Ageing

Contents

Origin of Ageing

		shows that there is considerable deviation from a linear relationship, and Figure 02 displays many exceptions including the primitive sea anemone, which can survive up to 70 years. Signs of senility, or extreme old age, are seldom seen in the wild. Animals living under natural conditions rarely approach their maximum possible age because of very high death rates due to infant mortality, diseases, predators, bad weather, accidents, or competition for food and shelter. For this reason, most of the reliable information about the length of the life span comes from the zoos.
Figure 01 Life Span[view large image]	Figure 02 Bio-longevity[view large image]

There are three theories on the origin and evolution of ageing. They are not mutually exclusive. The combination actually provides a consistent hypothesis.


1. Mutation Accumulation - As mentioned above, most animals in the wild do not have the opportunity to reach senescence. Natural selection has no chance to operate on a wide range of alleles with late deleterious effects. They are allowed to accumulate over the generations with little or no check. Thus, the problems with senescence occurs only in modern human or animals in the zoos within an environment, where "life expectancy" of living organisms have been artificially extended. Life expectancy is the average (over the population) total number of years (or days, or hours) that an organism expects to live. It is fundamentally different from life span, which is the maximum time interval that an organism can live.
2. Antagonistic Pleiotropy^¶ - This theory suggested that pleiotropic genes with good early effects would be favoured by selection even if these genes had bad effects at later ages, i.e., a small beneficial effect early in life can outweight a late deleterious effect even if the latter results in senescence and death.
3. Disposable Soma - This theory suggests that organism will benefit by investing any spare resource into reproduction or survival, rather than into better repair capacity, even though this means that damage will eventually accumulate to cause ageing.

Ageing Process and Symptoms

		The ageing process occurs over all the body and for everyone, but the pace may be different depending on the type of organ or individual. Certain cells in our tissues simply stop working after a while. When enough tissue is rendered dysfunctional, we come face to face with the debilitation of ageing. However, these cell deaths do not happen all at the same time. Some tissues remain viable for many decades, some wear out rather quickly. And ageing does not occur in the same way in every human being. It turns out that people's lifestyles also has additional influence on ageing. Table 01 lists the ageing symptoms for a few selected organs and biological functions to illustrate "how we age". More details can be found in Figure 03 and 04 for some of the organs.
Figure 03 Symptoms 1 [view large image]	Figure 04 Symptoms 2 [view large image]

Table 01 Ageing Symptoms

Table 02 Leading Causes of Death in the U.S.

Causes

Ageing is caused by the accumulation of damage to the cells. Some of the causes are unavoidable such as ultraviolet radiation, free radicals, and genetic effects; others involve environmental and behavioral influences. Followings are some of the causes under investigation by scientists:



DNA Damage - Usually DNA damages (such as from uv light) are corrected by repair enzymes. When the repair mechanism breaks down, it causes a progressive process in ageing, in many age-related diseases like cancer and in genetic diseases such as Down´s syndrome, cystic fibrosis and Werner´s syndrome. People with DNA repair disorders often have broken chromosomes, following exposure to ionizing radiation or chemicals that affect cell division. Figure 05 depicts the processes to repair two different kinds of DNA damages.

Figure 05 DNA Repair[view large image]

• Free Radicals in Metabolism - Even though if cellular damage by external causes can be avoided, an inherent problem is bound to arise by internal metabolism. The metabolic pathway in mitochondria relies on the transportation of free electrons, which eventually attach to oxygen and are normally neutralized by hydrogen ion to form water. This is usually referred to as respiration. Sometimes the process breaks down; the electrons do not attach to the oxygen and instead, attach to other oxygen species. Specific molecules, each carrying a wayward electron, were created. They are call free radicals (such as hydroxyl, superoxide and peroxide - collectively called reactive oxygen species or ROS). These free radicals are highly reactive and can do tremendous damage to the cell. The ROS can indiscriminately damage anything that gets in their way - proteins, fats, RNA, and DNA. The effect is cumulative and a serious problem will occur if ROS numbers get too high. Not surprisingly, the cell has responded to this threat by creating various enzymes that bind to free radicals and inactivate them. Collectively, molecules that destroy free radicals are called anti-oxidants. Aging is probably

