Maladaptive trained immunity as a hematopoietic stem cell driver of inflammaging

Trained immunity is a phenomenon in which the innate immune system retains a form of immunological memory, allowing it to respond more vigorously to subsequent infections or inflammatory stimuli. In the context of aging, this process has been implicated in the development of age-related diseases, including cardiovascular disease, diabetes, and cancer. Recent studies have suggested that hematopoietic stem cells (HSCs) play a critical role in the regulation of trained immunity, but the precise mechanisms by which they do so remain unclear. The authors of the current study have made significant progress in this area, revealing that aging HSCs trigger a form of trained immunity that fuels chronic low-grade inflammation. This process is characterized by the activation of specific immune cells, including neutrophils and macrophages, which release pro-inflammatory cytokines and chemokines that contribute to the development of age-related diseases. The authors have also identified SIRT3, a mitochondrial deacetylase, as a key molecular brake on this process. SIRT3 expression wanes with age, and its loss is associated with increased inflammation and tissue damage. The authors propose that SIRT3 plays a critical role in regulating the activity of HSCs and preventing the development of trained immunity, and that its loss contributes to the chronic inflammation that underlies age-related physiological decline. Overall, the current study provides important insights into the mechanisms by which aging HSCs contribute to the development of age-related diseases, and highlights the potential of SIRT3 as a therapeutic target for the prevention and treatment of these conditions. However, it is essential to note that this study was conducted in a research-use-only laboratory setting, and the findings should not be interpreted as evidence of the efficacy or safety of any particular therapeutic intervention. As such, this study should only be used for research purposes, and not for any clinical or therapeutic application. The authors emphasize that the results of this study should be interpreted with caution, and that further research is needed to fully understand the mechanisms by which aging HSCs contribute to the development of trained immunity and inflammaging.