Sci. There were, however, several differences between these two composites. Genes 7:58. doi: 10.3390/genes7090058, Yuan, X., Kronstrm, M., Hellenius, M. L., Cederholm, T., Xu, D., and Sjgren, P. (2018). The size of critically short (uncapped) telomeres may be stabilized by telomerase, a reverse transcriptase enzyme that can elongate chromosome ends de novo. Sci. In humans, this enzyme is known to be expressed during early in-utero development, is inactivated in most adult cells except for the germ line and embryonic stem cells and immune cells, and reactivated in the majority of cancers (Shay and Wright, 2019). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). (2017). 10:128. doi: 10.3389/fendo.2019.00128, Kimura, M., Gazitt, Y., Cao, X., Zhao, X., Lansdorp, P. M., and Aviv, A. It remains far from clear whether correlations exist between TLs in leukocytes and in tissues with low proliferative activity, such as neurons (Mather et al., 2011). Maintaining telomere length plays a crucial role in regulating cellular life span. Br. Int. (2015). Differential shortening rate of telomere length in the development of human fetus. (2016). Telomere length and telomerase activity in osteoporosis and osteoarthritis. NutritionFacts.org Video Podcast: What to Eat to Prevent Telomere Regression lines belonging to these groups are indicated by the same color. Telomeres and telomerase: three decades of progress. (2020). Med. doi: 10.1016/j.it.2009.03.013. doi: 10.18632/aging.100007, Evans, M. A., Sano, S., and Walsh, K. (2020). (2019). (2017). Med. All these studies, however, were performed with a cross-sectional design, which do not allow an inference of causality. For example, in the Swedish Twin Registry study, individuals with the shortest LTL quartile had 44% higher risk of all-cause mortality than those with the longest quartile (Wang et al., 2018). Leukocyte telomere length and epigenetic-based mortality risk score: associations with all-cause mortality among older adults. (2019). Reflections on telomere dynamics and ageing-related diseases in humans. Furthermore, LTL is largely dependent on the blood-sample leukocyte composition. Cell 107, 6777. Proc. Rev. Comparative approaches to understanding the relation between aging and physical function. Correlation between skeletal muscle TL (MTL) and LTL. Exp. Res. This inconsistency was, however, so great that some authors have even questioned whether the link between TL and aging-associated processes really exists and, consequently, it has led to hot debates about whether TL is really a reliable and valid tool to evaluate the rate of aging in human populations (Sanders and Newman, 2013). 125:56001. doi: 10.3791/56001, Johnson, T. E. (2006). However, while TL satisfactorily meets the criteria 3 and 4 of the American Federation for Aging Research due to an opportunity to a minimally invasive, repeated testing without harm to human subjects and a testability in both laboratory animals and humans, its compliance with the criteria 1 and 2 is rather questionable (Sanders and Newman, 2013). Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page. DNA methylation aging clocks: challenges and recommendations. Telomere shortening rate predicts species life span - PNAS doi: 10.1177/1535370217694096, Khalangot, M. D., Krasnienkov, D. S., Chizhova, V. P., Korkushko, O. V., Shatilo, V. B., Kukharsky, V. M., et al. Genet. doi: 10.18632/aging.101216, Tedone, E., Arosio, B., Gussago, C., Casati, M., Ferri, E., Ogliari, G., et al. (2020). (2016). Sci. According to a two-hit developmental model of accelerated aging (Belsky and Shalev, 2016; Shalev and Belsky, 2016), shorter TL in early life may be associated with poor health status later in life. Sci. Summarizing the results of these studies, it can be stated that the validity of LTL as a single measure of aging rate and as a prognostic tool in clinical settings remain questionable. doi: 10.1016/j.mehy.2016.03.002. doi: 10.1158/1055-9965.EPI-16-0968, Zhao, J., Miao, K., Wang, H., Ding, H., and Wang, D. W. (2013). Therefore, LTL is commonly used as conventional biomarker of aging now. (2017). The authors emphasize, however, that the fact that TL only modestly contributed to the composite biomarker of aging can lead to misleading interpretation of the study results, depending on whether they are used for the prediction or explanation of biological aging. Aging 9, 11301142. 