Rustam Gilfanov, a Venture Partner at the LongeVC Fund shares his ideas.
How a small region of human chromosome can change our perception of medicine, life, and death
Telomeres are structures at the end parts of chromosomes. Consisting of repetitive nucleotide sequences, they do not encode any data and are highly conserved, with TTAGGG repeats found in most vertebrates, and TTTAGGG repeats observed in almost all plants.
Every time a cell divides, its DNA sequence replicates to get to a new cell — this applies both to the coding region and the telomeres. Due to the functioning specifics of DNA polymerase enzymes responsible for the replication process, the DNA strands of each chromosome become shorter during the division. These shortened strands are called under-replicated.
To avoid damaging the genetic information, this process affects only the telomere regions; in most cells, they get shortened as many times as possible and can take up to 50 divisions on average. This limit is known as the Hayflick limit, named after anatomist Leonard Hayflick, whose experiments have demonstrated this phenomenon. Once a cell reaches this limit and shortens its telomeres to the maximum, the process of apoptosis (programmed cell death) starts.
Telomere structures were believed to cause cell aging. However, studies have found that not all cells age that way. In the 1970s, Alexey Olovnikov suggested that cells may have a special mechanism that elongates telomeres and prevents cells from aging. By the way, Olovnikov had assumed that cells have a limit of divisions even before Hayflick published his studies.
In 1981, Olovnikov’s ideas were confirmed to be accurate: the telomerase enzyme and its functions were discovered. Telomerase activation turned out to be able to overcome Hayflick’s limit and increase the number of cell divisions. In 2009, a group of scientists was awarded the Nobel Prize in Physiology or Medicine for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase. Unfortunately, Olovnikov did not receive a share of the prize, even though he was listed as a candidate for nomination.
The more attention science paid to telomeres and telomerase, the more popular the idea of manipulating them for achieving immortality or prolonging youth became.
It was clear that those components somehow affect not only cells but also the aging of the body. For example, accelerated shortening of telomeres due to an LMNA gene mutation is the cause of progeria — a disease that makes patients age faster, look like old people in early childhood, and die before reaching adulthood.
An opposite situation occurs when telomeres are excessively long — for example, in cancer cells, where telomerase is highly active (as well as in constantly replicating reproductive and stem cells). A classic example of immortalized cancer cells is the HeLa cell line, derived from cervical cancer cells taken from American woman Henrietta Lacks and named after her. HeLa cells were found to be remarkably useful for experiments and are cultivated in many laboratories all over the world.
The more information on telomeres and telomerase was obtained, the more evident it became that telomerase must be kept under control. Both excessive activity and inactivity of this enzyme can damage the cells and the body.
The first studies on life prolongation involved cell cultures and laboratory animals. By the way, a special award was established to incentivize anti-aging research — the Methuselah Mouse Prize (MPrize), organized by the Methuselah Foundation (named after a biblical character famous for his enormous longevity).
In 2003, Andrzej Bartke (US) and his colleagues received the MPrize for creating a dwarf mouse that lived for almost five years (1819 days). However, Bartke did not impact the telomeres of the mouse: he applied genetic modification methods to alter its hormones. The award-winning mouse had lower insulin secretion and blood sugar levels, while its antioxidant defenses were more active.
When it became clear that excessive telomerase activity can cause tumors instead of prolonging youth, scientists started looking for a way to temporarily activate the enzyme. Researchers from Spain conducted one of the most productive experiments in that area, with its results published in 2019.
The researchers generated mice with hyper-long telomeres and injected stem cells containing telomeres into ordinary mice embryos. Thus, they generated chimeric mice with both ordinary and hyper-long telomeres. The chimeras demonstrated several outstanding characteristics, compared to the control group with normal-length telomeres: they had lower cancer rates and improved metabolic fitness, while their lifespan was 13% longer.
Experiments on animals, no matter how successful, do not provide similar results when human participants are involved. Besides, it is more complicated to conduct human trials than to experiment on laboratory animals and stem cultures.
