Aging Impairs Wound Healing by an HSC-Autonomous Mechanism - Project Summary/Abstract The world's population is aging rapidly, and by 2050, the population over 60 years will exceed 2 billion people or 25% of the total global population. Tissue repair is critical for the survival of all organisms. Aging causes a gradual decline in tissue integrity, partly due to a decline in stem cell function, a major hallmark of aging. Due to its accessibility and temporal predictability, cutaneous wound healing provides a valuable model framework to characterize the effects of aging on tissue injury1. Aging disrupts the precisely coordinated immune cell response that orchestrates the three phases of cutaneous wound healing. However, it is unknown whether this disruption is initiated by the aging of the tissue itself or the aging of the immune system. Recently, a breakthrough study showed that the aging immune system or “immunosenescence” precedes and drives organ aging2. Thus, an inference from this concept is that the mechanism by which aging impairs wound healing is largely dependent on how aging impairs the immune system. Our long-term goal is to identify how aging impairs immune cell function and show that we can restore youthful wound healing by reversing immune aging. Hematopoietic stem cells (HSCs) are remarkable cells in our bone marrow that make at least one trillion new blood cells daily. We have shown that HSCs produce all of our circulating immune cells and regulate their gene expression by “epigenetic reprogramming”. We will use sophisticated “single-cell epigenomics,” some of which were developed in our laboratories, to characterize how aging affects the gene expression of individual immune cells and how that expression is regulated by epigenetic modifications. We have three Aims: Aim 1: Determine if aging impairs wound healing by an HSC-Autonomous mechanism. Aim 2: Identify the aging-specific- HSC oxidant stress that drives immune aging and impairs wound healing. Aim 3: Identify the master epigenetic enzyme(s) in aged HSCs that epigenetically reprogram the gene expression of wound macrophages and their cross-talk with fibroblasts and keratinocytes. Once we identify the “master epigenetic enzyme” affected by aging in HSCs that reprograms the gene expression of immune cells, we will reverse the effects of aging on the master epigenetic enzyme to restore youthful wound healing. The fact that the effects are “epigenetic” implies that the effects of aging, at least on the immune system, are reversible and, by proof of principle, would open the door to new molecular therapies to reverse the effects of aging.
