At the ends of each of our chromosomes, there are little areas called telomeres. Opposed to the rest of a chromosome, telomeres do not encode any information. Being present in the majority of organisms, in vertebrates, it is a TTAGGG sequence and in plants, it is TTTAGGG.
In the process of cell division, all the DNA is replicated — the coding part with the information and telomeres at the ends. However, there is a part that is not replicated. Certain peculiarities of the DNA polymerase (an enzyme taking part in DNA replication) influence the process, making the strand of each chromosome shorter after every division. New shorter strands are known as under-replicated.
Obviously, with the loss of a part of a strand upon every division, we would lose a part of information. This is where telomeres stand guard: under-replication only happens to the telomere region. Thus, the DNA code itself is not damaged. Telomeres have certain limits, though: in the majority of cells, telomeres can survive about 50 divisions. This limit was discovered by the anatomist Leonard Hayflick and thus is named after him ‒‒ the Hayflick limit. After those 50 divisions are done, telomeres become too short of supporting their function, which leads to apoptosis (programmed cell death).
Because of this link to apoptosis, scientists first thought that telomeres cause the aging of cells. Later it was discovered that some cells age in a different way. Alexey Olovnikov had done several studies in the 1970s and came up with a theory that there might be a certain mechanism making telomeres longer and thus retarding the process of aging. An interesting fact: Olovnikov had a theory about cell division limits before the scientific community saw Hayflick’s studies.
A bit later, in 1981, Olovnikov’s theory was proven right with the discovery of the telomerase enzyme. It turns out the telomerase enzyme can make the cell overpower Hayflick’s limit and divide more times. The Nobel Prize in Physiology or Medicine of 2009 was awarded for the discovery of the protective role of telomeres and the enzyme telomerase in chromosomes. Olovnikov was on the list of nominees but had not received any praise for his work.
Since then, telomeres and telomerase have been meticulously studied by various scientists. With more data revealed, many scientists think we could use these mechanisms to stop the aging process or even to prolongate life eternally, as the process of aging of the body is directly related to the aging of each cell.
There are studies to prove that. It was discovered that progeria (a condition making people age faster than normal) is caused by a mutation in the LMNA gene. This condition is so dramatic that it makes children look like old people and eventually die at a young age.
Too much is also not good: excessively long telomeres can be found in cancer cells. Together with active telomerase, it can be both very beneficial (as in infinitely replicating stem cells) or a problem (as in cancer cells). An astonishing example would be an immortalized cancer cell called HeLa. It was taken in 1951 from a woman called Henrietta Lacks (this is where the cell name comes from) in the process of her cervical cancer therapy. Since then, those cells have been replicated indefinitely in numerous laboratories all over the world for various studies.
As we can see, telomeres and telomerase are complex phenomena and should not be perceived irresponsibly. Too short and too long telomeres might damage a human’s body.
Mice-superagers
Anti-age research is gaining popularity. There is even a special award in this area now — the Methuselah Mouse Prize (MPrize), established by the Methuselah Foundation (Methuselah is the longest-living biblical character).
Early studies of ways to prolongate life have been underway for quite some time already. They are done with cell cultures and laboratory animals.
The MPrize of 2003 was awarded to the team of Andrzej Bartke (US), who managed to raise a dwarf mouse that almost reached 5 years old (1,819 days). Their studies did not include telomeres — they concentrated on genetic modifications of the mouse’s hormones. The superager mouse ended up having lower insulin production and blood sugar, and a higher antioxidant defense level.
Several studies have shown that excessive telomerase activity leads to tumors and not to a longer life. Thus, scientists turned their attention to a way to activate telomerase for necessary timespans. In 2019 Spanish scientists published the most interesting (so far) results in this area .
The scientists created mice with excessively long telomeres, took their stem cells and injected them in the embryos of ordinary mice. In the result, they got chimeras — mice that had both normal and long telomeres. These chimeric mice showed impressive characteristics in comparison to normal mice in the control group: lower rates of cancer development, improved metabolism and a 13% longer lifespan.
Experiments on humans
Holding human experiments are by far more complicated than stem studies or even animal tests. Also, the results with humans differ profoundly.
