A new study in Nature Aging is drawing attention to a possible biological engine behind inflammaging—the chronic, low-grade inflammation that rises with age and is linked to cardiovascular disease, neurodegeneration, metabolic disorders, frailty and declining immune function. In “Maladaptive trained immunity as a hematopoietic stem cell driver of inflammaging,” Moshe Divangahi and Kelly Y. King examine how the immune system’s ability to remember earlier challenges may gradually become harmful. Their analysis focuses on hematopoietic stem cells, the rare cells in bone marrow that continuously produce the body’s blood and immune cells.
Unlike adaptive immune memory, which is associated mainly with B cells and T cells, trained immunity describes a long-lasting functional change in innate immune cells. The innate immune system responds rapidly to threats without relying on the highly specific receptors used by adaptive immunity. After exposure to infections, vaccines, inflammatory signals or other stressors, innate immune cells and their precursors can become “trained,” responding more strongly to a later challenge. This phenomenon can improve protection against unrelated pathogens, but the new study highlights how persistent or improperly regulated training may turn into a liability over time.
The proposed connection begins in the bone marrow, where hematopoietic stem cells, or HSCs, reside in specialized microenvironments known as niches. HSCs are normally maintained in a relatively quiet state, dividing only when new blood cells are needed. During infection or tissue injury, inflammatory cytokines and other danger signals can activate these cells and redirect blood production toward myeloid cells, including monocytes, macrophages and neutrophils. This emergency response is useful in the short term. However, repeated or prolonged exposure to inflammatory signals may leave a durable imprint on HSCs, changing how they behave even after the original threat has disappeared.
That imprint can involve several layers of cellular regulation. Inflammatory stimulation may alter chromatin, the DNA-protein structure that controls access to genes, as well as DNA methylation, metabolic pathways and the activity of transcription factors. These changes can influence which genes are switched on when an HSC produces descendants. A stem cell affected by trained immunity may therefore generate blood cells with an enhanced tendency to produce inflammatory mediators. Over years, this could create a self-reinforcing system in which inflammation modifies stem cells, and the altered stem cells continually replenish inflammatory immune populations.
This mechanism offers a framework for understanding why aging is accompanied by a gradual shift in blood-cell production. With advancing age, HSC populations often become more heterogeneous and may favor myeloid output over the generation of lymphoid cells. The result can be a larger supply of innate immune cells alongside a weaker capacity to produce certain lymphocytes, contributing to an immune system that is simultaneously more inflammatory and less adaptable. The authors’ concept of maladaptive trained immunity places this imbalance upstream, suggesting that long-term changes in stem-cell behavior may help organize the broader immune dysfunction seen in older adults.
The idea also overlaps with research into clonal hematopoiesis, a process in which genetically or epigenetically altered HSCs expand and produce a substantial fraction of a person’s blood cells. Some of these clones carry mutations in genes involved in epigenetic control or inflammatory signaling. Their descendants can release elevated levels of cytokines such as interleukin-1 beta and interleukin-6, molecules that help coordinate immune responses but can damage tissues when persistently produced. Trained immunity and clonal hematopoiesis are not identical, yet both illustrate how long-lived changes in HSCs can influence the inflammatory state of the entire body.
The proposed model may help explain why inflammation can persist without a continuing infection. In younger individuals, inflammatory responses are generally followed by resolution, a coordinated process involving anti-inflammatory signals, tissue repair and the removal of activated cells. Aging can weaken these resolution pathways while increasing exposure to inflammatory stimuli from damaged tissues, altered gut microbes, metabolic stress and recurrent infections. If HSCs retain a memory of these pressures, the bone marrow may continue producing immune cells primed for aggressive responses. The immune system would then remain prepared for danger, but at the cost of damaging healthy tissues.
The implications extend beyond basic immunology. If maladaptive trained immunity is a major driver of inflammaging, interventions might need to target the bone marrow and HSC regulatory networks rather than suppress inflammation throughout the body. Possible strategies could include selectively interrupting inflammatory cytokine signaling, restoring metabolic or epigenetic balance in HSCs, improving the bone-marrow niche, or reducing the expansion of harmful blood-cell clones. Such approaches would require caution because completely blocking trained immunity could impair protection against infection and weaken beneficial vaccine responses. The challenge would be to distinguish protective immune memory from the persistent, pathological form described by the authors.
The study also points toward new ways of studying biological age. Blood-cell composition, inflammatory proteins, HSC activity and epigenetic signatures could potentially be combined to identify people whose immune systems have entered a maladaptive state. Future research will need to determine how permanent trained-immunity signals are, whether they can be reversed, and which exposures are most important in establishing them. By placing hematopoietic stem cells at the center of the inflammaging process, Divangahi and King provide a unifying hypothesis: the aging immune system may not simply become weaker, but may be actively reprogrammed by its history of inflammatory encounters. Understanding that history could become essential to slowing age-related disease while preserving the immune system’s ability to respond when real threats arrive.
Subject of Research: Hematopoietic stem cells, trained immunity, inflammaging and age-related immune dysfunction
Article Title: Maladaptive trained immunity as a hematopoietic stem cell driver of inflammaging
Article References: Divangahi, M., King, K.Y. Maladaptive trained immunity as a hematopoietic stem cell driver of inflammaging. Nat Aging (2026). https://doi.org/10.1038/s43587-026-01197-w
Image Credits: AI Generated
DOI: 10.1038/s43587-026-01197-w
Keywords: trained immunity, hematopoietic stem cells, inflammaging, aging, innate immunity, bone marrow, clonal hematopoiesis, inflammation, immune memory, cytokines
Tags: aging and immune systembone marrow immune regulationcardiovascular disease and immune agingchronic low-grade inflammationhematopoietic stem cell dysfunctionhematopoietic stem cellsimmune system memory mechanismsInflammaginginflammation-driven neurodegenerationinnate immune memorymaladaptive trained immunitytrained immunity and age-related diseases
