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A recent study led by Associate Professor Takuya Yamamoto and Researcher May Nakajima-Koyama has uncovered a crucial mechanism that helps maintain intestinal stem cells (ISCs) during aging. The research highlights the importance of a delicate balance between interferon-gamma (IFN-γ) and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling in preserving the ISC population. The findings were published in the journal Cell Reports.
Unraveling the Aging Process in Intestinal Stem Cells
The intestinal epithelium undergoes the highest cell turnover in the adult body, necessitating strict regulation of ISCs to sustain continuous production of absorptive and secretory cells. Growth factors and cytokines from the stem cell niche and immune cells control ISC renewal and differentiation. Despite aging-related environmental changes, ISCs persist in generating new cells, hinting at protective mechanisms that shield them from microenvironmental fluctuations.
To investigate how aging affects ISCs, researchers examined intestinal tissues from young (2–4 months old) and aged (22–27 months old) mice. Using an Lgr5 reporter gene as an ISC marker, they found that the ISC pool remains stable with age. However, while ISC proliferation capacity was unchanged, progenitor cell proliferation declined, and ISCs showed an enhanced tendency to differentiate into enteroendocrine cells, which regulate metabolism.
Single-Cell Analysis Reveals Key Genetic Changes
By analyzing over 10,000 individual cells from young and aged intestines, the research team identified age-related alterations in gene expression. Enterocyte maturation was notably affected, with aged enterocytes exhibiting metabolic adaptations. These findings suggest that differentiated cells are more vulnerable to aging than ISCs.
Further analysis identified MHC class II genes, Ceacam10, and Ly6e as aging markers in ISCs. The expression of these genes was elevated but did not correlate at the single-cell level, indicating multiple independent regulatory mechanisms at play.
Balancing IFN-γ and ERK/MAPK Signaling
To explore the regulatory pathways involved, researchers used bioactive molecules to manipulate signaling in intestinal organoids. They discovered that IFN-γ activation and ERK/MAPK signaling inactivation contribute to aging-related intestinal changes. When ISCs were exposed to IFN-γ and MEK/ERK inhibitors, a quiescent state was induced, which could be reversed by IFN-γ treatment.
Further transcriptome analysis showed that IFN-γ counteracted the global transcriptomic changes induced by ERK/MAPK inhibition, partly by influencing Wnt/β-catenin signaling and the transcription factor Myc. The study concluded that while IFN-γ and ERK/MAPK signaling are crucial for ISC maintenance, they also contribute to age-related dysfunction in differentiated cells.
Implications for Anti-Aging Therapeutics
This research suggests that the mammalian intestinal epithelium prioritizes ISC preservation, potentially at the cost of differentiated cell function. Restoring ERK/MAPK and IFN-γ signaling to a youthful state could be a promising anti-aging strategy with minimal effects on ISCs.
The study provides valuable insights into how ISCs are safeguarded during aging and opens new avenues for therapeutic interventions aimed at maintaining intestinal health in aging populations.
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Readers should consult healthcare professionals before considering any therapeutic applications based on this research.
