Aging Gene Chil4 Found Essential for Lifelong Olfactory Neuron Renewal

The olfactory epithelium (OE) is one of the few tissues in the mammalian body capable of lifelong neuronal self-renewal, relying on globose basal cells (GBCs) to continuously generate new olfactory sensory neurons (OSNs). This regenerative capacity declines with age, contributing to the well-documented loss of smell in older adults. Understanding the molecular drivers of this decline is therefore critical to developing interventions for age-related olfactory dysfunction.

This study from Fudan University focused on Chitinase-like 4 (Chil4), a member of the glycoside hydrolase family 18 previously linked to tissue repair and immune regulation. Using public transcriptomic datasets and experimental aging mouse models, the authors first established that Chil4 expression is significantly upregulated in the aged OE, particularly in sustentacular (supporting) cells. This aging-associated upregulation prompted investigation into what happens when Chil4 is lost.

Chil4 knockout (Chil4−/−) mice were analyzed by single-cell RNA sequencing (scRNA-seq), immunofluorescence, and flow cytometry. The knockout animals showed a marked reduction in GBC numbers and a corresponding decrease in immature OSNs (iOSNs). Cell cycle analysis revealed that Chil4−/− GBCs accumulate in G2/M phase, with aberrant expression of key regulators including Cdk1, Ccna2, and Birc5, indicating impaired cell cycle progression. A particularly novel finding was the identification and loss of a distinct iOSN subcluster—termed iOSN_CeStLNq—characterized by co-expression of GAP43, Cebpb, Nqo1, and low levels of the mature OSN marker Stoml3. This subpopulation appears to represent a transitional state between immature and mature neurons, and its selective depletion in Chil4 knockouts suggests Chil4 is required for this critical neuronal maturation step.

Beyond neurogenesis, Chil4 deletion triggered inflammatory activation in Iba1+ microglia-like cells within the OE, with upregulation of pro-inflammatory markers including H2-Ab1, C3, and Ccl11. This neuroinflammatory response mirrors patterns seen in aging and neurodegenerative contexts, suggesting a potential mechanism linking Chil4 loss to broader age-associated OE deterioration. Aged olfactory organoids with Chil4 knockdown also showed reduced mature neuron production, reinforcing the in vivo findings in a more translatable system.

Collectively, the study establishes Chil4 as a previously unrecognized regulator of OE homeostasis, operating through at least three mechanisms: supporting GBC proliferation, enabling a transitional neuronal maturation state, and suppressing neuroinflammation. These findings open new avenues for understanding and potentially treating age-related olfactory loss, though the translation to human biology requires further validation.