Is the telomere theory of aging valid?
We will explore, but first some necessary background.
Our body is made up of roughly 30 trillion cells which create a diverse range of tissues and organs. Within almost every cell is a structure known as the nucleus which contains 23 pairs of chromosomes.
Each of these chromosomes is made up of millions of “bases” which all together describe our individual genome. The four DNA bases A, T, C and G combine in specific long chains known as genes, which can be read by the cell to produce proteins required for its survival and function.
As you can imagine, the specific DNA code which makes up a gene is very important. When errors are introduced, e.g. a DNA base is changed or missed, then the protein coded for by that gene may not be produced at all, may not be as functional or may act in a completely different way altogether. When a specific disease arises from one of these changes they are termed “mutations.”
For example, mutations in the TP53 gene are strongly associated with the development of cancers.
Therefore, protecting our DNA sequence from damage or degradation is of great importance in our cells if we want to stay healthy. Whilst each cell in our body contains numerous mechanisms to prevent DNA damage; today I’m going to talk about the role of a structural feature of our chromosomes, called telomeres, and importantly how they are associated with aging and longevity.
What are telomeres?
Telomeres are structural ‘caps’ at each end of a chromosome. You can think of them as “helmets” that protect our essential DNA.
Each telomere is comprised of a short repetitive sequence of DNA bases (…TTAGGG…) which is repeated thousands of times. This repetitive sequence doesn’t encode for any genes but has important structural functions including preventing the ends of the chromosomes from fusing with one another, helping to organise the chromosomes in the nucleus of the cell and, importantly, protecting against loss of important DNA sequences required for normal cellular processes (1).
Every time a cell divides, on average, a few hundred bases are lost from the ends of the chromosome as they replicate.
Telomeres form a buffer so we don’t lose “essential DNA.” Because there are thousands of bases of the repetitive telomere sequence, this sequence is lost instead of important DNA sequence encoding genes. Without telomeres, every time a cell divided, whole genes could be lost, losing critical pieces of the genetic code. When the telomere becomes short enough that a chromosome reaches a ‘critical length’ (where further replication of the cell could result in loss of gene sequence), cell division stops and the cell becomes ‘senescent’ (no longer divides) or undergoes cell death. So it could be said that telomeres provide ‘genomic stability’ (1), but also that their length can be indicative of the relative age of a cell.
As telomere length is so key in cell survival, a specific enzyme known as ‘telomerase’ exists which functions to maintain telomere length after cell division. Telomerase adds the lost TTAGGG repeat sequence back onto the ends of chromosomes maintaining their length, which is nicely shown in the image below.
Image from Wall Street Journal, U.S. Cell-Aging Researchers Awarded Nobel
However, telomerase is not found in every cell within the body. Rather, it is expressed specifically in germ and stem cells. Germ cells are those that divide to produce gametes (sperm and egg cells) and stem cells are those cells embedded within tissues which divide to replenish and maintain the cell population within the body.
The cells which are produced from stem cell division are termed somatic cells, and they make up the vast majority of cells found within the body. Importantly, telomerase is not expressed in these cells, meaning that telomere shortening will occur eventually leading to the cells becoming senescent or undergoing cell death.
Right now I bet you’re asking, if telomerase is so useful why is it not expressed in every cell? Well, senescence and cell death are key steps in maintaining healthy tissue. Somatic cells are typically highly active and often susceptible to damage and so their ‘death’ and replacement is key in maintaining normal tissue function.
Additionally, regulating telomerase expression is a good way of preventing uncontrolled cell division. A major hallmark of many cancers is expression of telomerase, whereby cells which shouldn’t, are able to divide, uncontrollably, forming tumors (1). Indeed, several novel anti-cancer therapies are focusing on targeting telomerase activity in order to ‘turn off’ the cancerous cells.
As you can see active telomerase leading to ‘immortal’ cells is not always desirable. But is it possible to draw any conclusions from telomere length and telomerase activity in regards to an individuals health and potential lifespan?
Telomere length and general aging
As shortening telomeres beyond a certain ‘critical length’ leads to cell death, the next logical step for researchers was to investigate whether telomeres shorten with increased age of the whole human body.
Most studies measure telomere length in the blood cells, known as leukocytes, or white blood cells, as this is the easiest tissue to get access to via a simple blood sample. The ‘leukocyte telomere length’ (LTL) has also been shown to correlate well with the telomere length in other tissues in the body, meaning the LTL is seen as a good overall indicator of telomere length in an individual as a whole.
