Steven P. Petrosino, Ph.D.^*, Boaz Nyona Matende, MSci

Clinical Scientist and President, Nutrition Advisor LLC, 8815 Tayport Drive, Dublin OH 43017, USA

*Corresponding Author: Steven P. Petrosino, Ph.D., Clinical Scientist and President, Nutrition Advisor LLC, 8815 Tayport Drive, Dublin OH 43017, USA

Abstract
The COVID-19 pandemic is by far the deadliest pandemic since the catastrophic Spanish Flu pandemic of 1918-1919. Coronavirus disease 2019 (COVID-19), the highly infectious viral agent responsible for the COVID-19 pandemic began as a cluster of pneumonia cases reported in the Wuhan region of China in late 2019. This novel infectious disease spread rapidly to all parts of the world within a few months, and as of mid-2020, COVID-19 was fully established as a global pandemic. The search for urgent and effective treatments, as well as biomarkers of adverse disease outcomes are still ongoing. Current management of COVID-19 is supportive, and respiratory failure due to acute respiratory distress syndrome (ARDS) is the leading cause of mortality. A clear link between disease severity, hyper-inflammation, and major comorbidities, including hypertension, diabetes, and CVD has been established. This paper will seek to delineate the interplay of those markers of poor disease outcome with telomere length.

Keywords: COVID-19, SARS-COV-2, Telomere Length, Oxidative Stress, Inflammation, Metabolic Syndrome,

Abbreviations: COVID-19: Coronavirus Disease 2019, [SP1] NADPH: Nicotinamide Adenine dinucleotide phosphate, CFR: Case Fatality Rate, CRP: C-Reactive Protein, WHO: World Health Organization, MT: metallothionein, CVD: Cardiovascular disease, CKD: Chronic Kidney Disease, OS: Oxidative Stress, COPD: Chronic Obstructive Pulmonary Disease, ROS: Reactive Oxygen Species, GSH: Glutathione, BMI: Body Mass Index, CKD: Chronic Kidney Disease, LTL: Leukocyte Telomere Length, SOD: Superoxide

Introduction
COVID-19 Overview:
The novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread around the world at an unprecedented rate (Mahase, 2020). Due to its high infectiousness and rapid transmission rates, coupled with inadequate prevention and control measures, the pandemic continues to pose a serious global health emergency (Zheng et al., 2020). Hospitalized patients rely mainly on supportive care for various comorbidities, including acute respiratory distress syndrome (ARDS), which is the leading cause of mortality (Mehta et al., 2020). While the COVID-19 CFR rate is slowing down, the condition remains deadly in patients presenting with certain risk factors (Rajgor et al., 2020). A small proportion of patients are hospitalized with a serious COVID-19 disease, and almost all these patients present with pre-existing conditions that also predict mortality (Atkins et al., 2020). To date, the identification of presenting characteristics, comorbidities, and clinical outcomes in COVID-19 patients is well understood, but the factors or mechanisms behind the association are not well understood. The Centers for Disease Control and Prevention (CDC) website lists a number of conditions as key risk factors for a severe disease that requires special attention, including asthma; chronic kidney disease, (especially during dialysis); chronic lung disease; diabetes; hemoglobin disorders; an immunocompromised status; liver disease; being aged 65 years and above; being a resident in a nursing home or long-term care facility; the presence of serious heart conditions; and severe obesity (Centers for Disease Control and Prevention, 2020). Individuals with these risk factors are significantly more likely to experience poor clinical outcomes (Guan et al., 2020).

