Many mammalian organs with high cellular turnover (e.g. skin, intestine and blood) are composed of short-lived cells that require continuous replenishment by somatic stem cells. Aging results in the inability of these tissues to maintain homeostasis. Evidence accumulated over the past decade has found measurable and successive age-dependent decline in stem cell activity from adulthood to old age, in various organs, including hematopoietic, intestinal and muscle. This age-associated decline in stem cell function leads to a decline in the regenerative capacity in humans and mice, which may limit lifespan. Identifying mechanisms under which aged stem cells become phenotypically and functionally similar to young stem cells may be a first step towards designing rationale approaches to ameliorate stem cell aging in the clinics. Based on our preliminary results we hypothesize that the declining beta-catenin signaling and associated microbiota changes play a causal role in ISC functional changes upon aging in both mice and humans. To pursue this hypothesis, we will perform three aims.
In aim 1, we will determine the extend of changes in beta-catenin signaling in single ISCs upon aging via single-cell sequencing approaches and the impact of Wnt expression changes on beta-catenin signaling and a decline in the function of ISCs upon aging.
In aim 2, we will investigate the contribution of various niche cells to aging-associated changes in beta-catenin signaling in ISCs in vivo.
In aim 3, we will determine the role of microbiota in Wnt ligand expression in the niche cells and in regulating beta-catenin signaling and the function of ISCs upon aging. The proposed studies will unveil a new mechanism of changes in associating beta-catenin signaling and microbiota with the physiologic aging process of intestinal stem cells and alterations in tissue homeostasis. The findings of the proposal may lead to future therapeutic interventions preventing or reversing tissue aging.
The molecular mechanisms underlying mammalian tissue aging remains largely unknown. The proposed studies will investigate a new mechanism associating beta-catenin signaling and microbiota with the physiologic aging process of intestinal stem cells of both mice and humans. The study results may lead to future therapeutic interventions preventing or reversing tissue aging.
