Telomeres and Telomerase

This summary is currently in draft form as it has not been reviewed by all reviewers.

Immune cell telomere length has become a common biomarker in health studies because it reliably predicts later onset of several diseases such as cardiovascular disease, it’s mechanisms of disease are understood, and it is easy to measure with blood. It is also associated with a wide range of exposome factors–chemicals, pollution, neighborhood safety, stressor exposures, and lifestyle. Telomerase is the intra-cellular enzyme that protects and lengthens telomeres. The GWAS determined genetic index for telomere length is another way to study the contribution of telomere length directly, although this accounts for only around 1% of actual telomere length (Codd et al, 2013).

Telomeres are made of non-coding sequences of DNA base pairs (TTAGGG), and wrap the tips of chromosomes. They protect the genes from damage, and they also shorten when there is cell division (since they cannot be fully replicated) or when there are biochemical stressors (oxidative stress) in the cell that can damage them or impair the telomerase enzyme, making them shorten prematurely with each division.

Telomere length is a marker of healthspan—in that shorter telomere length (TL) predicts earlier onset of many diseases of aging (such as cardiovascular disease, diabetes, and dementia), as shown by meta-analyses (D’Mello et al, 2015; Willeit et al, 2014; Forero et al, 2016), as well as worse functional immune outcomes in some studies (Cohen et al, 2013). However, telomere effects are complex when it comes to cancer. Short genotypically-estimated telomeres can be protective of certain types of cancer such as melanoma and glioma.

Short telomere length indicates that the cell is closer to ‘replicative senescence” or the end state of a cell when it can no longer divide.Senescent cells become proinflammatory, and lose their ability to divide and proliferate.

Mechanism linking telomeres to psychological stress:

Telomere length appears to shorten after exposure to multiple childhood traumas or deprivation, in a dose response fashion, and these effects are observed prospectively in childhood as well as cross sectionally (using retrospective measures) in adults (Epel & Prather, 2018). It is shorter in most psychiatric disorders (Darrow et al, 2016) and in elderly caregivers (Damjanovic et al, 2007).

The mechanisms are likely different for exposure to in utero stress, childhood stress, and adulthood stress, although these are difficult to study in humans. The mechanisms likely involve over exposure to the biochemical changes induced by stress, such as over-exposure to cortisol, insulin resistance, pro-inflammatory cytokines, and possibly changes to stem cells, the source of all hematopoietic cells, that replace them through life (Epel & Prather, 2018).

Timescale:

Telomere length measurement is helpful when we want a stable and static measure of the status of one’s immune system. Telomeres reflect one’s genetic inheritance (at least 50%, Broer et al, 2013), and are influenced by long term exposures rather than acute exposures. We know that telomere length at midlife can predict earlier onset of disease. Telomere length can predict how vulnerable people are to the common cold in young healthy people (Cohen et al, 2012), and a robust response to vaccination (Najarro et al, 2015).

Telomere length shortens rapidly during early childhood, during pruning of the immune system, and then more slowly throughout adulthood (Frenck et al, 1998). It is thought that telomere length at birth (initial setting) may be the most important predictor of health risks, although no studies have examined whether telomere length at birth or early childhood also tracks throughout life and predicts early disease. If so, prenatal stress exposures (Send et al, 2017) and possible epigenetic transmission of telomere length (Collopy et al, 2015) may be particularly critical for understanding late-life health.


Telomerase activity can change acutely, within minutes. Acute psychological stress appears to boost PBMC telomerase by around 90 minutes, particularly in healthy people (Epel et al, 2010), whereas in vivo studies on lymphocytes have shown that cortisol exposure can dampen telomerase over days (Choi et al, 2008).

Collection and measurement:

Telomere length can be measured in any type of somatic cells but is most commonly measured in immune cells, using whole blood (leukocyte telomere length or LTL), and in more experimental studies, with peripheral blood mononuclear cells (PBMCs). Telomerase activity can be measured by labs very experienced in the specific method.

