Telomere Shortening: Causes and Effects

Telomere Shortening Causes and EffectsHarry McLellanIntroductionTelomeres be a repeating sequence TTAGGG, a couple gramme nucleotides long (Kim, et al, 1994) at the end of chromosomes that prevents the degradation of deoxyribonucleic acid and stops the ends of chromosomes binding together as well as preventing unnecessary repair. The main function of telomeres is economy of DNA. During cell replication there is a trim down of the telomeric sequence with distributively cell constituent (Kim, et al, 1994). Once telomeres become short enough, approaching a hypercritical distance the cell begins senescence (Blasco et al. 1997). Therefore, it has been suggested telomere aloofness produces a mitotic clock which could predict cell and existence death (Harley, 1991). Telomeres degrade natur eachy with each cell division but certain breedingstyle factors may zip degradation and negatively affecting the health and fitness of an individual. This literature review exit explore ho w telomere distance is affected by lifestyle factors and ultimately how this has an effect on get oning. This literature review will specifically focus on the telomere length and aging unconscious process in humans. A subject gathering a lot of attention and understanding in recent years with the power to predict the longevity of an organism and opportunities to thin the aging process.Structure and function of telomeresTelomeres cap the ends of chromosomes (Fig. 1) and protected the connected DNA sequences during cell division.Figure 1 a schematic of the end DNA replication problem and how group pairs argon lost. Retrieved online at http//senescence.info/telomeres_telomerase.html (viewed on 18/03/2017) When the cell divides, DNA must be replicated. However, because DNA plenty only be replicated 5 to 3, the lagging desolate is replicated through backwards stitching. While the leading strand is replicated continuously, the lagging strand requires RNA primers, which provide 3 h ydroxyl groups to plant from. Then once the primers are removed, a gap is left at the extreme end of the lagging strand template. To stop chromosomes shortening, the end of the DNA strand is a repeating sequence (a telomere) recognised by an enzyme telomerase, which fills in the missing nucleotides to complete the template and ensure no information is lost (Klapper et al. 1998). While telomerase drill is detected in cells with high proliferation potential, in somatic cells it is virtually undetected resulting in the overall shortening of telomeres with each cell division. In immortal or stick outcerous cells however, telomerase activity is reactivated providing the basis for unregulated and potentially infinite divisions as telomere length is repaired after division (Dunham et al. 2000).Figure 2 human chromosomes (grey) capped with stained telomeres (white) retrieved online at http//science.nasa.gov/media/medialibrary/2006/03/16/22mar_telomeres_resources/caps.gif (viewed on 11/0 3/2017)Effects of shorteningIt might be possible to predict a cells lifespan by measuring telomere length, an investigate development cultured human liver tissue reported results of 29-60 base pair loss per year (Takubo et al. 2000). Jiang et al. (2008) and Song et al. (2010) measured the levels of stathmin and EF-1a, which mark DNA vituperate and dysfunction and bring that there is a steady extend with increasing age in humans. Resulting in the overall negative relationship with telomere length and age.Cawthon et al. (2003) found certain genetic disorders like dyskeratosis congenital, the progressive failure of bone marrow leading to early mortality can accelerate telomere shortening. Whilst normal cells loose telomere fragments with each cell division, sufferers of dyskeratosis congenital will experience premature deaths and early development of age related sicknesss. The same field of view also compared people of the same age group and lifestyle and found those with natura lly shorter telomeres where likely to suffer from a wide range of diseases and had light survival. Without being affected by life factors, telomere length changes between individual and can give an indication to the life span. Shorter telomeres can lead to genome instability and a higher risk of genetic disease.Gender, genetics and diseaseIn humans there is a negative correlation between telomere length and age, Valdes et al. (2005) published a study that looked at one thousand women and cerebrate that the human telomere sequence is depleted by 27 base pairs a year by measuring the mean TRF (telomere restriction factor) length using a Southern blot method. Brouilette et al. (2003) found there was no significant difference in telomere shortening rates or length between males and females.Inherently, telomeres can be short and when shorter than average the individual becomes at risk of disease and a bring down lifespan (Farzaneh et al. 2008 Cawthon et al. 2003). Cardiovascular disea se is commonly associated with short telomeres (Yang et al. 2009). Telomere length can also be affected by environmental factors (Steinert et al. 2004) not just genetic factors. Factors