Why does COVID-19 disproportionately affect older people?

Amber L Mueller, Maeve S McNamara, David A Sinclair, Amber L Mueller, Maeve S McNamara, David A Sinclair

Abstract

The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient's age. Adults over 65 years of age represent 80% of hospitalizations and have a 23-fold greater risk of death than those under 65. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea, and from there the disease can progress to acute respiratory distress syndrome, lung consolidation, cytokine release syndrome, endotheliitis, coagulopathy, multiple organ failure and death. Comorbidities such as cardiovascular disease, diabetes and obesity increase the chances of fatal disease, but they alone do not explain why age is an independent risk factor. Here, we present the molecular differences between young, middle-aged and older people that may explain why COVID-19 is a mild illness in some but life-threatening in others. We also discuss several biological age clocks that could be used in conjunction with genetic tests to identify both the mechanisms of the disease and individuals most at risk. Finally, based on these mechanisms, we discuss treatments that could increase the survival of older people, not simply by inhibiting the virus, but by restoring patients' ability to clear the infection and effectively regulate immune responses.

Keywords: COVID-19; aging; cytokine storm; epigenetic clock; immunity.

Conflict of interest statement

CONFLICTS OF INTEREST: AM and MM declare no conflicts. DAS is a board member, equity owner and inventor on patents licensed to MetroBiotech, Liberty Biosecurity, and Jumpstart Fertility, both developing molecules for the treatment of diseases by raising NAD+ levels. Other affiliations are listed here https://genetics.med.harvard.edu/sinclair-test/people/sinclair-other.php.

Figures

Figure 1
Figure 1
Ineffective clearance of SARS-CoV-2 infection in the aged respiratory system. The SARS-CoV-2 virus binds to ACE2 enzymes on airway epithelial cells in the upper respiratory tract where they are endocytosed and replicated (top left), alerting the immune system. Viruses then travel to the alveoli and infect type 2 pneumocytes which, in the youthful system (lower left), are recognized by alveolar macrophages (AMs) or dendritic cells (not pictured) that release cytokines and present antigens to T cells and other adaptive immune cells. T cells with the appropriate receptors activate other lymphocytes or directly kill infected cells, preventing the spread of the virus. Neutrophils migrate to the sites of infection to clear infected cell debris. In the aged system (top right), viral alert signals are initially slow, resulting in greater viral replication. Defective macrophages and T cells with a limited repertoire of receptors are less effective (lower right). More cells are infected, inducing high levels of inflammatory cytokine signaling. The endothelial cell lining of the capillary becomes inflamed, fibroblasts are activated, and SARS-CoV-2 viral components and cytokines enter the bloodstream. Fluid fills the alveolus, reducing lung capacity and the virus infects microvascular pericytes in other organs. A cytokine storm initiates microvasculature clotting, causing severe hypoxia, coagulopathy and organ failure. Created with BioRender.
Figure 2
Figure 2
Factors that increase the fatality risk of COVID-19. Epigenetic dysregulation, immune defects, advanced biological age, and other factors increase the risk of cytokine storm and COVID-19 fatality. Tightly controlled activation of the innate immune system is essential for viral recognition and clearance. Cytokine storm is the result of sustained activation of the inflammatory signaling cascade and can result in hypercoagulation in small blood vessels, which leads to tissue damage, DIC and multi-organ failure. Inflammaging and immunosenescence contribute to the development of cytokine storm. D-dimer, a fibrin degradation product and prognostic of disseminated intravascular coagulation (DIC), and elevated levels of the cytokine, IL-6, are associated in the clinic with increased fatality. Epigenetic dysregulation of the immune system and of the renin-angiotensin system (R)AS may increase fatality risk. A variety of biological clocks have been shown to predict human health and longevity more accurately that chronological age. An individual with a biological age greater than their chronological age is thought to be undergoing accelerated aging, which may increase the risk of COVID-19 fatality. Individuals with comorbidities such as cardiovascular disease, diabetes, obesity and COPD, are at greater risk for COVID-19 fatality. Conversely, individuals who live healthy lifestyles and consume geroprotectors such as metformin, resveratrol and NAD+ boosters may have a decreased risk of fatality. Created with BioRender.
Figure 3
Figure 3
Age-related changes that increase COVID-19 susceptibility. The aging immune system undergoes immunosenescence, T-cell diversity alterations and chronic activation of the innate immune system, known as inflammaging. These hallmarks of the aging immune system cripple the body’s ability to clear the SARS-CoV-2 virus, initiate and sustain cytokine storms, than cause acute organ injury, DIC and multi-organ failure. An age-associated decline in NAD+ results in derepression of NLRP3 and inflammasome in older people, further exacerbating the cytokine storm. Coronaviruses also possess an ADP-ribosylhydrolase that further depletes already-low NAD+ levels in older people. Leveling of the epigenetic landscape during aging results in changes in immune cell composition and function that decrease the immune system’s ability to mount a response to infection. Epigenetic dysregulation of ACE2 may also impact increased viral loads in older people. Dysregulation of the RAS during aging and in the context of age-associated disease, such as cardiovascular disease, hypertension, COPD and obesity, contributes to severity of COVID-19 infection. The glycome which controls a variety of immune signaling pathways changes during aging and in the context of metabolic diseases. For example, decreases in IgG galactosylation contribute to chronic inflammation. Biological clocks that measure different biomarkers of biological age may explain increased COVID-19 susceptibility more accurately than advanced chronological age. Created with BioRender.

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Source: PubMed

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