Kirin and the University of Tokyo Achieve World’s First Confirmation that Cellular Senescence Reduces Nutrient Absorption Using Human iPS Cell-Derived Intestinal Organoids

Research Findings (Summary)

1. Induction of cellular senescence in human iPS cell-derived intestinal organoids resulted in decreased expression of genes related to nutrient absorption and metabolism, suggesting a decline in nutrient uptake associated with cellular senescence (Figure 1).
2. Increased expression of EMT-related genes and mesenchymal cell marker genes was observed, suggesting that cellular senescence promotes EMT (Figure 2).

Implications

We confirmed that cellular senescence reduces nutrient absorption in small intestinal epithelial cells. Furthermore, the findings suggest that this may be driven by EMT-induced loss of epithelial cell function.

Future Outlook

By elucidating the mechanisms underlying age-related intestinal dysfunction, we aim to develop new functional ingredients that help maintain intestinal health, which serves as a foundation for healthy longevity in the era of 100-year lifespans.

Background and Objectives

Intestinal aging is associated with systemic aging, and reduced nutrient absorption in particular is thought to contribute to malnutrition and frailty in the elderly. However, because direct evaluation of the intestines in elderly individuals is challenging, detailed elucidation of the mechanisms and the development of preventive strategies have remained limited. We previously established a cellular senescence model using human iPS cell-derived small intestinal organoids. In this study, we aimed to reproduce the age-related decline in nutrient absorption using this model and to elucidate its underlying mechanisms.

Research Method

Cellular senescence was induced in monolayer-cultured human small intestinal organoids by treatment with cisplatin, an anticancer drug. Gene expression related to nutrient absorption (e.g., sugars, amino acids) and epithelial-mesenchymal transition (EMT) was evaluated using quantitative PCR (qPCR).

Results

Gene expression related to nutrient absorption was compared between normal human intestinal organoids and senescent organoids. Induction of cellular senescence resulted in decreased expression of SLC5A1, a gene involved in glucose absorption, and SLC16A10, a gene involved in amino acid absorption (Figure 1). In addition, glucose uptake was significantly reduced in senescent organoids.

Further investigation of the mechanism underlying reduced nutrient absorption revealed increased expression of TGFB1, an EMT-inducing gene, as well as ACTA2 and CDH2, mesenchymal cell marker genes (Figure 2).

Research Results

This study demonstrated a decline in nutrient absorption and induction of EMT in human small intestinal organoids under a cellular senescence model, suggesting that EMT may contribute to the loss of intestinal functions, including nutrient absorption. Future development of functional ingredients aimed at improving nutrient absorption and suppressing EMT is expected to help prevent intestinal aging.

What is Epithelial-Mesenchymal Transition (EMT)?

EMT is a biological process in which epithelial cells, which line surfaces such as the skin and intestinal tract, lose their epithelial characteristics and acquire mesenchymal traits. This transition weakens the barrier function that protects against external substances and instead confers mesenchymal features, including secretion of extracellular matrix components such as collagen and increased invasiveness. EMT plays an essential role in physiological processes like wound healing. However, excessive EMT is associated with pathological conditions, including tissue fibrosis and the progression of cancer cell invasion and metastasis, underscoring its role in disease.