One of the well-known human experiments with telomeres is a study by Elizabeth Parrish. Being the first (and, probably, the only) client of BioViva company, she states that she was injected with viruses charged with telomerase-producing and follistatin genes. The aim was to prove that telomeres should rejuvenate the cells making telomeres longer and the follistatin should block myostatin (a protein inhibiting the growth of muscle).
In 2016 the first paper on this experiment was published. The reaction was varied. Media presented this paper as a new medical breakthrough, while Parrish’s colleagues-scientists were much less enthusiastic. Parrish stated that she looked 20 years younger than her real age based on the average speed of telomere loss. According to her, the telomerase from injections made her telomeres longer by the same amount that would be lost over 20 years. However, the conclusion that it made her body 20 years younger was rather bogus.
Later scientists ran some checks on her studies and found out that the way of telomere measurement was not reliable enough to be accepted.
Parrish did not stop with the publication of her first results. In order to support her findings, she compared MRI scans of her thighs from before the injections and two years after. She claims that decreased muscle fats prove the effect of follistatin. Again, the scientific community debunked her findings: the MRI pictures do not clearly show any significant difference and could be explained by only different positions of the body during both scans. Also, scanners used “before” and “after” might have been different, hence the difference in the pictures.
Currently, there is one more similar experiment on the way: Libella Gene Therapeutics, a new startup, aims to hold similar research. In 2019 they planned to start a clinical trial on the transduction of active telomerase in order to retard aging and treat Alzheimer’s disease and critical limb ischemia therapy. However, the company is still recruiting volunteers, so there is no more information about the advancement of their project so far.
Do telomeres hold any future for us?
There are some findings from geneticists Richard Cawthon and his colleagues (University of Utah): their study has revealed that people over 60 years old with shorter than normal telomeres face a three times higher risk to die from heart disease and eight times — from infection.
And yet, any results should be taken with a grain of salt: Cawthon reminds us that after the person is 60 years old, the risk to die increases two times every eight years. And here telomeres make only 4% of the difference, which is incomparable to the influence of other factors such as sex, biological age, and oxidative stress (i.e., free radicals damaging the DNA and other cells). Our body does cope with free radicals that appear as a result of various biological reactions, but when their quantity reaches the body’s limits (which is the case if the person smokes, has a bad diet, and is often under stress) they accumulate and influence our DNA.
Even though telomeres are not proven to make a significant influence on aging, we cannot ignore their influence as in all aging (senescent) cells we observe the loss of telomere. Such cells change their metabolism and start producing molecules that may damage the health of cells and the whole body (anti-inflammatory cytokines, growth factors, and proteases). When the amount of such cells in the tissues rises, they start influencing the whole organ and cause inflammation and malign tumors. This is more noticeable in older patients.
Maybe telomeres are eventually not the solution to aging, but there is evidence that we can increase the length of telomeres without resorting to risky procedures — just by having a healthy lifestyle, enjoying physical activity, and eating healthy foods.
The medical industry is already working on drugs affecting telomerase. Their main application is to help cure cancer. Scientists are now trying to prove that by fighting telomerase activity in cancer cells we can make the cancer development slower or even stop it altogether.
The most complicated part of the task is to create a drug that is going to target only telomerase in cancer cells, not in healthy cells of our body, as, obviously, its suppression in other cells (e.g., reproductive cells) would be dangerous.
In this research, scientists employ artificial intelligence and machine learning technologies. They help search for a good drug substance. One of the applications of IT is to interpret big amounts of data from a genome-wide screening — for one of the experiments scientists needed to hold a genome-wide functional screening of cancer cell telomerase genes. They were trying to point out promoter mutations leading to increased enzyme activity. Once they identify the mutations, we could try to suppress the enzyme activity with a specific therapy.
Since almost any research now includes big data analysis, it is virtually impossible to go without a supercomputer for analysis. Using the computer makes finding or designing a necessary drug faster and easier. If we are ever able to find a drug that can suppress telomerase in cancer cells only, leaving out other functional cells, it is not going to be done without a computer.
At this point, it is already clear that the length of telomere and the activity of telomerase are not the only factors to be taken into account for fighting aging and age-related conditions. Even though they are important factors, the extent of their influence is limited.
About the author
Rustam Gilfanov, investor, benefactor, and a partner of the LongeVC fund.
