Telomere length has long been considered an important biomarker in human aging and disease, but most studies on the relationship between telomere length and health have looked only in a single tissue type: blood.
This limitation has raised the question of whether blood cells are a reliable proxy for other tissues for researchers studying the effects of aging, disease and lifestyle factors on telomere length.
A new study, published in the September 11 issue of Science, answers this question by examining telomere length in over 20 different human tissue types, from nearly 1,000 individual post-mortem donors.
The results show that telomere length in whole blood can serve as a stand-in for telomere length in most other tissues, and further bolsters existing research on the relationship between telomere length, ancestry and aging.
Telomeres are repetitive, non-coding sequences of DNA found at the ends of chromosomes, acting like protective caps to prevent deterioration of the genome.
Each time a cell divides, the chromosomes have to be replicated, giving each new cell a new copy. The enzymes that do this can’t quite reach the end of the chromosome, so a little bit of the tip is lost in every duplication. Telomeres provide a small amount of extra chromosome as a buffer, protecting important genetic information from being lost.
Normal aging is associated with telomere shortening, and telomere shortening has been linked to mortality and age-related diseases.
But the relationship between telomere shortening, aging and disease is not completely clear—partly because scientists don’t fully understand the ways in which telomeres vary between different tissue types.
“Most studies on human telomere length focus on tissue types that are easy to collect from living subjects, like whole blood or saliva,” said first author Kathryn Demanelis, Ph.D., a postdoctoral scholar in the Department of Public Health Sciences at the University of Chicago.
“We wanted to see how well the length of telomeres found in whole blood cells aligned with those found in other tissues.”
In the study, the scientists took advantage of the Genotype-Tissue Expression (GTEx) project, a massive public resource focused on collecting samples from many different tissues from hundreds of human subjects.
“The GTEx study was originally designed to study how inherited genetic variation regulates gene activity in different tissues, and how tissues differ from one another,” said senior author Brandon Pierce, Ph.D., Associate Professor of Public Health Sciences and Human Genetics at UChicago.
“We saw the GTEx tissue bank as an opportunity to access tissue types that we normally can’t study easily, and to look at an important biomarker – telomere length – and start to ask deeper questions about the relationship between telomere length and diseases like lung cancer, and how telomeres shorten with age in different kinds of tissue.”
The researchers used a new type of assay for measuring telomere length, comparable in cost to traditional methods but with “higher throughput and better precision,” according to study co-author Muhammad Kibriya, MD, Ph.D., Research Associate Professor at the Institute for Population and Precision Health at UChicago.
By analyzing more than 6,000 tissue samples across over 20 tissue types and nearly 1,000 unique post-mortem human subjects, Kibriya said, “We were able to find statistically significant tissue-to-tissue differences in telomere length within the sample set.”
This allowed the investigators to compare telomere length in a variety of tissues, such as skin, brain, lung, colon and kidney, to measurements of telomere length in blood cells.
They found that out of the 23 tissues they studied, telomere length in 15 tissues showed a clear, positive correlation with telomere length in whole blood cells, supporting the use of easily collected whole blood cell telomere length as a proxy for telomere length in harder-to-access tissues, like brain and kidney.
“We were also able to look across all of these tissue types to answer questions that have been looked at repeatedly for blood cell telomeres,” said Pierce.
“Some patterns held up across different tissues, like shorter telomeres in aging, and longer telomeres in people of African ancestry, but others didn’t, like longer telomeres in females. We observed shorter telomeres among smokers in only a few tissues.”
This helps to clarify conflicting results from past studies indicating relationships between individual traits and telomere length, or a lack thereof.
These results will help the researchers understand what aspects of telomere length are consistently due to genetic inheritance versus those that may be affected by lifestyle, environmental exposures or epigenetic changes during a person’s lifetime. This in turn will make it easier for scientists to study and understand the roles of specific biomarkers in aging and disease.
“As epidemiologists, we’re often trying to answer questions by studying blood samples, so we have to be aware of how these biomarkers might vary across different tissue types,” Pierce said. “It’s a big limitation.
But we know that the inherited genome sequence is the same in every tissue, so if we can understand how certain genetic variations affect biomarkers, like telomere length, in specific tissue types, that makes it easier to study those biomarkers in human populations. We can use inherited genetic variation to predict tissue-specific biomarkers.”
Future projects will further explore the GTEx samples to look at various biomarkers across different tissue types. “This first study provides a resource to better understand what telomere length looks like in various tissues and will allow other researchers to compare their data against our results,” Demanelis said.
“In the future, we’ll be looking at other markers like DNA methylation and somatic mutations in different types of tissues to try and understand their relationship to telomere length and aging.”
