Functional decline is a hallmark of aging in multiple tissues, a process thought to be driven in part by deterioration in resident stem cell function. Th intestine serves as a prototypical example of a tissue that relies on its stem cell niche, and displays features of age-related dysfunction. Indeed, intestinal stem cells and their niche have been well characterized and are responsible for maintaining the integrity of the intestinal epithelium, but as our data show, intestinal stem cell function deteriorates with aging, and may perpetuate the overall decline in intestine and whole organismal aging. Remarkably, utilizing heterochronic parabiosis, we have determined that intestinal stem cell and tissue homeostasis are markedly impaired in young mice exposed to old blood, suggesting that intestinal aging is modulated by circulating factors in the old systemic milieu (Fig. 1). Through a series of preliminary experiments, we have identified `inflammaging' as a key regulator of this decline, and hypothesize that TNF? and IL-1? serve as the primary pro-geronic candidates in mediating these phenotypes. Based upon these data, we hypothesize that chronic overexposure of the intestinal stem cell niche to TNF? and IL-1? during normal aging, drives intestinal decline. Importantly, this decline could underlie geriatric disorders and syndromes of the gut including malabsorption and mucosal barrier dysfunction, with implications beyond the intestine. Thus, we propose several innovative approaches to determine the role of TNF? and IL-1?, including (i) aberrations in intestinal stem cell decline, (ii) intestinal barrier dysfunction, inflammation and stress, and (iii) causal role in transposition of intestinal aging phenotypes by heterochronic parabiosis. In order to demonstrate the role of TNF? and IL-1? as pro-geronic proteins in the intestine, we will perform the following three specific Aims. First, we will focus on intestinal stm cell function, by determining the contribution of Lgr5+ intestinal stem cell and niche cell intrinsc aging and TNF? and IL-1? mediated extrinsic aging to intestinal stem cell niche decline.
This aim will utilize a combination of aged genetic models and animals treated with neutralizing antibodies (Abs) targeting TNF? and/or IL-1? in aged mice, as a tool to characterize pro-geronic functions on stem, niche and epithelial cells in the aging gut. This will be carried out using both ex vivo organoid assays as well as transcriptomic and proteomic assays in well-defined cell populations. Next, we will focus on intestinal function with aging, by determining the contribution of TNF? and IL-1? on intestinal inflammation, oxidative damage, and mucosal barrier dysfunction with normal aging. We hypothesize that TNF? and IL-1?, derived from local and/or systemic immune cells, drives oxidative damage, intestinal leak of microbial byproducts into the lymph, leading to induction of pro-inflammatory phenotypes. Thus, this aim will utilize TNF? and/or IL-1? Abs and genetic models as a strategy to characterize effects on tissue and cellular oxidative stress, the aging mucosal barrier and lymphatics, and local and systemic inflammation. Finally, we will perform parabiosis rescue experiments, in order to determine the contribution of TNF? and IL-1?-mediated signaling in the transposition of the aging intestinal phenotype to young mice by the old systemic environment. This novel aim will utilize parabiosis [isochronic young-young (Y-Y), old-old (O-O), and heterochronic (Y-O)] and genetic models, to determine if young TNFR1R2 double knockout (YTNFRko), and/or young IL-1 receptor knockout (YIL1r1ko) mice, rescues young mice from the transposition of intestinal decline by exposure to an old environment. Further elucidating and validating the role of TNF? and IL-1? as candidate pro-geronic proteins in intestinal aging, as well as their mechanistic actions, will not only shed greater light onto the underlying biology of intestinal decline and dysfunction, but should also important insights toward new therapeutic targets, in an effort to promote healthy aging and longevity in humans.
The intestinal stem cell niche is critical for maintaining homeostasis of the gut. With aging, there is a decline in intestinal function, and we have found that this may be due to age-related dysfunction of the intestinal stem cell niche. Utilizing parabiosis, we have determined that this decline may be due to the pro-geronic factors, TNF? and IL-1?, which are elevated in old blood. Thus, determining the causal and mechanistic actions of these cytokines on intestinal aging, will shed greater light onto the underlying biology with relevance to improving human health.
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