10:624. doi: 10.3389/fneur.2019.00624, Tomita, K. (2018). If the latter, telomere shortening can be rather a proxy for life-course stress exposures than a genuine cause of aging (von Zglinicki and Martin-Ruiz, 2005). Sci. Heart 106, 267272. R. Soc. AV and DK contributed equally to the drafting, editing, and final composition of the manuscript. In addition, components of telomerase have been found to be more highly expressed in testis than in any other tissue. Int. Telomere attrition, telomere length and telomerase. (2013). (2013). Biomarkers Prev. Figure 8. Rev. Therefore, further efforts should be made to optimizing these techniques in order to improve their sensitivity, repeatability and throughput. Therefore, TL is suggested to limit the cell division number and acts as a mitotic clock in the cell (Olovnikov, 1996), and telomere shortening may cause decreasing of proliferative potential and be a marker for cellular senescence (Liu et al., 2019a). Telomere shortening can impact tissue homeostasis in a cell-autonomous manner by impairing cell proliferation and giving rise to genome instability, providing the 'seed' for disease development. doi: 10.1093/gerona/gly184, Victorelli, S., and Passos, J. F. (2017). 7:3,E29. doi: 10.1111/j.1474-9726.2005.00171.x, Mather, K. A., Jorm, A. F., Parslow, R. A., and Christensen, H. (2011). 48, 1120. B12 is crucial in maintain DNA integrity through nucleotide biosynthesis and methylation. Sci. doi: 10.1089/ars.2020.8048. A total of 612 complete measurements assessed from 288 individuals were included to estimate the correlations of BAs. doi: 10.1073/pnas.1306639110, Wang, J., Dong, X., Cao, L., Sun, Y., Qiu, Y., Zhang, Y., et al. In predicting the mortality of the study participants, two estimators of methylation age (Horvath and GrimAge) and the frailty index remained predictive in joint models, indicative of the complementarity between them, and all biological age measurements except for LTL have been related to mortality risk independently of chronological age (Figure 6). However, findings from available epidemiological studies on the links between TL and age-related diseases and mortality are rather inconsistent and contradictory. Rev. 20:3032. doi: 10.3390/ijms20123032, Barnes, R. P., Fouquerel, E., and Opresko, P. L. (2019). 371, 24772487. Using blood, venous cord blood and semen samples from healthy volunteers, and blood samples from patients with well-established RA, the Weyand group tested whether HLA-shared epitope (SE) alleles were associated with T cell telomere erosion [51].In healthy individuals, HLA-SE alleles were associated with excessive loss of telomeres in CD4+ T cells. J. Alzheimers Dis. Zhang, C., Chen, X., Li, L., Zhou, Y., Wang, C., and Hou, S. (2015). (B) Median telomere length in granulocytes (gray dots). doi: 10.1016/j.bbrc.2013.11.022, Dagnall, C. L., Hicks, B., Teshome, K., Hutchinson, A. 63, S343S350. Trends Immunol. Assessment of epigenetic clocks as biomarkers of aging in basic and population research. 245, 11151121. Telomere length in Parkinson's disease:a meta-analysis. 47, 356. doi: 10.1093/ije/dyx233, Martin-Ruiz, C. M., Gussekloo, J., van Heemst, D., von Zglinicki, T., and Westendorp, R. G. (2005). Epub 2013 Dec 28. 71, 10691073. doi: 10.1371/journal.pone.0045166, Dhabhar, F. S., Malarkey, W. B., Neri, E., and McEwen, B. S. (2012). Average cell TL and other TL-related parameters may be determined by the fluorescent in situ hybridization (FISH) technique by using flow cytometry (flow FISH) or digital microscopy (quantitative FISH, Q-FISH) (de Pedro et al., 2020). Moreover, it is recognized as an attractive biomarker candidate to track changes in the human aging rate over the course of intervention trials designed to delay the onset or retard the progression of aging-associated pathological conditions. B., Dalgrd, C., Mller, S., Steenstrup, T., Kimura, M., and Christensen, K. (2015). Prognostic role of telomere length in malignancies: a meta-analysis and meta-regression. In the study by Dlouha et al. This is an important point because relative frequency of shortest telomeres which may trigger a cell cycle arrest is a parameter critical for cell viability and chromosome stability, and it is highly associated with mortality (Hemann et al., 2001). 103, e29e46. 