This report outlines the main theories of how the process of aging works. Sinceresearchers have not discovered a universally-accepted theory of aging, thetheories discussed are potential explanations of how we age. The likelihood ofeach hypothesis is considered roughly equal. The different theories discussedfocus on the workings of different parts of the body, from the molecular levelof DNA mutations and replication, to the organism level of becoming wornout. Aging is a very complex and gradual process, and its ongoing operationis present to some degree in all individuals.
It is a journey to the maturity,as well as to the degeneration of the body. Because aging affects every part ofthe body, many different steps are involved and various types of reactionsoccur. Changes in DNA take place, which can and often do affect the way the bodyfunctions; harmful genes are sometimes activated, and necessary onesdeactivated. A decrease in important body proteins like hormones and certaintypes of body cells is almost inevitable. These, among many, are characteristicchanges that take place in our bodies as time moves on and aging continues.
Atpresent, a universal explanation for how we age or why we age does not exist,but there are many theories to explain this puzzle, and they are supported bycontinuous research. In this report, some of the how theories of aging will beexamined. Among them are theories concerning spontaneous mutations, damage fromfree radicals, the clock gene, cellular aging, a weakened immune system, wearand tear, and hormonal and neuroendocrinous changes. Spontaneous Mutations Thespontaneous mutations theory, also known as the somatic mutation hypothesis,states that the crucial events that cause aging are mutations. These are changesin a cell=s DNA, which are passed on to daughter cells during mitosis. Sincegenes on DNA code for specific proteins, mutated genes may produce defectiveproteins, which do not work properly. Many proteins can be affected, such asenzymes, proteins comprising muscle tissue, and a recently discovered type ofprotein called transcription factors, which bind to DNA and regulate theindividual activities of genes themselves. Physical mutagens are substances thatincrease the chance of mutation and include such physical phenomena as x-raysand radioactivity from radium. The atomic bombs dropped on Hiroshima andNagasaki in Japan are examples of physical mutagens that caused an increase inthe number of cases of leukemia. Certain chemicals and radiation cause mutationsto occur in DNA by giving off high energy particles. These particles collidewith the DNA and knock off atoms of the DNA randomly, damaging it. DNA consistsof sequences of four possible nitrogenous bases: adenine, guanine, cytosine, andthymine, paired so that adenine always pairs with thymine, and guanine alwayspairs with cytosine. As cells repair the damaged DNA, a different DNA base isoften substituted. This base-substitution is known as a point mutation and cancause the production of a defective or damaged protein. Apart from being causedby radiation or chemicals, mutations also occur spontaneously but at lowerrates. Physicist Leo Szilard and biochemist Denham Harmon proposed that becausemost mutations are harmful, the more spontaneous mutations that arise, the moreabnormalities that arise as defective proteins are produced. These couldultimately kill an individual (Ricklefs and Finch, 1995, 20). Although it hasbeen proven that many proteins undergo alterations during aging, the spontaneousmutations theory is not the cause (Ricklefs and Finch, 1995, 21). It has,however, been proven that DNA is chemically altered during aging. Modificationsin DNA bases, called I-spots, have been found to increase in number duringaging. Besides I-spots, another modified base known as 8-hydroxyguanine, the DNAbase guanine with an added OH group, has also been found to increase duringaging. It is unclear how changes such as these arise, but similar changes seemto be caused be exposure to mutation-causing chemicals, some of which are foundin tobacco smoke (Ricklefs and Finch, 1995, 21). Another factor supporting thespontaneous mutations theory may lie in the temporal occurrence of geneticmutations. Certain cancers and abnormal growths seem to appear more frequentlyas the process of aging continues. Two tumour suppressor genes called p16 andp53 are responsible for slowing cell proliferation, and therefore keep certaincells from becoming cancerous. However, if they become mutated, they do notcarry out their function properly so cells with these mutations begin to growand divide quickly, causing cancer and other growths (Ricklefs and Finch, 1995,22). Werners syndrome is a disorder that significantly accelerates the agingprocess starting at around 20 years of age. Molecular geneticist GerardSchellenburg has suggested that the function of the enzyme helicase, whichnormally unzips the DNA double helix before replication and removes randomlyoccurring mutations like base substitutions, does not function properly inpeople afflicted with Werners. Therefore, the unzipping of the DNA doublehelix is disrupted and mutations are overlooked (Lafferty et al., 1996, 60).
