In a literal sense, a person begins to age the moment he or she is born; however, true aging at the cellular level doesn’t commence until early adulthood. The pathophysiology of aging is complex; it is characterized in each cell by a limited number of mitoses and is largely associated with the accumulation of mutations, which lead to death of the cell and, eventually, the organism.
In a teleological sense, aging occurs to allow evolutionary changes in a species. Many naturally occurring human disorders exist whereby the aging process is greatly accelerated. Despite the elucidation of many of these conditions at a genetic level, the exact regulation of the aging process is, as yet, poorly understood.
Life expectancy varies among different species; flies live for about 30 days, rabbits 6 years, and horses 25 years. Even within a species, there is a genetic basis for life expectancy; for example, children of long-living parents usually live significantly longer than average. What is the molecular basis for cellular aging, and in what way is aging determined by our genes? If one examines the tissues of younger individuals and compares them to those of older individuals of the same species, there are significant differences, especially with regard to posttranslational modification of proteins.
For many mammalian species, it has been shown that, with increasing age, some of the enzymes in their tissues lose a portion of their activity even though immunological methods show that the proteins are still present. It is assumed that chemical processes, such as the generation of free radicals due to oxidative stress, contribute to conformational and consequently functional damage to various structural and nonstructural proteins of the cell.
Under certain circumstances, oxygen forms highly reactive compounds (e.g., superoxide anions, hydroxyl peroxide radicals, and hydroxyl radicals). These free radicals react with certain amino acids, including histidine, arginine, lysine, and proline, as well as with the sulfhydryl groups of methionine. The changes in the normal polypeptide chains, such as an enzyme, can lead to a conformational change that results in inactivation of the enzyme’s catalytic function. Experiments with drosophila have shown that overexpression of catalase and superoxide dismutase, enzymes that trap free radicals and convert them back into H2O and O2, can significantly extend the life span.
Glycosylation of Proteins
There is evidence that glycosylation of proteins, meaning the spontaneous, nonenzymatic reaction of the proteins with glucose, significantly contributes to aging. During glycosylation, the aldehyde of glucose reacts with a free amino group of a protein. Subsequent reactions, which may involve free radicals, result in complex final products, so-called advanced glycation end products (AGEs). The content of AGEs rises with age depending on the blood glucose level.
AGEs are able to cross-link other proteins and change their physical as well as biological characteristics. It is assumed that AGEs are involved in the development of atherosclerosis, cataracts, and peripheral neuropathies. AGEs, and their reaction products, are recognized by macrophages and, in this way, promote the secretion of inflammatory cytokines and tumor necrosis factor.
Nutrition as an Aging Factor
Can alteration of nutrition and lifestyle prolong life expectancy? A large study on rhesus macaques shows that animals that are fed a low-calorie diet live significantly longer than animals that are fed normal diets. Lower fasting insulin levels, lower fasting glucose levels, higher insulin sensitivity, and lower low-density lipoprotein (LDL)-cholesterol levels are associated with lower atherogenesis in the dietary-restricted animals.
This correlates with previous studies in mice, which used biochemical analyses to show that the levels of glycated proteins in the caloric-restricted mice were significantly lower than those in the control group. It was also shown that caloric restriction has a positive influence on the defense mechanisms against free radicals. This may be an indication that free radicals, as well as glycated proteins, contribute to the aging process or even complement each other, synergistically.
Studies of human DNA reveal that somatic mutations accumulate, and chromosomal instability is more likely as an organism ages. Presently, it is not known whether these aberrations are the result of or the cause for the aging process.
Some especially striking age-related changes of the nuclear genome occur at the telomeres of the chromosomes. These regions are characterized by multiple tandem repeats of a specific sequence, 5?-TTAGGG-3?, stretching over many thousand nucleotides (approximately 9 kb). Telomeres have an important function in stabilizing the chromosome structure by “capping” the chromosomal ends and preventing interaction with other chromosomes that could lead to rearrangements or chromosomal fusion. They have been compared to aglets at the end of shoelaces that keep them from fraying.