  		the result of the breakdown in the cellular safety nets - not enough anti-oxidants are produced naturally. In addition, modern life has enormously increased the number of toxic free-radicals introduced into our bodies every day from the surrounding environment. The most significant sources of excess free-radicals are dietary or environmental. Dietary sources are usually fats, either rancid or hydrogenated fats, and fats that have been heated to high temperatures during cooking. Environmental pollutants include automobile exhaust, cigarette smoke and numerous other chemicals, physical exercise, stress, and radiation. Table 03 summarizes the variety of defenses prevent or repair molecular damage caused by free radicals, but as a group they are thought to be imperfect. Some evidence indicates that certain of the defenses also become less effective over time (ageing). New study found that in the course of ageing, certain people are more vulnerable than others to age-related
  Figure 06 ROS [view large image]	Table 03 Defenses [view large image]	damage from ROS, and genes related to memory and learning appear to be more vulnerable than other genes. Further research is needed to identify the causes.

  Telomere - The telomeres lie at the tips of the chromosome. They have hundreds to thousands of repeats of a specific 6-nucleotide DNA sequence. The telomeres lose 50 to 200 of these nucleotides at each mitosis; gradually shortening the chromosome. After about 50 divisions, a critical amount of telomere DNA is lost, which somehow signals the cell to stop mitosis. The cell may remain alive for a while but is unable to divide further. Some have likened the process of telomere shortening to a genetic biological clock that winds down over time. Today, researchers continue to probe the telomeric "timepiece," hoping to better understand the aging process. For example, It is found that in yeast, the est1 mutation causes gradual loss of telomeric DNA and eventual cell death mimicking senescence in higher eukaryotic cells. It is also found that the amount and length of telomeric DNA in human fibroblasts§ does in fact decrease as a function of serial passage during ageing in vitro and possibly in vivo. But it is not yet clear whether this loss of DNA has a causal role in senescence.

  Figure 07 Telomere etc. [view large image]

• Program Death - Recent research in 2003 points to another biological clock, which determines the life span of an organism. It is found that although the yeast cell normally goes through about 30 cell divisions in its five-day life span, DNA errors in daughter cells started appearing 100 times faster than normal after about 25 cell divisions - the equivalent of middle age in humans. It is noticed that about 80 percent of cancers are diagnosed in people over 55. Since both yeasts and humans use similar mechanism for copying DNA, so the rapid accrual of mutations after midlife is probably not coincidental. It could have something to do with an accumulation of damaged proteins within the cell or with breakdown in the proteins that control DNA replication and repair or with damage in the DNA itself - there is no definite answer at this point. But there seems to be a powerful force in all cells that operates on its own clock with a predetermined expiration date.
• The Genes of Ageing - Another recent research on ageing has identified a gene in the roundworm called daf-2. When this one gene is mutated (its function destroyed), the life span of the organism is doubled. This daf-2 gene can be considered a "master gene" of aging. This is because its protein can control the activities of many other genes. Its expression gradually shuts down the cellular repair mechanism as we aged. Cellular damages are inevitable; all multicelluar organisms eventually succumb to the exposure of chemicals, pathogen, extreme temperature and UV radiation because of the crumbling repair mechanism.
• Mitochondrial Theory of Ageing - Mitochondria are little pockets of energy within cells, shouldering the important task of converting food into usable energy forms. To meet demands, every cell contains thousands of them. Unlike most other cellular compartments, mitochondria have their own genomes, which encode a few mitochondrial proteins. This theory proposes that accumulation of mutations in mitochondrial DNA leads to progressive bioenergy deficiency, cellular damage, degeneration and eventually death. To test the theory, mice were genetically engineered to have