Telomere length and COVID-19 Overview:
Telomere is the repetitive DNA sequences located at the terminal end of chromosomes, (like the endcaps on shoelaces), and which are characterized by TTAGGG tandem repeats. These repeats cap the ends of chromosomes, protecting them from degradation (“fraying”), and end-to-end fusion, hence, maintaining genome integrity (Greider, 1996; Valdes et al., 2005). Chromosomal abnormalities have been associated with shortened telomeres, particularly in replicative senescence cells (Allsopp et al., 1992). In humans, telomerase is expressed all cell lines during the initial few weeks of embryogenesis, and subsequently the down-regulated most cell types (Herman et al., 2001). DNA loses telomeric repeats with each cell division, and these losses are estimated to amount to 25 base pairs per year, and eventually resulting in replicative cellular senescence (Revesz et al., 2014). Shortened telomere length is a marker of an advanced chronological age, which associates with the comparatively higher frequency of disease morbidity/mortality (Rizvi, Raza, & Mahdi, 2014), (Herman et al., 2001), reported that it was the shortest telomere and not the average telomere length that determined cell viability and chromosome stability. The clinical significance of telomeres has been extensively investigated, with evidence pointing to the association of shorter telomere length with conditions such as depression, poor health behaviors, age-related diseases, progeria, and premature mortality. Children with the rare condition progeria have much shorter telomeres than do healthy children. A team of pediatric researchers led by Cooke and co- workers used a new technology called RNA therapeutics, which delivers small molecules into cells to alter their gene expression. These researchers were able to get the cells from children with progeria to produce telomerase, which suggests that this devastating disease may be altered. (Walther BK, Li Y, Thandavarayan RA, Cooke JP. Progeria and accelerated cardiovascular aging. Cardiol Plus [serial online] 2018 [cited 2021 Feb 22]; 3:81-9. Available from: https://www.cardiologyplus.org/text.asp?2018/3/3/81/242082 [SP2] ) In addition, there is mounting evidence of a link between shortened telomere length and the development of various infectious diseases (Kiecolt-Glaser et al., 2013). The COVID-19 outbreak has presented immense challenges to the global community, leading to concerted research efforts to enhance knowledge and understanding of this viral respiratory disease [SP3]. As part of the efforts, this review presents data on the association between telomere length and COVID-19, with a focus on the known link between telomere length and COVID-19 comorbidities, the shared deficiencies and mechanisms, and proximate link through other respiratory ailments. The knowledge gained contributes to the wider strategy to control COVID-19, particularly in relation to the risk of severe COVID-19 disease that has been found to significantly associate with hospitalization and the risk of adverse disease outcomes.

Major Comorbidities in Hospitalized COVID-19 Patients:

Telomere Shortening and Health Risk:
A key function of telomeres is to oversee cell surveillance by preventing nucleolytic degradation and the irregular fusions and recombination’s (Beilfuss, Camargo, & Kamycheva, 2017). The enzyme telomerase maintains telomere length at equilibrium as telomeres shorten with each replication cycle (Blackburn, 1991). Shortened or dysfunctional telomeres is one way through which cells from organisms with renewable tissue can permanently withdraw from the cell cycle, other ways can include DNA damage, strong mitogenic signals, and disputed chromatin (Campisi, 2005). The observed gradual loss of telomeric DNA may lead to chromosome instability (Beilfuss, Camargo, & Kamycheva, 2017). Telomere length serves as a clock indicating the pace of cellular aging (Jeanclose et al., 2000). Findings from cross-sectional studies have demonstrated the role of advancing age in the steady decline of telomere length, highlighting how the decline is associated with various diseases that occur with aging, and how environmental factors may impact on differences in telomere length between individuals or ethnicities (Rizvi, Raza, & Mahdi, 2014; Mundstock et al., 2015). Generally, telomere shortening has been associated with cellular changes that usher in age-related changes and, hence, an increased susceptibility to age-related diseases (Beilfuss, Camargo, & Kamycheva, 2017).

COVID-19 Comorbidities and Telomere Length: Longevity studies conducted over three decades have shown a link between telomere length, aging, and death. Telomere length in replicating somatic cells has an inverse correlation with age (Fitzpatrick et al., 2007). The finite replicative capacity, as determined by telomere length, is associated with the onset of age- related chronic diseases (Rizvi, Raza, & Mahdi, 2014). Various COVID-19 comorbidities (hypertension, obesity, diabetes, cardiovascular disease [coronary artery disease and congestive heart failure] chronic respiratory disease [asthma, and chronic obstructive pulmonary disease], kidney disease [chronic and end-stage], and cancer) have been established to associate with telomere attrition.

Nutrient Deficiencies linked to Telomere Length and COVID-19:
Vitamin D Deficiency
Prolonged exposure to the sunlight degrades both pre-vitamin D3 and vitamin D3 into inactive photoproducts (Holick, 2007). The synthesis of vitamin D in the skin is also affected by factors such as latitude, total ozone, altitude, ground, cover, cloud thickness and skin color (Engelsen et al., 2005). Vitamin D2 and D3 sources from the diet are incorporated into chlyomicrons and transported by the lymphatic system into the venous circulation. Only a small fraction of foods naturally has vitamin D and include oily fish such as mackerel, salmon, herring, and oils obtained from fish, including cod liver oil (Holick & Chen, 2008). Circulating vitamin D is bound to the vitamin D binding protein and transported to the liver, where it is converted by vitamin D-25-hydroxylase to 25-hydroxyvitamin D [25(OH)D]. The vitamin 25-hydroxyvitamin D [25(OH)D] is a major circulating vitamin that is used by clinicians to determine vitamin D status (Holick, 2007). Most countries around the world have a relatively low supply of foods rich in vitamin D and a deficient natural exposure to natural UBV radiation from the sunlight and, hence, a high prevalence of vitamin D deficiency (> 20 % prevalence of 25(OH)D < 30 nmol/L) or the risk of vitamin D deficiency is identified around the globe (Roth et al., 2018). The high prevalence of vitamin D deficiency relates with high rates of prevalence of morbidity and mortality in vitamin D correlated diseases in health outcomes.

