Damaged telomeres in the elderly may increase susceptibility to SARS-
CoV-2

Date:
December 2, 2021
Source:
EMBO
Summary:
DNA damage signaling induced by aging telomeres increases the
expression of ACE2, the human SARS-CoV-2 cell receptor, scientists
report.



FULL STORY ========================================================================== SARS-CoV-2 causes the pandemic coronavirus disease COVID-19, that is
more harmful for elderly people, who show 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 reports
that the expression of the cell receptor for the virus, ACE2, which
is essential for mediating cell entry of the virus, increases in the
lungs of aging mice and humans. They further show that ACE2 expression increases upon telomere shortening or dysfunction - - common hallmarks
of aging -- in cultured human cells and in mice. This increase depends
on a DNA damage response elicited by dysfunctional telomeres.

The findings published today by EMBO Reports provide one possible
molecular explanation for the increased sensitivity of elderly people
to SARS-CoV-2.


==========================================================================
The reasons for the higher probability of severe symptoms and death in
the elderly in response to a SARS-CoV-2 infection remain unclear. ACE2 expression has been positively related to patients' age, 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 prevalent in children, and the expression and distribution of
the ACE2 receptor may be relevant for the progression and prognosis of COVID-19. The research findings now show that ACE2 protein expression
is elevated in aging human and mouse lungs, including in alveolar
epithelial type II cells (ATII). In the lungs, ACE2 is mostly found on
the surface of ATII cells, and these cells are thus likely the primary
target of SARS-CoV-2 infection in the lungs. SARS-CoV- 2 mainly spreads
via respiratory droplets and the lung is the first target organ of the
virus. Indeed, pneumonia is the most common complication seen in COVID-19 patients, at an occurrence of 91%.

In order 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 different
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 sensed as DNA breaks and activate DNA damage response pathways. D'Adda
di Fagagna working at IFOM in Milan and CNR-IGM in Pavia and colleagues
either inhibited the general DNA damage response by targeting ATM, a
major enzyme of the DNA damage response pathway, or they inhibited the telomeric DNA damage response specifically using telomeric antisense oligonucleotides (tASO). Both approaches prevent ACE2 gene and protein upregulation following telomere damage in aging cultured cells and in
mice. The group also used a cell culture model in which the DNA damage
response is activated specifically at telomeres in the absence of telomere shortening, with the same results. These findings indicate that it is
the DNA damage response activation, rather than telomeric shortening
per se, that is responsible for ACE2 upregulation. Understanding the
mechanism of age susceptibility to SARS-CoV-2 infection is important
for targeted therapeutic approaches, which might in principle include
the use of tASO-mediated inhibition of the telomeric DNA damage response.

ACE2 also has 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 kidney. The findings reported here may thus also have
broader medical implications beyond COVID-19.

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

========================================================================== Story Source: Materials provided by EMBO. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. 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, Fabrizio d'Adda di Fagagna. DNA
damage response at telomeres boosts the transcription of
SARS‐CoV‐2 receptor ACE2 during aging. EMBO reports,
2021; DOI: 10.15252/embr.202153658 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211202191141.htm

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