Since approximately 50 nucleotides at the end of each chromosome are lost during each cell division cycle (Section 2.7), the telomeres become progressively shorter during a person’s lifetime. When too short, they lose their function as protective chromosomal “caps,” and the cell enters growth arrest and apoptosis. This mechanism appears to prevent genomic instability and development of cancer in aged human cells by limiting the number of cell divisions.
Cell cycle arrest is mediated through cyclin-dependent kinases. While DNA damage can possibly be repaired during cell cycle arrest, lengthening of the telomeres is not possible, since normal body cells do not have telomerase activity. Additional signaling cascades lead to the programmed death (apoptosis) of these cells.
Changes in the mitochondrial DNA (mtDNA) are thought to cause some of the phenotypes of an aging organism. The accumulation of mitochondrial mutations, including deletions, duplications, and point mutations, has been found in many tissues of older individuals. There are two reasons why the mitochondrial genome is particularly vulnerable to mutations. First, mitochondria lack DNA repair enzymes that maintain a low cumulative mutation burden in the nuclear genome. The mitochondrial genome, therefore, has mutation rates that are 100 to 1,000 times higher than the rate of mutations of the nuclear genome.
Second, mtDNA is the preferred target of free radicals, because the latter develop during oxidative phosphorylation in the mitochondria themselves. The proximity of mtDNA to the sources of free radicals and the absence of a scaffold of histone molecules render mtDNA far more vulnerable and mutable than nuclear DNA. As with mitochondrial disorders, the accumulation of mtDNA mutations particularly affects tissues with high energy needs and a dependence on oxidative phosphorylation.
Reduced mental and physical strength, ataxia, retinal degeneration, hearing loss, cardiac arrhythmias, and myopathy with rapid fatigue are not only typical symptoms of mitochondrial disorders, but also phenomena that manifest themselves in the aging organism, though in varying degrees.
Human Progeria Syndromes
Human aging is a highly complex and multifactorial process, yet there are monogenic disorders—the so-called progeria syndromes—that are characterized by clinical features of premature aging in young persons.
Syndromes that recapitulate the phenotype of the aging person in an accelerated manner.
The prototype of this group of diseases is Werner syndrome (progeria adultorum), which is an autosomal recessive disorder resulting from mutations of the WRN gene. In most cases it manifests itself as the absence of the normal growth spurt in adolescence. At the age of 20 years, most of the patients have gray hair with progressive atrophy and hardening of the skin, premature development of cataracts, osteoporosis, diabetes mellitus, and varying degrees of atherosclerosis.
The average life expectancy is 47 years. The most frequent causes of death are myocardial infarction and malignant neoplasms. More than 400 cases of Werner syndrome have been reported in the literature. The gene product of the WRN gene belongs to a family of DNA helicases that are required for DNA replication, recombination, chromosome segregation, DNA repair, transcription, or other processes requiring unwinding of DNA. Hindered DNA repair, increased telomere shortening, and increased genomic instability all may contribute to premature senescence in Werner syndrome.
While Werner syndrome manifests itself in adolescence, children with Hutchinson-Gilford syndrome (progeria infantilis) begin to show symptoms of premature aging in their first year of life (Fig. 8.1). The disorder was first described in 1754. Most affected children have distinct alopecia by their second birthday. Subcutaneous lipodystrophy makes the children look old at a very young age. Periarticular fibroses result in the stiffening of the joints; there is early osteoporosis with bone fragility.
By the time they are 5 years old, patients have generalized atherosclerosis. The average life expectancy is 14 years. Hutchinson-Gilford syndrome is caused by mutations of the LMNA gene, which codes for laminin A/C, an essential component of the nuclear membrane. Lamins form microfilaments in the nucleus and are important in maintaining the proper structure of the nuclei. They also influence chromatin structure, regulation of gene expression, and other functions.
Figure 8.1.Hutchinson-Gilford Progeria in a 3½-Year-Old Boy.
Note the sparsity of hair of the scalp and eyebrows, as well as the atrophy of subtemporal fatty tissue, facial hypoplasia with microgenia, and the typically prominent cranial veins.
(Courtesy of R. Hennekam, Institute of Child Health, London.)