Xian H, et al. in pathogen immunity with increased age. This diminished capacity of the aged immune system is clinically evident, as ageing is associated with high morbidity and mortality rates for various infections and significant reductions in vaccine efficacy1-6. Thus, as the emergent SARS-CoV-2 coronavirus began to circulate the globe early in 2020, it was reasonable to expect the elderly population may be especially susceptible to poorer outcomes of COVID-19, the disease caused by SARS-CoV-2. Indeed, data from Wuhan, China showed that age was the primary risk factor associated with COVID-19 progression to acute respiratory distress syndrome (ARDS) and end-organ failure7, which has since been corroborated by many others8-10. COVID-19 has taken a devastating toll on the entire population, but particularly older adults. As of May 24, 2021, the Centers for Disease Control and Prevention (CDC) reported nearly 590,000 total deaths from COVID-19 in the United States alone, with an estimated 80% of those deaths occurring in individuals aged 65 years or older11,12. Compared to a 5-17 year-old reference group, the rate of hospitalization Amyloid b-Peptide (10-20) (human) and death due to COVID-19 is approximately 1,300 times higher in individuals between the age of 65-74, and 8,700 times higher in individuals 85 years and older in the United States11. While aged individuals have a higher prevalence of comorbidities that are also independently associated with increased risk to severe COVID-19, including cardiovascular disease, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, cancer, and others10, chronological age is still the single greatest risk factor for COVID-19 mortality13. Thus, this review will focus on the intersect between ageing and detrimental SARS-CoV-2 host-pathogen interactions during severe COVID-19 and detail the physiological and immunological mechanisms underpinning both circumstances. We will also highlight targets for new or adapted therapeutics that may improve aspects of immunosenescence implicated in these shared pathways. Directed enhancement of the ageing immune system may subsequently reduce the burden of death and long-term Mouse monoclonal to ROR1 disability caused by COVID-19. AGEING, INFLAMMAGEING, and IMMUNOSENESCENCE: AN OVERVIEW As humans age, the presence of systemic basal inflammatory mediators increases independently of acute immune challenges in a phenomenon known as inflammageing. This persistent, low-grade, chronic inflammation is speculated to drive many chronic diseases associated with ageing, and is also a main contributor to immunosenescence, a term defined as the overall changes to the immune system as we age, including its reduced ability to fight novel infection14. It is generally accepted that inflammageing occurs in response to an accumulation of exogeneous Amyloid b-Peptide (10-20) (human) and endogenous physiological stresses over time and is primarily mediated by immune cells and senescent cells (Figure 1)14,15. The relative variability in these many stressors from person to person likely explains why humans have wide variances in their biological inflammatory age across set chronological age time-points15,16. This is important to consider when studying the elderly, as those aged 65 years old are not a monolithic group. Open in a separate window Figure 1. Factors that contribute to inflammageing and immunosenescence. Both exogenous and cell-endogenous factors contribute to chronic inflammation with age, which is primarily mediated by immune cells and senescent cells. Senescent cells persist and accumulate during ageing, and they display an abnormal secretory phenotype, characterized by the production of inflammatory mediators, matrix metalloproteinases (MMPs), fibronectin, and reactive oxygen species. These inflammatory mediators contribute to inflammageing, Amyloid b-Peptide (10-20) (human) which, over time, affects immune cell function, promoting immunosenescene. The endogenous and exogenous factors listed here can also directly affect the inflammatory potential of the immune system, which further promotes a feed-forward loop of inflammageing and immunosenescence. Immune cells produce many of the inflammatory mediators found in ageing tissues, which can also impact their own function. The increased presence of proinflammatory cytokines or danger signals leads to constitutive low-level engagement of immune cell signaling events such as JAK-STAT, MyD88, NF-B, and inflammasomes, resulting in high.