In a groundbreaking study recently published in Nature Communications, researchers have unveiled a critical molecular mechanism underlying age-related olfactory dysfunction. This research, led by Wang, Cha, Xie, and their colleagues, sheds light on how the cytokine IL-17a plays a pivotal role in the decline of the sense of smell as mammals age. Their work not only advances our understanding of sensory deterioration with age but also opens new avenues for therapeutic interventions aimed at restoring olfactory function.
The sense of smell, or olfaction, is an essential sensory modality that profoundly influences nutrition, safety, and quality of life. However, olfactory capacity naturally diminishes with age, a phenomenon observed across many species, including humans. Age-related olfactory dysfunction (AROD) can lead to decreased appetite, nutritional deficiencies, and increased risk of accidents due to the inability to detect hazards such as smoke or spoiled food. Despite its clinical significance, the precise molecular drivers of AROD have remained elusive, hampering the development of effective treatments.
The research team focused on interleukin-17a (IL-17a), a pro-inflammatory cytokine previously implicated in autoimmune diseases and chronic inflammation. IL-17a is chiefly produced by a subset of T-helper cells known as Th17 cells but also by innate immune cells. The cytokine is notorious for orchestrating inflammatory cascades, but its role in sensory tissue aging and regeneration was unexplored prior to this publication. The team’s hypothesis posited that elevated levels of IL-17a in the aging olfactory system might interfere with the regenerative processes that maintain olfactory neurons, ultimately leading to olfactory decline.
To examine this hypothesis, the study utilized an aged murine model, enabling detailed molecular and histological analyses. The researchers demonstrated that IL-17a expression markedly increases in the olfactory epithelium of aged mice compared to young controls. This elevated IL-17a correlated with a significant reduction in olfactory receptor neuron (ORN) populations, suggesting an inhibitory effect on neurogenesis. Single-cell RNA sequencing further revealed that the receptor populations responsible for IL-17a signaling, including IL-17 receptor A (IL-17RA), are selectively upregulated in olfactory progenitor cells during aging, rendering these progenitors susceptible to inflammatory cues.
Mechanistically, IL-17a was found to induce changes in the olfactory epithelium that promote respiratory metaplasia, a pathological transformation wherein olfactory sensory neurons are replaced by respiratory epithelial cells, which lack olfactory capabilities. Respiratory metaplasia is a hallmark of chronic inflammation and is detrimental to olfactory function. The presence of metaplastic respiratory epithelium not only decreases the niche for olfactory neurons but also alters the local microenvironment, perpetuating inflammatory cycles and further impairing regeneration.
The team meticulously assessed the regenerative capacity of olfactory tissues by labeling newly generated neurons with thymidine analogs and tracking their survival and integration. IL-17a exposure was shown to significantly impede progenitor cell proliferation and differentiation into mature olfactory neurons. This effect was attributed, in part, to the cytokine’s ability to activate downstream inflammatory signaling pathways, including NF-κB and MAPKs, which are known to mediate cellular stress responses and apoptosis in numerous cell types.
Notably, genetic ablation or pharmacological inhibition of IL-17a signaling signaling pathways in aged mice led to a restoration of olfactory neurogenesis and a reduction in respiratory metaplasia. These interventions reversed much of the age-associated olfactory decline, reaffirming the central role of IL-17a in this pathological process. Electrophysiological recordings further confirmed improved olfactory epithelial responsiveness to odorants following IL-17a neutralization, underscoring the functional relevance of the findings.
These observations carry important implications for human health. Age-related olfactory dysfunction often goes under-recognized but significantly impacts the elderly population. This research suggests that targeted modulation of IL-17a or its downstream effectors could serve as a novel therapeutic strategy to mitigate or even reverse sensory decline. Drugs that inhibit IL-17a are already approved for other inflammatory conditions, such as psoriasis and psoriatic arthritis, indicating that repurposing these agents for olfactory preservation is a tantalizing prospect that warrants rapid exploration.
Beyond the therapeutic horizon, this work provides a critical advance in our understanding of how age-associated inflammation — sometimes termed “inflammaging” — directly compromises sensory system integrity. It highlights the dual role of the immune system, capable of both protecting and damaging tissues based on context and regulatory balance. The identification of respiratory metaplasia driven by IL-17a adds a new dimension to the study of mucosal aging, bridging immunology, neuroscience, and regenerative biology.
The broader biological significance extends to other tissues where IL-17a influences epithelial remodeling and degeneration. Understanding the cellular cross-talk that leads to metaplasia offers insights into chronic disease etiologies beyond the olfactory system, including airway diseases and certain cancers. Furthermore, delineating how inflammation impairs progenitor cell function paves the way for enhancing tissue regeneration in multiple organs.
Future studies are expected to explore the translational potential of these findings. Critical questions include determining the precise cellular sources of IL-17a in the aged olfactory mucosa, the interplay with other cytokines and growth factors, and the impact of systemic versus local inflammation. Longitudinal studies in human populations will be essential to confirm whether IL-17a elevation correlates with olfactory decline and whether existing IL-17a inhibitors can restore smell in elderly patients.
Ultimately, this pioneering work by Wang and colleagues marks a watershed moment in sensory neuroscience and aging research. It moves the field beyond correlative descriptions of decreased olfaction with age toward mechanistic insight, solidifying IL-17a as a master regulator of olfactory epithelium integrity and function in aging. As our global population ages, interventions safeguarding sensory function will become increasingly vital for maintaining well-being and independence in older adults.
This study exemplifies the power of integrating immunology with sensory biology to decode complex aging processes. It underscores that immune modulation need not be restricted to classical inflammatory diseases but may also be the key to preserving the senses that enrich human life. With continued collaborative efforts and translational momentum, the era of immune-targeted therapies for sensory rejuvenation appears on the horizon.
Subject of Research: The role of IL-17a in age-related olfactory dysfunction, olfactory epithelium regeneration, and respiratory metaplasia in mice.
Article Title: IL-17a induces age-related olfactory dysfunction by impairing regeneration and promoting respiratory metaplasia in mice.
Article References:
Wang, S., Cha, X., Xie, Y. et al. IL-17a induces age-related olfactory dysfunction by impairing regeneration and promoting respiratory metaplasia in mice. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67786-2
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