The Function of Telomeres in Obesity - Term Paper Example

The Function of Telomeres in Obesity Introduction Telomeres are DNA sequences that occur at the end of chromosomes. The process of telomere shortening has been associated with replicative aging of cells, and is linked to age-related diseases and diseases involving cell proliferation or DNA damage. This paper shall review a recent study on the association between telomere shortening and childhood obesity, and shall discuss earlier works that laid the ground for subsequent studies, back to the pioneering study that first laid the ground for research on telomeres. Discussion Buxten et al. (2011) studied the association between childhood obesity and shorter telomere length of leukocytes. Since previously published research showed an association of obesity, cardiovascular disease, type 2 diabetes, insulin resistance, hypertension, cigarette smoking and psychological stress with shorter telomere lengths in adults, the authors of this paper found it worthy to explore whether shorter telomere length was associated with childhood obesity as well. It had been previously established that shortening of telomeres indicated cell aging. The association of shorter telomere lengths with cardiovascular disease and obesity suggested that these conditions accelerated biological aging, although it remained to be fully explained. The investigators carried out a case-control study involving 793 children, obese (above 97th percentile for weight) and non-overweight (below 90th percentile for weight). Their peripheral blood samples were taken and leukocyte DNA extracted, from which measurements of telomere lengthening was done using PCR. Statistical analysis showed that mean leukocyte telomere length in the obese group was significantly lower than in the non-overweight group, equating to about a 24% decrease. No statistical differences were found across gender, age, blood pressure or total cholesterol levels, however, telomere length was inversely related to height and weight (and therefore to age). The investigators concluded that telomeres of obese children are significantly shorter than those of non-obese children of comparable age, and therefore obese children have a biological age that is significantly higher than their actual chronological age – an alarming conclusion which stresses the importance of reducing obesity in order to reduce the risk of future diseases. Buxton et al (2011) cited a number of published articles. More than one of the cited papers demonstrated how obesity in various ways – by waist-hip ratio in women, for example - was linked to shorter telomere length. Among the references, the paper that was most critical to the study objectives of Buxton et al (2011) was the study by Farzaneh-Far et al (2010). This is because it was the largest, most robust, and most popular study, with the highest standards of research methodology. This was a prospective cohort study, the most reliable study design, involving 608 participants over 5 years. Participants were patients with cardiovascular disease. The investigators found that over 5 years, 45% of these patients developed telomere shortening, 32% maintained the same telomere length, and 23% lengthened telomeres. Independent predictors of telomere shortening in cardiovascular disease patients included older age, male sex, and abdominal obesity (higher waist to hip ratio). Study participants with the longest telomeres experienced the greatest amount of shortening, while those with shorter telomeres maintained or increased their length. This suggested that there may be negative feedback regulation of leukocyte telomere length in humans. The shortening of telomeres was postulated to be done by the enzyme telomerase. In contrast with prior cross-sectional studies, the authors found no significant associations between telomere trajectory and blood pressure, insulin resistance, smoking, body mass index, or physical activity. It was recognized that many genetic and environmental stressors may have acted as confounders to influence the observed results on telomere shortening. It was also proposed that abdominal obesity may be leading to excessive cellular oxidative stress, which accelerated intracellular damage and aging. Farzaneh-Far et al (2010) based their study objectives on the results of previous cross-sectional studies demonstrating an association between telomere length and cardiovascular events. One of the most influential studies to suggest this association was carried out by Brouilette et al (2007), which was published by the American Heart Association. This study was therefore a critical source for Farzaneh-Far et al (2010). The investigators hypothesized that shorter leukocyte telomere length was associated with premature, or early-onset, myocardial infarctions and carried out a case-control study. They recruited patients who had suffered early myocardial infarctions, as well as normal healthy people as controls, and determined the difference in telomere lengths in these groups. They found a highly significant association, and concluded that having a shorter telomere length increased the risk of myocardial infarction by about 3-fold. They hypothesized that low-grade inflammation, increased oxidative stress, and higher homocysteine levels in atherosclerosis led to leukocyte cell damage and telomere attrition. Although Brouilette et al (2007) conducted the study to validate similar previous small-scale studies on myocardial infarctions and telomere lengths, the underlying theory behind their study was to explore the suggestion that telomeres, the