Aging & COVID-19 susceptibility, disease severity, and clinical outcomes: The role of entangled risk factors.

The emergence of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) in late 2019 has been associated with a high rate of mortality and morbidity. It has been determined that the old population are not only at an increased risk for affliction with COVID-19 infection, but also atypical presentations, severe forms of the disease, and mortality are more common in this population. A plethora of mechanisms and risk factors contribute to the higher risk of infection in the old population. For instance, aging is associated with an increment in the expression of Angiotensin-Converting Enzyme-2 (ACE-2), the receptor for SARS-CoV-2 spike protein, which precipitates replication of the virus in the old population. On the other hand, immune dysregulation and changes in gut microbiota as a result of aging can contribute to the cytokine storm, one of the main indicators of disease severity. Decrement in sex steroids, especially in women, as well as growth hormone, both of which have crucial roles in immune regulation, is a key contributor to disease severity in old age. Senescence-associated oxidative stress and mitochondrial dysfunction in both pneumocytes and immune cells contribute to the severity of infection in an exacerbative manner. In addition, lifestyle-associated factors such as nutrition and physical activity, which are compromised in old age, are known as important factors in COVID-19 infection. Aging-associated comorbidities, especially cardiovascular diseases and diabetes mellitus, also put older adults at an increased risk of complications, and disease severity.

Pathophysiological Clues to How the Emergent SARS-CoV-2 Can Potentially Increase the Susceptibility to Neurodegeneration.

Along with emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019, a myriad of neurologic symptoms, associated with structural brain changes, were reported. In this paper, we provide evidence to critically discuss the claim that the survived patients could possibly be at increased risk for neurodegenerative diseases via various mechanisms. This virus can directly invade the brain through olfactory bulb, retrograde axonal transport from peripheral nerve endings, or via hematogenous or lymphatic routes. Infection of the neurons along with peripheral leukocytes activation results in pro-inflammatory cytokine increment, rendering the brain to neurodegenerative changes. Also, occupation of the angiotensin-converting enzyme 2 (ACE-2) with the virus may lead to a decline in ACE-2 activity, which acts as a neuroprotective factor. Furthermore, acute respiratory distress syndrome (ARDS) and septicemia induce hypoxemia and hypoperfusion, which are locally exacerbated due to the hypercoagulable state and micro-thrombosis in brain vessels, leading to oxidative stress and neurodegeneration. Common risk factors for COVID-19 and neurodegenerative diseases, such as metabolic risk factors, genetic predispositions, and even gut microbiota dysbiosis, can contribute to higher occurrence of neurodegenerative diseases in COVID-19 survivors. However, it should be considered that severity of the infection, the extent of neurologic symptoms, and the persistence of viral infection consequences are major determinants of this association. Importantly, whether this pandemic will increase the overall incidence of neurodegeneration is not clear, as a high percentage of patients with severe form of COVID-19 might probably not survive enough to develop neurodegenerative diseases.

Understanding the Immunologic Characteristics of Neurologic Manifestations of SARS-CoV-2 and Potential Immunological Mechanisms.

Similar to its predecessors, coronavirus disease 2019 (COVID-19) exhibits neurotrophic properties, which lead to progression of neurologic sequelae. Besides direct viral invasion to the central nervous system (CNS), indirect CNS involvement through viral-mediated immune response is plausible. Aberrant immune pathways such as extreme release of cytokines (cytokine storm), autoimmunity mediated by cross-reactivity between CNS components and viral particles, and microglial activation propagate CNS damage in these patients. Here, we review the currently available evidence to discuss the plausible immunologic pathways that may contribute to the development of COVID-19 neurological complications, namely Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis, Guillain-Barre syndrome, seizure, and brainstem involvement.