Molecular Biology Of Cancer And Ageing Biology Essay

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Lots of theories

Over the past couple of years it has been noticed that ageing has increased as more people are living longer due to the average and maximum lifespan lengthened / lengthening and thus effecting economics such as the national expenditure (GDP) spent on elderly is increasing and because of this the percentage of elderly people living in western / developed countries has tremendously increased thus the study of ageing processes (gerontology) has attracted lots of interest and this is why a lot of research is being carried out in the subject area to find out how people / humans are ageing and why longevity / lifespan is increasing and with better research that will be able to find more medical advances for disease or any break-throughs that can help improve the medical technology

People are living longer due to better health care system, good availability of foods and vaccination) (Weinert and Timiras, 2003).

Ageing not due to single factor

Physiologist Max Ruber developed "The rate of living theory" in 1908 where they stated that factors such as metabolic rate, body size and overall longevity all are interlinked together (Brys, et al., 2007). Yet till today the precise / correct biological and cellular mechanisms of how ageing occurs and is regulated is still not known.

Earlier theories on ageing linked its occurrence due to the cause of a single gene or a malfunction in an important body function yet this has not been proved and the idea was later dropped and as the study of ageing growing over the last couple of years it has been found out that ageing actually is a complex and multifactoral process which can effect many processes / functions / areas in the body and can be itself affected / influenced / initiated by anything from the body, to the environment or people or genetics factors (Weinert and Timiras, 2003).

2groups for all theories on ageing

There are many theories around to explain how ageing occurs / works and are grouped into multiple categories of which the two main commonly used groups are known as 'error theories' and 'programmed theories' (Weinert and Timiras, 2003).

Error theories discuss how environmental factors that either can cause or stimulate faster ageing (Weinert and Timiras, 2003).

Programmed theories state that the 'biological clock' regulates the growth cycles, maturation and old age in humans. The theories in this group support that once genes are activated this stimulates signals required for the interaction and regulation / maintenance of functional continuity of all systems in the body such as immune, endocrine, and nervous systems (Weinert and Timiras, 2003).

Lots of theories on ageing looking at briefly

As stated before there are lots of theories around who have attempted / tried to explain the ageing of humans / how humans age and many of them agree on the speculative ideas of how this happens / occurs - lots of theories overlap (Weinert and Timiras, 2003).

One of the theories most commonly used is the 'theory of evolution' / evolution theory which was formulated / made / developed in 1940s - and states that the survival of the fittest organisms occurs by the means of natural selection. So therefore it can be said that longevity is an important characteristic required for the survival of fittest (Weinert and Timiras, 2003).

Another theory states / suggests that ageing occurs due to changes in gene expression and this is known as the gene regulation theory where gene expression and longevity / ageing are linked together. Furthermore it is thought that it is unlikely that one gene is the main cause for ageing but multiple genes that together have an affect on longevity / ageing / lifespan (Weinert and Timiras, 2003). Genes play an important part in regulating lifespan as researchers recently discovered Insulin like signalling pathway that is found in many organisms such as worms, rodents, and flies. The regulatory mechanism in the organisms is initiated once there is a decrease in the insulin like signalling and thus activates conserved transcriptional factors that are required in regulating lifespan (Weinert and Timiras, 2003).

The cellular theory believes / supports the hypothesis that ageing is affected / influenced by the regulation of cell division as when cells have attained / archived their 'replication limit', the cell will automatically stop and is modified with the new physiological changes it developed during cell division (Weinert and Timiras, 2003).

There are lots of theories related to cellular effects on longevity.

There are several theories that support the hypothesis that cellular changes directly / indirectly affect longevity and thus this is why they come under the general / common cellular theory. Such theories that are part of this group include the pathways of p53 as it is already known once there is any sort of DNA damage p53 (known as the tumour suppressor protein and multi-functional transcription factor) activates DNA repair mechanisms, stops Cell cycle processes and initiates Apoptosis in order to maintain genomic integrity. Thus p53 is required to regulate all cellular processes (Serpi, 2003). In a study carried out on mice in order to find out more about p53 pathways, the mice were genetically modified thus their p53 functions were enhanced and this resulted in the mice becoming resistant to cancer but their lifespan were shortened / reduced considerably suggesting that p53 pathways are important for determining lifespan / longevity (Campsisi, 2005).

