User:291653ABC/Antagonistic pleiotropy hypothesis

DNA repair and aging[ edit]
A prominent explanation for aging at the molecular level is the DNA damage theory of aging. It has been proposed that genetic elements that regulate DNA repair in somatic cells may constitute an important example of age-dependent pleiotropic "genes". As pointed out by Vijg, genome repair and maintenance is beneficial early in life by swiftly eliminating DNA damage or damaged cells. However, studies of DNA repair in the brain and in muscle indicate that the transition from mitotic cell division to the post-mitotic condition that occurs early in life is accompanied by a reduction in DNA repair. The reduced expression of DNA repair is presumably part of an evolutionary adaptation for diverting the resources of the cell that were previously used for DNA repair, as well as for replication and cell division, to more essential neuronal and muscular functions.

The harmful effect of this genetically controlled reduction in expression is to allow increased accumulation of DNA damage. Reduced DNA repair causes increased impairment of transcription and progressive loss of cell and tissue function. However, these harmful effects of DNA damage are cumulative and most severe in chronologically older individuals whose numbers diminish with time (by causes of death that can be independent of senescence). As a consequence, the beneficial effects of the genetic elements that control the reduction of DNA repair early in life would predominate. Thus regulatory genetic elements that reduce expression of DNA repair genes in post-mitotic cells appear to be important examples of the postulated pleiotropic "genes" that are beneficial in youth but deleterious at an older age.

*** Note Above was copied from Antagonistic Pleiotropy Hypothesis Article

Another example related to aging is the Telomere theory. Telomere theory proposes that telomeres shorten with repeated cell division which attribute to cell senescence and tissue damage. The end replication problem explains the mechanism behind the inability of DNA polymerase to commence the RNA primer to perform its function in completing the lagging strand due to the shortening of DNA. Telomere shortening is common in somatic cells. However, germ line and stem cells prevent the end replication problem with the help of telomerase. Telomerase elongates the 3’ end that is then formed into a t-loop to prevent the cell from entering the G0 phase and cell senescence.

Inflammation and damage to tissue are the underlying problems due to increased senescent cells. In several studies shortened telomeres have been associated with age related sarcopenia, atherosclerotic cardiovascular disease , and cancer. However, there is still the question whether telomere length causes these diseases or if the diseases cause shortened telomeres. Hence, the shortening of telomeres complies with antagonistic pleiotropy theory. The trade-off exists as the cell benefits from telomerase which prevents permanent growth arrest but telomere shortening is associated with functional loss.

Another example related to aging is the Free Radical theory. Free Radical Theory suggests that the free radicals, which are being produced by aerobic respiration, are causing oxidative stress to be put on the body. This oxidative stress will result in aging and lead to death. Oxygen centered radicals are very reactive and can cause the accumulation of damage on lipids, nucleic acids as well as proteins within the body. This accumulation of damage on the biological molecules the changes the framework and leads to a reduction in the molecules activity levels. Lipid peroxides accumulate in the membrane phospholipids which in turn diminishes the mitochondrial membrane's effectiveness as a barrier. The process of DNA transcription and translation also acquires oxidative damage. The result is alterations in the base pairings of the DNA sequence. Research has found that DNA mutations from free radical damage is highly uncommon but would still lead to the build up of damaged proteins as well as decreased biological activity.