Abstract:The intestinal epithelium consists of cells derived from continuously cycling Lgr5hi intestinal stem cells (Lgr5hi ISCs) that mature developmentally in an ordered fashion as the cells progress along the crypt‐luminal axis. Perturbed function of Lgr5hi ISCs with aging is documented, but the consequent impact on overall mucosal homeostasis has not been defined. Using single‐cell RNA sequencing, the progressive maturation of progeny was dissected in the mouse intestine, which revealed that transcriptional reprogr… Show more
“…4E ). This dietary suppression of cell developmental progression was also reported in mice in which genetic manipulation of mitochondrial structure downregulated stem cell function ( 51 ) and in human patients with IBD ( 36 ), and was also identified by us in aging mice, reversed by geroprotectors ( 56 ).…”
NWD1, a purified diet establishing mouse exposure to key nutrients recapitulating levels that increase human risk for intestinal cancer, reproducibly causes mouse sporadic intestinal and colonic tumors reflecting human etiology, incidence, frequency and lag with developmental age. Complex NWD1 stem cell and lineage reprogramming was deconvolved by bulk and scRNAseq, scATACseq, functional genomics and imaging. NWD1 extensively, rapidly, and reversibly, reprogrammed Lgr5hi stem cells, epigenetically down-regulating Ppargc1a expression, altering mitochondrial structure and function. This suppressed Lgr5hi stem cell functions and developmental maturation of Lgr5hi cell progeny as cells progressed through progenitor cell compartments, recapitulated by Ppargc1a genetic inactivation in Lgr5hi cells in vivo. Mobilized Bmi1+, Ascl2hi cells adapted lineages to the nutritional environment and elevated antigen processing and presentation pathways, especially in mature enterocytes, causing chronic, pro-tumorigenic low-level inflammation. There were multiple parallels between NWD1 remodeling of stem cells and lineages with pathogenic mechanisms in human inflammatory bowel disease, also pro-tumorigenic. Moreover, the shift to alternate stem cells reflects that the balance between Lgr5 positive and negative stem cells in supporting human colon tumors is determined by environmental influences. Stem cell and lineage plasticity in response to nutrients supports historic concepts of homeostasis as a continual adaptation to environment, with the human mucosa likely in constant flux in response to changing nutrient exposures. Implications: Although oncogenic mutations provide a competitive advantage to intestinal epithelial cells in clonal expansion, the competition is on a playing field dynamically sculpted by the nutritional environment, influencing which cells dominate in mucosal maintenance and tumorigenesis.
“…4E ). This dietary suppression of cell developmental progression was also reported in mice in which genetic manipulation of mitochondrial structure downregulated stem cell function ( 51 ) and in human patients with IBD ( 36 ), and was also identified by us in aging mice, reversed by geroprotectors ( 56 ).…”
NWD1, a purified diet establishing mouse exposure to key nutrients recapitulating levels that increase human risk for intestinal cancer, reproducibly causes mouse sporadic intestinal and colonic tumors reflecting human etiology, incidence, frequency and lag with developmental age. Complex NWD1 stem cell and lineage reprogramming was deconvolved by bulk and scRNAseq, scATACseq, functional genomics and imaging. NWD1 extensively, rapidly, and reversibly, reprogrammed Lgr5hi stem cells, epigenetically down-regulating Ppargc1a expression, altering mitochondrial structure and function. This suppressed Lgr5hi stem cell functions and developmental maturation of Lgr5hi cell progeny as cells progressed through progenitor cell compartments, recapitulated by Ppargc1a genetic inactivation in Lgr5hi cells in vivo. Mobilized Bmi1+, Ascl2hi cells adapted lineages to the nutritional environment and elevated antigen processing and presentation pathways, especially in mature enterocytes, causing chronic, pro-tumorigenic low-level inflammation. There were multiple parallels between NWD1 remodeling of stem cells and lineages with pathogenic mechanisms in human inflammatory bowel disease, also pro-tumorigenic. Moreover, the shift to alternate stem cells reflects that the balance between Lgr5 positive and negative stem cells in supporting human colon tumors is determined by environmental influences. Stem cell and lineage plasticity in response to nutrients supports historic concepts of homeostasis as a continual adaptation to environment, with the human mucosa likely in constant flux in response to changing nutrient exposures. Implications: Although oncogenic mutations provide a competitive advantage to intestinal epithelial cells in clonal expansion, the competition is on a playing field dynamically sculpted by the nutritional environment, influencing which cells dominate in mucosal maintenance and tumorigenesis.