Moreover, DNA occasionally loses one or more bases through the process ofspontaneous deletion. This type of mutation seriously affects the mitochondriaof the cell, a main source of energy within the cell. Mitochondria have theirown DNA, mtDNA, which allows them to self-replicate. The mtDNA encodes forenzymes found within the mitochondria which help produce ATP, energy-storingmolecules. During aging, the amount of mtDNA that possess lost segments of DNAincreases. Although still unproven, it is believed that this abnormal mtDNA maycause defects in energy production. Most mtDNA deletions occur in brain, muscle,and other tissue with little cell division. By the end of ones lifespan,certain parts of the brain consist of as much as 3% abnormal mtDNA (Ricklefs andFinch, 1995, 22). Many characteristics of aging have been proven to develop as aresult of spontaneous mutations. However, many other changes associated withaging cannot be adequately explained by this theory. Damage from Free Radicals Afree radical is a fragment of a molecule or atom that contains at least oneunpaired electron. Because unpaired electrons are unstable, an uneven electricalcharge is created and the electrons attract those of other atoms or molecules tobecome stable and rectify the electrical imbalance. As they gain electrons fromother molecules, they modify the other molecules. In this way, free radicals candamage DNA, and it is known that damaged DNA is involved in the aging process.
Free radicals can be formed when atoms collide with one another, as in theimpact of x-rays or UV radiation from sunlight on living cells. They can start achain reaction in which atoms or molecules snatch electrons from one another.
This process of losing electrons is known as oxidation. Though oxidative damagecan be slowed through the help of enzymes and the absorption of free radicals byantioxidants like vitamins E and C, free radicals continue to cause damage,however little, to DNA (Kronhausen et al., 1989, 78). Cross-linking, orlarge-scale fusion of large cell molecules, is involved in a process responsiblefor the wrinkling of skin, the loss of flexibility, and rigor mortis. It occurswhen little or no antioxidant activity is present to alleviate the rapidstiffening of body tissues (Kronhausen et al., 1989, 74). In older individuals,oxidized proteins in tissues have been found, and when proteins become oxidized,they usually become inactive. Lipids, which constitute a large part of the cellmembrane, may also become oxidized, thereby reducing the fluidity of the cellmembrane. Also, it is possible that vascular diseases are caused by oxidativedamage since oxidized lipids in the blood cause arteries to thicken abnormally (Ricklefsand Finch, 1995, 24). In addition, some scientists believe that difficulty in,or slowness of movement (when we age), as well as tremors associated with theaging disease called Parkinson=s disease are caused by oxidative damage (Ricklefsand Finch, 1995, 26). The neurotransmitter dopamine, found in the brain isdamaged by free radicals produced by enzymes during the removal of dopamine fromthe synapses of the brain. During aging, damaged mtDNA is thought to collect inparts of the brain with high dopamine concentrations and is thought to be causedindirectly by the presence of these free radicals (Ricklefs and Finch, 1995,25). Some regions of the brain high in dopamine and damaged mtDNA happen to bethe basal ganglia, the parts that aids in movement control (Ricklefs and Finch,1995, 25). A Free Radical Reaction with Glucose As the body continues its normalsurvival processes, insulin becomes less effective in encouraging the uptake ofglucose from the blood. In this way, the body develops insulin resistance. Thiscondition is similar to the more serious type of diabetes called maturity-onsetdiabetes, or type II diabetes. If diabetes was left untreated, the excessglucose in the bloodstream would not be taken into cells because of insulinresistance. Instead, the excess glucose in the blood would react with hemoglobinin a free radical reaction through a process called non-enzymatic glycation.
Other proteins such as collagen and elastin, which make up the connectivetissues between our brain and skull, and in our joints, can also become glycated.
Once this occurs, they stop functioning properly. The result of this is thatdiverse compounds called advanced glycosylation end products (AGEs) becomeattached to proteins. The combination of AGEs with proteins forms a stickysubstance that could dramatically reduce joint movement, clog arteries, andcloud tissues like the lens of the eye, leading to cataracts (Lafferty et al.,1996, 56). Once glycated proteins are formed, they can cause further damage byinteracting with free radicals from other sources (Ricklefs and Finch, 1995,26). The Lethal Clock A gene called clock-1, which was believed to determine anorganism=s lifespan was found in small organisms and a very similar gene hasalso recently been found in humans (Lafferty et al., 1996, 58). Although it isuncertain whether the clock genes affect how susceptible cells are toinfections, or if they control the actual aging process, it is generally agreedupon that these genes have something to do, either directly or indirectly, withaging (Allis et al., 1996, 64). It has been proposed in the clock theory thatthe demise of brain cells, of which we lose thousands each day, is due toregular, programmed cellular destruction, and not to random *accidents= (Keeton,1992, 50). As cells divide, the number of divisions that they undergo ismonitored and kept track of. After a certain number of divisions, the clockgenes are triggered and may produce proteins responsible for cell destruction(Keeton, 1992, 50). Cellular Aging In 1961, a discovery made by Leonard Hayflickshowed that normal, diploid cells from such continually emailprotected parts of thebody as skin, lungs, and bone marrow, divide a limited number of times. Althoughthe cells stop dividing at the point just before DNA synthesis, they do not die.
