Inflamm-aging: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by a high mortality of elderly men with age-related comorbidities. In most of these patients, uncontrolled local and systemic hyperinflammation induces severe and often lethal outcomes. The aging process is characterized by the gradual development of a chronic subclinical systemic inflammation (inflamm-aging) and by acquired immune system impairment (immune senescence). Here, we advance the hypothesis that four well-recognized features of aging contribute to the disproportionate SARS-CoV-2 mortality suffered by elderly men: i. the presence of subclinical systemic inflammation without overt disease, ii. a blunted acquired immune system and type I interferon response due to the chronic inflammation; iii. the downregulation of ACE2 (i.e. the SARS-CoV-2 receptor); and iv. accelerated biological aging. The high mortality rate of SARS-CoV-2 infection suggests that clarification of the mechanisms of inflamm-aging and immune senescence can help combat not only age-related disorders but also SARS-CoV-2 infection.

Keywords: COVID-19; Cardiovascular diseases; Host-directed therapies; Inflamm-aging; SARS-CoV-2; interleukin-6.

Fig. 1

Overview of the framework where inflamm-aging is the main phenomenon contributing to the high COVID-19 mortality rate seen in male, elderly, and frail patients. In these individuals, acute SARS-CoV-2 infection compounds their chronic, subclinical, aging-related proinflammatory state (inflamm-aging) which, together with immune senescence and the age- and gender-specific distribution of ACE2 in the airway epithelia, could blunt the antiviral response to inflammation. This model could explain the delayed viral clearance and the high rate of adverse outcomes observed in older patients in the late disease stages. The assessment of selected biological and immunological aging markers could be a valuable strategy for COVID-19 patient risk stratification in the earliest disease stage irrespective of their chronological age. Figure based on the classification of COVID-19 disease states proposed by Siddiqi and Mehra and adapted from the accompanying paper [78]. ACE2, angiotensin converting enzyme 2; cfDNA, cell-free DNA; IFN, interferon.