such as body mass, diet, have and exercise (Valdes et al. 2005 Cherkas et al. 2008) all cause a decrease in telomere length and eventual cell senescence (Stiewe and Ptzer 2001). Factors like smoking and poor diet will accelerate telomere shortening and lead to disease development. Coronary heart disease associated with short leukocyte telomeres (Brouilette et al. 2003), increased risk of mitochondrial diseases (Zee et al. 2009), atherosclerotic diseases (Van der Harst et al. 2006), diabetes (Sampson et al. 2006) and increased risk in various cancers (Wu et al. 2003). In summary gender has no effect on telomere length but short telomeres are linked to a variety of cancers and disease.CancerWhen telomere length becomes withal short, the telomere can be subject to repair or recombination (Klapper, et al, 1998). De Lange (2005) published findings that repaired lesions are the probable cause of a cell let go ofing cancerous. In conjunction with this Meeker (2006) state that short dysfunctional chromosomes are involved in carcinogenesis. Using laser capture microdissection Shammas et al. (2008) looked at the function of telomeres and telomerase activity in adenocarcinoma (types of tumour) cells and found that when telomeres expire a critically short length telomerase activity increases. The same study also found when telomerase activity is suppressed the tumour cells did not proliferate set off telomeres and telomerase involvement in cancerous cells.Poor diet and smokingTelomere shortening to a critical length can cause damage to the genome and potentially turn cancerous. Long term smoking is linked to carcinogenesis in cells (Valdes et al. 2005). Telomere length in circulating lymphocytes is show to be significantly shorter in long term smokers compared with the mesh none smo kers. The exposure to tobacco has a negative effect on the telomere length and accelerates shortening (Morla, 2006). Using biomarkers accumulative DNA damage can be monitored. During ageing and or obesity there is a significant increase in biomarkers human blood. Smoking also cause there to be an increase in biomarkers (Song et al. 2010). When analysed telomeres shorten by roughly 27 base pairs a year but with introduction of smoking 20 cigarettes a day, around 31 base pairs are lost (Valdes et al. 2005) an overall detrimental effect on telomere length. In conjunction with this Epel et al. (2004) produced a study on oxidative stress linked to smoking and telomeres and results showed cells under high oxidative stress had lower levels of telomerase activity and were more susceptible to telomere shortening, aiding the ageing process. Overall smoking has a negative effect and accelerates shortening of telomeres, which can lead to development of tumours or cell death (Meeker, 2006).Oxida tive stress is linked with telomere shortening, which leads to DNA damage or premature cell death (Epel et al. 2004). Another factor that increases oxidative stress is poor diet and obesity. A study on obese mice (Furukawa, 2004) showed a positive correlation between fecund accumulation and increase in oxidative stress. The study also introduced a NADPH oxidase crucifyor which caused a reduction in adipose tissue (fat/ loose connective tissue) bring out that fat accumulation is directly linked to oxidative stress. The study concluded with the introduction of the NADPH oxidase inhibitor, caused the conditions of the mice to improve. The reduction in oxidative stress also overturns the telomere shortening (Valdes et al. 2005) and cut down damage to the genome. In summary an increase in oxidative stress has a negative impact on telomere length and ageing.Stress and environment lifestyle choices impact telomeres length and so does environment an individual lives or works in. A stud y was conducted to look at the airborne pollutants like toluene and benzine within a city that humans are exposed to on a daily bases (Hoxha et al. 2009). 77 traffic officers and 57 office workers had blood samples interpreted that where ulterior analysed using real time PCR. Hoxha et al. (2009) analysed the leukocyte telomere length and found a significant difference. Traffic officers who are exposed to traffic pollutants had shorter telomere length compared to office workers. depiction to pollutants increases telomere shorting and risk from disease and ageing. In conjunction to this Pavanello et al. (2010) studied the leukocyte telomere length in 48 coke over workers compared to 44 controls. All none smokers and all in the same age group the coke oven workers are exposed to polycyclic aromatic hydrocarbons on a daily basis. Pavaello et al. (2010) concluded that coke oven workers exhibited a significantly shorter leukocyte telomere length and higher genome instability linked wit h disease and ageing (Farzaneh et al. 2008 Cawthon et al. 2003).When an individual becomes stressed, the adrenal steroid glucocorticoid is released. Glucocorticoid has the potential the increase oxidative stress as it is known to inhibit the activity of glutathione peroxidase (an antioxidant enzyme) (Patel et al. 2002). In rats corticosterone (adrenal steroids in rats) caused a