Sci. Aging Knowl. Environ., 8 February 2006
Vol. 2006, Issue 5, p. pe6
[DOI: 10.1126/sageke.2006.5.pe6]


Olfactory Loss in Aging

Nancy E. Rawson

The author is at the Monell Chemical Senses Center in Philadelphia, PA 19104, USA. E-mail: rawson{at}

Key Words: smell • volatiles • olfactory receptor neurons • G protein-coupled receptor • odor signaling • odor processing


The volatiles from plants account for a myriad of flavors and fragrances that contribute greatly to the pleasure we all derive from a delicious meal, a fine wine, or a special perfume. Volatile stimuli can also represent a warning of danger--from smoke to spoiled food. Perception of these sensory stimuli represents an important quality-of-life and safety issue, yet the importance of our sense of smell is often underappreciated until it is lost. This special sense accomplishes the remarkable task of detecting, identifying, and discriminating among thousands of volatile chemicals at concentrations below the level detectable by even the most sensitive of instruments. Olfaction brings us intimate information about our surroundings, beginning before birth and continuing throughout life, persisting, in healthy individuals, with little or no interruption in the face of ongoing replacement (every month or so) of the primary receptor cells and their connections as they are lost because of damage or senescence. Despite the remarkable robustness of this sensory pathway, a gradual loss of olfactory function often occurs with aging that affects both quality of life and personal safety (see "The Flavor of Aging").

The extent of this sensory deficit has been well documented in many populations. One-third of the elderly report dissatisfaction with their sense of taste or smell (1), and in one study, 45% of elderly subjects were unable to detect the warning odor in natural gas (ethyl mercaptan) at the safety standard level (2). In a large population-based, cross-sectional study of 2491 subjects aged 53 to 97 years, 24.5% of all subjects and 62.5% of those over 80 exhibited impaired performance on an eight-item odor identification test (3). Whether this sensory decline is a direct consequence of aging, or whether it is primarily a result of secondary, age-associated conditions remains controversial. Functional deficits and anatomical pathology have been documented in a variety of animal models of aging in which environmental exposures and health status are not confounds (4-7). In addition, the vast majority of subjects over the age of 80 exhibit reduced sensitivity and odor-identification ability on common olfactory tests (1, 8). In contrast, a study with a prosimian primate (the gray mouse lemur) showed no decrement in olfactory function between young and old age groups (9). Similarly, a study with 21 healthy centenarians found that odor-detection thresholds and identification ability were within normal ranges for young subjects (10). In addition, olfactory performance was found to be the product of an interaction between age and other causes of olfactory injury, including environmental exposures, sinus disease, and smoking (3, 11). These data suggest that much of what has been termed "age- related" decline in olfaction is really secondary to other factors that adversely affect peripheral or central olfactory pathways (11, 12).

Nature of Age-Related Olfactory Loss

Perhaps the most notable aspect of age-related olfactory loss is the frequency with which it goes unreported or unnoticed. The frequency of self-reported olfactory impairment was about one-third of the measured frequency (9.5% versus 24.5%), and only 12 to 18% of subjects over 80 accurately report that they have impaired sensitivity (that is, an increased detection threshold for an odor) (3). This situation is most likely a result of the gradual nature of the change, which may be first noticed as a change in "how food tastes" and thus confused with or reported as a change in taste (13). It may also relate to greater deficits in retronasal olfaction (perceived through the oropharynx and more closely linked to "flavor" or taste) versus orthonasal (through the nose) olfaction (Fig. 1), although additional studies are needed.

Figure 1
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Fig. 1. Sensing circuitry. Volatile chemicals enter through the nose (orthonasal) and oropharynx (retronasal) to interact with receptors residing in the cilia of the receptor neurons in the upper part of the nasal cavity. These receptor neurons send their axons through a thin, bony structure (the cribriform plate) to synapse with mitral cells within the olfactory bulb. From there, the signals are relayed to a variety of brain regions where the information is processed and integrated with other sensory input (from "The Flavor of Aging").

Studies have reported age-associated deficits in several parameters of olfactory function, including detection thresholds, odor identification, discrimination, and intensity perception (3, 8, 14-21). Whether these changes are uniform across odors (16) or heterogeneous (8, 22) remains unclear. Heterogeneous loss appears to represent an early stage in a gradual process (22). Given the anatomical and molecular design of the olfactory system and the nature of the anatomical pathology seen with aging (see below), it seems likely that initial deficits are heterogeneous, but with further aging, more extensive peripheral damage, perhaps combined with central processing deficits, causes a more general loss of sensitivity. Data also suggest that older subjects adapt more quickly to odors and resensitize more slowly (23). This phenomenon could contribute to measured threshold deficits, as no studies have attempted to determine the effect of varying interstimulus interval on detection thresholds. The loss of olfactory function impairs our ability to discriminate food flavors (24), alters food preferences, and contributes to reduced appetite and food intake (25, 26). Flavor enhancement improves appetite and nutritional status among elderly patients (27), and the importance of palatability is finally beginning to be recognized in dietary recommendations for the elderly (28).

