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Basic Theory of Ageing
There are many theories of ageing. Put to keep things easy we will start with two basic categories; oxidation reactions and sub-optimal hormone levels. Oxidation reactions occur when the combustion of oxygen that keeps us alive and well produces by-products called oxygen free radicals. Free radicals are molecules that have lost an electron. When this happens to oxygen, we call it singlet oxygen, because it has only one of its electrons left. This is a highly unstable condition and to restore balance the radical either tries to steal one away from, or donate the remaining one, to another nearby molecule. In doing so, the free radicals create “molecular mayhem”, disrupting, damaging and destroying nearby cells. If DNA is involved, mutations occur, a favored theory of a common cause of cancer. In time, free radical damage accumulates, “thereby ageing us”.
Free radicals are not only produced inside us, but we take them in through smoking, food, air and water pollution, x-rays, sun exposure and various poisons, to name the most common. The other major theoretical cause of ageing is sub-optimal hormone levels. As we age some hormones begin a precipitous decline that strongly parallels the onset of ageing signs and symptoms. These include human growth hormone (HGH), melatonin, DHEA (de-hydro-epi-androsterone, a steroid hormone), androstenedione, testosterone, estrogen and progesterone. Conversely, Insulin levels tend to rise, culminating in adult onset of diabetes. Also, a relative rise in cortisol, the stress hormone (which is catabolic, that means it literally “eats you up inside”) is all too common as well.
How ageing cells retire? “Recent work suggests that an old cell stops replicating when its telomeres are too short to function, not when they are completely gone”. Most cells in our body can duplicate themselves only a limited number of times before they retire, or enter senescence – the last stage of their life when they van no longer produce. Telomeres, which are located on the ends of each chromosome in the cell's nucleus, shorten in length will each cell division, thereby ticking away the days until an ageing cell finally retires.
Two years ago, de Lange, in collaboration with Jack Griffith showed that telomeres don't stick out as previously believed but form closed loops, called “t-loops”. They proposed that “t-loops” act to “cap” or protect chromosome ends. However, just how shrinking telomeres trigger an ageing cell to retire has puzzled scientists until now. According to the Rockefeller researchers, a cell ceases to divide when its telomeres become too short to protect the ends of chromosomes – and not when they completely run out, as many scientists previously believed.
Perhaps the short telomeres in old cells are no longer able to form these protective loops, and it is the opened telomeres that trigger senescence. If scientists can figure out what triggers a cell to enter senescence, they might be able to delay this process for the treatment of diseases in which a cell ages too fast, such as dyskeratosis congenital, Bloom and Werner syndromes. The findings also may lead to new strategies for regenerating cells that are lost in degenerative diseases.
Conversely, it may one day be possible to destroy the immortal cells of cancer – which have figured out a way to keep their telomeres long – by manipulating them into an early retirement.
Replicative senescence – Hayflick's model: In 1961, Leonard Hayfick and Paul Moorhead discovered that human fibroblasts derived from embryonic tissues could only divide a finite number of times in culture, usually around 50 CPDs or cumulative population doublings, a phenomenon herein called replicative senescence (RS). RS has been described in cells derived from adults of all ages and in different cell types as well as in cells taken from several animals including mice, chickens and the Galapagos tortoise. Exceptions exist and certain human and animal cell lines never reach RS. These are said to be immortal and include embryonic germ cells and most cell lines derived from tumors, such as HeLa cells. The most likely scenario is that the mechanisms of cellular senescence evolved as an anti-cancer mechanism to prevent uncontrollable cellular growth, DNA damage or other oncogenic signals. In conclusion, the mechanisms behind in vitro cellular senescence as derived from the study of RS, appear to be casual factors in tumorigenesis, could be involved in certain age-related pathologies, but do not appear to be major players in human ageing. Cellular changes occur with age but the essence of those changes remains unknown and so new approaches are necessary to investigate ageing at a cellular level. “Ageing and cancer are flip sides of the same coin, says Kariseder Ph.D., a postdoctoral fellow at Rockfeller. “The trick for scientists is to be able to influence one without adversely affecting the other”. Previously, many scientists believed that an ageing cell entered senescence when its shrinking telomeres disappeared. In a new study, the Rockfeller scientists show that a protein called TRF2 can allow old cells to continue to replicate even when their telomeres are very short. TRF2 helps critically short telomeres function better and this, in turn, allows these cells to live just as long as cells with longer telomeres,” says Kariseder. “This is significant because it means that a change in the protected status of telomeres and not their complete loss, is what triggers senescence.
Since the 1970s scientists have known that the ends of every chromosome in a cell contain identical regions of DNA repeats that make up the telomeres. It wasn't until recently that scientists realized that these fragile chromosomal ends hold secrets to ageing and cancer. This insight arose from the finding that an enzyme called telomerase elongates the telomeres of both reproductive cells and cancer cells and as a result extends the life span of these cells. Currently the scientists have added another chapter to the story, as they have found that human cells are made to overproduce TRF2, a protein they first identified in1997, exhibited an increase in the rate at which their telomeres shortened. While normal cells lose their telomeric DNA at a rate of 100 units per cell division, cells overproducing TRF2 exhibited a rate of up to 180 units per cell division. These same cells entered senescence when their telomeres were shorter than normal, thereby compensating for the increased rate of shortening. Moreover, in some cases, these cells lived longer than normal cells. They also showed that TRF-2, by protecting short telomeres, allows cells overproducing TRF2 to have longer life spans. Furthermore, the researchers speculate that TRF2 is stimulating the ability of telomeres to form t-loops and that the loss of these protective structures is what triggers cells to enter senescence. “Our model suggests that old human cells have telomeres that can't form t-loops and this is something we are now trying to test”, says Karlseder.