Telomeres, short tandem repeats of TTAGGG located at the ends of chromosomes (Blackburn, 2000; Blackburn & Gall, 1978), are highly dynamic structures that are tightly linked to the life history strategies of species (Gomes, Shay, & Wright, 2010; Haussmann & Marchetto, 2010; Rollings, Uhrig, et al., 2017), and even morphs within species (Rollings, Friesen, et al., 2017).
Telomeres are highly dynamic because they are affected by several factors, to a degree which may be determined by the life history strategy of the organism through the allocation of resources (Haussmann & Marchetto, 2010).
Every round of cellular division typically shortens telomeres, due to incomplete chromosomal replication (Olovnikov, 1973), but telomeres may be extended again through activity of the enzyme telomerase (Giardini, Segatto, Silva, Nunes, & Cano, 2014; Greider, 1990).
Telomeres may also become shorter when damaged by reactive oxygen species (ROS, Houben, Moonen, Schooten, & Hageman, 2008, Olsson, Friesen, et al., 2018, Selman, Blount, Nussey, & Speakman, 2012, von Zglinicki, 2002). Reactive oxygen species are produced in mitochondria when electrons leak from the electron transport chain during oxidative phosphorylation and interact with molecular oxygen (Beckman & Ames, 1998; Turrens, 2003).
As oxidative phosphorylation produces most of an organism’s ATP (Bertram, GRAM PEDERSEN, M., LUCIANI, D. S., & SHERMAN, A., 2006), an increase in metabolism may increase ROS production and cause oxidative stress. However, ROS may be countered by antioxidants (Magwere et al., 2006; Monaghan, Metcalfe, & Torres, 2009), reducing telomeric attrition.
Organisms that prioritise reproduction or growth over cellular maintenance (such as antioxidant production) often age more quickly, have shorter life spans, and experience higher rates of telomere loss (Promislow & Harvey, 1990; Ricklefs & Wikelski, 2002).
Metabolic rates may vary between organs and tissues (and are frequently correlated with organ size, Piersma, Gudmundsson, & Lilliendahl, 1999, Wang et al., 2010), often influenced by life history strategy (Ricklefs & Wikelski, 2002). Thus, ROS concentrations may also vary among tissues, and tissues or organs may experience unique telomere dynamics, depending upon the life history strategy of the organism. We would predict that organs with higher oxidative stress would experience higher rates of telomeric attrition.
Many studies of telomeres, particularly those in evolutionary biology, focus on telomere lengths (TL) in whole blood or white blood cells (Badas et al., 2015; Barrett & Richardson, 2011; Bize, Criscuolo, Metcalfe, Nasir, & Monaghan, 2009; Froy et al., 2017; Lopez‐Arrabe et al., 2018; Olsson, Wapstra, & Friesen, 2018; Rollings, Uhrig, et al., 2017).
This focus on blood is largely due to ease of collection, relatively low invasiveness, and because it allows repeated collection of samples. However, without knowing whether blood TL are representative of the various organs and tissues within an organism, it is difficult to determine whether blood TL provides meaningful inferences about the organism as a whole.
Telomeres, DNA and Chromosomes
The DNA is the genetic code thatcontains the information for the structuring and functioning of our body. It’ s like the hard disk in a computer that contains all the information for the programs that run within a computer. Our DNA is a long thread of the double helix that is packaged in the form of the chromosomes. There are 23 pairs of chromosomes in human cells.
The end parts of the chromosomes (see the orange tips of the chromosomes in the picture above) are called telomeres. Their name derives from Greek telos- that means ‘end’ and -meros that means ‘part’, and they are literally ‘the end part’ of chromosomes. Telomere ends serve to protect the DNA. They are often compared to the plastic protective tips in shoelaces that protect a shoelace from unravelling. At the same way telomeres play an important role in protecting the DNA and keeping it stable.
Human cells start at conception with an average telomere length of 15.000 base pairs (unit of measurement of telomeres length, abbreviation bps). During the embryonic period we lose an important part of our telomeres, due to the high cellular replication rate. We lose almost as much telomere length as we are going to lose during the whole of our lifetime.
At birth the average telomere length is 10.000 bps. At 20 years of age the average telomere length is around 8.000 bps. We keep losing 35-150 base pairs per year until we reach a level of less than 4500 bps where the chromosomes gets unstable and the probabilities for serious health problems and death increase exponentially.
More than the absolute length value it’s the rate of loss that is important to our health. A person that loses 35 bps instead of 150 bps per year, ages at a five times slower pace. It’ s also important at this point to mention that our cells possess inherent mechanisms that repair and can even re-lengthen telomeres.