56, 237250. Antioxidant supplementation slows telomere shortening in free-living Telomere shortening rate predicts species life span - PMC A Biol. Would you like email updates of new search results? Therefore, the measurement of LTL is not yet widely-used in routine clinical diagnostics. However, despite these issues and limitations, TL remains to be very informative marker in accessing the biological age when used along with other markers such as indices of homeostatic dysregulation, frailty index, epigenetic clock, etc. Mol. Possibility of developmental programming of initial TL and rate of age-related telomere erosion could be particularly important in the context of aging and aging-associated pathology. The composition of this cellular population is known to be highly variable, even in healthy persons, depending on various stress exposures (Semeraro et al., 2020). Trans. Telomere Shortening: Causes and Effects - UK Essays Long-term longitudinal studies measuring intra-individual changes in both LTL and cognitive outcomes are scarce, precluding strong conclusions about a potential aging-related relationship between LTL shortening and cognitive decline. Telomere Length as a Marker of Biological Age: State-of-the-Art, Open A Biol. doi: 10.1007/7651_2018_120, Shalev, I., and Belsky, J. The paradoxical elongation of TL in centenarians may likely be explained by a survivor effect (Mather et al., 2011). Impact of nutrition on telomere health: systematic review of observational cohort studies and randomized clinical trials. Telomere dynamics in mice and humans. Trans. 730, 5967. J. Gerontol. Immunosenescence and rheumatoid arthritis: Does telomere shortening To answer this question, several studies have been recently conducted. Telomeres and Longevity: A Cause or an Effect? - PMC However, in a meta-analysis by Zhang et al. Diposit Digital de la Universitat de Barcelona, Canela A., Vera E., Klatt P., Blasco M. A., High-throughput telomere length quantification by FISH and its application to human population studies. Biol. Given this, and also because of a very high inter-individual variability of TL in same-age individuals, longitudinal research of intra-individual rates of age-related decline in TL is likely a more useful design than the cross-sectional one in studying the relationship between TL and mortality. Rev. Chebotarev Institute of Gerontology, Kyiv, Ukraine. Physical activity, a modulator of aging through effects on telomere biology. Dis. Effect of pre-analytic variables on the reproducibility of qPCR relative telomere length measurement. JAMA Oncol. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Telomere length and associated factors in older adults with hypertension. In a systematic review comprising 119,439 individuals in total, a weak to moderate association between obesity and TL was observed in 39 of 63 included studies; a significant heterogeneity, however, was observed between studies (Mundstock et al., 2015). Please enable it to take advantage of the complete set of features! Weng, N. P., Levine, B. L., June, C. H., and Hodes, R. J. Longitudinal trajectories, correlations and mortality associations of nine biological ages across 20-years follow-up. Moreover, unexpectedly, poor agreement was observed among all applied measures of biological aging. (2020). Chromosomes have repeated base segments called telomeres that shorten with each replication cycle (cell division). Med. doi: 10.1371/journal.pgen.1002696, Aubert, G., Hills, M., and Lansdorp, P. M. (2012b). (2020). an analysis that corrects for 'regression to the mean'. To answer this question, Der et al. Interestingly, the correlations among LTL and other biological age measurements were lower than among all other measurements (Figure 5B). Gerontol. J. Cardiovasc. J. 3, 636651. Chem. Cancer incidence increases exponentially with age when human telomeres are shorter. In addition, the prevalence of CHIP was shown to be higher in the general population in subjects with relatively short LTLs, including males, who are known to have shorter LTLs than females, and elderly, who have shorter LTLs than younger individuals. Cell Neurosci. In a combined cohort analysis, TL and DNAm age explained 2.8 and 28.5% of the variance in age, respectively, and jointly they explained 29.5%. Bethesda, MD 20894, Web Policies Telomere length maintenance in aging and carcinogenesis. Hyperglycemia attenuates the association between telomere length and age in Ukrainian population. This method allows determine the number of copies of telomeric repeats (T) compared to a single copy gene (S) and its results are expressed as a T/S ratio. Copyright 2015, Elsevier. Perinat. Copyright 2020 Hiam et al. Oncotarget 7, 85248531. An official website of the United States government. JAMA Netw. Regression to the mean: what it is and how to deal with it. J. Surg. Another important limitation of the TRF technique is that restriction enzymes used in this method lead to the inclusion of sub-telomeric DNA that is contiguous to the telomere, thereby resulting in an overestimation of the true TL (Montpetit et al., 2014). Telomere length: a review of methods for measurement. 