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At present, the biological basis of ageing is unknown. Most scientists agree that substantial variability exists in the rates of ageing across different species and that this, to a large extent, is genetically based. In model organisms and laboratory settings, researchers have been able to demonstrate that selected alterations in specific genes can extend lifespan quite substantially in nematodes, less so in fruit flies and less again in mice. Life span extension can occur as the result of genetic alterations that increase DNA repair, reduce oxidative damage or reduce cell suicide (apoptosis) due to DNA damage.[57] Even in the relatively simple and short-lived organisms, the mechanism of ageing remain to be elucidated. Less is known about mammalian ageing, in part due to the much longer lives in even small mammals such as the mouse (around 3 years). The US National Institute on Aging currently funds an intervention testing program, whereby investigators nominate compounds (based on specific molecular ageing theories) to have evaluated with respect to their effects on lifespan and age-related biomarkers in outbred mice.[58] Previous age-related testing in mammals has proved largely irreproducible, because of small numbers of animals and lax mouse husbandry conditions. The intervention testing program aims to address this by conducting parallel experiments at three internationally recognised mouse ageing-centres, the Barshop Institute at UTHSCSA, the University of Michigan at Ann Arbor and the Jackson Laboratory. Many have argued that life-span, like other phenotypes, is selected. Evolutionary Theories: Telomere Theory: Telomeres (structures at the ends of chromosomes) have experimentally been shown to shorten with each successive cell division.[59] Shortened telomeres activate a mechanism that prevents further cell multiplication.[60][61] This may be particularly limiting to tissues such as bone marrow and the arterial lining where cell division occurs repeatedly throughout life.[62] Importantly though, mice lacking telomerase enzyme do not show a dramatically reduced lifespan,[63] invalidating at least simple versions of the telomere theory of ageing. Laboratory mice may be an exception for the theory, as they have long hypervariable telomeres,[64] which prolong the period after which telomere shortening would affect life-span. However, wild mouse strains do not, and telomere length in these breeds is unrelated to lifespan[65] Reproductive-Cell Cycle Theory: The idea that ageing is regulated by reproductive hormones that act in an antagonistic pleiotropic manner via cell cycle signaling, promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence (dyosis).[1][66] Some theories suggest that ageing is a disease. The examples are DNA damage theory of aging (Main article): Known causes of cancer (radiation, chemical and viral) account for about 30% of the total cancer burden and for about 30% of the total DNA damage. DNA damage causes the cells to stop dividing or induce apoptosis, often affecting stem cell pools and hence hindering regeneration.[67] DNA damage is thought to be the common pathway causing both cancer and ageing. Viral infection would appear to be the most likely cause of the other 70% of DNA damage especially in cells that are not exposed to smoking and sun light. It has been argued, too, that intrinsic causes of DNA damage are more important drivers of ageing.[68][69] Autoimmune Theory: The idea that ageing results from an increase in autoantibodies that attack the body's tissues. A number of diseases associated with ageing, such as atrophic gastritis and Hashimoto's thyroiditis, are probably autoimmune in this way. While inflammation is very much evident in old mammals, even SCID mice in SPF colonies still experience senescence. mTOR Theory: mTOR, a protein that inhibits autophagy has been linked to aging through the Insulin signaling pathway. It has been found, in various model species, that caloric restriction leads to longer lifespans, and it is thought that mTOR is the reason why. mTOR functions through nutrient and growth cues leading scientists to believe that dietary restriction and mTOR are related in terms of longevity. When organisms restrict their diet their mTOR’s activity is reduced which allows for more autophagy, or cell self-eating, to occur. Autophagy is a cells way to clean house and recycle old or damaged cell parts, and keep the cells and the body running efficiently. When cells self-eat or clean up their damaged or old parts often, your body is healthier and functions properly which increases ones longevity and decreases the chances of being obese. This is thought to be because people can metabolize glucose better, never allowing glucose to spike in blood concentration. Since there is less glucose entering the body there will be less Insulin signaling occurs. This has been linked to less mTOR activation as well. Therefore longevity has been connected to caloric restriction and insulin sensitivity inhibiting mTOR, which in turns allows autophagy to occur more frequently. Since autophagy cleans cells of damaged proteins and cell parts it may be that mTOR inhibition and autophagy reduces the effects of Reactive Oxygen Species on the body, which damaged DNA and other organic material. Since Autophagy recycles damaged or old parts of cells reactive oxygen species damage would be reduced and recycled to make functioning cells, and longevity would be increased.[70] |
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