DNA Damage Response in the Elderly May Increase Susceptibility to COVID-19

Signaling DNA damage caused by telomere aging increases expression of ACE2, the human SARS-CoV-2 cell receptor.

SARS-CoV-2 causes the pandemic coronavirus disease COVID-19, which is more harmful to the elderly, who exhibit more severe symptoms and are at higher risk of hospitalization and death. A group of Italian and American researchers led by Fabrizio d’Adda di Fagagna now report that expression of the cell receptor for the virus, ACE2, which is essential for mediating cell entry of the virus, is increasing in the lungs of aging mice and people . They further show that ACE2 expression increases with telomere shortening or dysfunction – common hallmarks of aging – in cultured human cells and in mice. This increase depends on a response to DNA damage induced by dysfunctional telomeres. The findings published today by EMBO Reports provide a possible molecular explanation for the increased susceptibility of the elderly to SARS-CoV-2.

The reasons for the increased risk of severe symptoms and death in the elderly in response to SARS-CoV-2 infection remain unclear. ACE2 expression is positively related to the age of patients, for example in the nasal epithelium, the first point of contact with SARS-CoV-2. Lower ACE2 expression in children relative to adults may explain why COVID-19 is less common in children, and the expression and distribution of the ACE2 receptor may be relevant to the progression and prognosis of COVID-19. The study results now show that ACE2 protein expression is increased in aging human and mouse lungs, including in alveolar epithelial type II (ATII) cells. In the lungs, ACE2 is most commonly found on the surface of ATII cells, so these cells are likely the primary target of SARS-CoV-2 infection in the lungs. SARS-CoV-2 mainly spreads through respiratory droplets and the lung is the virus’s first target organ. Indeed, pneumonia is the most common complication in COVID-19 patients, with an incidence of 91%.

To reveal the molecular mechanism underlying the upregulation of ACE2 during aging, the researchers turned to in vitro and in vivo models that recapitulate some key aspects of aging. Aging is associated with telomere shortening and damage in a range of tissues in several species, including humans. Telomeres are the regions at the ends of linear chromosomes that are essential to protect chromosome ends from shortening during repeated cell replication cycles, which would result in the loss of crucial genetic information. When telomeres become critically short, they are observed as DNA breaks and activate the reaction pathways for DNA damage. D’Adda di Fagagna, who works at IFOM in Milan and CNR-IGM in Pavia and colleagues, either inhibited the general DNA damage response by targeting ATM, a key enzyme of the DNA damage response pathway, or they inhibited the telomere DNA damage response specifically using telomere antisense oligonucleotides (tASO). Both approaches prevent the upregulation of ACE2 genes and proteins after telomere damage in senescent cultured cells and in mice. The group also used a cell culture model in which the DNA damage response is specifically activated at telomeres in the absence of telomere shortening, with the same results. These findings indicate that it is the activation of the DNA damage response, rather than telomere shortening per se, that is responsible for the upregulation of ACE2. Understanding the mechanism of age susceptibility to SARS-CoV-2 infection is important for targeted therapeutic approaches, which in principle may involve the use of tASO-mediated inhibition of the telomere DNA damage response.

ACE2 also plays a role in the regulation of blood pressure and the balance of fluids and salts and is expressed in other human tissues, for example the heart and kidneys. Thus, the findings reported here may also have broader medical implications beyond COVID-19.

However, further research is needed to determine whether decreasing ACE2 expression has beneficial effects on SARS-CoV-2 infection rates and on severity of COVID-19 symptoms in in vivo models. Further work also needs to be done to understand how DNA damage response signaling leads to increased Ace2 gene expression.

Reference: “Response to DNA damage at telomeres increases transcription of SARS-CoV-2 receptor ACE2 during aging” by Sara Sepe, Francesca Rossiello, Valeria Cancila, Fabio Iannelli, Valentina Matti, Giada Cicio, Matteo Cabrini, Eugenia Marinelli, Busola R Alabi, Alessia di Lillo, Arianna Di Napoli, Jerry W Shay, Claudio Tripodo and Fabrizio d’Adda di Fagagna, December 2, 2021, EMBO Reports.
DOI: 10.15252/embr.202153658