Roads to the Fountain of Youth? Rejuvenating Intestinal Stem Cells

The intestinal stem cells (ISCs) of old mice and humans exhibit a reduced capacity for regeneration and repair. Compromised intestinal function may play a key role in systemic aging-related changes: not only in the affected gut, but also in the nervous and cardiovascular systems. For example, progression of age-related neurodegenerative diseases such as Alzheimer's and Parkinson's has been linked to increased inflammation from gut microbiota in old mammals, which, in turn, may be linked bidirectionally with reduced ISC function. Intestinal organoid formation has been used to dissect the mechanisms of decline of ISC function. Alterations of the Wnt pathway, including downregulation of Wnt ligands in ISCs and upregulation of Wnt ligand inhibitor Notum in Paneth cells, and dysregulation of mTORC1 contribute to the observed age-related decline. Short-term fasting, caloric restriction, and peroxisome proliferator-activated receptor delta agonists have been reported to increase ISC function in adult mice. Moreover, the mTOR inhibitor rapamycin, NAD+ precursor nicotinamide riboside, and ABC99, a small molecule Notum inhibitor, have all been reported to rejuvenate ISC function in old mice and thus may have promise in humans. However, there is some controversy over the key mechanisms involved in loss of function of ISCs, which likely results, in part, from differences in how the in vitro organoid assays are performed. Moreover, how the microbiome modulates the function of ISCs and vice versa remains to be elucidated.