There are numerous studies on both sides of the fence debating whether telomere length is significantly associated with mortality and age-related diseases. The final final conclusions from a few papers are shown below, with my emphasis added in bold:
Leukocyte telomere length had a statistically discernible, but weak, association with mortality, but it did not predict survival as well as age or many other self-reported variables. Although telomere length may eventually help scientists understand aging, more powerful and more easily obtained tools are available for predicting survival. (2)
Although telomere length is implicated in cellular aging, the evidence suggesting telomere length is a biomarker of aging in humans is equivocal. More studies examining the relationships between telomere length and mortality and with measures that decline with “normal” aging in community samples are required. These studies would benefit from longitudinal measures of both telomere length and aging-related parameters. (3)
The evidence supporting the hypothesis that telomere length is a biomarker of aging is equivocal, and more data are required from studies that assess telomere length, aging-related functional measures, and collect mortality data. An area for future work is the clarification of which telomere length measure is the most informative and useful marker (e.g., mean, shortest telomere, longitudinal change). Nevertheless, in the near future, longitudinal designs will provide important information about within-individual telomere length dynamics over the life span. Such studies will also elucidate whether the relationships between telomere length and aging-related measures vary across the life span. (4)
SNPs, telomere length and TERT genes
There are many diseases, ranging in severity, associated with telomere dysfunction, termed ‘telomere syndromes’. In these syndromes genes that are involved in maintaining telomere length are mutated in such a way as to cause the resulting protein to function incorrectly or not at all (reviewed here (6) and also shown in the figure below).
Image from: The Short and Long Telomere Syndromes: Paired Paradigms for Molecular Medicine. Stanley et al., 2015. Curr Opin Genet Dev.
The lines mark out typical telomere length by age, with the lines divide the population into percentiles based on average telomere length. As you can see most short telomere syndromes are associated with those in the bottom percentile of telomere length.
However, we’re interested in seeing if there are any more ‘common’ SNPs, such as the raw SNP data you’re likely to find in direct to consumer offerings, which may have an impact on telomerase activity or telomere length, and if these can have any impact on aging and health.
As it stands, results are unclear, with a major reason for this lack of clarity being the high variability in telomere length between individuals. This large variability means that only very large studies are going to identify any important trends.
One large genome-wide association study (GWAS) meta-analysis of LTL in over 37,000 European individuals identified seven SNPs which were associated with mean LTL. These SNPs and the ‘effect allele’ are listed in the table below (8).
|refSNP ID||Major allele, Minor allele (Risk)||Relative SNP position||Genes in region with known function in telomere biology|
|rs11125529||C/A||Synonymous change in MYNN||TERC|
|rs10936599||C/T||Within intron of TERT||TERT|
|rs7675998||G/A||Downstream of NAF1||NAF1|
|rs2736100||G/T||Within intron of OBFC1||OBFC1|
|rs9420907||A/C||Upstream of both ZNF257 and ZNF208||–|
|rs8105767||A/G||Synonymous change in ZBTB46||RTEL1|
|rs755017||A/G||Within intron of ACYP2||–|
Table adapted from (8). Synonymous change = no effect on protein. Intron = non-coding section of gene. Upstream = in DNA sequence before the start of a gene. Downstream = in the DNA sequence after the end of a gene.
As with all GWAS studies it is important to remember that any findings are associative only. Meaning they correlate with the change the researchers are investigating, but may not be causative of that change. Whilst it may not be possible to link the SNPs above directly to telomere length and aging; one SNP does have a strong link with several telomere related diseases.
rs10936599 is located within the telomerase reverse transcriptase (TERT) gene, which forms a key part of the enzyme telomerase. The C>T change in this SNP is associated with shorter telomere length and numerous diseases including several cancers (9,10,11), and heart disease (12). Whilst unable to present any evidence it is thought that shortened telomeres lead to increased DNA damage in these patients, which in turn leads to the development of cancer or heart disease.
Taking this, together with the weak association between telomere length and mortality/age-related diseases discussed above, it may still be a few more years yet before a concrete link is made between SNP data and how long you are likely to live.
But this is cutting edge, exciting science, so expect to see lots of new data soon! Also, researchers are already developing compounds that are capable of extending telomere length in humans (13), which may eventually be used to target telomere associated diseases and disorders, or potentially even extend the life of our cells and tissues.
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