Potential role of cellular senescence on coronavirus infections

The disproportionate incidences of COVID-19-related hospitalization and mortality for different age groups and various underlying health conditions is a result of a complex social predisposition to the exposure, resistance, and tolerance for the infection. Based on the observed data as well as the molecular mechanisms for viral entry and replication, cellular senescence related to aging, obesity, hypertension, and diabetes appears to be strongly correlated with the SARS-CoV-2 infections resulting in higher COVID-19 related complications and mortality. Establishing such a correlation may allow us to better explain the pathobiology as well as the differential nature of the SARS-CoV-2 infections and consider targeted control and therapeutic strategies to combat the disease.


Introduction
It has become abundantly clear that older adults and individuals with underlying health conditions such as diabetes, obesity, or heart problems, or smoking are at most risk of serious complications or death due to COVID-19 1

. A recent population-based study by the Center for
Disease Control and Prevention (CDC) using the surveillance network COVID-NET showed that nearly 75% of all patients hospitalized for COVID-19 during a 4-week period in March 2020 were aged >50 years 2 . Similarly, hospitalization data suggested that males and black population are disproportionately affected by the disease. Among younger adult (18-64 years) patients, obesity was the most prevalent underlying condition, followed by hypertension, diabetes, and asthma 2 .
The disproportionate incidences of SARS-CoV-2 infections in different age group, race, or gender is a result of a complex social predisposition to the exposure, resistance, and tolerance for the infection. Understanding the molecular mechanisms of how SARS-CoV-2 differentially infects individuals will allow targeted control and therapeutic strategies to combat the disease. So, why does COVID-19 disproportionately affect the elderly, obese, and diabetic demographics? Based on the observed data as well as the molecular mechanisms for viral entry and replication, cellular senescence related to aging, obesity, and diabetes appears to be strongly correlated with the SARS-CoV-2 infections resulting in higher COVID-19 incidences of infections and mortality (Box 1).
This means that these viruses are possibly exploiting the very mechanism intended for eliciting the immune response for senescent cell removal. Very recently, Malavolta et al. 3

Cellular senescence
Cellular senescence is a process of irreversible cell-cycle arrest that renders previously replication-competent cells non-proliferative but still metabolically active 5 . A number of factors such as DNA damage due to oxidative or chemotherapy-induced stress, mitochondrial dysfunction, telomere erosion contribute to cellular senescence 6 . Normal cells are equipped with repair mechanisms and the process may include temporary growth arrest. If the repair fails, damaged cells may either initiate regulated cell death or become senescent. In general, it is a regulated response to stress and plays important roles in several essential physiological processes, from regulating bone growth during childhood to wound healing or tissue regeneration after injury and suppressing tumor progression (see reviews 7,8 ). Key features of senescent cells include damage sensing signaling pathways activation and expression of anti-proliferative molecules resulting in durable growth arrest. While cellular senescence has important functions, the accumulation of senescent cells with age is implicated in a number of age-associated conditions, including diabetes 9 as well as cardiovascular 10 and pulmonary diseases 11 . The increase in stress-induced cellular senescence is a result of cumulative cell damage with age and failure of the immune system to eliminate them 12 . In addition to aging, obesity also leads to an increase in senescent cells [13][14][15] . Fat tissues acquired from patients with diabetic tissues show characteristics of senescent-like state with elevated expression of p53 and p21, suggesting that diabetes is associated with cellular senescence in fat tissue 16 . Similarly, hypertension is shown to cause cellular senescence 16,17 . Conditions such as age, obesity, diabetes, and hypertension are, therefore, inter-related and associated with cellular senescence. Interestingly, all of these conditions are increased risk factors for COVID-19 complications. In addition, one of the primary markers of cellular senescence is leukocyte telomere shortening 18 , which seems to occur at a differential rate among different demographics, with a higher rate among men and the black population 19,20 .
Senescent cells are tagged with markers that can be recognized by the immune system for elimination 21 . They express factors such as MHC class I polypeptide-related sequence A (MICA) and UL16 binding protein 2 (ULBP2) which serve as the ligands to bind to the natural killer (NK) cell receptor NKG2D, thereby activating the cell removal 22,23 . This process plays a central role in tissue remodeling during carcinogenesis and tumor progression. In this respect, senescent cells don't just block the cell proliferation but also prime themselves for elimination 24 . They also secrete a plethora of pro-inflammatory cytokines, chemokines, and growth factors, grouped as senescenceassociated secretory phenotype (SASP) 25 . For example, the accumulation of tumor suppressor molecules p16 INK4a and P53 are key markers of senescent cells.
In addition to the NK cell and macrophages, other innate and adaptive immune systems are also suggested to play a role in senescent cell surveillance. For example, the adaptive response to oncogene-induced senescent cells involves T cells (CD4) and MHC class II molecules on the cell surface 26,27 . Similarly, IgM antibodies are able to recognize senescent cells by binding to surfaceexposed molecules, including an oxidized form of vimentin filament presented on the outer surface of senescent cells 28 , suggesting the availability of a variety of new antigens presented on the senescent cell surface for immune system recognition and elimination 24 . Therefore, reduction in immune clearance in immunosuppressive conditions due to aging results in the accumulation of senescent cells.