Multiple factors activate this mechanisms: vitamins, antioxidants, diet, omega 3 fatty acids, exercise and nutraceuticals have been associated with longer telomere length and telomere re-lengthening.
Telomeres relation to Health and Aging Relates Diseases
If the telomeres were not there or they were not long enough, the ends of the different chromosomes would fuse together causing the cells to dysfunction or die. Indeed when telomeres get too short the chromosomes ends of different chromosomes fuse together and this has been identified as the starting event of cancer formation (carcinogenesis).
During our lifetime our telomeres get shorter and shorter and this is the basic reason why we age.
With every cell division a small part of our telomeres is not copied and this causes them to gradually shrink. Shorter telomeres cause our DNA to become unstable and prone to express disease.
The shorter our telomeres the older we become biologically. While the opposite is also true. The longer our telomeres the younger our cells are biologically; and the better our health.
In 2009 the Nobel Prize in medicine was awarded to 3 scientists (E. Blackburn, C. Greider, J. Szosak) for their work in telomere biology and the discovery of the mechanisms of aging in humans. In the past it was thought that the way we age was through accumulation of damage at a cellular and organ level. We believed that damages accumulate and our body gets older like a machine wears off. The truth came to be different though in view of the telomere biology discoveries.
We grow old not because of accumulated damage at a cellular level but mainly because aging is programmed within our DNA. Accumulated biological damage causes our cells to replicate faster and this shortens our telomeres and thus we get older and die. The wear off is not the cause but the accelerating factor in the aging process. This may look similar but it makes a great difference actually in the way we can influence our longevity and health.
Our cells have a limited amount of divisions available through a lifetime. This number is around 50 times and is regulated through the length of our telomeres. We thus get born with a finite number of cellular divisions at our disposal and the way we contact our lives determines how much those cellular divisions are going to last.
If we do things that damage our cells like smoking, not sleeping enough, following bad nutritional habits, suffering vitamins deficiencies, consuming too much alcohol, using drugs, being obese, not exercising, conducting a stressful life, being dehydrated and getting exposed to toxins; we force our cells to divide faster in order to repair damaged tissues and we consequently age faster. In fact all the above factors are correlated to increased incidence of disease and premature death.
The faster our cells divide the faster our telomeres shrink. Depending on the amount of damage at a cellular level, the more damage the more cellular divisions are required.
It can be easily understood then how two individuals can have the same chronological age but be in a completely different biological condition and thus biological age.
Telomere length has been found to be an accurate index of the biological vs. the chronological age of an individual. The longer our telomeres the younger our biological age while shorter telomeres are associated with higher mortality and aging related diseases.
Research suggests that preserving telomeres length has the potential to prevent and treat diseases associated with aging and possibly allow humans to increase their longevity beyond the current theoretical maximum of 125 years.
Telomere Length Measurement
Our cells have 46 chromosomes. Each chromosome has 4 telomeres for a total of 184. Not all telomeres shrink at the same speed though. Some of them shorten faster than others, so some of our telomeres may be long while some of them may be short.
Telomere analysis that measure only the average length gives us no data about the percentage of long and more important, the percentage of the short telomeres present in our chromosomes.
An individual could have a good average telomere length but a high percentage of short telomeres that would not show in an average length measurement. His or her DNA could then get unstable, because of the shorter telomeres, and increase the possibility for chronic disease and death even in the presence of a good average telomere length.
The percentage of short telomeres of an individual, is the most important element in order to evaluate the biological age and the propensity to disease of a person.
It is thus vital to measure not just the average length but also the length of each of the 184 telomeres separately. This can be done with a method called Q-FISH (Quantitative Fluorescent in Situ Hybridization).
Our clinic is the only one worldwide that combines the Q-FISH Telomere Analysis with Metabolomics Analysis and treatment. This permits the assessment of both the DNA and the biochemical pathways condition simultaneously.
In our clinic we measure separately each of the 4 telomeres in all the 46 chromosomes, for a total of 184 telomeres.
Repeated measurements at a distance of 6 months or a year reveal vital information about the rate of change of the short telomeres, response to therapy and the formulation of further treatment.
As the percentage of short telomeres has been associated with almost all chronic diseases their measurement can be an invaluable tool in the hands of a physician applying personalized medicine. Telomere Length Analysis is a major breakthrough for medicine in addressing chronic diseases and improving longevity.
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More information: K. Demanelis el al., “Determinants of telomere length across human tissues,” Science (2020). science.sciencemag.org/cgi/doi … 1126/science.aaz6876