Telomere shortening, a feature of aging, could increase the susceptibility to Sars-CoV-2 infection. This is the conclusion of a study published on EMBO Reports by a team of scientists led by Fabrizio d’Adda di Fagagna of the FIRC Institute of Molecular Biology (Ifom, Milan, Italy), which demonstrated that the DNA-damage response elicited by shortened telomeres upregulates ACE2 (Angiotensin Converting Enzyme 2), the Sars-Cov-2 receptor. According to the researchers, this upregulation would contribute «to make the elderly more susceptible to the infection».
Telomeres and aging
Telomeres are the structures located at the end of the chromosomes. Composed of repetitive Dna associated with proteins, they protect chromosomes from losing important genetic information. In fact, chromosomes tend to shorten at every cell cycle. Until telomeres are sufficiently long, this phenomenon leads to the loss of part of the telomeres but not of genetic information. However, that means that telomeres progressively shorten.
In the elderly, critically shortened telomeres are managed by the cell as damaged Dna. So, they trigger a DNA-damage response. Animal models demonstrated that the progressive telomere shortening and the consequent activation of the Dna-damage response at telomeres are associated with aging and aging-related diseases.
Telomeres and ACE2
To infect lung cells, Sars-CoV-2 binds to ACE2. The authors of the study published on EMBO Reports demonstrated that ACE2 levels of expression are higher in old than in young people, and that telomere shortening is sufficient to increase its expression in human cells.
Also, the researchers demonstrated that the mechanisms linking telomere shortening to ACE2 upregulation depend on the DNA-damage response elicited at shortened telomeres. Thus, telomeric Dna-damage response that accumulates during aging seems to increase the susceptibility to Sars-CoV-2 infection via ACE2 upregulation.
As highlighted by d’Adda di Fagagna and collaborators, «aging correlates with the severity of pathological progression and poor prognosis of COVID-19», and «the evidence that blocking the interaction between Sars-CoV-2 […] and ACE2 or modulating ACE2 level by different means […] can in turn regulate the Sars-CoV-2 cell entry suggests that reducing ACE2 expression can have a beneficial effect on COVID-19 infection rates and on the severity of symptoms». Therefore, targeting telomere shortening to reduce ACE2 expression could represent another strategy to reduce the susceptibility to Sars-CoV-2 and the severity of Covid-19 symptoms in people at high risk of infection because of shortened telomeres.
How to unveil telomere shortening
Telomere length analysis could help identify people at high-risk of severe pathology development because of shortened telomeres. «Nowadays, it is possible to measure telomere length chromosome by chromosome» Giuseppe Mucci, Bioscience Institute CEO, explains. «Available assays provide a picture of the mean telomere length, the percentage of short telomeres and of cells with shortened telomeres, and other parameters that are useful in determining the level of telomere shortening in an individual».
Besides aging, telomere dysfunction is associated with smoking, dietary factors, body mass index, and other factors promoting oxidative stress, chronic inflammation and cancer. «That is why», Mucci adds, «telomere length analysis is recommended to people of every age, to actively monitor increased health risk».
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- Sepe S et al. DNA damage response at telomeres boosts the transcription of SARS-CoV-2 receptor ACE2 during aging. EMBO Rep. 2021 Dec 2;e53658. doi: 10.15252/embr.202153658
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