Judith Campisi states that organisms contain large numbers of renewable tissues that over the many years have evolved to prevent cancer from occurring and a common mechanism they have used to do so is cellular senescence where cell growths have been irreversibly stopped in order to minimise the risks of developing specific cancers such as neoplastic cancers. Research has also shown that the senescence mechanism is also very complex and results in unexpected effects in the organisms. It has also been said that cellular senescence is also similar to how apoptosis works only difference is that the senescence stops cell growths and apoptosis kills cells (Campisi, 2001). These senescent cells as stated before function normal but can not divide and replicate. The cells have demonstrated that they function in such a way that can lead to age related changes such as skin becoming wrinkly. Campisi and other scientists have developed new techniques by which senescence functions can be modified and changed so effective drugs and genes can be made to treat age-related diseases / problems but it is still important to know that reversing all senescence in cells will stop to prevent cancers as it does today (Kahn, 1994). The tumour suppressor protein pRB and other tumour repressor genes such as p16 are found in these senescent cells. The pRB pathway inhibits cell growth by stopping cell cycle when DNA damaged by environmental factors cause mutations for cancer to develop / grow occurs and p16 is required to regulate the cell cycles and not only that when p16 gene expression induces senescence signals these connect / engage with the pRB pathway and promotes cellular senescence growth to stop further damage to other cells. This study supports the idea that cellular ageing is induced by ageing phenotypes and that in turn was induced by the cellular senescence mechanisms (Campsisi, 2005).

Another commonly used theory is the free radical theory which was developed in 1957 and it states that cellular DNA damages occur from reactive oxygen species (ROS) which are produced by processes as a result of / in the mitochondrial respiration and environmental factors like UV exposure. With increasing age, ROS related damaged DNA and proteins accumulate in cells / body and this promotes mutation and cellular apoptosis (Weinert and Timiras, 2003).

Neuroendocrine theory is about how functional changes in neural and endocrine systems affect / influence ageing. These neural and endocrine systems are important for the body's physiological mechanisms to respond to environmental stimuli and work and communicate with the rest of the body's systems to bring about an effect / change and still maintain optimum functioning state for survival and reproduction. These physiological changes / mechanisms are important / crucial in life which therefore brings about changes in lifespan. But this isn't that simple as it seems as there are other more complex processes involved. Such processes come under the Neuro-endocrine-immuno theory (Weinert and Timiras, 2003).

There are lots of other theories that could have been discussed only due time constraints they can not be looked at.

Calorific Restriction

Calorific Restriction being an environmental variable / factor that has shown to extend / lengthen lifespan in many animals (in lots of studies).

Calorific Restriction known as Calorie Restriction and Caloric Restriction (CR) is a dietary regimen that has shown to extend lifespan by restricting the calories in food taken by 30-70% in the regimen only essential nutrients and vitamins taken (Weinert & Timiras, 2003; Fontana et al., 2007).

Calorific restriction was found by Clive Main McCay in 1930s when he was doing a study on rats and mice at Cornell University. The study showed that when calories intake was restricted this resorted in maximising the lifespan and preventing or stopping chronic diseases from occurring.

This same effect of extended maximum lifespan and preventing chronic diseases was found in many organisms such as yeasts, flies, worms, fish and rodents in other studies. Their lifespan was increased by 50% (Fontana et al., 2007; Koubova & Guarente, 2003).

The organism's lifespan extends to a certain stage and this is determined by many factors such as the age of the animal / person under going the Calorie Restriction, how strict the restriction was / is and their genetic background. In rats and mice the Calorie Restriction was reduced by 30-60% and this resulted in their maximum lifespan extending / increasing by 30%-60% which was only seen / sawn / viewed in childhood / young rats and mice but in the adult rodents the increase was only 10-20% (Fontana et al., 2007).

Over the last 20 years there have been many studies carried out to find out how ageing works / occurs and how CR helps to extend lifespan in many organism. The mechanism by which all this occurs has yet not been fully confirmed.

As stated before CR was 1st found to increase lifespan in rodents but other studies have shown that it affects many organisms such as yeast, rotifers, spiders, worms, fish, mice and rats and including non-human primates (Koubova & Guarente, 2003).

No studies have been carried out with humans but with Rhesus monkeys who have shown to have lower mortality rates than control animals and have had lower body temperatures and insulin concentrations again in comparison to control monkeys. Body temperature and insulin concentrations are used as biomarkers for longevity. Also it was noticed the monkeys had high levels of Dehydroepiandrosterone sulphate (DHEAS) which is also used as a biomarker in humans for ageing but don't know what its function is (Heilbronn & Ravussin, 2003).

CR rodents - rats / mice have shown to increase lifespan by preventing or delaying chronic diseases such as diabetes, atherosclerosis, autoimmune disease, kidney and respiratory disease and cancer (Koubova & Guarente, 2003; Fontana et al., 2007). And there also is an improvement in brain's plasticity, self repair mechanism and general memory that worsens with age (Koubova & Guarente, 2003).