mtDNA polymerase with poor proof-reading activity, and hence an enhanced mutation rate. These mice develop signs of premature ageing and die aged about a year instead of 2-3 years. The finding strongly support the idea that mutations in mitochondrial DNA can cause at least some features resembling ageing instead of just correlative (the manifestations of growing old). Figure 08 compares the mutating mice (mut) with the littermate wild-type (wt) at the age of ~ 40-45 weeks. It shows the mtDNA-mutator mice with reduced body size, kyphosis (curving of the spine), reduced hair density and different stages of alopecia (baldness) - delineated by dashed line (from bottom to top).

Figure 08 Mutating Mice [view large image]

New study on human have linked unhealthy mitochondria to Alzheimer's, Parkinson's, type 2 diabetes and other degenerative diseases.

Reliefs

		France's Jeanne Calment (see Figure 10), who lived to be 122 years and 164 days old. Longevity ran in her family. Calment's mother lived until she was 86 and her father until he was 94. Her personal outlook of life may also contribute; it is said that she was immune to stress. She was once quoted: "If you can't do anything about it, don't worry about it."
Figure 09 Fountain of Youth [view large image]	Figure 10 Jeanne Calment [view large image]

Followings are some suggestions, which may soften the impact of ageing:



Defence Against Free Radicals and Diets - To increase the defence against these ROS, it is suggested that consumption of special kinds of foods, herbs, and dietary supplements (including vitamins C and E, beta carotene and selenium) will scavenge excess free-radicals and provide raw materials necessary for the body to produce antioxidant enzymes. Many of the foods high in antioxidants are vegetable matter. Tomatoes, broccoli, cauliflower, peppers...are all excellent choices (Figure 11). The key is to focus on eating those fruits and vegetables that have rich hues of color. These are high in what are known as phytonutrients. Phytonutrients are nutrients concentrated in the skins of many vegetables and fruits, and are responsible for not just their color, but scent, and flavor as well. Phytonutrients are the best antioxidant foods that exist in nature. Clinical trials are now revealing that phytonutrients can enhance the strength of the immune system, and may play

Figure 11 Vegetables [view large image]

a role in preventing certain cancers. Blueberries and bilberries are two of the best antioxidant foods you can buy -- and are very rich in phytonutrients.

Recently researches try to understand the interplay of nutrition and genetics - the link between foods and genes. The goal is to take the guesswork out of the things we eat. Besides pinpointing the specific gene expression triggered by certain food, they also want to find out how different alleles (variants of a gene) interact differently with a certain substance. For example, cardiologists used to put people with high blood pressure on a low-salt diet, knowing it doesn't work for as much as half the population. The rationale is: even if it doesn't work, it can't hurt. In the future, an examination of the gene would determine if the patient is susceptible to the treatment. And nutrition plan will no longer be one rule for all (people). It will be tailored to each individual according to the genetic make-up. Table 04 listed a few of the "good foods" and their link to the genes.



Food	Link to the Genes	Specific Gene	Function of the Gene	Long-term Effect
Green Tea	Helps to inhibit genes that fuel breast cancer	HER-2	Triggers growth signals in cells	Slow HER-2 signaling in tumors
Broccoli	Boosts genes that protect against heart disease	GST	Produces the body's master antioxidant - glutathione	The additional glutathione helps keep arteries healthy
Soybeans	Affect 123 genes in- volved in prostate cancer	p53	Kill mutant cells	Increase activity of the p53 gene to block tumor formation
Turmeric (a curry ingredient)	Suppresses genes that bump up inflammation	Cox-2	Makes inflammatory compounds	Help to ward off heart disease, colon cancer and Alzheimer's

