Understanding the Mechanisms of Age-Dependent Decline of Intestinal Stem Cell Function

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7. Project Summary/ Abstract A number of mammalian tissues possess regenerative capacity and rely on tissue-specific somatic stem cells cells for renewal. A fundamental question in the aging field is whether there is a functional decline in somatic stem cells with age and whether we can use dietary or therapeutic interventions to decelerate or reverse age-dependent decline of adult stem cell function. In this proposal, we seek to answer these questions using the mammalian intestine, which undergoes age-dependent functional decline and regenerates through pools of Lgr5+ intestinal stem cells (ISC). In preliminary studies we found that: 1) aged crypts have both decreased function and frequency of ISCs; 2) short-term starvation enhanced the capacity of organoid formation from aged crypts and induced strongly a Peroxisome Proliferator-Activated Receptor Delta program in the ISCs; 3) we can recapitulate fasting effects with the highly specific PPARδ agonist GW501516. In Aim 1 we will use mouse genetics to determine the necessity and sufficiency of PPARδ signaling in mediating the effects of fasting in intestinal stem cells. In Aim 2 we will utilize LC-MS and Seahorse metabolic assays to determine if mitochondrial metabolism is augmented in aged ICSs. We will also determine if CPT1A mediates augmented ISC function in the fasted state. In the independent phase and Aim3, I will examine the interplay of diet, aging and microbiota by characterizing the function and regulation of the Gasdermin C family of genes in transit-amplifying progenitor (TA) cells.