239, 197201. N. Engl. Measuring biological aging in humans: a quest. Sci. Figure 9. Cell Stem Cell 8, 34. (2018) study, eleven different methods were used to quantify biological aging in the same individuals. Aging 12, 1380313823. Nat. Evidence was obtained that centenarians can maintain TL and telomerase activity better than non-centenarians, and that healthy centenarians have significantly longer telomeres than unhealthy centenarians (Terry et al., 2008; Tedone et al., 2014, 2019). Figure 7. 177, 3745. Rouan A, Pousse M, Djerbi N, Porro B, Bourdin G, Carradec Q, Hume BC, Poulain J, L-Hoang J, Armstrong E, Agostini S, Salazar G, Ruscheweyh HJ, Aury JM, Paz-Garca DA, McMinds R, Giraud-Panis MJ, Deshuraud R, Ottaviani A, Morini LD, Leone C, Wurzer L, Tran J, Zoccola D, Pey A, Moulin C, Boissin E, Iwankow G, Romac S, de Vargas C, Banaigs B, Boss E, Bowler C, Douville E, Flores M, Reynaud S, Thomas OP, Troubl R, Thurber RV, Planes S, Allemand D, Pesant S, Galand PE, Wincker P, Sunagawa S, Rttinger E, Furla P, Voolstra CR, Forcioli D, Lombard F, Gilson E. Nat Commun. Both these composite biomarkers of aging have been found to be better predictors of overall health outcomes than chronological age. The emerging roles of TERRA in telomere maintenance and genome stability. Thus, since age-related TL attrition in adult T cells reflects the history of their antigen-mediated induction, this process may mirror, at least partly, the aging of the immune system of an individual. Recently, a new method called Telomere Shortest Length Assay (TeSLA) was developed for measuring the distribution of the shortest telomeres in heterogeneous telomere backgrounds (Lai et al., 2017). J. Mol. This structure ensures that loose DNA ends are housed internally within the nucleoprotein structure (Turner et al., 2019). Ageing Res. and transmitted securely. equation from this curve can be used to predict the life span of a species when given the telomere shortening rate without us-ing any information about the initial telomere length with an R2 value of 0.782 (Fig. Zhan, Y., and Hgg, S. (2020). Accelerated telomere shortening and low telomerase activity were shown to be associated with skeletal pathologies mediated by the age-related abnormal reconstruction of the subchondral bone, such as osteoporosis and osteoarthritis (Fragkiadaki et al., 2020). doi: 10.1093/molehr/7.10.947, Xu, X., Hu, H., Lin, Y., Huang, F., Ji, H., Li, Y., et al. Telomere length and mortality in the ludwigshafen risk and cardiovascular health study. -. Biomarkers of Aging: An introduction to Aging Science Brought to You by the American Federation for Aging Research. Many authors, however, acknowledge that biomarkers of aging can change over the life course. These chromosomal structures are known to be crucially involved in the process of cellular senescence (Victorelli and Passos, 2017) and their age-associated shortening is commonly regarded as an important contributor to organismal aging (McHugh and Gil, 2018). (2016). Disclaimer. Telomeres of vertebrates represent repetitive (TTAGGG)n sequences located at the ends of linear chromosomes. It is an important point because a question still remains whether TL can be used as a single biomarker of aging or as a part of composite biomarker panel only. Evidence that TL and epigenetic clock estimates are independent predictors of chronological age and mortality risk was obtained in the study by Marioni et al. 47, 105122. Telomere length in white blood cells is not associated with morbidity or mortality in the oldest old: a population-based study. Robust measurement of telomere length in single cells. Med. Recently, a novel DNAm-based TL estimator was introduced by Lu et al. Telomere length and telomerase activity in T cells are biomarkers of high-performing centenarians. All these measures correlated with participants' chronological ages. Copyright 2016 BJS Society Ltd Published by John Wiley & Sons Ltd. TL and the rate of age-related telomere shortening depend on both genetic and environmental factors. Telomere shortening is usually a by-product of either oxidative stress or inflammation. (2010) study, the highest level of the telomerase activity and longest TLs were observed in B cells while CD4+ T cells had slightly higher telomerase activity and similar TLs than CD8+CD28+ T cells. 