Monocyte subpopulations exhibit distinct TNF-dependent aging signatures

Abstract Monocytes are a key cell type contributing to age-associated inflammation or inflammaging. Since monocytes have the potential to enter circulation and differentiate into macrophages in tissues, they are capable of having a systemic effect on health. Here, we characterize the effect of aging on the transcriptional regulation of monocyte subpopulations in the bone marrow. We find that aging classical (Ly6c high) and non-classical (Ly6c low) monocytes exhibit distinct transcriptional profiles. These were associated with changes to the epigenomic landscape driven by the activity of specific TFs that often had opposing effects in monocyte subpopulations. Next, we determined that the aging signature was diminished in TNF-KO mice indicating that monocytes are altered in a TNF-dependent manner. Finally, we found that a subset of the aging signature was triggered by TNF over-expression. Together, our results implicate key factors driving age-associated changes to the transcriptional regulation of monocyte subpopulations. This study provides a better understanding of the impact of aging on monocytes and identifies targets for future investigation aiming to improve health in aging.