Programed and genetic theories propose that the process of aging follows a biological timetable, perhaps a continuation of the one that regulates childhood growth and development. There are a number of lines of evidence supporting these theories.
Longevity genes It is clear that aging is controlled to some extent by genetic mechanisms. The distinct differences in life span among species are a direct indication of genetic control, at least at the species level. A number of genes have been identified in yeast, nematode worms (Caenorhabditis ele-gans), and fruit flies (Drosophila melanogaster) that significantly increase the organism's potential maximum life span. The products of these genes act in a diverse number of ways and are involved in stress response and resistance, development, signal transduction, transcriptional regulation, and metabolic activity.
However, the genetics of longevity have not been as revealing in mammalian studies. In mouse systems genes involved with immune response have been implicated in longevity, as has the 'longevity gene p66shc, which is involved in signal transduc-tion pathways that regulate the cellular response to oxidative stress. In humans, a number of mitochon-drial DNA polymorphisms are associated with longevity. Linkage analysis in humans systems has associated certain genes on chromosome 4 with exceptional longevity. Further support for human longevity genes may be provided by the observation that siblings and parents of centenarians live longer. The major histocompatibility complex (MHC), the master genetic control of the immune system, may also be one of the gene systems controlling aging, since a number of genetic defects that cause immunodeficiency shorten the life span of humans. Certain MHC phenotypes have also been associated with malignancy, autoimmune disease, Alzheimer's disease, and xeroderma pigmentosum in humans.
Accelerated aging syndromes No distinct pheno-copy exists for normal aging, but there are several genetic diseases/syndromes that display some features of accelerated aging, including Hutchinson-Gilford syndrome (classic early onset Progeria), Werner's syndrome, and Down's syndrome. Patients with these syndromes suffer from many signs of premature aging including hair loss, early greying, and skin atrophy, and also suffer from premature age-related diseases such as atherosclerosis, osteoporosis, and glucose intolerance. The defined genetics involved in these syndromes provide strong evidence for the genetic basis of aging.
Neuroendocrine theories These theories propose that functional decrements in neurons and their associated hormones are pivotal to the aging process. An important version of this theory suggests that the hypothalamic-pituitary-adrenal (HPA) axis is the key regulator of mammalian aging. The neuroendocrine system regulates early development, growth, puberty, the reproductive system, metabolism, and many normal physiological functions. Functional changes to this system could exert effects of aging throughout an organism. However, the cells of the neuroendocrine system are subject to the normal cellular aging processes found in all cells, and the changes occurring in the neuroendocrine system may be secondary expressions of the aging phenotype.
Deterioration of the immune system with aging ('immunosenescence') may contribute to morbidity and mortality due to decreased resistance to infection and, possibly, certain cancers in the aged. T-cell function decreases and autoimmune phenomena increase in elderly individuals.
Although the immune system obviously plays a central role in health status and survival, again the cells of the immune system are subject to the normal cellular aging processes found in all cells. Changes to the immune system may be secondary expressions of the aging phenotype.
Cellular senescence At the cellular level, most, if not all, somatic cell types have a limited replicative capacity in vitro before they senesce and die. The number of cell population doublings in vitro is inversely correlated with donor age. This is called the 'Hayflick phenomenon' after the scientist credited with its discovery. This limit in the capacity of a cell type or tissue to divide and replenish itself would have major repercussions in vivo. There is evidence that replicative senescence is related to in vivo aging, but definitive evidence that senescent cells accumulate in vivo is lacking to date. Many alterations to normal cellular physiology are exhibited with the senescent phenotype, indicating that senescent cells exist in a growth state that is quite distinct from that of young cells and are subject to a complex alteration to their cellular physiology.
A number of possible explanations for limiting the number of cell population doublings have been proposed, including a tumor suppressive mechanism. One proposal is that the shortening of telomeres, the sequences of noncoding DNA located at the end of chromosomes, is a measure of the number of cell divisions that a cell has experienced. These telomeres may act as specialized regions of the genome, a sacrificial 'sentinel' zone, for the detection of DNA damage being noncoding, more prone to damage, and less prone to repair than the genome as a whole. Damage to telomeres transposes to tel-omere shortening, and loss of telomere higher order structure may trigger senescence and/or apoptosis.
Studies involving fusion of normal cells (subject to senescence) with immortal cell lines in vitro have clearly demonstrated that the senescent phenotype is dominant, and that unlimited division potential results from changes in normal growth control mechanisms. These fusion studies have also revealed the existence of several dominant genes associated with the process of cellular senescence. These genes reside on a number of chromosomes, including 1,4, and X.
Disposable soma theory The disposable soma theory suggests that aging is due to stochastic background damage to the organism, i.e., damage that is not repaired efficiently because the energy resources of the somatic cells are limited. So, instead of wasting large amounts of energy in maintaining the whole body in good condition, it is far more economical to simply repair the heritable stem cell genetic material, in order to ensure the survival of the species. In this way the future of the species is secured at the expense of individual lives. When the somatic energy supply is exhausted, the body ages and dies, but the genetic material survives (in the next generation).
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