6:82. doi: 10.3389/fgene.2015.00082, Krasnienkov, D. S., Khalangot, M. D., Kravchenko, V. I., Kovtun, V. A., Guryanov, V. G., Chizhova, V. P., et al. Epub 2020 Jan 24. doi: 10.1016/j.psyneuen.2012.05.008, Dixit, S., Whooley, M. A., Vittinghoff, E., Roberts, J. D., Heckbert, S. R., Fitzpatrick, A. L., et al. 373, 20170151. doi: 10.1098/rstb.2017.0151, Epel, E. S. (2020). Telomere shortening is a well-known hallmark of both cellular senescence and organismal aging. Another analytical issue in human studies is that TL is most commonly determined in peripheral blood leukocyte samples. Med. In May 2023, Frontiers adopted a new reporting platform to be Counter 5 compliant, in line with industry standards. These tests, however, are too sensitive to transient changes in health status caused by non-chronic diseases such as colds and indigestion, so they can hardly provide a reliable estimate of the aging rate per se. [Epub ahead of print]. The figure and its legend are reproduced from the article by Hiam et al. HHS Vulnerability Disclosure, Help 58, 162177. Thus, the composite measures definitely have larger predictive value in assessing the aging rate than single measures, including the TL-based ones. Psychosocial stress and telomere regulation, in Genes, Brain, and Emotions: Interdisciplinary and Translational Perspectives, eds. The figure and its legend are reproduced from the article by Kalmbach et al. 19, 16261632. The quantitative polymerase chain reaction (PCR) assay is most widely used now. This G-strand overhang loops back to form a t-loop and invades the 5 double stranded telomeric duplex, thereby forming so-called D-loop. Celtikci, B., Erkmen, G. K., and Dikmen, Z. G. (2020). Eleven telomere, epigenetic clock, and biomarker-composite quantifications of biological aging: do they measure the same thing? Reply to Udroiu: Interesting mathematical analysis of telomere shortening rate and life span. TL differs across tissues and correlates among tissue types. Sci. Cells 8:73. doi: 10.3390/cells8010073, Turner, S., Wong, H. P., Rai, J., and Hartshorne, G. M. (2010). Sci. Series A 66, 202213. After birth, telomeres are steadily shortened with age. Telomere attrition due to infection. doi: 10.1016/j.exger.2014.06.018, Tedone, E., Huang, E., O'Hara, R., Batten, K., Ludlow, A. T., Lai, T. P., et al. A., and Kuh, D. (2016). Telomere length measurement by qPCR - Summary of critical factors and recommendations for assay design. Front Cell Neurosci. Hot and dry conditions predict shorter nestling telomeres in an - PNAS Front Genet. Mol. Copyright 2019 the Author(s). In this context, it should be noted, however, that TL is not the only unique indicator of mitotic aging. (2019), composite measures of biological aging along with TL were quantified. Telomeric aging: mitotic clock or stress indicator? Cawthon et al. From this, it is commonly thought that the risk of diseases mediated by increased proliferative activity including most cancers have to be correlated with long telomeres (Celtikci et al., 2020). The continuum of aging and age-related diseases: common mechanisms but different rates. Within the genome, long telomeres are more informative than short telomeres with respect to fitness components in a long-lived seabird. Results of many studies support this hypothesis. Med. Lab. Moreover, a single biomarker could not sufficiently reflect the aging process across various biological systems. Leukocyte telomere length is inversely associated with post-load but not with fasting plasma glucose levels. However, whether telomere length is a universal determinant of species longevity is not known. Int. The challenges of estimating biological age. The rate of leukocyte telomere shortening predicts mortality from In both cohorts studied, combined whole-blood TL and DNAm age explained more variance in age than each of them individually. Cell. Aging Cell 12, 615621. Indeed, if individuals with shorter TLs are more susceptible to age-associated pathologies and, consequently, are at higher risk of mortality, then these individuals will tend to die earlier. Clonal hematopoiesis was found in only 1% of persons younger than 50 years of age but it was evident in about 10% of persons older than 65 years of age), and about 20% of octogenarians were shown to be CHIP carriers (Genovese et al., 2014; Aviv and Levy, 2019). 