The longer-lived the species, the more divisions the cells undergo. As the ageof an individual increases, the number of potential divisions decreases (Ricklefsand Finch, 1995, 29). This discovery was found using fibroblasts, or cells foundin the connective tissues throughout the body. The cells were placed in alaboratory dish under sterile conditions and allowed to grow and divide untilthey filled the dish. Then some of these cells were placed in a new dish untilit was filled. The number of emailprotected necessary until the cells no longergrew and filled the dish represented the number of cell divisions (Ricklefs andFinch, 1995, 29). It is not known why the cells stop dividing, but theseAHayflick emailprotected may be caused by some genes responsible for halting thedivision of neurons during developmental stages (Ricklefs and Finch, 1995, 30).
This limited number of cell divisions is often thought of as cellular aging(Lafferty et al., 1996, 55), a microcosm of the process of gradual, yet, actualdeceleration and deterioration of the body. Though remarkable discoveriessupport the fact that cells stop dividing, this theory does not seem torecognize why cells stop dividing. Shortened Telomeres The theory that shortenedtelomeres are involved in aging is an extension of the cellular aging theory.
Telomeres are highly repetitive sequences of nucleic bases found at the tips ofchromosomes. They contain only a few genes. Their function is to protectchromosomes in a manner similar to Athe way a plastic cuff protects a emailprotected(Lafferty et al., 1996, 57). After each DNA replication, telomeres on thedaughter chromosomes become shorter than those on the parent strand. So afterenough replications, which happens to be the Hayflick limit, the telomeres havebecome strikingly diminished and cell reproduction ceases. It has been theorizedthat at this point, genes previously protected by telomeres become revealed andproduce proteins that aid in the deterioration of tissue, characteristic of theaging process (Lafferty et al., 1996, 57). To back up this theory, researchershave found that cells that do not stop dividing, such as sperm cells and manycancer cells, do not lose telomere DNA. These cells possess an enzyme calledtelomerase, which maintain telomeres (Lafferty et al., 1996, 57). If this istrue, then with an extra boost of telomerase, DNA may replicate many more timesand in turn, we may be able to live longer. Yet instead of slowing or stoppingthe process of aging, this possibility may only prolong it, since it has alreadybeen accepted that damaged, not a shortage of, DNA plays a large role in aging.
The Bodys Weakened Immune System During aging, the efficiency of the immunesystem declines. Normally, novel antigens, foreign molecules found on thesurface of viruses and bacteria, activate the production of antibodies secretedby white blood cells, or lymphocytes, called B-cells. The antigens act toneutralize the virus or bacteria, rendering it harmless. If the novel antigensare missed by the antibodies, a emailprotected process comes into play. Macrophagecells safeguard the body and envelope foreign antigens that they later expose toT-cells for destruction. The pieces of virus that the macrophages pick uptrigger the appropriate T-cell, which in turn replicates, producing more copiesof itself. These T-cells, called memory T-cells, can recognize and destroy cellsinfected with the virus (Ricklefs and Finch, 1995, 35). These two methods ofprotecting the body from invasion make up the primary immune response, and thisis the component of the immune system that decreases in efficiency as we age.
The secondary response is the body=s resistance against pathogens it has alreadymet. The reason for the decline in the immune system=s efficiency is that overtime, we come in contact with more viral and bacterial infections so that moreof our T-cells have been stimulated, converted to memory T-cells, and therefore,used. That is, they cannot be used to fight off any new viruses or bacteria thatinvade the body. It is possible that the total number of T-cells is set early inlife. If this is so, then as we grow older, having already fought off a numberof infections, we have a smaller amount of emailprotected T-cells available tofight of infections that come our way (Ricklefs and Finch, 1995, 34). Inaddition to the decrease in unused T-cells, antibodies used against the body=sown proteins are occasionally made. This faulty process is common in autoimmunediseases like multiple sclerosis (Ricklefs and Finch, 1995, 36). Whereas thistheory of how we age is a very practical one, it almost assumes that olderpeople die as a result of infections, no matter how mild, because of a weakenedimmune systems. This is often, not so. Wear and Tear Just as machinery and otherequipment gets worn down through use, so too do our organs and cells. It isalmost inevitable that once our first cells have developed and our organs beginfunctioning, they also begin a very gradual deterioration through use. In fact,heavy use of our organs and bodies can accelerate this deterioration we callaging (Ricklefs and Finch, 1995, 33). In typists, for example, carpal tunnelsyndrome and other degenerative problems come