There are several methods for assaying telomere length that vary greatly in ease, cost, and information provided. The qPCR method is the least expensive but has a relatively high inter-assay coefficient of variation (ranging from 2% to 15% depending on the lab). The Southern blot requires more DNA, is more expensive, but has higher precision with lower assay coefficient of variation (1 to 2% CV). The Q-FISH flow method is typically used for clinical studies of telomere disorders, requires fresh blood, and can yield telomere length data in various cell types. These methods have been compared in various studies. Researchers should carefully consider the pros and cons of each of the methods, for each of their specific studies (Aubert and Lansdorp 2012, Mutat Res. 2012 Feb 1;730(1-2):59-67. doi: 10.1016/j.mrfmmm.2011.04.003. Epub 2011 Jun 12. ). Further work developing a low-cost high accuracy assay is a critical goal for the field.

Collection of blood for telomere length may depend on the type of assay done and the lab. An example of the collection of blood for telomere length using the qPCR method, as done in the Blackburn lab, can be sent by Dr. Jue Lin.

Saliva is often used, but this includes both immune cell and epithelial cells and is not as strongly correlated with venous blood draw telomere length. In a small study of 24 adults, saliva and venous blood telomeres were correlated r = .56, whereas blood spots and venous blood were more highly correlated, r = .84 (Stout et al, 2018).

Strengths:

Telomere length is appropriate when one wants an overall measure of the robustness of the immune system. It is relatively stable over time, and with one measure, it is often a weak but reliable predictor of health outcomes. It will likely serve best as one indicator among many, such as when used in an algorithm (Belsky et al, 2015).

Limitations:

Telomere length is not thought to be a sensitive measure to short term interventions. One study did find changes in telomere length after 3 weeks of an intensive residential retreat intervention, compared to a control group. However, it is not possible, when using leukocytes or PBMCs (mixed cell types) to know how much of the change was due to a redistribution of cell types (pseudo-lengthening, Epel, 2012), rather than a per cell lengthening. The use of single-cell types, either through sorting cells, or collecting buccal cells, eliminates the confound of cell redistribution.

It seems that given the error from noise, and the variance in long term adherence to interventions, telomere length is likely a crude outcome for documenting long term intervention effects on health. However, when the intervention is strong and maintained, it will be more likely to be impacted. For example, immediate weight loss was not related to telomere length change at six months, but weight loss maintenance of at one year was. These effects were significant but weak for 5% weight loss, and larger for the group who maintained a 10% weight loss, which was an infrequent outcome (Mason et al, 2018).

Telomere length is a weak predictor of outcomes. In humans, it will be difficult to get a granular understanding of telomere biology in vivo, during aging, without sampling from birth to older age, multiple tissue types rather than relying on blood, including post-mitotic tissue. It is important to refine assay methods and develop better assays.

Author and Reviewer(s):

This was written by Elissa Epel and reviewed by members of the Stress Network leadership team, and Dr. Jue Lin, and is pending review by other experts. To make suggestions or comments email elissa.epel@ucsf.edu. Version date: March 1, 2018.

References:

Belsky, D. W., Caspi, A., Houts, R., Cohen, H. J., Corcoran, D. L., Danese, A., … Moffitt, T. E. (2015). Quantification of biological aging in young adults. Proceedings of the National Academy of Sciences of the United States of America, 112(30), E4104-4110. https://doi.org/10.1073/pnas.1506264112

Broer, L., Codd, V., Nyholt, D. R., Deelen, J., Mangino, M., Willemsen, G., … Boomsma, D. I. (2013). Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect. European Journal of Human Genetics: EJHG, 21(10), 1163–1168. https://doi.org/10.1038/ejhg.2012.303

Choi, J., Fauce, S. R., & Effros, R. B. (2008). Reduced telomerase activity in human T lymphocytes exposed to cortisol. Brain, Behavior, and Immunity, 22(4), 600–605. https://doi.org/10.1016/j.bbi.2007.12.004

Collopy, L. C., Walne, A. J., Cardoso, S., de la Fuente, J., Mohamed, M., Toriello, H., … Dokal, I. (2015). Triallelic and epigenetic-like inheritance in human disorders of telomerase. Blood, 126(2), 176–184. https://doi.org/10.1182/blood-2015-03-633388

