A fundamental question in the aging field is whether the age-related decline in tissue-specific adult stem cell function is reversible. Focused on the gut, our preliminary studies suggest that intestinal stem cell (ISC) numbers are reduced in old mice and humans and that intestinal crypts isolated from old mice are less functional in an in vitro organoid assay of ISC function. We also find that calorie restriction (CR) reverses the effects of aging on ISCs. In the mammalian intestine, a majority of ISCs express Lgr5 and are adjacent to Paneth cells, which constitute a component of the stem cell cellular neighborhood or "niche". We have recently demonstrated that CR in young mice augments ISC function by reducing mechanistic target of rapamycin complex 1 (mTORC1) signaling in Paneth cells, and that these effects of CR can be mimicked by rapamycin (an mTORC1 inhibitor). This interaction between Paneth cells and ISCs is mediated by expression in Paneth cells of bone stromal antigen 1 (Bst-1), an ectoenzyme that produces the paracrine factor cyclic ADP ribose (cADPR). Identification of the mechanistic steps in this process through the three aims of this proposal wil increase our understanding of how CR protects an organism against the age-related decline in tissue function. Specifically, we will test the hypotheses that induction of niche Bst-1 by CR and rapamycin boosts ISC function in old mice (Aim 1);that the transcription factor PPAR-gamma mediates this response in Paneth cells (Aim 2);and that cADPR-activated signaling mediates this response in ISCs (Aim 3).
The adult mammalian intestine is a rapidly renewing organ that is maintained by stem cells. In order to function properly, these intestinal stem cells often require signals from their cellular neighborhood or niche, which consists of Paneth cells. The intestine with age undergoes progressive loss of tissue function that includes a reduced ability to regenerate after injury. However, it is unknown how much of the age-related decline in intestinal repair is due to aging of the niche or aging of the stem cells themselves. We will investigate the molecular mechanisms involved in stem cell function by the Paneth cells, and study the role of intestinal stem cells and their niche in aging and in lifespan extending interventions such as calorie restriction.
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