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February 20, 2022Significance of Telomere Length For Aging and Human Health
What are the telomeres?
Genetic information encodes the structure and function of cells. It is stored in molecules of deoxyribonucleic acid (DNA) and passed from generation to generation. In humans, DNA molecules, together with proteins known as histones, are organized in chromosomes, thread-like structures in the cell nuclei.1
DNA replicates during each cell division. However, DNA located at the ends of the chromosomes cannot be completely replicated. Interestingly, there are repetitive DNA sequences at the ends of chromosomes, repeating hundreds to thousands of times, known as telomeres. The repetitive telomere sequence varies among species and is TTAGGG in humans. By capping chromosomes, telomeres prevent the loss of coding DNA information during division. Moreover, telomeres protect chromosome ends from fusion and rearrangements. Reduced telomere length has been correlated with cell aging, and changes in telomere structure may lead to impairments of cell function. Telomeres have been shown to play a very important role in the health and function of cells and organisms.2
The loss of telomere length occurring with cell division and DNA replication is counteracted by the enzyme telomerase, which promotes telomere extension. Enzymes, including telomerase, are proteins that increase the rate of chemical reactions in living organisms. Telomerase activity is very low in most cells of the body but is pronounced in cells with high division potential.3
Telomere length is affected by both genetic and environmental or lifestyle factors
Both genetic and environmental or lifestyle factors have been shown to affect telomere length and the rate of age-related telomere length reduction. Studies on pairs of twins have demonstrated the important role of genetic and inheritable factors for telomere length. However, many environmental and lifestyle factors can also influence telomere length, including, among others, adversity in early childhood, unfavorable conditions during the fetal period, stress, infections, nutrition, and physical activity.4
Telomere length as a mark of aging
The DNA sequence of telomeres shortens with cell division. In turn, this gradual reduction of telomere length slows down the process of cell division, and, once telomere length falls below a certain threshold, cells lose their ability to divide further. A negative correlation between telomere length and chronological age has been confirmed by numerous studies, even though this correlation is not linear, and the speed with which telomeres shorten varies during different life stages. Therefore, telomere length has been proposed as a key biological marker of aging.4,5 Notably, telomere length is most pronouncedly correlated to cell senescence, which is associated with cell cycle arrest (with the inability of cells to divide further). However, alternative biological markers of age have also been proposed and investigated. They include the epigenetic clock, which relies on age-related changes in DNA methylation, as well as composite scores of the age-related expression of certain genes, proteins, or metabolites.5 Recent studies have investigated whether the different markers of aging measure identical or different aspects of the aging process. Most investigations have found only a partial correlation among the findings for different markers of biological aging, suggesting that they may measure distinct parameters of the aging process, and that using these aging markers in combination may further increase their informativeness.4
Telomere length and mortality risk
A number of studies have found an inverse correlation between telomere length and mortality risk. For example, in a very large study involving 64,637 participants recruited from the general population, short telomeres were associated with an increased risk of all-cause mortality.6 These findings have also been confirmed by a meta-analysis (a research study that systematically and quantitatively summarizes the results of previous investigations on a topic).7 It included 25 individual studies on individuals recruited from the general population and confirmed a correlation between short telomere length and an increased mortality risk. It also detected variability of the results based on the techniques used to measure telomere length and on the participants’ age.8
Telomere length and risk of aging-related disorders
Shorter telomere length has also been associated with an increased risk for several serious, age-related diseases,8 including cardiovascular disorders (conditions affecting the heart or blood vessels)9 and diabetes mellitus type 2 (an impairment of glucose regulation, leading to an increased concentration of blood glucose).10 A meta-analysis, encompassing 24 individual studies, assessed previous publications on the association between telomere length and cardiovascular disease, including coronary heart disease (characterized by insufficient delivery of blood and oxygen to the heart due to narrow or blocked blood vessels) and cerebrovascular disease (caused by disrupted delivery of blood and oxygen to the brain due to blood vessel impairments, which may include a rupture, clot formation, narrowing, or blockage).9 This meta-analysis found a statistically significant correlation between shorter telomere length in the participants’ leucocytes and an increased risk of coronary heart disease.9 The correlation between telomere length and cerebrovascular disease was less clear in this study but has been confirmed by other investigators.9 Shorter telomere length has also been associated with an increased risk of diabetes mellitus type 2, which may partially be due to more pronounced oxidative stress in patients with type 2 diabetes mellitus.10 However, the association between telomere length and type 2 diabetes mellitus can also be influenced by many additional factors, including patients’ age, sex, and weight.4