Viral infections and the role of cellular senescence
Cellular senescence appears to play a dual or differential role in infections by different viruses. While cellular senescence is implied in impaired viral infection and is considered to be an important protection mechanism against oncogenic virus effects 29,30 , it is also suggested to enhance viral replication 31  activities by its inhibitor nicotinamide, enhanced viral replication, providing further evidence that senescent cells lacking SIRT1 can accelerate IFV replication 31 .

Potential Role of senescence on molecular mechanisms of coronavirus infections
Although our understanding of how SARS-CoV-2 exploits cellular senescence is still lacking, a multitude of studies on the coronavirus entry as well as the features of the senescent cells provide a strong ground that cellular senescence plays an indispensable role in virus particle attachment on the host cell surface and infection. A few specifics that connect the related viral infections to cellular senescence and their relevance to SARS-CoV-2 are given below.

Efficient SARS-CoV and Enterovirus 71 (EV71) infections require surface Vimentin, which is a key component of the senescent cell surface.
It has recently been shown that senescent lung fibroblasts express and expose an oxidized vimentin for viral entry of SARS-CoV and other viruses and the abundance of exposed surface vimentin in senescent cells, it is prudent to hypothesize that cellular senescence plays an essential role in SARS-CoV-2 infection (Fig. 1A). It is yet unknown whether the exposed cell surface vimentin interacts with the receptor-binding domain or the fusion core helices. It is also not known clearly which domain of vimentin is utilized.

MERS-CoV spike protein binds with DPP4, a key receptor that is abundantly expressed in senescent cells
In an attempt to find novel senescent cell surface markers on the plasma-membrane, a recent study used Mass Spectrometry to survey membrane-and cell surface-associated proteins and found that Dipeptidyl peptidase 4 (DPP4) is the most abundant membrane-bound protein localized on the plasma-membrane surface 42 . In fact, normal proliferating cells showed senescence upon overexpression of DPP4, confirmed by the elevated levels of senescence markers p16 and p21, and decrease in anti-senescent marker SIRT1. Importantly, DPP4 is involved in the regulation of glucose level that results in the reduction in insulin secretion, abnormal metabolism of visceral adipose tissues, and the increase in inflammation in type 2 diabetes.

Senescence in the respiratory system
Cellular senescence has increasingly been implicated in aging lungs as well as lungs with conditions such as chronic obstructive pulmonary diseases (COPD), idiopathic pulmonary fibrosis (IPF), and asthma 54,55 . Bronchial and alveolar epithelial cells can develop senescence due to a number of assaults such as smoking, microbial infections, and pollution. Although development of senescence is part of the lung repair mechanism, continuous exposure to the stress factors can result in excessive cellular senescence causing several chronic conditions 56,57 . As such, cigarette smoking is known to cause epithelial inflammation with increased p16 activities in the airways with increased p16 activity and is a major causal factor in COPD pathologies 58 .

Further outlook
In summary, this brief review aims to explore the potential role cellular senescence plays in the disparity observed in COVID-19 infection. Mortality. aging, as well as various conditions such as obesity, diabetes, and hypertension, are intricately related to cellular senescence, and individuals with any of these conditions are at increased risk of COVID-19 complications.