Aging Theory — Free Radical and Oxidative Damage
Reactive radicals of nitrogen (nitric oxide and derivatives such as peroxynitrite) and of oxygen (superoxide anion, hydrogen peroxide, hydroxyl radical) can inflict considerable damage on macromolecules (proteins, nucleic acids, complex lipids), give rise to carcinogens (e.g., nitrosamines), and trigger (or sometimes prevent) apoptotic death of cells such as macrophages and vascular epithelial cells. There are mechanisms for scavenging and antagonizing those highly reactive species of molecules and for repairing damage caused by them. However, unless such mechanisms are absolutely effective, damage inflicted by free radicals may accumulate, even in a self-potentiating or exponential manner.
There is evidence that the efficiency of mitochondrial electron transport and energy-generating processes deteriorate with age, resulting in increased appearance of oxidizing free radicals. Moreover, antioxidant resistance declines with age. Thus, the free radical and nitric oxide theories of aging are topics of considerable significance and research.
Post synthetic Modifications and Molecular Cross linking of Proteins Contribute to Aging
Following translation, proteins are susceptible to several chemical modifications including oxidation, prenylation, homocysteinylation, glycation, and the formation of crosslink or advanced glycosylated end products. It is presumed that the gradual accumulation of altered proteins such as cross linked collagens, elastins, and other structural proteins will lead to morphological and functional alterations of cells and tissues and the manifestations of senescence. There is compelling evidence of an increasing pool of oxidized, defective enzymes during aging that probably parallels the increase in oxygen free radicals. As Stadtman expressed it: “substantial decreases in the amounts of important enzymes and the accumulation of massive amounts of damaged protein as occurs during aging seriously compromise cellular integrity.” The gradual enlargement of intracellular pools of defective proteins, especially enzymes, could partially explain the well-known senescent decline in reserve functional potential that is characteristics of major organ systems such as the immune system, the kidneys, and the liver.
Genes Influence Aging: “Gerontogenes” and “Virtual Gerontogenes”
Is there a small number of dedicated genes that control senescence and impose themselves on all other genes at some predetermined rate or express themselves at some predetermined time in the lives of individuals of a species? Is there a single gene, or perhaps a few, that control the average longevity of a species? These are difficult questions to answer at the present time. There are data, however, and a plethora of opinions and interpretations. There is reason- able agreement with the conclusion that senescence and life expectancy are not controlled in a simple manner by a few genes. Even within inbred lines of a given species such as mice or fruit flies there is considerable variation in the apparent rate of aging and life expectancy. Several lines of evidence lead to the conclusion that aging and longevity are controlled in complex fashion by both genes and environmental influences.
There are several recent demonstrations of genes that influence longevity. These include genes in Drosophila, yeast, the nematode Caenorhabditis elegans, and the Mediterranean fruit fly, Ceratitis capitata. In related work, investigators have identified genes in human cell lines that are responsible for converting cells considered to have an immortal phenotype into a senescent phenotype. One such gene, termed MORF4, appears to encode a transcription factor that regulates expression of several other genes that are involved in the senescent phenotype. The term gerontogenes has been applied to genetic factors that regulate aging.
Although it is highly unlikely that a single gene, or even a very few genes, play a determining role in the rate of aging or the duration of life-span, it is possible for a single gene that affects the expression of a panel of other genes to play a considerable role. A particularly informative example is the age-1 gene in C. elegans that is involved in the resistance to various types of stress that affect life-span of the organism . Such genes, acting together in closely coordinated fashion, may resemble the action of a single gene and initially appear to be an “aging gene.” The several existing examples of such genes have led to the notion of “virtual gerontogenes” defined as “several genes whose functions are tightly coupled and whose combined action and interaction resemble the effect of one gene”. Referring to such genes as “virtual” implies that upon dissection and sequencing the individual component genes will be found to control some precise function concerned most likely with nor- mal maintenance and repair.
An immunological theory of aging was proposed at a time when the only system that could be demonstrated to age in quantitative terms was the immune system. Because it was evident that the immune system plays such a central role in protection against infectious and neoplastic diseases, and because it appeared that diseases of the immune system, especially autoimmune, were associated with advanced age, the theory had merit at the time. In precise terms, the immune system plays no causal role in aging. However, as a factor in influencing length of life in relation to disease it assumes major importance as is shown later.