decrease in NADPH which is an oxidase inhibitor, (Furukawa, 2004) leading to an increase in oxidative stress and telomere shortening.Stress is associated with oxidative pressure, which is linked to shorter telomeres and poor health. Epel et al. (2004) took a group of women who perceived to have a lot of stress in their life and compared them to a control group who had little stress in their life. The participants consisted of 58 mothers, 19 whom had healthy children and 39 who had chronically ill children. The women with chronically ill children where perceived to have a higher level of stress in their life. The study on shortening in response to stress concluded that women who have a high amount of perceived stress in their life had shorter telomeres equivalent to that of a decade of ageing compared to their control counterparts (Epel et al. 2004). Stress negatively affects telomere length and can lead to poor health and development of disease.AntioxidantsTwo groups of women and their dietary intake where monitored over the course of five years. The study looked at diets containing high amount antioxidants, mainly vitamin C and E rich foods (fish, fruit and vegetables) against diets which did not (Farzaneh-Far et al. 2008). By measuring telomere length, using quantitative PCR and monitoring the levels of fatty acids in blood, Farzaneh-Far et al. (2008) concluded that an increase in antioxidants correlated with a reduction in shortening of telomeres and the women participants with stiff antioxidant intake generally had longer telomeres in comparison to the other dietary group. In a sim ilar study involving 1,067 cases and 1,100 controls, the dietary intake of antioxidants is recorded to study its involvement with the development of breast cancer in women (Shen et al. 2009). In correlation to Farzaneh-Far et al. (2008), Shen et al. (2009) found the same link of a reduction in telomere shortening with increase in antioxidants in the diet. The same paper revealed women with poor diet and low antioxidant intake were far more at risk of developing breast cancer. Antioxidant reduce oxidative damage and telomere shortening.Oxidative stress and nutrition restrictionOxidative damage increases telomere shortening and telomeres are linked to cell senescence. Oxidative damage is indeed linked to the longevity of an organism (Jennings et al. 2000). Dietary restrictions have been placed on organisms such as rats to test whether a decrease in nutrition will decrease oxidative damage. Jennings et al. (2000) found that when nutrition is decreased so that optimal growth cannot be sustained there is an increase in longevity and this is on-key for a large range or organisms. In an earlier study, Jennings et al. (1999) made the link between early growth and shortened kidney telomeres in rats in later life. The rats with diet restrictions had a reduced maternal growth followed by a postnatal growth catch up but had longer kidney and liver telomeres, which are associated with increased longevity of up to 15% (Jennings et al. 1999). To summarise telomere shortening is accelerated by oxidative stress which in turn can be reduced by nutrition restrictions which will increase longevity.ExerciseOxidative stress from poor diet and general perceived stress can cause an quickening in telomere shortening (Epel et al. 2004 Farzaneh-Far et al. 2009). Exercise can reduce the effects of stress shortening. Two groups of mice where placed into containers. A group given the plectrum to exercise on a running wheel and the other group given no option to exercise. All running don e was voluntary. At the end of the experiment, the mice given the option to exercise showed an increase in telomere stabilisation proteins and a suppression of cell apoptosis regulators (Werner et al. 2009). When tested on humans similar results occurred. When track and field athletes are compared to untrained individuals the data obtained showed an increase in expression of telomere stabilisation proteins in athletes and reduced leukocyte telomere shortening (Werner et al. 2009). Regular exercise will supress the effects of stress and reduce the effects of ageing by preservation of telomeres. ConclusionTelomeres naturally shorten with time and are reflected in the aging of a human. A cell can only divide so many times before the genome becomes damaged (Klapper, et al, 1998), in this instance the cell must begin cell senescence or apoptosis. Many lifestyle factors like obesity, smoking, poor diet, genetic inheritance, pollution, and stress can accelerate telomere shortening and agei ng causing premature death or disease. another(prenominal) factors work the opposite way, consumption of antioxidants can reduces oxidative stress and slow down telomere shortening (Farzaneh-Far et al. 2008). Regular exercise can increase expression of telomere strengthen proteins (Werner et al. 2009). Restricting nutrition to limit optimal growth will increase the longevity of an organism (Jennings et al. 2000). Telomere length analysation using quantitative PCR can be used to predict the lifespan of an organism and help stop the onset of premature age related diseases.