Ageing is a result of accumulating damage of our body's cells, DNA and tissues over time. The development of ageing varies upon the lifestyle we live, environmental factors as well as our genetic make-up. This leads to susceptibility to age-related illnesses and disease eventually leading to death. Many theories have been suggested to explain the process of ageing. The most popular theory of ageing is the free radical theory ageing (FRTA) suggested by Denham Harman. Free radicals are any molecule that retains a single free unpaired electron and cause damage in a highly volatile and destructive manner. The huge amounts of free radicals are produced through metabolism and oxidative processes in the mitochondria. Other sources of free radicals attack our cells can initiate from ultraviolet radiation, metal ions and smoking. An important class of free radicals are reactive with oxygen known as reactive oxygen species (ROS). Studies on invertebrates, mice and monkeys have helped to analyse the effects of over and under expression of genes and enzymes within the body. Calorie restriction and antioxidants have provided some support to increasing lifespan, however evidence contradicts with FRTA with regards to resistance to free radicals and oxidative stress. Similarly the telomere theory of ageing states chromosomal shortening of the telomeres in cell cycle contributes to ageing however, this theory is absent of free radicals hence does not support FRTA. Many observations and theories can also account for this. Anoxic animals lack mitochondria and live in anaerobic environments but still age. The FRTA can therefore be an account for how the process of ageing occurs but is not the ultimate theory to explain ageing. FRTA still exists and can supply a foundation for future theories of ageing.
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Ageing is an indication of growing old with changes biologically and mentally. The way we age varies upon genetics, environment and our lifestyle. The process of ageing is a result of increasing damage of our body's tissues which occurs over a length of time. The collective damage to our biological DNA causes the cells to inhibit the ability to function and express its appropriate genes correctly. This leads to or is responsible for the raised susceptibility of disease and death linked to the time-related changing process of ageing. This process is a universal biological phenomenon which indicates that both genetic and environmental factors donate to ageing. Lifespan on average differs from species greatly. All together the nature of the ageing process has been subject to substantial opinion in the way we age.
In this modern world, some individuals find ageing hard to accept. These individuals begin to lose the youth and see the physical signs of ageing. Many of these changes include wrinkling, illnesses, hair- loss, slower performance and changes in figure. Millions of pounds are spent each year by people trying to reverse the signs of ageing or in other words visually stop the ageing clock. Cosmetic surgery is currently a popular field which offers to reduce or erase the signs of ageing.
The history of anti- ageing goes back several centuries drawing significant ideas from other cultures. For example the Egyptian civilisation had traditions to use and derive products from olive leaves to preserve their beauty and charm. Therefore, at present the use of olive leaves are included as a component in numerous anti-ageing medicines to help reduce wrinkles.
Theories of ageing
Over the years, many theories have been suggested to account for the way ageing occurs.
Telomere theory of ageing
Variations in our genetic inheritance are responsible for the initiation in ageing. Recently, cellular senescence has become an interest to explain ageing equally. The continuous chromosomal shortening of the telomeres in cell cycle is considered to affect the vitality of the cell, thus contribute to ageing. In 1973, Olovnikov proposed the telomere theory in that cells lose a bit of DNA followed by a round of replication because the lack of ability for DNA polymerase to fully copy telomeres (chromosome ends), eventually an acute deletion triggers cell death.
Evolution theory of ageing
An alternative view indicates that ageing is due to DNA programming. The survival of only the best genes exists to assure offspring have vital living conditions, omitting any mutations. Senescence genes have harmful effects on the vitality of the cells, therefore are eliminated using natural selection. The cells are deceived as mutations in these genes delay its harming effects. It is paused in an individual at a later stage to escape the natural selection of the best genes. The harmful genes that is invisible till after it has reproduced then passes through to the next stage of replicating. In spite of this, there is no actual evidence to prove this theory.
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The DNA damage/repair theory
DNA damages occur constantly within cells. These damages can be repaired but the rate of damage can accumulate far more than it can be restored. DNA polymerase and other mechanisms are unable to correct these damages as fast as they occur, and so interfere with RNA transcription. The inability of DNA to serve as a template for further gene expression can for that reason promote ageing. Most of the damage occurs due to oxidative damage.
This theory suggests that the efficiency of the immune system is at its peak during puberty and this slowly declines as we mature. This idea is based on T-cells and its link with more vulnerability to infections and autoimmune diseases in aged people. The break-down of the thymus gland (where T-cells are produced) causes a shortfall in the effectively of T-cells earlier in life. This implies that antibodies decrease in quality and quantity in attacking invading pathogens, leading to cell stress and death as we age.
