Abstract
Background: The incidence of olfactory impairment increases with age; however, the detailed molecular and cellular mechanisms underlying this increase are yet to be determined.Methods: We examined the influence of aging on olfactory receptor neurons (ORNs), which are maintained by a unique stem cell system, from olfactory progenitor cells to mature ORNs, by histological comparisons of the physiological status of the olfactory epithelium between young adult and aged mice. Furthermore, we clarified the expression of genes encoding inflammatory cytokines, neurotrophins, growth factors, and extracellular matrix proteins to reveal the molecular mechanisms underlying olfactory impairment caused by aging.Results: The numbers of mature and immature ORNs, but not olfactory progenitors, decreased in the aged olfactory epithelium, with a concurrent reduction in Ki-67-positive proliferating cells. Transcriptome analyses revealed an increase in Il6, encoding a component of senescence-associated secretary phenotypes (SASP), and a decrease in Igf1, encoding a growth factor for ORNs, in the aged nasal mucosa. Interestingly, expression levels of several extracellular matrix genes, including Col1a2, decreased in the aged nasal mucosa. Consistent with the transcriptional changes, the number of Col1a2-GFP-positive cells decreased in the aged lamina propria.Conclusions: Our data suggest that reduction in ORN number and cell proliferation, reduced extracellular matrix gene expression, and increased SASP contribute to olfactory impairment during aging.
Highlights
Olfaction is impaired by a variety of factors, including environmental chemicals, upper respiratory tract infection, trauma, and, in particular, aging
Our data suggest that reduction in olfactory receptor neurons (ORNs) number and cell proliferation, reduced extracellular matrix gene expression, and increased senescence-associated secretary phenotypes (SASP) contribute to olfactory impairment during aging
Primitive olfactory progenitors were identified based on SOX2 expression in the basal layer, and immature ORNs and mature ORNs were identified based on Growth associated protein 43 (GAP43) and OMP expression in the OE, respectively
Summary
Olfaction is impaired by a variety of factors, including environmental chemicals, upper respiratory tract infection, trauma, and, in particular, aging. The olfactory system consists of peripheral compartments such as the olfactory mucosa including olfactory receptor neurons (ORNs), and central structures such as the olfactory bulb, the piriform/entorhinal cortex, anterior insula, orbitofrontal cortices, or the cortical nucleus of the amygdala. The OE of the olfactory mucosa has a unique regenerative stem cell system; it is maintained by the life-long replenishment of mature ORNs in the luminal layer from the stem/progenitor cells in the basal layer (Costanzo, 1991; Schwob, 2002; Su et al, 2009; Ueha et al, 2014). The incidence of olfactory impairment increases with age; the detailed molecular and cellular mechanisms underlying this increase are yet to be determined
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