Vitamin D Deficiency and Telomere Shortening: Changes in vitamin D metabolism and activity occur during aging, including intestinal resistance to dihydroxyvitamin D (1, 25(OH)2D), which affects intestinal calcium uptake, and a decrease in the population of vitamin D receptors (de Jongh, van Schoor, & Lips, 2017). A national survey conducted on the association between telomere length and serum levels of 25(OH)2D in the United States adult population reported a possible association between 25(OH)D levels and telomere length (Mazidi, Michos, & Banach,2017). A study examining the relationship between plasma 25(OH)2D and relative leukocyte telomere length by sex and race in the US partly supported the findings, whereby, a significant association between vitamin D deficiency (defined as 25(OH)D < 30 nmol/L) and short leukocyte telomere length in whites only was identified, but no association was established between continuous 25(OH)2D and long leukocyte telomere length in all participants (Liu et al., 2018). A general population study, found that age, sex, BMI, and non-Hispanic black race/ethnicity were significant predictors of leukocyte telomere length (Beifuss, Camargo, & Kamycheva, 2017). Notably, a cross- sectional study failed to show any association between 25(OH)D and 1,25(OH)2D and relative leukocyte telomere length (Julin et al., 2017).

Vitamin D Deficiency and COVID-19
A significant proportion of COVID-19 research has been devoted to understanding the role played by vitamin D. Findings by (Merzon et al., (2020) showed that low plasma 25(OH) vitamin D level was associated with an increased risk of COVID-19 infection. A possible link between vitamin D deficiency and latitude, ethnicity, alongside the impact on cytokines, ACE2, and thrombosis was demonstrated (Rhodes et al., 2020). Optimization of the vitamin D status has also been used widely to enhance immune-protection against COVID-19 (McCartney & Byrne, 2020). Therefore, there is a strong link between COVID-19 and vitamin D deficiency.
Vitamin D Deficiency and COVID-19 Comorbidities
COVID-19 is new phenomenon and, therefore, its direct link to vitamin D deficiency is currently not well understood. A proximate association between vitamin D and COVID-19 can be established through the already understood association between vitamin D and COVID-19 comorbidities. The findings can be used to develop a hypothesis between vitamin D and COVID-19.

Zinc Deficiency:
Zinc is an essential trace element that has attracted a lot of medical attention due to its role in human nutrition and health. Zinc has three major roles, including catalytic, regulatory, and structural (Myers, Nield, &Myers, 2012). Besides functioning as a structural component in proteins, Zinc is essential for other cellular functions, including cell proliferation, DNA and RNA synthesis, stabilization of cell structures/membranes, redox regulation, and apoptosis (Maywald, Wessels, & Rink, 2017). Zinc is the second most abundant trace element in the human body after iron, but the body lacks the capacity and, hence, the need for regular intake through food or supplementation (Jarosz et al., 2017). The physiological role of zinc is best explained through its association with metallothioneins (MTs), which are cysteine-rich proteins that bind to metal ions such as zinc. The MT as a protein isoform with unique amino acid sequence has affinity to different ions, including Zn²⁺ and Cu⁺, mainly functioning as an antioxidant or a radical scavenger (Gammoh & Rink, 2017). Several MTs, including 14 zinc importers (SLC39/ZIPs), and 10 zinc exporters (SLC30/ZnTs) have been described in mammals (Myers, Nield, & Myers, 2012). Mild cellular oxidants readily oxidize MTs, followed by a concomitant release of Zn²⁺ in a mechanism whereby changes to a more oxidizing conditions leads to the release of zinc, while changes to a more reducing environment results into zinc binding (Krezel & Maret, 2012). Evidence shows that MTs themselves act as potent electrophilic scavengers and cytoprotective agents against inflammation and inflammatory injury, with ability to capture a wide range of ROS, such superoxide, hydroxyl radicals, hydrogen peroxide, and nitric acid (Jarosz et al., 2017). MT traduce signals through the release of zinc ions, which in turn activate intracellular response to antioxidant stress. Zinc deficiency has an inverse relationship with cellular oxidative stress and has also been demonstrated to increase the production of ROS in various cells, such as mouse 3T3 cells, rat C6 glioma cells, human fibroblasts, and epithelial and neuronal cells (Choi, Liu, & Pan, 2018).