Human Mortality: Developed countries have been keeping fairly careful birth and death records for hundreds of years partly because this data is central to calculations involved in life insurance, pensions and annuities. There is a very simple birth-death equation that applies to populations of living things.
Average Birth Rate = Average Death Rate
If long-term average birth rate for a species exceeds average death rate by even a little bit, then in a significant time period (say 5,000 years) the planet would be completely covered by organisms. If average death rate exceeds birth rate then the species becomes extinct.
The evolution of Ageing Theories: Ageing also varies somewhat between individuals and ageing also varies greatly between species. Teeth characteristics are inheritable. Ageing is also somewhat inheritable. If your ancestors lived long lives, you are also likely to live a long life. Animals that have developed to become mature rapidly and could breed rapidly tended to have shorter life spans. Animals that needed a longer time to develop and become sexually mature tended to have longer life spans. Some deep-sea fish seem to consist mainly of teeth! Similarly there are bizarre examples of ageing such as the salmon which lives for several years in the sea, swims up a stream to spawn and then dies almost immediately from a tremendously accelerated ageing process. Darwin and the theory of natural selection resulted in ageing being considered a substantially different type of phenomenon from teeth and most other animal characteristics. If natural selection can lead to longer life spans and the physiological mechanisms exist for longer life, why has natural selection not produced this result in all species?
Darwin determined that most characteristics or traits of organisms were evolved adaptations that aided the organism in surviving. That is, if sharper teeth resulted in animals of a given species surviving longer and therefore having more descendents than other animals with dull teeth, eventually, all the animals in the population would have sharper teeth because the genetic design for sharper teeth would be passed to the larger number of descendents. Sharper teeth resulted from the process of evolution, the process of adapting to conditions in the animal's external world.
The mechanics or “how it works” aspect of Darwin 's theory of natural selection [“survival of the fittest”] is very simple and readily understood. Even the slowest reproducing species, would, if allowed to breed in an uncontrolled manner, occupy the entire planet in a relatively short period of time (an idea earlier put forth by Thomas Malthus (1766 – 1834). This is the idea of geometric progression where one rabbit has two progeny and they each have two and they each have two, etc.
The growth of the populations of all species is therefore checked by a variety of factors such as predators, diseases, food supply and environmental conditions so that in a stable population each individual has an average of only one progeny which survives to produce one progeny and so on. All wild organisms are in competition for survival with other species and even more acutely with members of their own species.
In connection with variation, Darwin recognized that genetic diversity was a benefit to survival. Highly inbred domestic animals and plants were generally weaker, less hardy and more susceptible to disease than crosses between more diverse specimens. Darwin referred to these as “monstrosities” because most such mutations (such as two-headed animals) were adverse and ugly. Darwin also concluded that evolution took place by means of tiny increments. Each generation was only minutely different from its parents. These two features, evolution by means of natural variation and evolution in tiny incremental steps were the center of “ Darwin 's Theory”. When Darwin referred to “my theory”, he was referring most specifically to these features in addition to the idea that species evolved from other species in the same manner. In addition to physical characteristics, Darwin included instincts and inherited behavior patterns in traits that evolved through natural selection. Behaviors would need to evolve in parallel with physical characteristics. A wing has no survival value unless used to fly. An eye is useless unless used to see. Flying and seeing would need to be supported by the appropriate brain and nervous system characteristics including inherited behaviors that lead to learning to fly and learning to see. Even a light sensitive spot on a worm would have no added survival value unless it somehow altered the behavior of the worm.
Some important implicit requirements of the theory of natural selection should be mentioned. First, the natural variations in characteristics in a population of animals must be genetically programmed and thereby inheritable. Variations that were not genetically recorded could not participate in evolution because they would not affect the genetic content of subsequent generations. Second, evolution requires a population. Evolution results from the difference in statistical life spans between animals that have a beneficial trait and those that do not. Third, in order to evolve, a trait must be expressed or displayed by the organism in such a way that it affects the differential in life span. A latent characteristic which was present but not expressed at the time of an animal's death could not have affected whether it lived or died. The death of that animal therefore could not have contributed to evolution of that characteristic. Finally, the probability that an animal would live longer and /or breed more is determined by the combined effect of all its characteristics. Besides natural selection, which is based on survival, Darwin recognized that sexual selection also played a role in evolution. Sexual selection would involve advantages that an individual might have that did not affect its survival but did represent an increase in its probability of breeding such as ability to attract the opposite sex. Darwin considered that sexual selection was weaker than natural selection. Humans would be classified in Darwinian terms as “domesticated” as opposed to “wild” animals because humans have probably not existed under “wild” conditions for thousands of years. Humans have also been selectively breeding themselves to an extent not generally seen in “wild” animals. For example, one would expect the incidence of genetic diseases among humans to be higher than in a wild species because the effects of civilization and medical intervention allow individuals with adverse mutations to survive and propagate in a way not possible in a wild species.
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