Anatomy and Physiology

The explosion of research in the field of olfaction has contributed to a comprehensive view of the mechanics of this sense. Odorants are detected when they bind to specific combinations of receptor proteins, expressed in olfactory receptor neurons (ORNs) residing in the dorsal region of the nasal cavity, including the superior aspect of the medial turbinate and the olfactory cleft (Fig. 1). A single dendrite extends from each ORN to the surface of the olfactory neuroepithelium, ending in a knob structure that in turn gives rise to a number of hairlike cilia. Each olfactory neuron expresses one of several hundred (in human) to nearly a thousand (in rodent) different olfactory receptor proteins (localized to the cilia), which are seven-transmembrane domain, guanosine triphosphate (GTP)-binding protein (G protein)-coupled receptors (GPCRs) similar in structure to rhodopsin (29, 30). Activation of the associated G proteins results in production of second messenger molecules (Fig. 2), including cyclic adenosine monophosphate (cAMP)--the primary transduction molecule for most odors--and cyclic guanosine monophosphate, which plays a modulatory role and may serve as a primary messenger for certain odors linked to social/reproductive behaviors (31, 32). These second messengers open nonselective cation channels that allow calcium and sodium into the cell, triggering depolarization (33-36). Recent data support the involvement of a calcium-activated chloride channel, which further accelerates the depolarization through chloride efflux (37), and release of calcium from intracellular stores (38), which facilitates distribution of the signal from the distal portion (cilia, knob, and dendrite) to the basal region of the cell.

Figure 2
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Fig. 2. Odor signaling. A complex cascade within the olfactory cilia acts to transduce and amplify the information that an odorant has bound to its receptor. Changes in receptor conformation activate an associated G protein leading to activation of enzymes (adenylyl cyclase or phospholipase C) that generate second messengers (cAMP or inositol 1,4,5-trisphosphate, respectively). These second messengers act on channels (including the cyclic nucleotide gated channel) and stores to trigger sodium and calcium elevations and chloride efflux, which collectively result in cell depolarization, triggering an action potential. Calcium and other second messengers elicit other intracellular events involved in adaptation and desensitization.

ORNs expressing the same receptor type converge onto the same loci (glomeruli) in the olfactory bulb (Fig. 3), which provides for faithful transfer of the combinatorial activity pattern for any given odorant to a specific set of mitral cells (the primary output neurons in the olfactory bulb). The mitral cells communicate with each other through interneurons to shape and refine the incoming signal before conveying the odor-specific activation patterns to higher processing centers (39). Recent data indicate that the information from mitral cells receiving input from ORNs expressing disparate receptor proteins converges onto individual cells within the olfactory cortex (Fig. 3) (40). Although further work is needed, data from a simple animal model, the catfish, suggest that the cortical neurons receive input from mitral cells collecting information from multiple odors with similar behavioral relevance, for example, all stimuli related to "food" (41) and, perhaps, in mice or humans, "chocolate" or "broccoli." It seems likely that this convergence accounts for the difficulty in deciphering the components of mixtures or the individual volatile chemicals in complex aromas (42).

Figure 3
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Fig. 3. Odor processing. Receptor cells expressing the same receptor (blue or red) project their axons to the same discrete glomeruli within the olfactory bulb. From there, information is sent to a variety of sites within the central nervous system for processing and integration with other sensory inputs and memories. Although the activity map within the epithelium and bulb maintains receptor segregation, in certain areas of the cortex, inputs are mixed such that clusters of neurons receive signals from receptor neurons expressing different receptor types. This phenomenon may indicate receptors with overlapping response profiles or receptors binding to odors of similar behavioral relevance. With aging, holes may occur in the epithelial and glomerular receptor array such that information is lost or misinterpreted. [Reproduced from (40) with permission from Nature Publishing Group]

Several features of the olfactory system make it particularly susceptible to age- and disease-associated changes that may lead to functional deficits. First, volatile stimuli must dissolve in and penetrate through watery protective layers to interact with odorant receptors residing on the cilia of the receptor neurons. Odor detection, adaptation (reduced sensitivity to an odorant after prolonged exposure), and resensitization rates are influenced by odor deposition and clearance rates, which in turn reflect mucociliary movement, mucus composition, epithelial thickness and composition, submucosal blood flow, and enzymatic degradation (43, 44). In addition to a general decline in hydration and mucus secretion with aging (45), changes in hormonal and metabolic function that affect nasal blood flow (46) may alter these biophysical processes in ways that have yet to be modeled. Odorous stimuli are often lipophilic and potentially damaging to the epithelium if allowed to reach a sufficient concentration for prolonged periods of time. Volatiles commonly in our environment, such as ammonia or alcohol, typically do not reside in the epithelium for long enough or at sufficient concentrations to cause injury, but in the face of reduced mucociliary movement, mucus depth, or detoxification capacity, exposure to these types of chemicals could contribute further to epithelial damage. The notion that the olfactory mucosa is more susceptible to injury with advancing age is supported by a variety of studies. Genter and Ali (47) demonstrated an age-related increase in susceptibility to olfactory mucosal damage from a neurotoxicant. Similarly, an age-related decline in the response of heat-shock protein 70 to stress in the olfactory mucosa has been reported (48), and a generally elevated level in the expression of genes classified as involved in stress response and immune function was seen in a microarray study of the olfactory mucosa from a senescence-accelerated mouse model (49). Apparently, the olfactory system, like other sensory and cognitive pathways, experiences changes as we age that directly contribute to dysfunction and also enhance susceptibility to damage from secondary causes to further increase the likelihood and severity of sensory loss with advancing age.

