Trained Immunity Improves Function in Aged Innate Immune Cells

Both the innate and adaptive immune systems decline in function and run awry with age. Taken as a whole, researchers view this as the combination of inflammaging and immunosenescence. Without delving into the details, inflammaging is chronic, unresolved inflammatory signaling, an overactivation of the immune system that produces harmful changes in cell behavior throughout the body, while immunosenescence is a decline in the effectiveness of the immune response, leaving an individual more vulnerable to pathogens and potentially cancerous cells, while also allowing senescent cells to accumulate in tissues. The two broad categories of dysfunction interact in a number of ways. Rising numbers of senescent cells, resulting from faltering immune surveillance, contribute meaningfully to inflammaging via their pro-inflammatory signaling, for example.

The aging of the innate immune system is quite different from that of the adaptive immune system, and arguably a great deal more is known about how to effectively deal with the latter issue. Restoring proper T cell production, via regeneration of the thymus and the hematopoietic cell populations of the bone marrow, and clearing out dysfunctional T cell populations may solve a great deal of adaptive immune aging. The innate immune system, on the other hand, suffers more complex, less well explored issues in cell behavior, and is also provoked into inflammatory signaling by problems such as the DNA debris that characterizes the aged tissue environment, for which researchers as yet do not have good solutions, or even paths to solutions.

Given that, it is interesting to note studies such as this one, in which researchers note that aged innate immune cells seem to react as well as young innate immune cells to approaches such as trained immunity, essentially vaccination with specific compounds, that can improve function and suppress inflammation in conditions involved excessive inflammatory signaling, such as respiratory infection and sepsis.

Trained Immunity Enhances Human Monocyte Function in Aging and Sepsis

Over the past two decades there has been an increased incidence of sepsis and this trend is likely to continue due to our aging population, increased use of immunosuppressive drugs and invasive procedures, and the emergence of antibiotic resistant opportunistic pathogens. Age has emerged as an independent predictor of morbidity and mortality in sepsis. Indeed, 60% of sepsis cases occur in patients over 65 years of age. It is generally accepted that age related immune senescence increases susceptibility to infection and sepsis, which raises the question of whether it is possible to modulate the aging immune system to improve resistance to infection. One possible approach to enhancing immune function during aging is innate immune training.

There is a substantial literature demonstrating that the innate immune system can be trained to respond more rapidly and effectively to infection. This phenomenon is referred to as "trained immunity" or "innate immune memory". Trained immunity is characterized by metabolic and epigenetic reprogramming in leukocytes in conjunction with enhanced antimicrobial functions. However, there is very limited information available on the effect of trained immunity in aging and/or sepsis. In 2011, it was reported that BCG vaccination prevented respiratory infections and improved cytokine production in individuals 60-75 years of age. Additionally, a 2020 clinical trial found that BCG vaccination increased protection from infection in individuals over 65 years old. While trained immunity increases inflammatory cytokine production upon restiumulation, interestingly it was found that BCG vaccination reduces systemic inflammation. It is now known that BCG, a potent immune training agent, induces the immune trained phenotype in humans, thus it is reasonable to speculate that the effect of BCG on respiratory infections in aging subjects may be mediated, in part, by trained immunity.

In this study, we examined innate immune training in monocytes isolated from healthy aging subjects and compared and contrasted their response to immune training with monocytes isolated from younger healthy individuals. We also examined innate immune training in monocytes derived from patients diagnosed with sepsis. We found that trained immunity increases metabolism and functionality of monocytes isolated from healthy aging subjects as well as in sepsis patients. In conclusion, this study confirms that innate immune training can be induced in aging healthy individuals as well as critically ill sepsis patients. We found that innate immune training can be induced regardless of age and there was no substantive difference in the immune trained phenotype as a function of age. We employed β-glucan as our immune training stimulus. The ability of glucan to induce the trained phenotype suggests that it may be possible to pharmacologically induce the immune trained phenotype in aging human immunocytes.