THEORIES OF AGING - a few discussed
The process of senescence (dying slowly) is complex, and may derive from a variety of different mechanisms and exist for a variety of different reasons. However, senescence is not universal, and scientific evidence suggests that cellular senescence evolved in certain species as a mechanism to prevent the onset of cancer. In other species, senescence is negligible and cannot be detected. Such species are not immortal, however, as they will eventually fall prey to trauma or disease. Moreover, average lifespans can vary greatly within and between species. This suggests that both genetic and environmental factors contribute to aging.
Theories that explain senescence can generally be divided between the programmed and error theories of aging. Programmed theories imply that aging is regulated by biological clocks operating throughout the life span. This regulation would depend on changes in gene expression that affect the systems responsible for maintenance, repair and defense responses. Error theories blame environmental insults to living organisms that induce cumulative damage at various levels as the cause of aging, examples which range from damage to deoxyribonucleic acid (DNA), damage to tissues and cells by oxygen radicals, and cross-linking.
Gerontologists also theorise that one potential cause of senescence is the accumulation of mutations in DNA, eventually leading to the progressive loss of key genes. Another is the shortening of telomeres in the process of DNA replication during cell division.
Senescence is studied in gerontology which is the branch of science involved with the aging process.
One view is that it is due to a particular DNA programming that has the sole purpose to "clean" the Earth of old genes and assure offspring better living conditions through benign mutations.
One possible mechanism may be "senescence genes". Genes which have a deleterious effect on individual's fitness are selected against by natural selection. Mutations in these genes which postpone the deleterious effect of the gene to a later time in individual's life history reduce the effect of natural selection to the gene, because the selection has less time to act on it. If the gene doesn't have a negative effect until after the individual has reproduced, the gene may escape natural selection altogether, because when selection starts to affect the gene, it has already propagated to the next generation. In a related fashion, some genes may help to ensure reproduction at the cost of diseases later in life. For instance, our immune system generally helps to keep us healthy during reproductive age, but many adults acquire autoimmune diseases such as rheumatoid arthritis as they age.
An alternative view of looking at this question is: why do humans live so long? No other primate has such an extended post-reproductive phase of life. The "grandmothering theory" of evolution holds that because humans can teach their young, there was an evolutionary advantage for groups of humans who had a few older survivors to teach and care for the young. There is no direct evidence for this theory.
A number of genetic components of aging have been identified using model organisms, ranging from the simple budding yeast Saccharomyces cerevisiae to worms such as Caenorhabditis elegans and fruit flies. Study of these organisms has revealed the presence of at least two conserved aging pathways.
One of these pathways involves the gene Sir2, a NAD+-dependent histone deacetylase. In yeast, Sir2 is required for genomic silencing at three loci: the yeast mating loci, the telomeres and the ribosomal DNA (rDNA). Yeast replicative aging is caused by homologous recombination between rDNA repeats; excision of rDNA repeats results in the formation of extrachromosomal rDNA circles (ERCs). These ERCs replicate and preferentially segregate to the mother cell during cell division, and are believed to result in cellular senescence by titrating away (competing for) essential nuclear factors. While ERCs are not believed to contribute to aging in higher organisms such as human, extrachromosomal circular DNA (eccDNA) has been found in worms, flies and humans. The role of eccDNA in aging is unknown.
Despite the lack of a connection between circular DNA and aging in higher organisms, extra copies of Sir2 are capable of extending the lifespan of both worms and flies. The mechanisms by which Sir2 homologues in higher organisms regulate lifespan is unclear, but the human SIRT1 protein has been demonstrated to deacetylate p53, Ku70, and the forkhead family of transcription factors. SIRT1 can also regulate acetylates such as CBP/p300, and has been shown to deacetylate specific histone residues.
Other genes regulate aging in yeast by increasing the resistance to oxidative stress. Superoxide dismutase, a protein that protects against the effects of mitochondrial free radicals, can extend yeast lifespan in stationary phase when overexpressed.
In higher organisms, aging is likely to be regulated in part through the insulin/IGF-1 pathway. Mutations that affect insulin-like signaling in worms, flies and mice are associated with extended lifespan. In yeast, Sir2 activity is regulated by the nicotinamidase PNC1. PNC1 is transcriptionally upregulated under stressful conditions such as caloric restriction, heat shock, and osmotic shock. By converting nicotinamide to nicotinic acid, it removes nicotinamide, which inhibits the activity of Sir2. A nicotinamidase found in humans, known as PBEF, may serve a similar function, and a secreted form of PBEF known as visfatin may help to regulate serum insulin levels.
