Aging effects on intestinal homeostasis associated with expansion and dysfunction of intestinal epithelial stem cells

Abstract

Intestinal epithelial stem cells (IESCs) are critical to maintain intestinal epithelial function and homeostasis. We tested the hypothesis that aging promotes IESC dysfunction using old (18-22 months) and young (2-4 month) Sox9-EGFP IESC reporter mice. Different levels of Sox9-EGFP permit analyses of active IESC (Sox9-EGFPLow), activatable reserve IESC and enteroendocrine cells (Sox9-EGFPHigh), Sox9-EGFPSublow progenitors, and Sox9-EGFPNegative differentiated lineages. Crypt-villus morphology, cellular composition and apoptosis were measured by histology. IESC function was assessed by crypt culture, and proliferation by flow cytometry and histology. Main findings were confirmed in Lgr5-EGFP and Lgr5-LacZ mice. Aging-associated gene expression changes were analyzed by Fluidigm mRNA profiling. Crypts culture from old mice yielded fewer and less complex enteroids. Histology revealed increased villus height and Paneth cells per crypt in old mice. Old mice showed increased numbers and hyperproliferation of Sox9-EGFPLow IESC and Sox9-EGFPHigh cells. Cleaved caspase-3 staining demonstrated increased apoptotic cells in crypts and villi of old mice. Gene expression profiling revealed aging-associated changes in mRNAs associated with cell cycle, oxidative stress and apoptosis specifically in IESC. These findings provide new, direct evidence for aging associated IESC dysfunction, and define potential biomarkers and targets for translational studies to assess and maintain IESC function during aging.

Intestinal Stem Cell Aging: Origins and Interventions

“…Other studies have reported sometimes similar, sometimes conflicting phenotypes of aging ISCs: Moorefield et al (179) report increased villus height and Paneth cells in 18-to 22-monthold mice, increased ISC proliferation, and expansion of the ISC population (identified in this study by moderate expression of Sox9), while also demonstrating that crypt organoid cultures from old mice yield fewer and less-complex organoids. The authors also find increased apoptosis Aging of the stem cell compartment of the small intestine of mice.…”

Advanced age promotes colonic dysfunction and gut‐derived lung infection after stroke

“…Indeed, our study showed that older animals displayed worse colonic inflammation and injury microscopically prior to stroke induction when compared to younger counterparts, indicating innate biological differences with age. Consistent with these findings, a recent study demonstrated that older mice showed increased apoptotic cells in intestinal crypts and villi, with functional impairment of isolated intestinal epithelial stem cells, suggesting a reduced capacity for tissue repair following injury (Moorefield et al, ).…”

Microbial Metabolites and Intestinal Stem Cells Tune Intestinal Homeostasis

“…[ 166,167 ] Accumulating evidence suggests the aged intestinal epithelium—instead of being hypo‐proliferative as suggested by instinct—contains more proliferating cells and has a higher proliferation rate. [ 168–171 ] Concomitantly, there is also an increase in apoptosis in the stem cell population, [ 170,171 ] and a retarded response to fasting or irradiation‐induced damage. [ 168,172,173 ] This increase in proliferation may be a strategy to combat aging‐associated increase in stem cell death.…”

“…Nevertheless, hyper‐proliferation may increase the risk of genetic abnormality and cancer development. Moreover, several studies report an increase in villi height, [ 171,173 ] possibly in attempt to expand the absorptive surface area of the gut to compensate the reduced absorptive capacity during aging.…”