Table 04 Link Between Foods and Genes

• pH Level - Similar to the body temperature, which has to be maintained at 98.6^o F; the pH level in our body fluid is kept at the narrow range about 7.36 (pH = 7.0 is neutral, pH < 7.0 is acidic, pH > 7.0 is alkaline, see Figure 12a) for the metabolic reactions to proceed properly. In the saliva test (with pH paper), most children are dark blue (colour of the pH paper), a pH of 7.5; over half of adults are green-yellow, a pH of 6.5 or lower, reflecting the calcium deficiency

  of aging and lifestyle defects; cancer patients are usually a bright yellow, a pH of 4.5, especially when the disease becomes terminal. You can test the pH level of your saliva or urine at home with pH paper strips. Figure 12b shows the colour index for standard pH paper corresponding to the pH scale. An acidic pH can occur from, an acid forming diet, emotional stress, toxic overload, and/or immune reactions or any process that deprives the cells of oxygen and other nutrients. The body will try to compensate for acidic pH by using alkaline minerals. If the diet does not contain enough minerals to compensate, a build up of acids in the cells will occur. The body has three mechanisms for the maintenance of normal

  Figure 12a pH Scale [view large image]

  acid-base balance:

  1. Rapid chemical buffering - The balance is restored by buffers in the blood. The buffers are supplied by withdrawing minerals from other organs including the bones, soft tissues, body fluids and saliva. This occurs almost instantly but buffers are rapidly exhausted, requiring the elimination of hydrogen ions to remain effective.
  2. Respiratory compensation - This mechanism uses breathing to eliminate carbon dioxide (which produces acid). The respiratory center in the brainstem responds rapidly to changes in CSF (Cerebrospinal Fluid) pH. Thus, a change in plasma pH results in a change in ventilation within minutes.
  3. Renal compensation - The kidneys respond to disturbances in acid-base balance by altering the amount of bicarbonate reabsorbed and hydrogen ions excreted. However, it may take up to 2 days for bicarbonate concentration to reach a new equilibrium.
  
  
  
  Diet adds one more way to control the pH level.
  
  Disturbance of the body's pH balance result in either acidosis or alkalosis. The dietary habit of most people tends to develop acidosis more often than alkalosis. They are prone to acquire diseases and symptoms that reflect the body's overly acidic state. Acute or emergency attempts to detoxify the body. The body may throw off acids through the skin, producing symptoms such as eczema, recurrent illnesses result from either the body trying to mobilize mineral reserves to prevent cellular breakdown or acne, boils, headaches, muscle cramps, soreness, swelling, irritation, inflammation, and general aches and pains. Chronic symptoms show up when all possibilities of neutralizing or eliminating acids have been

exhausted. Virtually all degenerative diseases, including cancer, heart disease, osteoporosis, arthritis, kidney and gall stones, and tooth decay are associated with excess acidity in the body. One of the solutions is to take foods that cause the blood to become alkaline. For example, almost all vegetables (except peppers, beets), and practically all fruits (except blueberries, plums, prunes, cranberries) are alkaline. Some dietitians recommand as much as 80% of the diet to be alkalizing foods. Many websites post complete listing on alkaline and acidic foods (see for

Figure 12b Colour Index for pH Paper

example: http://www.essense-of-life.com/info/foodchart.htm).

