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 some key features of aging contribute to the disproportionate SARS-CoV-2 mortality suffered by elderly men. At least four well-recognized aging-related characteristics that are strongly expressed in older men go some way towards explaining why these patients account for the vast majority of fatalities: 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 (SARS-CoV-2 receptor), which triggers inflammation, particularly in patients with age-related comorbid diseases such as type II diabetes; and iv. accelerated biological aging, as measured by epigenetic and senescence markers (e.g. telomere shortening) associated to the chronic inflammatory state. Though typical of the aged, especially of elderly men, it is conceivable that these features are also shared by some subsets of the younger population. 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.

Alternating quarantine for sustainable epidemic mitigation

“…More generally, our AQ strategy can, and should, be reinforced by other complementary policies, to ensure mitigation success, from avoiding social gatherings to establishing isolation facilities, with the purpose of reducing in-house transmission. As a specifically relevant example, we consider, in Supplementary Note 3.1, the selective protection of vulnerable populations, addressing a crucial aspect of COVID-19, whose impact on the elderly or on individuals with co-morbidities, is disproportionately more severe [46][47][48] . In Supplementary Note 3.2, we examine how population-wide testing can further enhance AQ's performance.…”

Intersection between ageing-related Genes and SARS-CoV-2 Interactome: Is it higher than expected?

“…In this work we observed that some of the genes that are involved in this process (both inflammageing and immune response decline) [52] are targeted by the SARS-CoV-2, thus giving a partial answer to the increased mortality in elderly people. Interestingly, we found that the intersection between targets of SARS-CoV-2 and ageing-related proteins is higher than by chance for some virus proteins (NSP2, NSP4, NSP6, NSP11, NSP13, Orf7a, Orf3a, Orf8, Orf9c and M).…”

Immunosenescence is both functional/adaptive and dysfunctional/maladaptive

“…The understanding of adaptation/maladaptation of the immune system with aging was never more relevant than during the COVID-19 pandemic. It is widely stated that the old individuals are more susceptible [6,9,206,207]. This should help us to better understand the immune changes with aging which may be detrimental and which may be beneficial.…”