From some studies it was shown that some rodents died without showing any signs of chronic disease and this therefore shows that ageing and chronic disease are not linked as before decrease in chronic disease did not explain the increase in lifespan and thus thought they were linked (Fontana et al., 2007).

There are people in different parts of the world with naturally occurring CR dietary regimens but these are not controlled and thus have energy restricted diets that lack in proteins and micronutrients.

These groups of people have high mortality rates due to contracting infectious diseases and being mal-nutritioned. Also suffer with numerous other problems such as short height, late maturation of reproductive system, low production of gonadal steroid, suppressed ovarian function, impaired lactation, impaired immune function and fertility problems. Other problems they also face with are changes in their metabolic rate, body temperature, and pulse and blood pressures. Also due to their poor-quality (controlled) dietary intake this resulted with them suffering from many psychological problems (Heilbronn & Ravussin, 2003).

In a report by Kagawa who stated that there is a Japanese Island where the people have a low calorie intake and there are many Okinawa centenuarians living there and it is thought that the cause of this is their CR diet lifestyle.

This report shows there are other naturally occurring people who follow a high quality CR diet and thus benefiting from it.

In the Kagawa report it states that the Okinawa adults consume only 83% of Japan's average calorie intake and these results were proved by Japan's National Nutrition Survey from 1972 onwards. Another report by Hokama states that the average Okinawa children consume about 62% of the calories consumed in total by all the Japanese children.

All these reports prove the facts stated in the CR theory. It was also noticed that there is a low risk of contracting any of the age related diseases (Willcox et al., 2007) and the mortality rates due to vascular diseases for the Okinawas in comparisons o all of Japan was 59%. Then the death rates due to malignancy were 69% for the Okinawas and lastly 59% for heart disease compared to rest of Japan.

These findings all are in favour of what is stated in the CR hypothesis. But it should be remembered to consider other factors such as genetics and environment.

But once the Okinawas leave the island and stop following their CR intake their mortality rates increase dramatically in comparison to those Okinawa that still live on the Japanese Island (Heilbronn & Ravussin, 2003).

In an epidemiological study by Willcox in 2007 regarding the Okinawas showed that Japan officially had the longest survival rate in comparison to the rest of the world due to their high functioning lifestyle / functional activity. Also the life expectancy for Okinawa men and women who were born in year 2000 was greater than rest of Japan and the world which had an average age of 65 years. The Okinawa men had 77.6 years and the women had 86 years.

From the study it shows that the Okinawa population had the greatest lifespan in comparison to rest of Japan and the world but this still does not prove that there is a link between CR diet and longevity. However / furthermore some scientist still believe CR has effect or can influence on longevity / lifespan.

The theories behind Calorific Restriction

From the various studies and reports there seems to be some sort of link between CR and longevity but the actual mechanism by which it works is still not known. The main reason for this is that the correct why to measure ageing from known biomarkers is still not known / unknown / unclear / not found / not determined.

There are lots of theories that support how CR functions to help extend longevity.

A specific gene was found that is suppose to be directly associated with longevity this was found in yeast cells that were used in earlier studies and it is called the Silent Information Regulator 2 gene (SIR2) and its function is to stop DNA instability by various genetic processes in a yeast cell (have not written about mechanism it uses) (Koubova & Guarente, 2003). From the study it was proven that there is a link between SIR2 gene was shortened by a mutation and the yeast lifespan would be reduced and when the SIR2 gene was over expressed in the yeast cells this would increase its lifespan proving that there is a link between the two. The CR activates the SIR2P enzyme in the yeast so that the process of respiration can start and produce ATP from the TCA cycle. And during respiration once more NADH is converted to NAD, this is how SIR2P enzyme is activated (Koubova & Guarente, 2003). There is no direct evidence that supports this mechanism but more studies are being carried out in the area.

The study using the yeast has shown that CR promotes the cells to produce and use energy in different ways so that the cell can still benefit in harsh situations / difficult times (North & Sinclair, 2006).

It has also been found out from recent studies that there are genes like SIR2 found in mammals that stop the activity of p53 and thus affecting the regulation of apoptosis process. This is thought to help extend lifespan of the mammalian cells (Koubova & Guarente, 2003).

Another study that supports the fact there is a link between CR and longevity proves this point by stating that when the calorie intake is reduced / restricted this results in decrease of metabolic rate and energy flow / production thus limiting any oxidative damage and this finally extends the lifespan.

After taking a CR diet a CR diet mammals experience two periods / stages. One / first the adaptive period which occurs right after the restricted diet is followed. The second is steady state which runs the mammal's whole lifespan.

