Aging-associated microbiota changes may be key to susceptibility rather than aging itself

Age is clearly one of the primary factors correlated with severe outcomes of COVID-19 and may be related to immunosenescence–the gradual reduction in immune function typically observed with age[14]. However, chronological age alone may not be the most important factor in recovery from the viral infection, since people under 40 years old have died, while others, who are over 90, have recovered. It is hypothesized here that factors that are often, but not always, related to aging are more important than age itself.
Clues as to these age-associated factors may come from the observation that individuals with the most severe outcomes frequently had preexisting conditions, including cardiovascular disease, hypertension, Type 2 diabetes mellitus and chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) or asthma[1,3]. Thus, a brief examination of some of these diseases in relation to the microbiome and respiratory infections might be useful.
All these diseases are associated with inflammation and have been linked to various types of imbalances, or “dysbiosis,” in the gut microbiota([15,16]. Microbes are also found in tissues in healthy controls, e.g., the blood[17] and lungs[18]. It has been hypothesized that what distinguishes the diseased state from a healthy state is increased levels of potentially pathogenic species from a variety of endogenous or exogenous sources[12].
Extensive evidence for the role of the microbiome comes from studies of the interactions between immune responses to various respiratory infections and the intestinal microbiome in animal models. A recent review[4] comprehensively surveys the research regarding a wide array of types of microbiome-viral interactions, noting that evidence supports the idea that a normal healthy microbiome tends to lead to resistance to viral infections. For example, in a chicken model of influenza, antibiotic-treated mice are more susceptible to influenza infection[19]. In a mouse model, the commensal bacteria, Clostridium orbiscendins, produces desaminotyrosine, which primes Type I interferon signaling, thus mediating protection from influenza[20]. In a model of respiratory syncytial virus, a probiotic was able to restore protection from viral infection in germ-free mice[21].
Many different microbes, including oral microbes associated with periodontal disease[22] and Chlamydia pneumoniae[23], have been found in atherosclerotic plaques, and these microbes have been proposed to lead to the chronic low-grade inflammation typical of atherosclerosis. COPD is associated with an abnormal or dysbiotic microbial community in the lungs[18] and the gut[24]. Diabetes and the obesity that is often associated with it are also characterized by inflammation and imbalanced microbial communities[25]. Although it is a low-grade inflammation, elevations of IL-6 and CRP indicate that an inflammatory process is occurring[26]. Although these inflammatory markers tend to increase with age, along with rates of aging-associated diseases, they can be normal in those experiencing healthy aging[26] and can be high in younger people under certain circumstances[27].
Although not the topic of this article, it should be noted in passing that there are other factors that might influence susceptibility to COVID-19.  A few of the possibilities include genetic effects on immune responses, nutritional status, prior chronic disease or therapy effects on immune responses and immune memory to coronaviruses or other potentially cross-reacting viruses. The infectious dose of the virus may also be important in determining outcomes.