about faster and more commonlythan in those who do not exhibit such specialized use of their fingers. On theother hand, problems can also arise from lack of use. Muscle atrophy, which isnoticed in the elderly is the result of a lack of muscle use (Ricklefs andFinch, 1995, 33). So assuming that moderate use of our bodies is healthy andwill not promote any degenerative problems seems safe. Still, even regular,moderate use of one=s body, however long it can prevent certain problems, doesnot hold the body=s performance at the same level for very long. As agingcontinues, a loss of elasticity from the connective tissues in various parts ofthe body is experienced, and muscle performance, among other things, is reduced(Ricklefs and Finch, 1995, 33). In 1900, the life expectancy in the U.S. was 47years. It may be thought that this was the length of time the human body couldwithstand *wear and tear= before it Abroke emailprotected Today, the life expectancy inthe U.S. is about 76 years because of modern technology, and many beneficialmedical breakthroughs (Lafferty et al., 1996, 55). This large increase in lifeexpectancies does not necessarily mean that human bodies can endure heavier use,or more wear and tear, but that it takes longer for our bodies to deterioratenow than it did in previous years. At the molecular level, lipofuscins, or agingpigments, appear with increasing frequency in non-dividing cells. Because theycontain oxidized lipids, it has been theorized that they are products ofoxidative chemical reactions such as those involving free radicals (Ricklefs andFinch, 1995, 34). Modifications in Hormonal and Neuroendocrine Systems Thepituitary, ovaries, and testes are part of a system of glands that secretehormones into the blood stream and which are controlled by the brain. Thissystem is called the neuroendocrine system. At puberty, a signal is sent by thepituitary gland to the ovaries and testes, telling them to produce more sexhormones such as estrogens and progesterone in women and androgens in men. Inwomen, menopause, a stage in which the reproductive system is shut down, isreached. From this point in a woman=s life these hormones are no longer producedand many changes are experienced. Because some neurons can become emailprotected toestrogens, the absence of these hormones induces the brain to respond indifferent ways, such as sending a surge of blood to the skin. This is sometimescalled a Ahot emailprotected (Ricklefs and Finch, 1995, 37). Unlike hot flashes, a womanmay experience harmful or dangerous changes because of menopause: osteoporosis,or the loss of compact bone is accelerated because bone-mineral metabolism isdependent on estrogen. Once this condition has reached a certain stage, itreduces the ability of bones to support body weight. It also immensely elevatesthe risk of bone fractures. In fact, as a woman increases in age, her risk ofbone fracture due to osteoporosis increases exponentially (Ricklefs and Finch,1995, 43). In men, the number of abnormal sperm, incidence of lower testosteroneproduction, and incidence of impotence have been found to increase with age.
Because the brain controls the pulses of testosterone, it can be said that someof these changes arise because of different signals in the brain (Ricklefs andFinch, 1995, 44). The hormonal and neuroendocrine theory collects evidencemostly from a female way of life, yet both men and women experience the agingprocess and many of the same characteristics that go with it. The knowledge thatthe process of aging is very complex can be deduced from the simple fact thatthere are many entirely different, yet plausible, theories of how aging works.
In fact, the possibility that several of these theories are connected, or play acombined part in aging is not far fetched. Yet because the process of aging isso multifarious, just how humans complete or even begin the transition fromyouth to old age remains a mystery to some extent. However, with new evidenceand proof supporting some of these hypotheses, opportunities for a healthier,longer life may arise.
BibliographyAllis, S. et al.., 1996. Older, Longer. Time Magazine. Fall 1996:60-64Keeton, K. 1992. Longevity: the Science of Staying Young. Penguin Books USAInc., New York, NY. Kronhausen, E. et al. 1989. Formula for Life. William Morrowand Company, Inc., New York, NY. Lafferty, E. et al., 1996. Can We Stay Young?.
Time Magazine. 25/11/96:53-62 Ricklefs, R.E. and Finch, C.E. 1995. Aging; ANatural History. W.H. Freeman and Company, New York, NY. Bibliography Aging, TheConcise Encyclopedia of Science and Technology, 1978 ed. Allis, S. et al..,1996. Older, Longer. Time Magazine. Fall 1996:60-64 Keeton, K. Longevity: theScience of Staying Young. New York, NY: Penguin Books USA Inc., 1992. Kronhausen,E. et al., Formula for Life. New York, NY: William Morrow and Company Inc.,1989. Lafferty, E. et al., 1996. Can We Stay Young?. Time Magazine.
25/11/96:53-62 Ricklefs, R.E. and Finch, C.E. Aging; a Natural History. NewYork, NY: W.H. Freeman and Company, 1995. Segall, P. and Kahn, C. Living Longer,Growing Younger. Toronto, ON: Random House of Canada Limited, 1989. New York,NY: Random House Inc., 1989.
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