The Free Radical Theory
The free radical theory of ageing (FRTA) is the most popular theory to describe ageing which was put forward by Dr Denham Harman, working at the University of Nebraskain 1956. A 'free radical' is any molecule that retains a single free unpaired electron. Free radicals oxidise other molecules in an exceedingly volatile and damageing way. These radicals are generated by the equal breakage of a covalent bond that holds the molecule together. These radicals are responsible for ageing, some diseases and tissue damage. A simple example to illustrate this is the reaction of water by ultraviolet radiation forming to hydroxyl radical and hydrogen radical.
H2O --> HOâ€¢- + Hâ€¢ ('â€¢' indicates a free radical).
Sources of Free Radicals - external Vs internal
External factors such as ultra violet (UV) light can affect the skin. UV light can cause more wrinkles, thinning of the skin, irregular pigmentation and formation of malignant skin tumours leading to cancer. This is known as photoageing of the radiation theory of ageing. Radiation can create free radicals in cells as it attacks surrounding water molecules. It affects numerous molecular processes and connective tissue which damages the skin. This initial stage of this process occurs by the activation of UV-induced reactive oxygen species that direct damage to cell DNA, membranes and proteins. Many of the modifications that occur on photoaged skin arise due to UVB and UBA wavelengths which are classes of UV light coming directly from the sun or sun beds which in turn cause burning, elastosis and skin cancer (Situm, 2010).
Through daily smoking ageing occurs much faster than non-smokers due to an addictive substance called nicotine. This narrows blood vessels and can also bind to haemoglobin preventing proper uptake of oxygen, leading to insufficient amount of oxygen reaching cells. Wrinkles become more visible as elasticity is lost. Dullness on the face is present due to deficiency of natural vitamin C content, which enables the skin to remain plump and moist (Metelitsa and Lauzon, 2010).
One important internal source of free radicals is the mitochondria. Mitochondria are a membrane enclosed membrane organelle found in most eukaryotic cells (Henze and Martin, 2003). Mitochondria contain a small fraction of its own DNA separate to the nucleus. They referred to the "energy factories "of the cells because they produce most of the cell's source of adenosine triphosphate (ATP), used in the form of chemical energy (Campbell, Neil, Robin and Heyden, 2006). This is carried out by oxidising glucose, pyruvate, and NADH which are made in the cyotosol. This method is known as cellular respiration and takes place in the presence of oxygen. Further steps occur in the citric cycle and the electron transport chain through oxidative phosphorylation where further ATP is produced. Mitochondria is involved in a variety of other useful processes for example, signalling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth (McBride, Nieuspiel and Wasiak (2006).
The huge amounts of free radicals are produced through our own metabolism, an unavoidable by-product. The rate, by which free radical generation occurs, appears to increase as we age. During oxidative phosphorylation some free radicals by-products are created. These free radicals damage the mitochondrial DNA (mtDNA) and the processes that occur. When free radicals prevent the pathways of oxidtative phosphorylation it prevents the production of vital proteins. In this situation a less efficient method is used to produce ATP. However, it has to exert at a much high level to produce the same amount of ATP. Lysozomes are organelles that neighbour the mitochondria to recycle and engulf damaged cells. But, if mDNA is damaged to a point where oxidative phosphorylation stops occurring, no more free radicals will be produced and further membrane damage will stop. As a result the mDNA will be recycled and no more free radicals will form via oxidative phosphorylation.
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Fig. 1: This image shows the mitochondrial damage that occurrs due to reactive oxygen and nitrogen species. Free radicals that occur in the electron transport chain via oxidative phosphorylation can cause oxidative damage to the mitochondria DNA and proteins, and the opening of mitochondrial permeability pore (Szeto, 2006).
Reactive oxygen species (ROS) are an important class of free radicals in body systems (Halliwell and Gutteridge, 1989). These strong oxidants can damage cells structure and molecules especially in fatty side chain residues. The body can defend against the harmful outcome of ROS by special enzymes and mechanisms to prevent them destroying further. There are many types of free radicals which are formed by different reactions with oxygen. Some other examples of these are hydroperoxyl radical (HPR), alkoxyl radical (AR), peroxyl radical (PR) and nitric oxide radical (NOR).
Another source of radicals is Nicotinamide adenine dinucleotide (NADH) oxidase on the plasma membrane as well as cytoplasmic enzymes (xanthine oxidase and nitric oxide synthase), which generate a superoxide anion which can damage cells (Szeto, 2006).