“…3c ). These findings are consistent with previous reports (GSE186811) analyzing Lgr5 hi cells from 12-month-old mice with bulk RNAseq which showed >95% of stem cell signature genes were down-regulated at 12 months when compared to 3 months 14 , 15 , which indicated that the stem cells damage appeared as early as middle age (12-month-old mouse) 16 . Fig.…”
Declined numbers and weakened functions of intestinal stem cells (ISCs) impair the integrity of the intestinal epithelium during aging. However, the impact of intestinal microbiota on ISCs in this process is unclear. Here, using premature aging mice (telomerase RNA component knockout, Terc−/−), natural aging mice, and in vitro colonoid models, we explore how heat-inactivated Bifidobacterium adolescentis (B. adolescentis) affects colon senescence. We find that B. adolescentis could mitigate colonic senescence-related changes by enhancing intestinal integrity and stimulating the regeneration of Lgr5+ ISCs via Wnt/β-catenin signaling. Furthermore, we uncover the involvement of Paneth-like cells (PLCs) within the colonic stem-cell-supporting niche in the B. adolescentis-induced ISC regeneration. In addition, we identify soluble polysaccharides (SPS) as potential effective components of B. adolescentis. Overall, our findings reveal the role of heat-inactivated B. adolescentis in maintaining the ISCs regeneration and intestinal barrier, and propose a microbiota target for ameliorating colon senescence.
“…Another study has revealed that CR preserves the functionality of adult stem cells in the intestinal epithelium by lowering mTORC1 activity, thereby safeguarding ISCs from DNA damage (Bruens et al., 2020). Rapamycin treatment improved the competitive reconstitution ability of aged HSCs, increased the frequency of ISCs and Paneth cells in young mice, partially restored aged mesenchymal stem cells (MSCs) functionality, and delayed the senescence of human epithelial stem cells (Choi et al., 2023; Kawakami et al., 2019; Nie et al., 2021). Studies on various types of stem cells have also shown that CR leads to an increase in stem cell quantity, regenerative potential, and reduced senescence (Bruens et al., 2020; Longo et al., 2021; Maharajan et al., 2020).…”
Section: “Old” Hallmarks Of Aging—longevity Perspectivementioning
confidence: 99%
“…Curcumin, a plant‐derived compound with well‐appreciated anti‐inflammatory properties, has shown variable results in regard to its impact on different stem cell types (N. Wang et al., 2016). Finally, senolytic drugs, including ABT263, dasatinib, and quercetin, have been shown to improve stem cell function by recycling senescent MSCs in mice (Chang et al., 2019; Choi et al., 2023; M. T. Islam et al., 2023).…”
Section: “Old” Hallmarks Of Aging—longevity Perspectivementioning
The revolution in aging research through the past decade has driven the progress in interventions that promote longevity. Dissection of the “old” hallmarks of aging has provided solid data for the definition of at least three “new” ones, opening avenues for the development of novel hallmark‐targeted pro‐longevity approaches. The quest for geroprotectors is of enormous interest with the ultimate goal of finding the alchemical stone that induces healthy aging and increases lifespan, pushing the limits of human longevity or even uncovering the absence of such limits. Several of the well‐appreciated geroprotectors that are recognized as longevity promoters are of natural origin such as metformin, resveratrol, aspirin, and spermidine. As the search for pharmacological modulators of healthspan and lifespan continues, numerous studies are focusing on the potential of plant secondary metabolites. The current review attempts to critically assess the available interventions and the breakthrough discoveries in the field of longevity research over the past decade. Correspondingly, novel approaches targeting the hallmarks of aging have been outlined, and the future goals in longevity research have been enlightened. Special emphasis has been placed on the potential of plant‐derived compounds as pro‐longevity agents.
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