As the body ages, its ability to fight off infection is severely compromised and its susceptibility to chronic inflammatory conditions is increased. This has been attributed to a process called “inflammaging” whereby aged immune cells exhibit symptoms of low-grade inflammation at steady-state. This condition is exacerbated by “myeloid skewing” in the bone marrow leading to the overproduction of myeloid cells when compared to lymphocytes. However, the underlying mechanism is not well understood. Our earlier studies have shown that myeloid cells are capable of reprogramming their epigenomic landscape in response to signals from the local environment, as evidenced by the distinct chromatin profiles of tissue-resident macrophages. We have demonstrated through functional assays that monocyte maturity is compromised in aged mice through a process that is mediated by exposure to an external cytokine, TNF, but the genomic landscape of monocyte differentiation in aging has yet to be explored. We propose that myeloid progenitors in the bone marrow are reprogrammed on the epigenomic level by the aging environment and that this leads to circulating monocytes with regulatory landscapes that are shifted towards inflammation. In order to test this hypothesis, we will use genomic techniques to compare the expression and chromatin profiles of myeloid cells in aging mice. Aim 1: we will isolate myeloid progenitors and blood monocytes from young, middle-aged, and old mice and perform RNA-seq for expression, ATAC-seq for chromatin accessibility, and ChIP-seq for histone modification to characterize regulatory elements. By comparing the results across aging, we can determine how the transcriptional and epigenomic profiles are altered in aging. We expect that the reprogramming of aged progenitors will persist into circulating monocytes causing them to express genes and regulatory elements associated with inflammation and immaturity. We will also perform computational analysis to recognize patterns and implicate key transcription factors that may be regulating this process. Aim 2: we will generate chimeras where the bone marrow of young mice is transplanted into old mice and vice versa. Then, we will collect myeloid progenitors and blood monocytes from the chimeric mice and perform genomic assays as described above. We will assess whether inflammaging is decreased through measures of systemic inflammation, such as serum chemokines and cytokines levels, and compare this with changes in the regulatory landscape of the transplanted cells in response to their host environment. If the aging environment is the source of inflammatory signals, then we would expect that aged monocytes in the young recipient would regain their youth, while young monocytes in the aged host would be prematurely aged. Our long-term objective is to understand the role of myeloid cells in aging and the effect on human health. This research will lead to a better understanding of the aging immune system and highlight targets for interventions to achieve a healthier old age.
|Effective start/end date||1/1/19 → 6/30/21|
- American Federation for Aging Research (Agmt 8/10/18)
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