Current Research and Scholarly Interests
Somatic Mutations in Aging
Aging is associated with an increased incidence of cancer and several other diseases. As a post-doctoral fellow, Dr. Jaiswal identified a common age-related disorder of the blood characterized by the acquisition of certain somatic mutations in hematopoietic stem cells (Jaiswal et al., NEJM 2014). These mutations allow stem cell clones to expand relative to normal stem cells; this clonal expansion is termed "clonal hematopoiesis of indeterminate potential", or CHIP (Steensma et al., Blood 2015).
The most commonly found mutations in CHIP are in genes involved in epigenetic regulation (DNMT3A, TET2, ASXL1). CHIP is very rare in the young, but becomes common with aging. Between 10-30% of the elderly have a clonal mutation meeting the definition of CHIP. Those with CHIP are at markedly increased risk of developing hematological malignancies such as myelodysplastic syndrome, acute myeloid leukemia, and lymphoma.
Surprisingly, CHIP is also associated with increased risk of atherosclerotic cardiovascular disease, and this relationship is thought to be causal based on mouse models (Jaiswal et al., NEJM 2017). Mechanistically, the mutations in CHIP lead to increased expression of inflammatory gene modules in mature immune cells such as macrophages. These immune effector cells are derived from the mutated hematopoietic stem cells in the marrow, hence they also harbor the CHIP-related mutations.
These observations suggest that somatic mutations in hematopoietic stem cells that arise during aging may have a variety of effects on health. The lab seeks to understand the biology and clinical impact of these mutations, as described in the projects below.