The FRTA expresses that ageing is the build up of oxidative damage to bodily cells and tissues that encounters due to aerobic metabolism. Harman (1956) based his theory on the three opinions: "(A) irradiation causes premature ageing; (B) irradiation creates oxygen radicals, which may mediate its effects; and (C) cells produce oxygen radicals under normal conditions". At the start he hypothesised that the manner by which a high reactive free radical for instance a presence of an OH group will put forth an ambiguous effect. They are also likely to react with other cellular components including nucleoproteins and nucleic acids, proteins and lipids. It is stated that genes will be affected by these radicals with mutations and cancer occurring occasionally. This led Harman to conclude that ageing and age-related diseases may be due to oxidative damage dependant to genetic and environmental factors. Subsequently free radicals in ageing have advanced to become one of theories of the ageing process.
The oxidative theory is a modification of FRTA; peroxides and aldehydes which are not free radicals but play a part in oxidative damage towards cells. The disproportion of the formation of antioxidants and prooxidents leads to the build-up of damage on macromolecules which further affect cells and tissues relating to the ageing process.
Joe McCord and Irwin Fridovich of Duke University discovered an enzyme in 1969, superoxide dismutase (SOD). It exclusively operates to impair the superoxide radical, SOR (O2â--). This is a form of free radical produced when an additional electron is uplifted by an oxygen molecule. This produces a number of short-lived intermediates including the formation of superoxide (O2âˆ’), hydrogen peroxide (H2O2) and the hydroxyl radical (OH). Both the superoxide and hydroxyl radicals have a free electron in their outer orbit and are highly reactive oxidants. Hydrogen peroxide is also toxic to cells and a cause of further free radical generation, particularly when reacting with reduced transition metals to form hydroxyl radicals.
Successive research has uncovered that SOR are formed within cells during oxidative metabolism and SOD enzymes are existent within a variety of organisms ranging from bacteria to humans. Three isoforms of SOD are present within cells; these are cytosolic, mitochondrial and extracellular types of isoforms. Roughly 1-2 per cent of the oxygen within the mitochondria cell changes into hydrogen peroxide rather than water, the end product during respiration.The significance of SOD is revealed through studies carried out on mutant bacteria and yeast, lacking the SOD enzyme. In the presence of oxygen these cells are unable to grow. Equally the lack of SOD2 mitochondrial enzymes in mice, were incapable of surviving for a week after birth. However, genetically engineered mice that have been altered with higher hydrogen peroxide- destroying enzymes are able to live 20 per cent longer than the controls. These results observed show that enhanced antioxidant defences can increase life span. But Drosophila (fruit fly) that over expressed SOD and catalase did not display variation in enhanced life span (Orr and Sohal, 2003).
High potential free radical especially SOR and Hydroxyl radicals are an important factor linking to ageing yet still remains a debatable topic. Harman's predications of free radicals are connected to the concept of ageing. Then we can expect that mammals with a longer lifespan possibly produce a small number of free radicals, better ability to destruct free radicals, or the facility to repair cellular damage due to free radical reactions far better than mammals with a shorter lifespan. This belief is supported by many studies, one in which the growth of mouse and human fibroblasts were compared under standard (20 per cent) and reduced (3 per cent) oxygen levels. Mouse fibroblasts grown under reduced conditions suffered up to a third of DNA damage and experienced many cellular divisions eventually till it stopped compared to those cells grown in normal conditions.Whereas mouse fibroblasts grown in standard conditions suffered up to 3 times more oxidative DNA damage compared to human fibroblasts under the same conditions. This study shows that human cells are far better in repairing and preventing oxidative DNA damage than mouse cells.
An interrelated area of research concerns the study of substances known as antioxidants that are able to destroy free radicals by the prevention of oxidation (Fusco, 2007). These substances can most commonly be bought over the counter in pharmacies and general stores. Familiar antioxidants in the body are glutathione, vitamin E and C, and beta-carotene. Even though these antioxidants may prove highly beneficial in the diet due to the ability to destroy free radicals, research on mice and rats has been unsuccessful in delivering realistic evidence that can stop the ageing process or increase life span. An antioxidant that is receiving substantial interest is resveratrol, which is a polyphenolic compound found in elevated strength levels in the skin of red grapes. It is believed that the substance resveratrol has many health benefits characteristic of red wine. Instead of searching for free radicals in the body, resveratrol acts by activating the enzymes Sir2 that has shown to prove increased longevity in yeast cells. Also another exception is phenybutylnitrone (PBN), which has shown to increase life expectancy by 10 per cent in mammals especially mice (Saito, Yoshioka and Cutler, 1998) but still this cannot be entirely representative as it has only been carried out in one laboratory and has not been reproduced.
