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

Inherited bone marrow failure syndromes, or IBMFS, are a diverse group of disorders caused by genetic changes present from birth. These conditions impair hematopoietic stem cells, the self-renewing cells responsible for generating red blood cells, immune cells and platelets. As the stem-cell pool becomes depleted or dysfunctional, patients may develop anemia, infections, bleeding problems and other complications. They also face an increased risk of MDS, a group of blood cancers characterized by ineffective blood production and the accumulation of abnormal blood cells.

For physicians, diagnosing IBMFS can be difficult because many patients do not carry mutations in the genes traditionally associated with the disorder. Young people who develop unexplained cytopenias, bone marrow abnormalities or MDS are often suspected of having an underlying germline condition, but the responsible genetic change may remain hidden even after extensive testing. The Kyoto University study suggests that SLF2 and SMC5 should now be considered among the genes that may explain these cases.

The researchers were led to the discovery while following patients with Atelis Syndrome, a recently described neurodevelopmental disorder linked to germline variants in SLF2 or SMC5. Several of the patients developed MDS at unusually young ages, while clinical examinations also revealed features consistent with inherited bone marrow failure. This unexpected combination prompted the team to investigate whether the same mutations affecting neurological development were also damaging the blood-forming system.

To test the mutations directly, the scientists generated induced pluripotent stem cells, or iPSCs, from a patient carrying pathogenic SLF2 variants. These cells can be reprogrammed from mature tissue into a stem-like state and then directed to form specialized cell types, including hematopoietic progenitor cells. Using CRISPR-Cas9 gene editing, the team corrected the patient’s SLF2 variants in otherwise genetically identical cells. These corrected lines, known as isogenic controls, allowed the researchers to compare diseased and repaired cells while minimizing the confounding effects of unrelated genetic differences.

The patient-derived cells displayed impaired blood-forming potential when differentiated into hematopoietic progenitors. Their abnormalities were observed in laboratory experiments and in animal models designed to assess stem-cell function in a living environment. In contrast, correcting the SLF2 variants restored key cellular properties, providing direct evidence that the mutations—not merely another inherited feature of the patient’s genome—were responsible for the bone marrow defects.

The study also points to a molecular explanation for the progressive nature of the syndrome. SLF2 and SMC5 participate in the organization and protection of chromosomes, processes that are essential when stem cells divide and preserve their genetic material. When these proteins are disrupted, hematopoietic stem cells appear to experience cellular stress and activate p53, a central tumor-suppressor protein. Although p53 can protect the body by stopping damaged cells from multiplying, chronic activation can cause stem-cell exhaustion, growth arrest or premature aging.

In the bone marrow, this process may create a damaging cycle. Genetic instability or defective chromosome maintenance triggers p53-dependent surveillance, removing or disabling stem cells that might otherwise replenish the blood system. Over time, the remaining stem cells become less capable of producing healthy blood cells. At the same time, surviving cells carrying additional abnormalities may gain a growth advantage, increasing the likelihood of progression toward MDS. The researchers’ results therefore link chromosome dysfunction, p53 activation and hematopoietic stem-cell aging in a single disease mechanism.

The findings could have immediate implications for genetic diagnosis and patient monitoring. Recognizing SLF2 and SMC5 mutations in children or young adults with unexplained bone marrow failure may allow clinicians to provide earlier surveillance for MDS and to make more informed decisions about treatment, including stem-cell transplantation. The work also demonstrates the value of patient-derived iPSCs and precise gene correction as tools for investigating rare diseases. By restoring the normal gene sequence in laboratory-grown cells, researchers can distinguish causal mutations from harmless genetic variation and begin testing possible therapeutic strategies.

“Our results show that genes originally linked to a neurodevelopmental disorder also play a critical role in maintaining hematopoietic stem-cell function,” said first author Sho Shibata. Corresponding author Kazuhisa Chonabayashi noted that correcting the variants reversed the cellular abnormalities, offering direct evidence that the mutations cause bone marrow failure. Published in Leukemia on 7 August 2026, the study expands the genetic landscape of IBMFS and inherited MDS susceptibility while offering researchers a new route for solving cases that have previously resisted diagnosis.

Subject of Research: Cells

Article Title: SLF2 and SMC5 dysfunction drives HSC aging and predisposes to MDS, defining a new inherited bone marrow failure syndrome

News Publication Date: 7 August 2026

Web References: https://doi.org/10.1038/s41375-026-03061-7

References: Leukemia, DOI: 10.1038/s41375-026-03061-7

Image Credits: Kyoto University / Sho Shibata

Keywords: inherited bone marrow failure syndrome, IBMFS, myelodysplastic syndrome, MDS, SLF2, SMC5, hematopoietic stem cells, HSC aging, p53, CRISPR-Cas9, induced pluripotent stem cells, iPSCs, Atelis Syndrome, germline mutations