Telomere shortening: the hallmark of aging

Among the nine key mechanisms identified by research that determine aging in animals, including humans, one of the best known is telomere shortening. The results of some recent studies, some of them related to COVID-19, however, suggest that telomere length is more indicative of an organism’s helath status, rather than its aging. We talked with Valentina Bollati, associate professor at the Department of Clinical and Community Sciences at theEpiget Lab of La Statale University of Milan.

Dr. Bollati, what are telomeres and what are they used for?

“TelomeresEnd parts of the chromosomes. They have the function of making DNA more stable and their length is inversely correlated with ageing. are the end part of the chromosome, a kind of protective ‘cap’ formed by a series of replications of the same genetic information, which are not essential for the life of the cell. They are needed because each time the DNA replicates–that is, at each cell cycle–the enzyme that makes the DNA copy attaches itself to the piece of the helix that it is supposed to copy. The precise spot on the helix to which it attaches, however, cannot be replicated and is lost in the process, resulting in a small shortening of the sequence. The region on which the enzyme attaches is, precisely, the telomere, and a ‘piece’ of the DNA that makes it up is lost with each cycle. What happens, then, is its progressive shortening. That is why the association between telomere length and age seems to be so straightforward. Iterating this process over time, then, a limit is reached when the telomere becomes too short, and the information lost during replication damages the cell. At this point, the cell goes into apoptosis, that is, it dies. This sort of programmed cell death is critical to avoid duplication errors that can be harmful.”

Until now, telomere length has been considered a good indicator of biological aging. Is this no longer the case?

“Doubts are beginning to be raised in the scientific community. Indeed, the organism’s cells have different duplication times which depend on the biological processes in which they are involved. It is true, then, that telomere length is related to the life cycle of a cell, but it is equally true that generalizing this concept to the whole organism can be misleading. So, if we look at an individual cell, the telomere is a very good indicator of its age. If we expand this reasoning to the whole organism, however, other factors need to be considered. First of all, we usually measure telomere length in peripheral tissues, and particularly in blood and immune system cells. These cells are involved in a great many processes, some of them transient, such as inflammation, that alter normal cell replication processes and, therefore, age estimation. Therefore, telomere length measured on immune system cells-as is often the case- may not provide a reliable estimate of biological ageDifferent from chronological age. It is a measure of the body's ageing, based on the effectiveness of the mechanisms that keep cells young and on markers of the functionality of organs and apparatus..”

What happens in those who become ill with COVID?

“During the pandemic, a number of studies were carried out that assessed telomere length in COVID-19 sufferers and in recently cured people. The SARS‑CoV‑2 virus generates a very strong inflammation process, so that the lymphocytesLymphocytes are the cells that make up the effective portion of the adaptive immune system; they are able to generate and modify antibodies that will recognize antigens in the future. They are present in primary lymphoid organs, secondary lymphoid organs, peripheral blood and lymph (where they are currently named). in the blood (the cells assigned to fight the disease), begin to replicate much faster and, as a result, age at a greater rate. We saw, first of all, that the telomere status of some cells is related to the severity of infections. Viral infections generate a huge turnover of inflammatory cells, and consequently have a major impact on telomere length. Typically, the trend is biphasic: there is an initial very fast shortening and then, when the cells reach the telomere shortening limit that causes them to die, a cell turnover occurs in which the telomeres will be long again. In other words, we observe a high rate at which telomeres shorten until the immune system cells die and new ones are formed.”

So telomeres can also shorten temporarily in response to external factors?

“Correct. Another example of how telomere length can be affected by external phenomena is air pollution. In some recently conducted studies, we have shown that the telomeres of people who are highly exposed to pollution undergo shortening at peak times. They become shorter, however, only in a transient phase due to the excess oxidative stress the body is subjected to due to environmental factors, and it is not a chronic condition.”

Can the organism put in place countermeasures to this process?

“It is natural to think that if cell death corrisponds with excessive telomere shortening, a process that prevents such shortening during replication would make this cell virtually immortal. And there is, within the body, an enzyme that can do this job. It is called telomerase and is activated in the presence of certain physiological or pathological processes. This is the case in embryos, stem cells and cancer cells. If we take a blood sample and find cells with unusually long telomeres, for example, this can be an alarm bell that signals the presence of blood cancer.”

“Telomeres of people highly exposed to pollution undergo shortening at peak times.”

Returning to the question of the biological clock, there are other methods that have been shown to be good indicators of aging. One of these is DNA methylation. What predictions can be made using one or the other?

“In the case of DNA methylation, a series of algorithms have been developed to calculate biological age. Thanks to these, we are able to convert a certain percentage of methylation into number of years, with a very good correspondence to the chronological age of the person considered. With regard to telomere length, however, the same does not apply. A person may have very compromised telomeres, indicative of an advanced state of biological aging, but the reason may simply be that this person has gone through an acute inflammatory phase. And, while the biological age estimated by methylation can be improved somewhat by changing the lifestyle, while still remaining fairly close to their chronological age, for telomeres the variation is much greater. As we have said, at the end of the inflammatory process and when the body regains its healthy state, they can be fully restored. With respect to biological age estimation, however, we can say that if we measure the length of the telomeres of a person with strong biological aging, it is very likely that they will be short, while the opposite is not said.”

Could telomeres therefore be an indicator of health?

“It is possible that, in light of these studies, the association between telomere length and age should be revised. What can be said is that with a proper lifestyle, the telomere length of circulating cells in the blood improves. We recently did a study on exercise in hypertensive people. We saw that moderate physical activity improves a lot of parameters, including telomere length. Our interpretation is that moderate physical activity reduces oxidative stress in the body and, as a result, health status.”