Project Summary
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.