Theories and observation contradicting FRTA
1)Oxidative stress theory- Studies on invertebrates and rodent displayed correlation between increased lifespan and resistance to oxidative stress. Experiments were carried out in the under and over expression of the genes that code for antioxidants enzymes. The deletion of one gene the sod1 out of 18 gene operations had an effect on lifespan (Pérez et al., 2009). Mice that lacked the p66shc displayed less oxidative stress level hence a longer lifespan (Migliacco et al., 1999). Similar mice that lacked IGFI- receptor were more resistant to oxidative stress n lived longer (Holzenberger et al., 2003). Nonetheless, mice that lacked the MnSOD gene exhibited an increase of oxidative damage which led to a shorter life span (Van Rammen et al., 2003).
2) Chemical damage- Chemical damage to the structure of cells and DNA can lead to mutations which result in result in the loss of its functions. Damage to long-lived organic polymers in the body caused by chemical mediators within the body includes oxygen and sugars that are responsible for ageing.
3) Genetic theory of ageing-The first genetic component of ageing by gene regulation was identified by the budding of yeast. The number of daughter cells reproduced from the mother cells via cell division is known as replicating cell ageing. Calorie restriction in yeast cells results in increased life span with the presence of the gene Sir2. Here more mother cells undergo cell division rapidly to reproduce more daughter cells. This gene is programmed to carry out certain processes during cell division, if repeats occur cellular senescence occurs which slowly degrades the cell away from its essential nuclear factors. According to the gene regulation theory we are pre-programmed in our genes when to self-destruct, which cause ageing and eventually death.
In addition, children with the Progeria disease are naturally liable to premature ageing. They have symptoms which involve progressive heart disease. Almost all Progeria patients die as of heart disease. Heart disease is one of the directing triggers of death across the world. Children with Progeria commonly experience cardiovascular events, such as high blood pressure (hypertension), stroke, angina, enlarged heart and heart failure-illnesses linked to ageing. Progeria has a mutation on the gene that codes for Lamin A, a protein that maintains the nucleus of the cell together. It is thought that the defective Lamin A protein makes the nucleus insecure. This variability appears to lead to the process of premature ageing between Progeria patients. Yet it occurs without any cause so it is hard to relate this idea to support the FRTA in anyway.
4) Evolution theory of ageing-whilst there is no evidence to prove this theory; it fails to support the FRTA because it bases it beliefs on DNA programming and the selection of cells that work well over cells that are mutated. There is no such formation of any free radicals.
5) Metal ions-Diet plays an important part in the formation of radicals on a molecular basis. Metal ions especially in foodstuffs contain high levels and diverse profiles of metals. Metal ions in this instance correlates to the formation of free radicals sharing key elements of the FRTA (Naughton el al, 2008). Other factors such as toxins and pollutants in the environment, and pesticides can similarly play a part in ageing due to formation of excess radicals.
6) Telomere theory of ageing-A study on the yeast cells lacking a functional EST1 gene showed progressive shortening of the terminal G1-3T telomeric repeats and a parallel increase in the frequency of cell death (Lundblad and Blackburn, 1993). Similarly research on loss of telomeric DNA during cell proliferation may play a role in ageing and cancer. Telomere length, telomerase activity and chromosome rearrangements in human cells were measured. Overall telomerase (enzyme) activity was not detectable in control or extended lifespan populations but was present in immortal populations (Counter et.al, 1992). Telomerase enzymes switches itself on to which adds to the telomeres when cells divide. There have also been accounts that cloning may perhaps vary the shortening of telomeres. For example dolly the sheep died of progressive lung disease and severe arthritis. The common live expectancy of sheep is 11- 12 years however dolly the sheep lived till she six years old. This could possibly be because the sheep she was cloned from was an old sheep. One understanding is that dolly the sheep had short telomeres which are the result of the ageing process (Campbell et al, 1999). This supports the telomere theory of ageing but not the FRTA. Telomere loss and uncapping leads to tissue degradation and organ failure which are symptoms related to ageing. An investigation on aged mice with telomere dysfunction showed that when telomerase was reactivated, tissue cells were regenerated (Jaskelioff et al., 2010).
7) Mitochondria DNA theory- A further notion of ageing is the mitochondria DNA theory. This theory suggests that the effectively of mitochondria; the power producing organelle found in every cell of each organ, surfaces age-related degenerative diseases. The mitochondria have their own genome (mtDNA), produced in locations of formation of extremely reactive oxygen species (Sanz, 2010). Mitochondrial DNA appears to frustrate the damage inflicted by the by-products of respiration because the nuclear genome lacks advanced repair mechanisms. Consequently, the cell fails to produce energy and progressively dies. This concept is backed by observations verifying the genomic variability of mitochondria, on top of many mtDNA deletions and more forms of injury to the mitochondrial genome.