The WHO in 1985 reported that adaptation of ageing is "a process by which new or different steady state is reached in response to a change or difference in the intake of food or nutrients" (Heilbronn & Ravussin, 2003).

The observations that are experienced during the adaptation state are weight and tissue loss and the rate of metabolism also gets reduced because of restricted calories and thus decreasing the energy produced (Koubova & Guarente, 2003). The large amounts / quantities of energy reduced causes the body to start breaking down carbohydrates and fats to amend the energy lost during the adaptive stage and calorie restriction intake stage.

After the end of the adaptive stage / phase the steady state commences where no more fat can be broken down due to low quantities of fat stores. And this helps to produce some glucose levels are not back to normal. As there still is deficiency in glucose, the body starts to produce ketones that help to full fill energy requirements in the body.

The low glucose levels also affect the insulin production in the pancreas which is also reduces. This is why in CR mammals / their cells are more insulin sensitive than in comparison to ad libitum animals (Koubova & Guarente, 2003; Heilbronn & Ravussin, 2003).

This insulin sensitivity is said to improve glucose metabolism.

In study by Kelley who stated that obese patients that have type 2 diabetes and were given a CR dietary regimen / intake which resulted in their weight being lost drastically and decrease the fasting glucose levels in the blood and improve their insulin sensitivity greatly.

These results were also supported by a study that was carried out carried out on monkeys that generally become insulin resistant with age but when they were put on the CR diet / intake their insulin sensitivity was improved. It is still not known if increased / improved insulin sensitivity is the mechanism by which longevity also increase. Thus / this is why a lot of research is still needed in the area (Heilbronn & Ravussin, 2003).

The mechanism by which the body regulates any changes in glucose levels in the blood is through / by producing insulin by the pancreas cells. And the brain detects low glucose levels from the hypothalamus.

Another theory that is thought to say how CR diet / intake increases longevity / lifespan is by decreasing the levels of the pituitary growth hormone. It is said that decreased levels of the hormone decreases / lowers the growth rate and thus increasing longevity. The study stated that SIR2 proteins in the hypothalamus and pancreas of the mammals are able to detect the changes that CR diet has caused in the body and thus down regulates the hormone which indirectly decreases insulin (Koubova & Guarente, 2003).

Another theory which supports the fact CR diet extends longevity is the oxidative stress and protein turn-over theory.

As stated before the free radical theory states that ROS species that are produced in / as a result of respiration damage DNA and proteins in the body by causing mutations in the DNA and proteins in the body by causing mutations in the DNA and influencing / initiating apoptosis through help of p53 and thus this results in ageing occurring.

So the process of ageing, growing old (senescence) and its related loss of bodily / body functions are due to the accumulation of molecular oxidative damage that is caused by the increased production of SOS species by multiple factors e.g. respiration. And thus with time the body's anti-oxidants stop to work effectively and the repair processes also reduce to fix the damage with help of / through use of p53.

As stated before ROS species production increases with age by the mitochondria (Sohal & Weindruch, 1996). So it thought by which CR works is to reduce steady state levels of oxidative stress and by stopping / delaying the age related build-up of oxidative damage in the body.

In study on rodents - mice and rats found that when they were given a CR diet their oxidative damage was reduced. But the study still hasn't been able to prove by which mechanism CR reduces levels of anti-oxidants and thus increasing the lifespan and that's why it is not thought that there is a link between CR and anti-oxidants (Sohal & Weindruch, 1996).

As stated before ROS species not only cause oxidative damage to DNA but proteins that can build-up and become harmful to the cells. With studies that have used CR diet it has shown that with the reduce energy production in the body damaged fats and proteins are used to generate excess energy and thus the protein-turn over rate is increased. In the various research studies it has shown that CR has effect on protein turnover but no direct link has been associated with CR and protein turnover and increased lifespan. Thus more research is required to prove the point fully.

Many theories have been considered but not all as there are lots of theories in this subject are a and thus would be difficult to discuss / include all the theories.

Once again many medical advances in healthcare system across the world have shown to affect / influence longevity by increasing it. As stated before some of the medical advances were the discovery of antibiotics to help (fight) against infectious diseases and development of good medications to help with other elderly associated diseases such as cardiovascular diseases.

With more research may be in the future CR diet could be used to treat a range of diseases in all humans after the clear mechanism and association by which CR diet helps / influences / affects to increase longevity / lifespan has been made / proven.

But due to the range of theories regarding longevity and CR works / functions - there is still lots of research required to find out exactly how they occur / function / work mechanistically.

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