Codd, V., Nelson, C. P., Albrecht, E., Mangino, M., Deelen, J., Buxton, J. L., … Samani, N. J. (2013). Identification of seven loci affecting mean telomere length and their association with disease. Nature Genetics, 45(4), 422–427, 427-2. https://doi.org/10.1038/ng.2528

Cohen, S., Janicki-Deverts, D., Turner, R. B., Casselbrant, M. L., Li-Korotky, H.-S., Epel, E. S., & Doyle, W. J. (2013). Association between telomere length and experimentally induced upper respiratory viral infection in healthy adults. JAMA, 309(7), 699–705. https://doi.org/10.1001/jama.2013.613

Darrow, S. M., Verhoeven, J. E., Révész, D., Lindqvist, D., Penninx, B. W. J. H., Delucchi, K. L., … Mathews, C. A. (2016). The Association Between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14,827 Persons. Psychosomatic Medicine, 78(7), 776–787. https://doi.org/10.1097/PSY.0000000000000356

Damjanovic, A. K., Yang, Y., Glaser, R., Kiecolt-Glaser, J. K., Nguyen, H., Laskowski, B., … Weng, N. (2007). Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer’s disease patients. Journal of Immunology (Baltimore, Md.: 1950), 179(6), 4249–4254.

D’Mello, M. J. J., Ross, S. A., Briel, M., Anand, S. S., Gerstein, H., & Paré, G. (2015). Association between shortened leukocyte telomere length and cardiometabolic outcomes: systematic review and meta-analysis. Circulation. Cardiovascular Genetics, 8(1), 82–90. https://doi.org/10.1161/CIRCGENETICS.113.000485

Epel, E. (2012). How “reversible” is telomeric aging? Cancer Prevention Research (Philadelphia, Pa.), 5(10), 1163–1168. https://doi.org/10.1158/1940-6207.CAPR-12-0370

Epel, E., & Prather, A. (2018). Chronic stress, telomeres, and psychopathology: Towards a deeper understanding of a triad of early aging. Annual Review of Clinical Psychology, 14.

Forero, D. A., González-Giraldo, Y., López-Quintero, C., Castro-Vega, L. J., Barreto, G. E., & Perry, G. (2016). Meta-analysis of Telomere Length in Alzheimer’s Disease. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 71(8), 1069–1073. https://doi.org/10.1093/gerona/glw053

Frenck, R. W., Blackburn, E. H., & Shannon, K. M. (1998). The rate of telomere sequence loss in human leukocytes varies with age. Proceedings of the National Academy of Sciences of the United States of America, 95(10), 5607–5610.

Najarro, K., Nguyen, H., Chen, G., Xu, M., Alcorta, S., Yao, X., … Weng, N. (2015). Telomere Length as an Indicator of the Robustness of B- and T-Cell Response to Influenza in Older Adults. The Journal of Infectious Diseases, 212(8), 1261–1269. https://doi.org/10.1093/infdis/jiv202

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. https://doi.org/10.1093/jnci/djv074

Send, T. S., Gilles, M., Codd, V., Wolf, I., Bardtke, S., Streit, F., … Witt, S. H. (2017). Telomere Length in Newborns is Related to Maternal Stress During Pregnancy. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology. https://doi.org/10.1038/npp.2017.73

Stout, S. A., Lin, J., Hernandez, N., Davis, E. P., Blackburn, E., Carroll, J. E., & Glynn, L. M. (2017). Validation of Minimally-Invasive Sample Collection Methods for Measurement of Telomere Length. Frontiers in Aging Neuroscience, 9, 397. https://doi.org/10.3389/fnagi.2017.00397

Willeit, P., Raschenberger, J., Heydon, E. E., Tsimikas, S., Haun, M., Mayr, A., … Kiechl, S. (2014). Leucocyte telomere length and risk of type 2 diabetes mellitus: new prospective cohort study and literature-based meta-analysis. PloS One, 9(11), e112483. https://doi.org/10.1371/journal.pone.0112483