As noted above, senescence is not universal, and senescence is not observed in single celled organisms that reproduce through the process of cellular mitosis. Moreover, cellular senescence is not observed in many organisms, including sponges, corals, and lobsters. In those species where cellular senescence is observed, cells eventually become post-mitotic when they can no longer replicate themselves through the process of cellular mitosis -- i.e., cells experience replicative senescence. How and why some cells become post-mitotic in some species has been the subject of much research and speculation, but (as noted above) it is widely believed that cellular senescence evolved as a way to prevent the onset and spread of cancer.
Lately the role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning. The successive shortening of the chromosomal telomeres with each cell cycle is also believed to limit the number of divisions of the cell, thus contributing to aging. There have, on the other hand, also been reports that cloning could alter the shortening of telomeres. Some cells do not age and are therefore described as being "biologically immortal." It is theorized by some that when it is discovered exactly what allows these cells, whether it be the result of telomere shortening or not, to divide without limit that it will be possible to genetically alter other cells to have the same capability. It is further theorized that it will eventually be possible to genetically engineer all cells in the human body to have this capability by employing gene therapy and thereby stop or reverse ageing, effectively making the entire organism potentially immortal.
It is also suggested that damage to long-lived biopolymers, such as structural proteins or DNA, caused by ubiquitous chemical agents in the body such as oxygen and sugars, are in part responsible for aging. The damage can include breakage of biopolymer chains, cross-linking of biopolymers, or chemical attachment of unnatural subtituents (haptens) to biopolymers.
Under normal aerobic conditions, approximately 4% of the oxygen metabolized by mitochondria is converted to superoxide ion which can subsequently be converted to hydrogen peroxide, hydroxyl radical and eventually other reactive species including other peroxides and singlet oxygen, which can in turn generate free radicals capable of damaging structural proteins and DNA. Certain metal ions found in the body, such as copper and iron, may participate in the process. (In Wilson's disease, a hereditary defect which causes the body to retain copper, some of the symptoms resemble accelerated senescence.) These processes are termed oxidant damage and are the target of the currently popular nutritional antioxidants.
Sugars such as glucose and fructose can react with certain amino acids such as lysine and arginine and certain DNA bases such as guanine to produce sugar adducts, in a process called glycation. These adducts can further rearrange to form reactive species which can then cross-link the structural proteins or DNA to similar biopolymers or other biomolecules such as non-structural proteins. People with diabetes, who have elevated blood sugar, develop senescence-associated disorders much earlier than the general population, but can delay such disorders by rigorous control of their blood sugar levels. There is evidence that sugar damage is linked to oxidant damage in a process termed glycoxidation.
Chemical damage to DNA can lead to mutations (see above). Chemical damage to structural proteins can lead to loss of function; for example, damage to collagen of blood vessel walls can lead to vessel-wall stiffness and thus hypertension, and vessel wall thickening and reactive tissue formation (atherosclerosis); similar processes in the kidney can lead to renal failure.
Reliability theory suggests that biological systems start their adult life with a high load of initial damage.
Senescence may also simply be a result of wear and tear overwhelming repair mechanisms. It is also possible that senescence is a mechanism to control the development and spread of cancer; if cells have built-in limits to how many times they can replicate, they must somehow overcome this before they can spread indefinitely.
Recently, early senescence has appeared as a possible unintended outcome of early cloning experiments, notably in the case of Dolly the sheep.
A set of rare hereditary (genetic) disorders, each called progeria, has been known for some time. Sufferers exhibit symptoms resembling accelerated aging, including wrinkled skin. The cause of Hutchinson–Gilford progeria syndrome was reported in the journal Nature in May 2003. This report suggests that DNA damage, not oxidative stress, is the cause of this form of accelerated aging.
Artificially-induced senescence, as a means of control over artificially-created humans, or androids, is a central plot motivation in the renowned 1982 science fiction film "Blade Runner", loosely based on Philip K. Dick's (1968) novel "Do Androids Dream of Electric Sheep?".
A centenarian is a person who has attained the age of 100 years or more.
Tobacco smoking accelerates senescence, or leads to premature senescence. Smokers age faster than non-smokers.
Eunuchs live 13 years longer on average than noneunuchs. Happy?