8) Anoxic animals- Small anaerobic multicellular organisms live their entire lifecycle in the absence of oxygen. Yet they are still able to reproduce and are metabolically active without oxygen. Electron microscopy shows they contain mitosomes to power their energy as an alternative to aerobic mitochondria. This feature resembles unicellular organisms (protozoan) having hydrogenosomes that occupy anaerobic environment (Danovaro et al., 2010).The incidence of anaerobic mitochondria and hydrogenosomes in other organisms showed the highlight to the evolutionary significance.This idea that does not support the FTRA is anoxic animals in that they lack mitochondria; hence the formation of free radicals cannot occur.
9) Mitochondrial hormesis-During times of mild stress, the body learns to adapt or has a hormetic response. This provides evidence that repetitive mild stress can play a part in anti-ageing (Rattan, 2008 and Gems and Partridge, 2008).ROS have an essential role other than destruction. White blood cells must produce ROS in order to kill of invading bacteria and pathogens. Also with the help of the enzyme, superoxide dismutase (SOD), hydrogen peroxide must be formed in order for it to bind to the thyroid gland, iodine molecules to attach for the synthesis of thyroxine. This shows that these radicals have many regulatory roles acting as signalling intermediates in a redox environment (Tuma, 2001). The formations of ROS readily, within the mitochondria cause a hormesis response. Therefore the amount of stress resistance is elevated on the level of long term reduction of oxidative stress. This reverse effect is known as mitochondrial hormesis. It has been suggested that it can play a part in longevity (Ristow and Zarse, 2010).this theory does not support FRTA because ROS have a reverse effect in its vital roles other than destroying.
10) Nutrient signalling- Animals that have minimal blood glucose levels, insulin and triglycerides are less prone to age-related disorders for instance diabetes and coronary artery disease. Reduced blood- insulin levels may possibly important in promoting longer life span, experiments on nematodes (Kenyon et al., 1993) and fruit flies (Clancy et al., 2001) suggest that the lessened activity of insulin-like hormones can spectacularly boost the lifespan within these vertebrates.
11) Hormonal signalling pathways are very powerful controllers of lifespan, possibly since they match the longevity of several key organs by acting in an organised manner. Research on mice with defected growth hormones (GH) unable to secrete via the pituitary gland showed that these mice had an extended life span by roughly 21- 40 per cent (Coschigano et al.,2003). Whilst transgenic mice that over expressed the GH hormone lived a shorter life span compared to wild mice (Wolf et al., 1993).
12) Calorie restriction-The animal life spans can be increased by restricting the amount of calories within their diet (Perez et al. 2009 and Ristow, 2010). At first the study on mice that maintained a strict diet, showed they typically lived longer by 30 to 40 per cent compared to mice that ate a normal calorific diet. Findings on the metabolic rates of these mice have shown inconsistent facts, but these studies show an overall agreement that animals that were fed with restricted calorific diets contain a visible decrease in O2 â-- and hydrogen peroxide formation, which could possible explain the increased longevity. Longitudinal studies on rhesus monkeys are currently being carried out with calorie- restricted diets to see if they live longer healthier lives. Though, this study has not been analysed over a long enough period to see if the top figure of lifespan which is 40 years in these monkeys, is increased.
Although studies on rodents especially showed that consuming reduced calories or restricting the diet enabling a longer lifespan by processes involving stress resistance, further experiments presented that restriction of diet by up 50 per cent led to more chances of mortality (Schulz and Zarse et al. 2007 and Mattson 2005).
The FRTA together with some selected points of the DNA damage/ repair theory and oxidative stress theory support each other and can explain the way we age. However it is not the ultimate reasoning of ageing. The sources of free radicals whether it be internal where majority of the time is formed in the mitochondria or externally where factors such as the environment play a part in radical formation. Studies on calorie restriction and the use antioxidants have shown to an extent to increase lifespan by reducing the amount of free radical produced or the pathways in which they occur. Although these findings are not reliable as further studies showed it increased the chances of death. Damage and accumulation of radicals can provide the highlight of some theories. However, theories like the telomere, evolutionary, immunological, signalling, hormesis and oxidation stress theory because free radicals are not actually produced which in fact to contradict to the explanations of FRTA. Also the new discovery of anoxic animals offers a new light. Free radicals that are believed to be formed in the mitochondria in aerobic conditions leads to ageing. Anoxic animals lack the key organelle (mitochondria) to produce free radicals yet they still age. Therefore the FRTA is not entirely dead and still exists as it supplies a basic reasoning to explain ageing and for other theories.