Aging-related olfactory loss is associated with olfactory stem cell transcriptional alterations in humans

BACKGROUNDPresbyosmia, or aging-related olfactory loss, occurs in a majority of humans over age 65 years, yet remains poorly understood, with no specific treatment options. The olfactory epithelium (OE) is the peripheral organ for olfaction and is subject to acquired damage, suggesting a likely site...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of clinical investigation 2022-02, Vol.132 (4)
Main Authors: Oliva, Allison D, Gupta, Rupali, Issa, Khalil, Abi Hachem, Ralph, Jang, David W, Wellford, Sebastian A, Moseman, E Ashley, Matsunami, Hiroaki, Goldstein, Bradley J
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Aging
Aging - metabolism
Causes of
Cell Differentiation
Clinical Medicine
Development and progression
Epithelial Cells - metabolism
Epithelium
Female
Gene Expression Regulation
Genetic aspects
Genetic transcription
Health aspects
Humans
Male
Medical research
Medicine, Experimental
Middle Aged
Neuroscience
Olfaction Disorders - metabolism
Olfactory Mucosa - metabolism
Prospective Studies
Smell disorders
Stem cells
Stem Cells - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:BACKGROUNDPresbyosmia, or aging-related olfactory loss, occurs in a majority of humans over age 65 years, yet remains poorly understood, with no specific treatment options. The olfactory epithelium (OE) is the peripheral organ for olfaction and is subject to acquired damage, suggesting a likely site of pathology in aging. Adult stem cells reconstitute the neuroepithelium in response to cell loss under normal conditions. In aged OE, patches of respiratory-like metaplasia have been observed histologically, consistent with a failure in normal neuroepithelial homeostasis.MethodsAccordingly, we have focused on identifying cellular and molecular changes in presbyosmic OE. The study combined psychophysical testing with olfactory mucosa biopsy analysis, single-cell RNA-Sequencing (scRNA-Seq), and culture studies.ResultsWe identified evidence for inflammation-associated changes in the OE stem cells of presbyosmic patients. The presbyosmic basal stem cells exhibited increased expression of genes involved in response to cytokines or stress or the regulation of proliferation and differentiation. Using a culture model, we found that cytokine exposure drove increased TP63, a transcription factor acting to prevent OE stem cell differentiation.ConclusionsOur data suggest aging-related inflammatory changes in OE stem cells may contribute to presbyosmia via the disruption of normal epithelial homeostasis. OE stem cells may represent a therapeutic target for restoration of olfaction.FundingNIH grants DC018371, NS121067, DC016224; Office of Physician-Scientist Development, Burroughs-Wellcome Fund Research Fellowship for Medical Students Award, Duke University School of Medicine.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI155506