In a new study published in Aging Cell, researchers have shown that two promising anti-aging agents, the antibiotic rapamycin and the anti-diabetic drug metformin, reverse aging in a population of intestinal stem cells .
The aging intestine
Older people are more prone to gastrointestinal problems . Moreover, aging is a major risk factor for various cancers, including colorectal cancer. Therefore, it is necessary to develop therapeutic approaches to rejuvenate the aging intestine.
The function and structure of the intestinal epithelium, a single cell layer that lines the small intestine and colon, is maintained by the residing stem cells. Intestinal stem cells continuously divide to generate several types of progenitor cells.
Intestinal stem cells are known for their expression of the Lgr5 gene, a receptor of a stem cell growth factor regulated by Wnt signaling. Stem cell exhaustion is a hallmark of aging, and reversing it requires an understanding of the transcriptional and metabolic changes that intestinal stem cells undergo with age.
In this study, the researchers explored the transcriptional profile of aging intestinal stem cells, paying great attention to Lgr5-expressing cells in particular. They also managed to bring them to a more youthful state by treating them with rapamycin and metformin.
The researchers used several groups of mice for the experiments. First, they harvested intestinal stem cells from young (5-month-old) and old (24-month-old) mice. Prior to tissue collection, the mice were fed a purified control diet with a clear composition for 3 months.
The researchers then performed single-cell RNA sequencing and showed that the transcriptomic profiles of both stem cells and their progenitors changed dramatically with age. The expression of Lgr5 was reduced by a third, and 71% of transcriptions known to be dependent on Lgr5 were decreased in old mice.
Further analysis showed that several metabolic pathways were perturbed in the stem cells of old mice: oxidative phosphorylation, fatty acid metabolism, glycolysis, and ribosome pathway were upregulated, while Wnt and cell cycle pathways were suppressed. These changes reduced the proliferative capacity of the cells, as confirmed by BrdU staining.
By applying bioinformatics tools, the researchers revealed that age-related transcriptional alterations of stem cells had been passed on to the progenitor cells. Moreover, aging led to a disturbed developmental trajectory of intestinal cells, which was also confirmed by immunofluorescence analysis of two proteins that were differentially expressed in early and later progenitor cells.
Rejuvenation by geroprotectors
Next, the researchers analyzed intestinal stem cells collected from two groups of old mice receiving diets supplemented with either 0.1% metformin or 42 ppm rapamycin. Both drugs restored the expression level of Lgr5 to 87% and 83% of young mice, respectively.
In addition, the transcriptional profiles of the cells taken from the old mice treated with either one of the drugs were significantly more similar to the young animals. Moreover, both drugs restored the proliferative capacity of the cells and reversed some of the metabolic changes observed in the old cells.
Interestingly, metformin appeared superior to rapamycin for stem cell rejuvenation in a number of aspects. First, it reversed age-related deficits in fatty acid metabolism and glycolysis, while rapamycin did not.
Second, metformin showed a greater effect than rapamycin in reversing perturbed oxidative phosphorylation in the “main stem cells” as labeled by the study’s software.
Finally, rapamycin was less efficient than metformin at restoring the developmental trajectory of the intestinal cells by speeding up cell maturation delayed by aging.
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 reprogramming with aging in Lgr5hi ISCs retarded the maturation of cells in their progression along the crypt-luminal axis. Importantly, treatment with metformin or rapamycin at a late stage of mouse lifespan reversed the effects of aging on the function of Lgr5hi ISCs and subsequent maturation of progenitors. The effects of metformin and rapamycin overlapped in reversing changes of transcriptional profiles but were also complementary, with metformin more efficient than rapamycin in correcting the developmental trajectory. Therefore, our data identify novel effects of aging on stem cells and the maturation of their daughter cells contributing to the decline of epithelial regeneration and the correction by geroprotectors.
This study revealed the stem cell reprogramming abilities of therapeutic agents that are well-known for their anti-aging abilities in animal models. Aging stem cells are a major obstacle to organismal rejuvenation, and drug repurposing, if effective in humans, is an attractive approach to targeting it.
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 Choi J, Houston M, Wang R, Ye K, Li W, Zhang X et al. Intestinal stem cell aging at single-cell resolution: Transcriptional perturbations alter cell developmental trajectory reversed by gerotherapeutics. Aging Cell 2023; : e13802.
 Dumic I, Nordin T, Jecmenica M, Stojkovic Lalosevic M, Milosavljevic T, Milovanovic T. Gastrointestinal Tract Disorders in Older Age. Can J Gastroenterol Hepatol 2019; 2019: 6757524.
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