end-portions of chromosomes, shortened with cell lifespan and as the cell replicated, that they represented a biological clock, that biological cell age was a distinct phenomenon from chronological age, and thus the early onset of age-related diseases, such as myocardial infarction, should be associated with shorter telomere lengths. One of the works cited by Brouilette et al (2007) summarized previous work on this area and demonstrated the role of telomeres as a signal of cell senescence. Allsopp and Harley (1995) expanded the findings of previous research showing an association between replicative aging of cells and telomere shortening. They hypothesized that the shortening of telomeres to a critical threshold could act as a marker of cell senescence. Using fibroblast clones in vivo that were stimulated to replicate and measuring the telomere lengths of successive clonal generations, they found significantly lower telomere lengths in senescent cells that had lost replicative capacity compared to earlier clones, although they could not propose a threshold. The study that most highly influenced the research of Allsopp and Harley (1995) was the publication that coined the term ‘the telomere hypothesis of cell aging’. This was the critical study source for Allsopp and Harley (1995) as it allowed an exhaustive review on the topic, and raised the research question of quantifying the extent of telomere loss with cell replication. Harley (1991) reviewed previously published research on telomeres and cell aging. He summarized recent observations that telomeres shortened with age in a replication dependent manner. The function of telomeres was identified as protecting the chromosome from recombination. It was also noted that immortal cell lines such as sperm and tumor cells expressed telomerase, an enzyme that protected telomeres from attrition. Harley (1991) paid tribute to the work that first proposed the cellular biological clock mechanism to explain the senescence of cells. This, thus, was the critical study source. Olovnikov (1973) discussed some of his theories regarding changes in DNA with cell replication, which could explain the senescence of cells and exhaustion of their replicative capabilities. He described as ‘marginotomy’, the phenomenon of the DNA replicate being shorter than the template, during DNA replication for cell division. The genes at the end of the chromosome were defined as telogenes, which were not essential for the cell, and these were explained to get shorter with every new mitosis. The function of the telogenes was to act as buffers, to be sacrificed during every cycle of mitosis. When the telogenes were exhausted, Olovnikov explained, the cell would start to lose essential genes in each mitosis and rapidly lose replicative ability, and thus have aged. He even presented a formula to predict the lifespan of a specific type of clonal cell, using the length of the telogene and the number of mitoses already taken place. He also proposed two theories to explain how marginotomy occurred; both included the activity of a DNA polymerase that fail to completely replicate the telogenes. Although contemporary usage terms have moved beyond ‘telogenes’ and ‘marginotomy’, most recent studies involving telomere shortening continue to mention the contribution of Olovnikov to our understanding of the function and role of telomeres in cell cycling and aging today. The first study discussed – by Buxton et al. (2011) on the association of childhood obesity with telomere shortening – demonstrates the advancement in our understanding of disease pathophysiology since the time of Olovnikov, and how it may lead to early death. The role of telomere shortening as a signal of cell aging has allowed researchers through the decades to explore how age-related disease processes such as atherosclerosis and myocardial infarctions occur in the setting of accelerated biological aging beyond the chronological age. The finding of telomere attrition in children with obesity provides further evidence of how disease can hasten cells’ aging. Although the pathophysiology of the process remains to be entirely elucidated, these findings help emphasize the importance of focusing on attenuating people’s risk factors in order to prevent early disease-related mortality. References Allsopp, R.C., Harley, C.B. (1995). Evidence for a critical telomere length in senescent human fibroblasts. Experimental Cell Research, 219(1):130-6. Buxton, J.L., Walters, R.G., Visvikis-Siest, S., Meyre, D., Froguel, P., Blakemore, A.I. (2011). Childhood obesity is associated with shorter leukocyte telomere length. Journal of Clinical Endocrinolology and Metabolism, 96(5):1500-5. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137462/?tool=pubmed Brouilette, S., Singh, R.K., Thompson, J.R., Goodall, A.H., Samani, N.J. (2003). White cell telomere length and risk of premature myocardial infarction. Arteriosclerosis, Thrombosis, and Vascular Biology, 23(5):842-6. Retrieved from http://atvb.ahajournals.org/content/23/5/842.long Farzaneh-Far, R., Lin, J., Epel, E., Lapham, K., Blackburn, E., Whooley, M.A. (2010). Telomere Length Trajectory and Its Determinants in Persons with Coronary Artery Disease: Longitudinal Findings from the Heart And Soul Study. PLoS One, 5(1):e8612. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797633/?tool=pubmed Harley, C.B. (1991). Telomere loss: mitotic clock or genetic time bomb? Mutation Research/ DNAging, 256(2-6):271–282 Olovnikov, A.M. (1973) A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. Journal of Theoretical Biology, 41(1):181-90. Read More