An emerging paradigm postulates that cellular aging is driven by epigenetic alterations of developmental signaling pathways. Alternative theories suggest that dysregulation of the oxidative stress response, DNA damage accumulation, global epigenetic drift, or metabolic byproduct accumulation are more important. Our inability to identify the primary drivers of cellular aging highlights a critical gap in our ability to design effective ways to treat and reverse age-related disease pathologies. Aging in humans is associated with reduced tissue repair, declining pulmonary function, and an enhanced susceptibility to chronic pulmonary diseases that are progressive, destructive and irreversible. Our overall objective in this proposed work is to identify the primary drivers of age-related functional decline in highly proliferative multipotent lung mesenchymal stromal cells (LMSCs). Like other tissue resident MSCs, LMSCs are tightly regulated, critical in development and adult tissue repair, and sensitive to age-related dysregulation. We have previously demonstrated that aging mice have reduced lung repair capacity and reduced LMSC function. Our proposed work will identify drivers of LMSC aging in companion dogs, a novel naturally-aging model in which we can identify broadly conserved mechanisms relevant to human aging. Our central hypothesis is that epigenetically-regulated changes in Wnt signaling and oxidative stress response pathways are interdependent primary drivers of reduced reparative function in aging LMSCs. This central hypothesis is based on our preliminary data showing that aLMSCs (isolated from aged dogs) have lower clonogenicity and proliferation, altered expression profiles of Wnt signaling components and oxidative response genes, and altered adaptive response to oxidative stress compared to yLMSCs (isolated from young dogs). We will test our central hypothesis by pursuing the following two specific aims.
Aim 1. Identify how regulation of Wnt signaling drives the age-related decrease in reparative capacity of LMSCs. From our preliminary data, our working hypothesis is that epigenetic changes in Wnt signaling drive reduced reparative capacity in aLMSCs versus yLMSCs.
Aim 2. Identify regulatory drivers of the cellular response to oxidative stress in aged LMSCs. From our preliminary data, our working hypothesis is that epigenetic changes in key adaptive oxidative stress response genes leads to a dysregulated oxidative response and reduced reparative capacity in aLMSCs versus yLMSCs. Our rationale is that we will identify conserved drivers of age-related functional decline in MSCs that will be critical for understanding the pathogenesis of age-related diseases in human patients.
The proposed research is relevant to public health because it will identify primary drivers of cellular aging in companion dogs, which represent a novel animal model for the study of aging in humans. This is critical in furthering our ability to design effective treatments for chronic human diseases associated with aging. The project is relevant to the NIH mission in general, and the mission of NIA and NIHLB in particular, by furthering our understanding of functionally important regulatory mechanisms in human aging.