One of the best-known tests was performed by Elizabeth Parrish. She was the first and seemingly the only client of her BioViva startup. Parrish claims to have received intravenous injections of viruses containing telomerase-producing genetic material and the follistatin gene. It was expected that telomeres would rejuvenate the cells by elongating their telomeres, while follistatin would block myostatin — a muscle growth inhibitor.
The first results of the experiment were published in 2016. Although the media positioned them as a real breakthrough, the response from the scientific community was much more skeptical. The claims that injections made Parrish look twenty years younger were based on the estimated average speed of telomere shortening. The injected telomerase elongated telomeres to the same extent they could have shortened in two decades; however, that does not mean the procedure had any rejuvenating effect on the body.
Besides, a more detailed examination of the results has revealed potential deviations in the telomere length measurements that significantly exceed tolerable calculation errors.
To make the experimental findings seem more convincing, Parrish published MRI scans of her thighs, taken before and two years after the therapy. The images were aimed to demonstrate the positive effect of follistatin, i.e., decreased muscle fats. However, many researchers argue that the scans do not show any changes, and similar images can be obtained simply by changing the position of the legs during scanning. Besides, the differences could be explained by using a more accurate MRI scanner for post-therapy scanning.
Libella Gene Therapeutics was another startup that planned to provide similar services. The company was going to launch its clinical trials on active telomerase transduction in 2019, covering three research areas: aging treatment, Alzheimer’s disease therapy, and critical limb ischemia therapy. At the moment, all three trials have “Recruiting” status and offer no further information.
Should we place our bet on telomeres?
Geneticist Richard Cawthon and his colleagues at the University of Utah have proved that telomere length impacts life expectancy. One of their studies has found that individuals over the age of 60 years with shorter telomeres have a three-fold higher mortality rate from heart disease and an eighth-fold higher mortality rate from infectious diseases.
However, Cawthon points out that the risk of death doubles every eight years after an individual turns sixty, with the influence of telomeres on this process not exceeding 4%. More impactful factors are sex, biological age, and oxidative stress (i.e., damage to the DNA and other cell structures by free radicals). Free radicals are formed in the body due to many biological reactions and are detoxified by the body’s defense system. However, the body cannot cope with a high concentration of free radicals (caused by smoking, bad diet, and permanent stress), so they start accumulating and damaging the DNA.
Telomeres and their length are not the ultimate factor that drives the process of aging; however, it should not be disregarded as insignificant. Telomere shortening is the phenomenon observed in aging (senescent) cells. They have specific metabolism and produce molecules that may unfavorably impact health cells and the body in general — anti-inflammatory cytokines, growth factors, and proteases. The higher the number of senescent cells is, the more they affect normal tissue, provoking inflammations and malign tumors — especially in old people.
That is why we should not have high hopes for telomeres. Still, we can take good care of them: scientific evidence suggests that their length can be increased without risky experiments and telomerase injections. A healthy lifestyle, physical activity, and correct nutrition are known to help elongate telomeres.
Nevertheless, telomerase-activating drugs are being developed, mainly to fight cancer. Medications capable of suppressing telomerase activity in cancer cells have the potential to slow down or stop the progression of a tumor.
That is easier said than done — the enzyme must be selectively suppressed only in cancer cells. Its functioning in other cells and tissues that require its activity (e.g., gametes) must remain unaffected.
Artificial intelligence and machine learning technologies are used to discover effective drug candidates. For example, they help analyze vast amounts of data collected by a genome-wide screening. A recent experiment has conducted the genome-wide functional screening of cancer cell telomerase genes to identify promoter mutations causing increased enzyme activity. Those mutations can be targeted during suppressant-involving therapy.
Nowadays, drug development is almost impossible without supercomputers analyzing big data. This approach simplifies and facilitates that process, helping find or design medications with required properties. For example, drugs that target telomerase genes in cancer cells only while ignoring the same genes in healthy body parts.
Telomere length and telomerase activity are important, but not the only targets that must be considered when combating aging and preventing age-related diseases. They definitely contribute to the process of aging, but not as extensively as thought before. Still, we should not ignore them completely.
About the author
Rustam Gilfanov is a philanthropist, private investor, and a partner of the LongeVC fund.