DNA.
Studies of mutants of budding yeast and C. elegans show that life span is increased if responses to DNA damage are enhanced. Thus, the balance between cumulative metabolic damage and the response to that damage could determine the rate at which we age. In this scenario, aging can be delayed by decreasing the accumulation of damage or by increasing the response to that damage.
Not only damaged DNA but damaged cellular organelles also accumulate as cells age. In part, this may be the result of declining function of the proteasome, the proteolytic machine that serves to eliminate abnormal and unwanted intracellular proteins.
Carrard G, et al: Impairment of proteasome structure and function in aging. Int J Biochem Cell Biol 34:1461, 2002.