Zinc Deficiency and Telomere Length:
The role of zinc in the maintenance of optimal health and genomic stability has been widely studied. Zinc plays a critical role in the activation of poly (ADP-ribose) polymerase that is involved in the repair at DNA damage sites (Paul, 2011). In humans, zinc deficiency has been shown to cause DNA damage. DNA damage may cause telomere shortening by triggering the fusion between chromosomes, which often takes place following telomere cap attrition associated with DNA damage (Paul, 2011). In older individuals, the percentage of cells of with critically shortened telomeres and a decrease in telomere length has been associated with the reduction in the concentration of intracellular labile zinc and zinc-binding protein MT in peripheral blood mononuclear cells (Cipriano et al., 2009). Shortened telomeres may create physiological conditions that mimic old age, possibly leading to the impairment of zinc homeostasis and MT expression, which may in turn contribute to further shortening of telomeres due to the role of zinc in the modulation of telomerase activity (Siren & Siren, 2010). Maternal diet that is deficient in zinc causes chromosomal abnormalities, including a demonstration of fusion between different chromosomes in rat models (Bell et al., 1975). The loss of telomere cap through attrition following DNA damage associated with zinc deficiency has been suggested to be one of the reasons as to why the fusion takes place.

Zinc Deficiency and Covid-19 Comorbidities:
Zinc deficiency is a common comorbidity in many chronic diseases, including major COVID-19 comorbidities in which the association is mainly described in terms of inflammatory and oxidant induction (Devirgilis et al., 2007). Epidemiological studies show that low zinc intake and low serum levels of zinc are linked to increased prevalence of obesity and its comorbid conditions, such as diabetes and CVD (Garcia, Long, & Rosado, 2009). In addition to the association with a high prevalence of obesity, zinc deficiency has also been associated with increased oxidative stress and the inflammatory response in obese individuals, which includes a link between low superoxide dismutase activity and obese individuals (Tungtrongchitr et al., 2003).As reported by (Chen et al., (1998) fasting plasma zinc concentrations have an inverse relationship to BMI and plasma glucose levels, a finding that also points to a possible role of zinc in diabetes (another key COVID-19 comorbidity). In relation to diabetes, essential dietary zinc and proteins that modulate zinc metabolism play a key role in metabolic homeostasis in peripheral tissues that respond to insulin (Myers, Nield, & Myers, 2012). Mounting evidence shows that insulin resistance may be associated with zinc deficiency, with some of the mechanisms proposed to explain insulin resistance during zinc deficiency including the following: zinc deficiency causes impairment in insulin secretion by the pancreas; zinc deficiency may interfere with insulin receptor binding; zinc deficiency may also lead to decreased insulin receptor synthesis; and that zinc deficiency may cause abnormal glucose carrier structure and/or translocation inside the cell due to increased lipid peroxidation (Salgueiro et al.,2001). Research findings also show that diabetic patients have significantly lower mean serum zinc levels compared with healthy controls, and that zinc supplementation for type-2 diabetics had a beneficial effect of elevating serum zinc level (Al-Maroof& Al-Sharbatti, 2006).