• Calorie Restriction - Recently, it is observed that the most efficient way to delay aging is through caloric restriction. It is found that healthy and long-lived mice and rats are produced by reducing 30 - 40 percent the calories in the animal's diet. It seems that the animals have switched their metabolism from a pro-growth mode to a pro-repair mode. Studies have shown that caloric restriction triggers a pathway that produces the Sir2 enzyme, which prolongs the life of yeast and worm. The latest research tries to manipulate the level of the IGF-1 (insulin-like growth factor-1) protein so that people can maintain the pro-repair mode without dietary restriction.
• Growth Hormone Supplements - The level of some important hormones, including growth hormone, do wane as we grow older, so it's tempting to suggest that supplementing them might slow down the ageing process. Today business is booming for companies that make human growth hormones such as hGH, DHEA and melatonin. When small doses were administered daily, there was increased mobility, less joint pain, more restful sleep, a greater sense of psychological well-being, and many other characteristics of ageing reversal. However, research also indicates that the growth hormone may have the opposite effect in the long run and may cause cancers.
• Exercise - Exercise in some form or other performed with appropriate attention to common sense and safety can help promote a healthier lifestyle to an advanced age even in the mentally and physically disabled. Estimates suggest that up to half of the physical decline associated with old age may be due to lack of physical activity. Factors such as muscle mass, bone strength and joint flexibility can be improved dramatically with regular exercise. Physical activity helps prevent the development of diseases such as cardiovascular disease, type II diabetes, osteoporosis, arthritis, colon cancer, obesity and injury prevention (by maintaining muscle strength). Gentle exercise helps make the bones stronger and less likely to break. A government recommendation urges the seniors to take part in 30 minutes of moderate physical activity, such as a brisk walk on most days of the week.

Recently in 2004, it is found that the activity level of skeletal muscle modulates a range of genes, which produce dramatic molecular changes - and keep us healthy. The skeletal muscle is the largest single tissue type in the human body. We have more than 640 muscles, accounting for between 30 and 40 precent of total body weight. It uses as much as 25% of the energy consumed by the body at rest. Skeletal muscle continuously adjusts its composition to meet the acute or chronic demands placed on it - a process called plasticity. It has been shown that one-third of skeletal muscle in an immobilized limb can disappear within weeks. It is as if

Figure 12c Exercise and Gene Expression [view large image]

skeletal muscle recognizes that it is not needed and "remodels" itself into weak muscle. In order for skeletal muscle to exhibit plasticity, specific genes in the muscle sense the change in its usage and respond by altering the quantities of proteins that

they produce. Figure 12c shows the types of gene expression triggered by exercise. They can be broadly divided into three categories based on the duration of their activity and on the change in concentration of the proteins they encode. "Stress response" genes are those that are activated quickly during the later phases of exercise, when their protein concentrations rise to hight levels, which drop back to normal soon after exercise ends. "Metabolic priority" genes can also be expressed at quite high levels, usually peaking a few hours after the end of the exercise bout but generally returning to pre-exercise levels within 24 hours. These genes assis with specific metabolic stresses, such as coping with low blood glucose. "Metabolic/mitochondrial enzyme" genes produce much lower concentrations of proteins, but the levels persist for considerable lengths of time - some have half-lives as long as a week (green). This last category of genes plays a role in muscle plasticity - the increase in mitochondrial and capillary concentrations that comes with fitness.
• Mental Activities - Dementia is largely a disease of old age, affecting 50% of those over 85. The leading cause of dementia is Alzheimer's disease. In the brains of sufferers, whole areas are filled with deposits, or plaques,and tangled whorls of protein that damage the surrounding neurons. The cause is still unknown, but people are more likely to succumb if members of their family have had it, if they have suffered a head injury, or if they have Down's syndrome. There is no known cure. But a study shows that leisure activities requiring some mental effort, like reading books or newspapers, playing cards or board games and doing crossword puzzles were beneficial, in that they seemed to delay the onset of dementia. The benefit is related to frequency - the more the better (use it or lose it). On the other hand, there is the unsettling possibility that the very choice of less-stimulating activities is a signal that the disease is already underway. In that case, the patients just could not help themselves. New study found that although nerve cells die off slowly with age resulting in slower reaction time, creativity remains viable throughout our 50s, 60s, and 70s. Dendrites still flourish and make fresh connections in the brain's critical informaiton processing sector. Older people may not find inspiration in a flash (the "Aha"); new idea will come slowly and quietly. It is suggested that creative activity such as community-based arts programs can help older people to keep healthy and to stay mentally vigorous.
• Coping with Stress and Meditation - It is found that chronic tension makes cells deteriorate faster by significantly shortened the length of telomeres. The shorter the telomere, the shorter the cell's life span and the faster the body's deterioration. As more cells die, the effects of ageing kick in: muscles weaken, shin wrinkles and eyesight and hearing worsen. Further study reveals that even the perceptions of emotional strain will produce the same damaging effect. Learning to cope with stress could potentially improve quality of life, longevity, and the mood.