The correlation between telomere length and psychological stress
Chronic and severe stress has been associated with dysregulation of a number of biological processes and with accelerated aging. The relationship between psychological stress and telomere length has also been investigated, and an association of psychological stress with decreased telomere length has been reported. For example, a study on telomere length in blood cells of premenopausal women found an association between psychological stress and shorter telomere length. Factors that were important for the strength of the association between stress and telomere length included perceived stress (indicating the degree to which individuals perceive a situation as stressful) and stress chronicity (referring to the duration of a stressful situation). The differences in telomere length between women subjected to variable degrees of stress was pronounced, with the difference in telomere length between the high-stress group and low-stress group corresponding to the equivalent of 9–17 years.11 A review of previous publications also highlighted the significant correlation between short telomeres and chronic social stress, with significant results both for childhood and adult stress exposure.12 The impact of adversity during the early stages of life on telomere biology is especially pronounced and may apparently reprogram the speed of telomere shortening.4
Telomere length and physical activity
Most studies investigating the relationship between telomere length and physical activity have found a positive correlation between the two parameters, even though discrepancies have been observed among studies, presumably due to the great variability in the type and extent of physical activity as well as the participants’ demographic characteristics.13 Moreover, longer telomeres have been observed in athletes than in individuals leading a sedentary lifestyle.13 These findings have been confirmed by a meta-analysis, which summarized the results of 11 studies on 19,292 individuals and identified longer telomeres in physically active individuals.14 However, the causality of the relationship between physical activity and telomere length as well as the implicated mechanisms still need to be investigated.
Telomere length and nutrition
The relationship between different eating patterns and telomere length has also been investigated.15-18 The consumption of several healthy diets has been associated with higher telomere length. For example, consumption of the Mediterranean diet, which includes vegetables, fruit, whole grains, nuts, and healthy fats, has been associated with longer telomeres.15 Other healthy eating patterns, including Dietary Approaches to Stop Hypertension (DASH), Healthy Eating Index Scores, and Alternate Healthy Index Scores, all of which reflect healthy diets, have also been associated with longer telomeres.16 These findings indicate that a high-quality diet including vegetables, fruits, vegetables, plant-based proteins, dairy products, and whole grains may be associated with higher telomere length.16 Contrarily, eating patterns including high content of sugary beverages and processed meat have been associated with telomere shortening.15 However, most studies investigating the relationship between nutrition and telomere length have been observational in nature, and future research should investigate the causality of the observed effects. In a randomized (with participants randomly assigned to the experimental groups), controlled pilot trial, a high dose of hydrogen-rich water (HRW) utilized Drink HRW hydrogen tablets was administered for a period of 6 months to older adults.19 A significant difference was observed between the telomere length of the two groups at the end of the trial, with higher telomere length in the group with HRW intake than in the control group.19 Finally, in a randomized, controlled trial, vitamin D or a placebo (an inert substance used as a control) was taken for 12 months by older individuals with mild cognitive impairment.20 Higher telomere length was observed in the vitamin D-administered group than in the control group in the end of the trial.20
What are the advances and challenges facing age-related telomere research?
Telomeres play an important role for the protection of chromosome ends from loss of coding DNA information, from fusion, and from recombination. Age-related shortening of telomeres has been identified as an important marker of aging that can be used alone or in combination with other biological markers. Telomere length has been negatively correlated with mortality risk, risk of several age-related medical conditions, and stress. Contrarily, physical activity and healthy nutrition have been positively associated with telomere length. However, the research on age-related changes in telomere length has also been confronted by important challenges. The majority of conducted studies are observational in nature and detect a correlation without proving the causality of the observed effects. Thus, additional studies with a longitudinal design and well defined control groups will be needed to prove the causality of the observed effects and to identify the most appropriate interventions related to physical activity and nutrition.
Literature sources:
- https://medlineplus.gov/genetics/understanding/basics/chromosome/
- Turner, K.J., Vasu, V., & Griffin, D.K. (2019). Telomere biology and human phenotype. Cells,8(1), 73. doi: 10.3390/cells8010073.
- Zvereva, M.I., Shcherbakova, D.M., & Dontsova, O.A. (2010). Telomerase: structure, functions, and activity regulation. Biochemistry (Moscow),75(13), 1563–1583. doi: 10.1134/s0006297910130055.
- Vaiserman, A., & Krasnienkov, D. (2021). Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. Frontiers in Genetics,11, 630186. doi: 10.3389/fgene.2020.630186.
