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As life expectancy increases globally, the prevalence of age-related diseases, particularly malignancies, is set to rise dramatically. This trend poses significant challenges, as approximately 80% of all new cancer diagnoses occur in individuals aged 55 and older, with hematologic malignancies representing a considerable portion of these cases. These malignancies are often linked to the aging of hematopoietic stem cells (HSCs), which undergo functional decline over time. This decline is characterized by diminished self-renewal capacity, biased differentiation towards myeloid and platelet lineages, and an accumulation of unrepaired DNA damage, potentially leading to clonal hematopoiesis of indeterminate potential (CHIP) and oncogenic transformation. Given that alterations in hematopoietic function are believed to drive the late onset of hematologic malignancies, understanding the aging process of hematopoiesis is crucial for devising effective treatments. Our research is exploring new pathways of hematopoietic regulation, particularly focusing on the role of mast cells, traditionally known for their involvement in immunity, in regulating hematopoiesis. Our findings using the mast cell-deficient KitW-sh mouse model suggest that the absence of mast cells leads to notable changes in the bone marrow, including peripheral neutrophilia, an increase in HSC populations, and enhanced resistance to myeloablative to stress. Further, we observed that treatment with Cetirizine, a second-generation antihistamine, results in an expanded myeloid cell and HSC population in the bone marrow. Our hypothesis is that inhibiting mast cell derived histamine signaling through pharmacological intervention can improve hematopoietic fitness in aging organisms and limit the progression of age-related hematopoietic diseases. This project, "Antihistamines to prevent age-associated hematopoietic decline," aims to demonstrate that repurposing a well tolerated and widely used drug could revolutionize the treatment of hematologic aging and its associated conditions.
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