The Concept of Immune Resilience and Its Relevance to Degenerative Aging
The aging of the immune system is widely considered a progressive loss of functional capacity, such as the ability to effectively destroy pathogens and errant cells (known as immunosenescence), coupled to rising levels of unresolved, chronic inflammation (known as inflammaging). In today's open access paper, the authors are more interested in how well the immune system brings itself back to an equilibrium state following the disruptions of an inflammatory response. They call this capacity for restoration "immune resilience". In this framework, aging brings a loss of the ability to restore normality to the immune system following a period of stress, such as that resulting from infection, and it is this loss of resilience to stress that leads to morbidity and mortality.
Is this a useful way to look at immune aging? It is similar to the view of aging as a whole, a loss of the ability to restore homeostasis in the face of disruptive perturbation, that has been presented by Gero in recent years. At some point, the disruption pushes the body beyond its capacity for restoration, and into terminal decline. Does this building of frameworks lead to any usefully different approach to therapy than the present concept of progressively greater immunosenescence and inflammaging, however? At some point one has to match frameworks to the underlying biology, the mechanisms, the targets for therapy.
Why do individuals manifest such wide differences in lifespan, health status across age, and susceptibility to infectious diseases? One possibility is that variations in an immune trait contribute to these differences. Given that infections are among the most impactful environmental factors that shape the human genome, optimal host responses to these microbial drivers of natural selection may have played a role in increasing longevity. Hence, immune mechanisms may have evolved based on conferred resistance to the ancestral burden of inflammatory stress associated with infectious diseases. Resistance mechanisms could include higher immunocompetence and prevention of uncontrolled inflammation. In contemporary times, these infection-resistance mechanisms may confer advantages for a lower comorbidity burden and longevity.
Our hypothesis regarding the identity of this advantageous trait is immunologic resilience (IR). We define optimal IR as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance and longevity (immunocompetence), as well as control inflammation during acute, repeated, or chronic immune (antigenic) stimulation associated with inflammatory stressors (e.g., infections or autoantigens). IR is rooted in the principle that repeated inflammatory (antigenic) exposures are inevitable throughout life, necessitating allostatic processes that mediate adaptation, ideally returning immunocompetence and inflammation to optimal or pre-exposure levels. With this definition, optimal IR is linked to a conjoined high immunocompetence (IC)-low inflammation (IF) state.
Individuals preserving optimal IR metrics manifested advantages for longevity and survival as well as resistance to severe COVID-19, HIV-AIDS, common acute respiratory viral infections, recurrent skin cancer, and sepsis-associated mortality. These advantages were observed after controlling for age, sex, and/or level of antigenic stimulation. Collectively, our findings suggest that the lower immune status observed with age may be driven by two distinct mechanisms, one being dependent on age and the other attributable to IR erosion/degradation, which occurs concurrently with age but is not dependent on age per se. Thus, among persons of similar age, an individual's susceptibility to disease risks/severity and mortality may relate to their antecedent and current capacity for preservation and/or restoration of optimal IR when experiencing inflammatory stress.