Aging Intestinal Niche: Regulation of Stem Cells and Disease

Abstract

The maintenance of intestinal epithelial homeostasis and regenerative potential is fundamentally orchestrated by intestinal stem cells (ISCs). Aging is associated with a pronounced decline in intestinal function, with ISC dysfunction emerging as a pivotal determinant of tissue-level senescence. This process does not occur in isolation but is profoundly influenced by the remodeling of the surrounding stem cell niche. This review systematically elucidates how the multidimensional remodeling of the intestinal niche contributes to the functional decline of ISCs during aging. We specifically dissect alterations in four principal constituents of the ISC niche: mesenchyme, epithelium, immune system, and microbiota, and focus on their consequences for stem cell fate decisions to emphasize the intricate crosstalk between cell-intrinsic aging programs and extrinsic niche-derived cues. We then assessed mechanism-based interventions targeting different components of the aged ISC niche, distinguishing the restoration of physiological ISC function from transient regenerative stimulation. We also evaluate how the aging of ISC-niche influences the process of age-associated intestinal disorders and increases their susceptibility and further consider the reciprocal effects of disease and treatment on the niche. Finally, we outline several unresolved questions concerning the temporal and causal organization of aging in the ISC niche, and underscore the critical need for longitudinal, cell-specific, spatial multi-omic, and functional studies to distinguish durable rejuvenation from mere transient regenerative stimulation.