Oxidative Stress, COVID-19 and COVID-19 Comorbidities:
Studies on the link between COVID-19 and oxidative stress are still on-ongoing. However, published scientific evidence shows that changes observed in COVID-19 patients show involvement of oxidative stress, including coagulopathy, cell hypoxia, and amplification and perpetuation of the cytokine storm (Cechini & Cecchini, 2020). Nevertheless, it is fairly understood that COVID-19 comorbidities, including diabetes, hypertension, cancer, and cardiovascular diseases, and severe asthma may involve oxidative stress and inflammation. Demissie et al., (2006) reported on the link between insulin resistance, oxidative stress, hypertension, and leukocyte telomere length. Using terminal restriction fragment (TRF) length, the authors explored how leukocyte telomere length was associated with insulin resistance, hypertension, and oxidative stress. Based on their findings, the researchers reported that hypertension, insulin resistance, and oxidative stress were associated with shorter leukocyte telomere length (Demissie et al., 2006). A study showed that arterial telomere uncapping could be playing a role in hypertension through tumor suppressor protein P53 (P53)/ cyclin- dependent kinase inhibitor 1A (P21) induced senescence (Morgan et al., 2014). Further logistic regression conducted to compare significant predictors of a hypertension status, and the results showed that localized telomeres and BMI status were both significant predictors of a hypertension status (Morgan et al., 2014). An increase in pulse pressure and stiffness of the central arteries are found associated with aging, and also serve as independent indicators of cardiovascular risk (Jeanclose et al., 2000; Benetos et al., 2001). (Fyhrquist et al., (2011), investigated the relationship between leukocyte telomere length and risk of cardiovascular diseases in high- risk hypertensive populations. The findings of the study showed that leukocyte telomere length was associated with risk factors for type 2 diabetes and served as a predictor of cardiovascular disease in elderly patients with hypertension (Fyhrquist et al., 2011). Studies have also shown that short telomere length was associated with obesity parameters, with some findings indicating that there was a gender difference in relation how the obesity phenotype was related to telomere length (Nordfjall et al., 2008). Chronic asthma, another key COVID-19 comorbidity, has significantly been associated with other chronic conditions in older adults, including obstructive pulmonary disease, cardiovascular disease, and cancer, in addition to creating a substantial risk for early mortality (Iribarren et al., 2012; Belsky et al., 2014). Using a cohort of 203, 595 Northern California adults with asthma and a parallel asthma-free cohort, (Iribarren et al., (2012) showed that asthma was prospectively associated with an increased risk of major cardiovascular disease (CVD). Obesity, a key COVID- 19 comorbidity is known to alter metabolic process in a manner that leads to the establishment of the other COVID-19 comorbidities. A study conducted by (Cattan et al., (2008) showed that chronic oxidative stress induced through the depletion of tissue glutathione resulted into telomere length attrition, and thus contributed to the understanding of the link between glutathione deficiency, oxidative stress, and telomere length.

Figure 1: Metabolic Syndrome and Oxidative stress

*With obesity at the center, the relationship between severe COVID- 19 comorbidities, oxidative stress and inflammatory mediators, and telomere length is clarified.

Source: Costela-Ruiz, 2020.

Chronic Inflammation Metabolic Syndrome, Shortened Telomere length, and COVID-19 Comorbidities
Chronic inflammation can be described as a failure in the resolution of acute inflammation, especially in relation to the clearance of macrophages from inflamed site (Lawrence & Gilroy, 2007). During the chronic inflammation phase, cytokine interactions result in monocyte chemotaxis to the cite of inflammation, where macrophage activating factors, including IFN-γ, MCP-1, activate the macrophages while migration inhibition factors (MIF), such as GM- CSF (38) and IFN-γ, retain them at the inflammatory site (Feghali & Wright, 1997). Oxidative stress may lead to inflammation through the activation of several transcription of factors, which result into the differential expression of various genes (Hussain et al., 2016). Chronic inflammation may also be associated with telomere shortening (Shin & Shin, 2019).

Figure 2: Association between Obesity, Zinc Deficiency, Oxidative Stress and Inflammation

It is not well understood whether telomere length predicts metabolic alterations over an extended period of time as most studies have tended to examine cross-sectional and longitudinal relationships between telomere length and components of metabolic syndrome. Even so, there is a general agreement that shorter telomere length at baseline, cross-sectionally associates with a worse metabolic profile and with worse predictable trajectories for metabolic syndrome (Revesz et al., 2014).

Telomere Length and Respiratory Infections:
COVID-19 is one of the many infectious diseases that affect the respiratory system. The nature of COVID-19 infection and pathogenesis in the lower and upper respiratory systems is largely comparable to other pathogenic respiratory infections and, hence, existing evidence on association between telomere length and respiratory infections may be indicative on the role of telomere length in COVID-19. The relationship between telomere length and respiratory infections has been explored by a number of studies. An investigation on the risk of experimentally induced upper respiratory infection in healthy adults and leukocyte telomere length showed that shorter leukocyte telomere length, particularly in CD8 and CD28 cells, was associated with an increased risk of infection and clinical illness (Cohen et al., 2013). The hypothesis was partly supported by Kiecolt-Glaser et al., (2013) by showing that telomere length acted as a limited mediator in the association between childhood socioeconomic status susceptibility to upper respiratory infections.

Evidence Summary: COVID-19 and Telomere Length: Based on the analysis conducted in the previous sections, there is evidence of an association between telomere shortening and COVID- 19, and includes shared deficiencies, mechanisms, finding.

Table 3: Biomarkers of Short Telomere Length (STL) and Association with COVID-19

Conclusion
The reviewed literature shows that COVID-19 comorbidities may be triggered by predictable trajectories of metabolic disturbances that occur in patients with shortened telomere length. The findings show that various biomarkers, including vitamin D deficiency, Zinc deficiency, glutathione deficiency, oxidative stress, and chronic inflammation are directly or indirectly correlated with both shortened telomere length and severity of COVID-19.

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