5, 197203. There are, however, differences in TLs amongst somatic tissues primarily related to the replicative history of stem/progenitor cells in these tissues. In this process, particular mutant cells receive a competitive advantage allowing their clonal expansion, a process referred to as clonal hematopoiesis (Evans et al., 2020). Blood 130, 742752. Aging Cell 19:e13080. doi: 10.1093/nutrit/nuaa097. (2011). Accessibility Similarly, telomerase reverse transcriptase (tert) mutant zebrafish have premature short telomeres and anticipate cancer incidence to younger ages.However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppressor mechanism and should . All measurements of biological age were more or less correlated with one another. 2045, 217224. It should also be noted that accuracy and reproducibility of TL measurements depend, along with assay procedures, on many other factors including the sample collection, processing and storage, DNA extraction, etc. doi: 10.1093/advances/nmz107, Gao, X., Zhang, Y., Mons, U., and Brenner, H. (2018). This website is using a security service to protect itself from online attacks. Finally, age-associated rise in the prevalence of CHIP also provides supporting evidence. ( A ) The estimated, MeSH doi: 10.18632/aging.101611. Exp. Exp. This cell source was chosen for TL analysis because it allowed avoid invasive procedures. In the subsequent study, a weak but significant inverse relationship between DNAm age acceleration and relative LTL was shown (Vetter et al., 2019). doi: 10.1016/j.arr.2018.09.002, Watson, J. D. (1972). Association between telomere length, specific causes of death, and years of healthy life in health, aging, and body composition, a population-based cohort study. Psychoneuroendocrinology 104, 210218. Aging 11, 58955923. Proc. Curr. doi: 10.1007/s10654-013-9845-4, Vetter, V. M., Meyer, A., Karbasiyan, M., Steinhagen-Thiessen, E., Hopfenmller, W., and Demuth, I. In a multicellular organism, TLs are highly heterogeneous across different tissues and cell types depending, at least partly, on the tissue-specific proliferation rate, but they generally tend to decrease with age in all proliferating tissues (Demanelis et al., 2020). In analyzing the potential role of this statistical artifact in age-dependent TL dynamics, Verhulst and co-authors revealed modest effect which, however, remained statistically significant even when correcting for the regression to the mean effect, indicating that high baseline TL is really associated with higher rate of age-related TL attrition (Verhulst et al., 2013). In conclusion, the inconsistency in the effects of TL on cancer outcomes can be likely explained by the variable measurement methods. These measures included indices of physical functioning (pulse pressure, lung function and grip strength), cognitive functioning (a general mental ability test and a four-choice reaction time scores) as well as overall measures of health status (registered disability, self-rated health and the total number of chronic conditions). Telomere lengths in human oocytes, cleavage stage embryos and blastocysts. U.S.A. 101, 1731217315. Telomere attrition in neurodegenerative disorders. doi: 10.3233/JAD-190759, Fasching, C. L. (2018). J. Epidemiol. Sci. acting during prenatal and early postnatal development can program the telomere biology in a way that promote cellular senescence and, as a result, lead to accelerated rate of organismal aging. Pauliny A, Wagner RH, Augustin J, Szp T, Blomqvist D. Mol Ecol. doi: 10.1016/j.envres.2017.06.038, Aubert, G., Baerlocher, G. M., Vulto, I., Poon, S. S., and Lansdorp, P. M. (2012a). | Find, read and cite all the research you . Cloudflare Ray ID: 7eecc8ccc968e863 Hematol. Climate warming is increasingly exposing wildlife to sublethal high temperatures, which may lead to chronic impacts and reduced fitness.

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