- Jylhävä, J., Pedersen, N. L., & Hägg, S. (2017). Biological age predictors. EBioMedicine,21, 29–36. Doi: 10.1016/j.ebiom.2017.03.046
- Rode, L., Nordestgaard, B.G., & Bojesen, S.E. (2015). Peripheral blood leukocyte telomere length and mortality among 64,637 individuals from the general population. Journal of the National Cancer Institute,107(6), djv074. doi: 10.1093/jnci/djv074.
- Wang, Q., Zhan, Y., Pedersen, N.L., Fang, F., & Hägg, S. (2018). Telomere length and all-cause mortality: a meta-analysis. Ageing Research Reviews,48, 11-20. doi: 10.1016/j.arr.2018.09.002.
- Armanios, M., & Blackburn, E.H. (2012). The telomere syndromes. Nature Reviews Genetics,13(10), 693–704. https://doi.org/10.1038/nrg3246.
- Haycock, P.C., Heydon, E.E., Kaptoge, S., Butterworth, A.S., Thompson, A., & Willeit, P. (2014). Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis. The BMJ,349, g4227. doi: 10.1136/bmj.g4227.
- Salpea, K.D., Talmud, P.J., Cooper, J.A., Maubaret, C.G., Stephens, J.W., Abelak, K., & Humphries, S.E. (2010). Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation. Atherosclerosis,209, 42–50. doi: 10.1016/j.atherosclerosis.2009.09.070.
- Epel, E.S., Blackburn, E.H., Lin, J., Dhabhar, F.S., Adler, N.E., Morrow, J.D., & Cawthon, R.M. (2004). Accelerated telomere shortening in response to life stress. Proceedings of the National Academy of Sciences of the United States of America,101(49), 17312–17315. doi: 10.1073/pnas.0407162101.
- Oliveira, B.S., Zunzunegui, M.V., Quinlan, J., Fahmi, H., Tu, M.T., & Guerra, R.O. (2016). Systematic review of the association between chronic social stress and telomere length: a life course perspective. Ageing Research Reviews,26, 37–52. doi: 10.1016/j.arr.2015.12.006.
- Arsenis, N. C., You, T., Ogawa, E. F., Tinsley, G. M., & Zuo, L. (2017). Physical activity and telomere length: Impact of aging and potential mechanisms of action. Oncotarget,8(27), 45008–45019. https://doi.org/10.18632/oncotarget.16726.
- Lin, X., Zhou, J., & Dong, B. (2019). Effect of different levels of exercise on telomere length: a systematic review and meta-analysis. Journal of Rehabilitation Medicine,51(7), 473–478. doi: 10.2340/16501977-2560.
- Navarro-Ibarra, M.J., Hernández, J., & Caire-Juvera, G. (2019). Diet, physical activity and telomere length in adults. Nutricion Hospitalaria,36(6), 1403–1417. doi: 10.20960/nh.02673.
- Leung, C.W., Fung, T.T., McEvoy, C.T., Lin, J., & Epel, E.S. (2018). Diet quality indices and leukocyte telomere length among healthy US adults: data from the National Health and Nutrition Examination Survey, 1999-2002. American Journal of Epidemiololgy,187(10):2192-2201. doi: 10.1093/aje/kwy124.
- Rafie, N., Golpour Hamedani, S., Barak, F., Safavi, S.M., & Miraghajani M. (2017). Dietary patterns, food groups and telomere length: a systematic review of current studies. European Journal of Clinical Nutrition,71(2), 151–158. doi: 10.1038/ejcn.2016.149.
- Galiè, S., Canudas, S., Muralidharan, J., García-Gavilán, J., Bulló, M., & Salas-Salvadó, J. (2020). Impact of nutrition on telomere health: systematic review of observational cohort studies and randomized clinical trials. Advances in Nutrition,11(3), 576–601. doi: 10.1093/advances/nmz107.
- Zanini, D., Todorovic, N., Korovljev, D., Stajer, V., Ostojic, J., Purac, J., Kojic, D., Vukasinovic, E., Djordjievski, S., Sopic, M., Guzonjic, A., Ninic, A., Erceg, S., & Ostojic, S.M. (2021). The effects of 6-month hydrogen-rich water intake on molecular and phenotypic biomarkers of aging in older adults aged 70 years and over: A randomized controlled pilot trial. Experimental Gerontology,155, 111574. doi: 10.1016/j.exger.2021.111574.
- Yang, T., Wang, H., Xiong, Y., Chen, C., Duan, K., Jia, J., & Ma, F. (2020). Vitamin D supplementation improves cognitive function through reducing oxidative stress regulated by telomere length in older adults with mild cognitive impairment: A 12-month randomized controlled trial. Journal of Alzheimer’s Disease,78(4), 1509–1518. doi: 10.3233/JAD-200926.
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