Fig. 2

COVID-19 and mechanisms of inflammaging in older individuals. Inflammaging (highlighted in yellow). Dysfunction of the basic mechanistic “hallmarks” and/or “pillars” of aging, including epigenetic alteration, oxidative stress, metabolic derangement, and genomic instability among other mechanisms, results in inflammation. Aging is associated with cellular senescence in many tissues, and it has been hypothesized that “in vivo,” similar to what has been demonstrated “in vitro,” such permanent state of proliferative arrest can be induced by many different cellular stressors in humans. One characteristic of cellular senescence is the secretion of a number of very active compounds (senescence associated secretory phenotype, or SASP) that include pro-inflammatory cytokines, which may leak in the circulation and contribute to a cycle of chronic inflammation with age (inflammaging). The accumulation of senescent cells in various tissues with age, especially with concurrent obesity, is considered part of the mechanism by which age is the strongest risk factor for many chronic diseases including atherosclerosis, osteoarthritis, chronic obstructive pulmonary disease (COPD), sarcopenia, and immunosenescence. These age-related diseases lead to an increased risk of morbidity, disability, and frailty. Serum levels of IL-6, a pro-inflammatory cytokine and a strong biomarker of inflammaging, also predict incident disability and frailty. COVID-19 (highlighted in blue). COVID-19 infection may hypothetically negatively impact several hallmarks of aging and theoretically accelerate inflammaging with an increased risk of age-related diseases (dashed blue lines) through various interrelated mechanisms. The overt activation of the immune response against the virus through the release of PAMPs and DAMPs can activate inflammation, which can adversely impact mechanisms of aging through the production of excessive oxidative stress, metabolic derangement, and DNA damage that can trigger cellular senescence and the production of SASP pro-inflammatory factors in multiple tissues. The immune response against the virus and the frequently superimposed bacterial infections may also represent an overwhelming challenge to the immune system and exhaust or dysregulate some of the physiological system, directly contributing to immunosenescence. Immunosenescence affects different aspects of the immune system that have vital implications to developing resistance to SARS-CoV-2 infection but may also contribute to deleterious sequalae, such as the maintenance of chronic inflammation. It is also possible that SARS-CoV-2 activates inflammation so strongly that there could be an exhaustion of the capacity to produce an inflammatory reaction (immune paralysis) such as seen in conditions like sepsis. The initial hyperinflammatory (cytokine storm syndrome; CSS) phase is followed by a powerful counter-regulatory, anti-inflammatory reaction and though the parameters of inflammation are still high, there is a reduced capacity to react to a new inflammatory insult, which can lead to immunosuppression and increased susceptibility to secondary infections. Many ICU patients that experience severe and prolonged illness suffer from post-intensive care syndrome (PICS) that manifests as cognitive, psychological and physical disabilities and a large percentage of them never fully recover their well-being and functional status. These clinical features are similar to those experienced by older persons with inflammaging and other age-related diseases such as sarcopenia, who are at increased risk for frailty. Survivors of SARS, ARDS, CSS, and PICS, all elicit physical and cognitive deficits that could be characterized as accelerated inflammaging raising the possibility that COVID-19 survivors may face accelerated inflammaging as well, with substantial long-term consequences on their well-being. For the COVID-19 experience, the ramifications of this syndrome may be worsened by the implementation of social distancing, socioeconomic stress and isolation that is unprecedented in world’s history, and whose long-term consequences on individuals may include accelerated inflammaging and development of age-related diseases and increased frailty risk. Whether blunting the cytokine storm by any type of intervention (highlighted in green) may prevent these long-term consequences, such as the development of inflammaging, is unknown and is one of the fundamental questions that should be addressed in future surveillance studies of COVID-19 patients, particularly older individuals, who recover from the acute infection and even those who face unprecedented COVID-19 social isolation who may have reduced physical activity and increased fear, stress, and depression