INTESTINAL STEM CELL FUNCTION IS IMPAIRED BY EXPOSURE TO AN OLD ENVIRONMENT

Intestinal aging is characterized by a decline in stem cell regeneration and renewal, inflammation, and loss of mucosal barrier integrity. Studies using heterochronic parabiosis indicate that circulating factors in old blood can mediate the transposition of aging phenotypes. In order to determine if intestinal aging is modulated by the systemic environment, we generated isochronic (Y-Y, O-O) and heterochronic (Y-O) C57BL/6 male parabionts. Utilizing an established organoid assay, we found that stem cell function in young crypts was significantly impaired by exposure to old blood (P<0.05). Furthermore, we observed a significant reduction in crypt area in these young mice to levels observed in old (P<0.05). Reassociation assays with young and old Lgr5+ stem cells and paneth cells confirmed that aging of the stem and niche cells, contributed to this decline. Several age-related intestinal phenotypes could be rescued in old mice by short-term rapamycin or salicylate treatment (P<0.05). Furthermore, while rapamycin had no effect on intestinal mTOR signaling, it reduced circulating levels of TNFα, IL-1β and INFy to youthful levels. An ex vivo screening assay confirmed that TNFα was able to potently disrupt stem cell function, suggesting its potential as a key pro-geronic factor in intestinal aging. Importantly, short-term treatment with a TNFα neutralizing antibody (60ug 3 x wk) partially restored stem cell function in old mice. Thus, these data demonstrate an important role for circulating pro-inflammatory factors in intestinal aging, and suggest that TNFα represents is a key pro-geronic factor in mediating the transposition of intestinal aging phenotypes by heterochronic parabiosis.