		Meditation has been practised in the East for thousand years and emerges in Western culture lately in various forms. If the mystical layers are removed from its traditional package, the net effect becomes very useful for reducing stress. The switch from "fight and flight" mode to maintenance mode would enhance greatly the health of everyone especially the elderly. Figure 13 and 14 show a standing and a sitting posture for the "simplified" meditation. It is not important whether the practitioner is standing, sitting or lying down. The most important requirement is to relax both the mind and the body. Initially it may be necessary to find a quiet place to minimize distraction. Eventually the mind learns to detach from the noise and other external stimuli. The effect also shows up in daily
Figure 13 Meditation, Standing [view large image]	Figure 14 Meditation, Sitting [view large image]	life. For example, there would be more tolerant toward alien beliefs, obnoxious behaviors, and other unpleasant happenings; it would also improve mental alertness and physical fitness.

Anti-ageing Research

• Anti-ageing Genes - Evolutionary theory and some crude experiments suggest that hundreds of genetically determined biochemical pathways (cascades of molecular interaction) influence longevity. It is relatively easy to prolong life span - in worms, at least - by changing hormone levels and enhancing the effects of fewer than 100 genes. Some of the target genes produce antioxidants; some make natural microbicides; some are involved in transporting fats throughout the body, and some, called chaperones, "keep the cell components in good working order". This kind of finding has opened the door for a neutraceutical company, Elixir, which is trying to develop a drug that would yield the same kind of results for humans (as in worms).
• Anti-ageing Alleles - A useful way to find alleles that might affect ageing would be to compare the genetic makeup of normal animals and of those displaying deferred ageing. Scientists will not only have to identify hundreds or thousands of alleles that occur most frequently in long-lived subjects, they will also have to decipher the biological functions and unique features of the corresponding proteins. The collected technologies needed to perform these tasks fall under the rubric of "functional genomics", which is very much a work in progress.
• Calorie Restriction without Dieting - It is known that calorie restriction can prolong life span in yeast, fruit flies, and mice by 70%. In fact, calorie restriction is an extremely effective strategy for survival during lean times, when it's an imperative, not a choice. The organism then waits till the end of the famine, then goes on to reproduce again. But since few people particularly want to limit their calories drastically. Scientists are searching for a pill that will have the same effect without dieting. A company called Sirtris is expected to get the drugs into clinics by 2010.
• New Anti-ageing Supplements - It is found that the combination of two chemicals - the acetyp-L-carnitine and alpha-lipoic - normally found in the cells (and also sold separately as nutritional supplements) can promote the performance of rats on problem-solving and memory test. These rats also moved around with more ease and energy. Researchers determined that the combination of these chemicals had improved the function of mitochondria, which serve as a cell's main energy source. A company called Juvenon plans to begin human trials soon to evaluate the cognitive effects of the dual supplements. Other chemicals such as lipoic acid is found to protect human tissue culture from oxidation when iron or hydrogen peroxide was added. The same company will try to replicate the result in human subjects. The goal of these researches is to add a few more years to people's lives.

References

• Theories of Ageing, a Summary -- http://mcb.berkeley.edu/courses/mcb135k/BrianOutline.html
• Theories of Ageing, in Details -- http://longevity-science.org/Evolution.htm
• Ageing -- http://www.niapublications.org/pubs/portfolio/html/biology.htm
• Longevity -- http://www.bio-itworld.com/archive/011204/youth_sidebar_4099.html