Second, perception of the full sensory spectrum depends on the proper expression and distribution of hundreds of receptor types, as well as the faithful and consistent reproduction of their activity patterns in the olfactory bulb and subsequent integration in the olfactory cortex. Failure to replace populations of cells expressing particular receptors or receptor classes could result in loss of sensitivity to certain types of odors, resulting in both poorer sensitivity and altered aroma quality. The commonly reported symptom that "food doesn't taste the same" could result from this type of age-related deterioration.

To accommodate their exposed position, the receptor cells can be replaced throughout life. This process requires ongoing neurogenesis, axon outgrowth, and targeting to the appropriate locations (glomeruli) within the olfactory bulb. Anatomical studies of the olfactory epithelium from aging animal models and human cadavers reveals a generally thinner epithelium, with frequent patches of respiratory epithelium interrupting the sensory regions (4, 50-52). Gliosis (53) and reduced basal cell proliferation (54, 55) may contribute to the development of pathology. In humans, the likelihood of obtaining functional olfactory neurons from biopsies from older subjects was found to be similar to that for biopsies from younger subjects (56, 57), suggesting that if there is a substantial net loss of ORNs with age in humans, it is likely to be distributed across the epithelial sheet and not localized to a particular region. A variety of growth factors (58-60) and cytokines (61, 62) have been implicated in basal cell proliferation and differentiation (Fig. 4). Understanding the influence of aging and age-related diseases on these processes will help to design new approaches to prevent or treat age-related olfactory impairment.

Figure 4
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Fig. 4. A section of human olfactory epithelium stained to visualize proteins involved in neurogenesis (nerve growth factor receptor, in red) and immune responses (interleukin-1 receptor, in green); cell nuclei are stained blue. Arrow indicates basal lamina. Chronic inflammation from allergy, infection, or chemical exposures may interfere with the normal replacement of olfactory neurons, contributing to the age-related decline in olfactory performance.

A further consequence of ongoing regeneration is the potential for axon mistargeting. Such mistargeting has been observed after axotomy (severing of an axon) or peripheral damage (63, 64), and these errors may be more frequent or less likely to be corrected in the aging olfactory system. Consistent with this notion is the finding that factors such as current smoking, nasal congestion, or upper respiratory tract infection, which are known to cause peripheral epithelial inflammation and damage, were associated with a higher risk of olfactory impairment in an older population (3). In addition to peripheral deterioration, and perhaps because of it, atrophy has also been observed in human olfactory bulb specimens: Smith (65) reported a gradual atrophy of the olfactory glomeruli from about 30% in tissue from 31- to 45-year-olds to more than 60% in samples from those over 75 years old. Given our current understanding of odor detection and coding on the basis of a distributed, combinatorial pattern of neuronal activity that must be translated faithfully into the olfactory bulb and from there to the cortex, this type of damage would result in an altered combinatorial activity profile such that not only is the intensity of odor perception reduced, but the quality is altered as well.

Finally, optimal odor detection, adaptation, and resensitization require a finely balanced ionic exchange between inside and outside the receptor cells that depends on the composition of the mucus, function of the surrounding supporting cells, and operation of all of the ion channels and transduction machinery within the receptor neuron [for a review, see (57)]. Age-associated changes in the density, distribution, and function of various types of calcium channels (66), neurotransmitter receptors, and other signaling elements have been reported in a number of brain areas [for example, (67, 68)]. Similar changes may occur in neuronal elements within the peripheral and central regions of the olfactory pathway, but little data are presently available that address this question specifically. Gross age-related deficits in odor-stimulated neural activity are seen in electro-olfactogram (field potential) recordings (which measure the locally summated activity of neurons in a particular site in the olfactory epithelium after stimulation by an odor) from mice (69) and functional magnetic resonance imaging (70) and chemosensory evoked potential recordings from humans (71, 72), but these methods do not give insight into the cellular basis for the reduced activity. Evidence for dysregulation of calcium signaling in isolated ORNs from aging human subjects suggests that reduced perceptual sensitivity is not a result of loss of ORN sensitivity per se, but perhaps to loss of selectivity (56). Proteomic and mRNA microarray studies may shed additional light on the molecular changes that occur as the olfactory pathway ages (73, 74).

Prospects for Prevention or Treatment of Age-Related Olfactory Dysfunction

As we begin to understand how odors are detected, identified, and remembered, we have gained an appreciation of why the olfactory system may be such a sensitive indicator of age-related neurological dysfunction. Yet we are still far from identifying preventive measures--other than the most general advice to maintain a generally healthy lifestyle to reduce infections and risk of exposure to environmental hazards. Recent studies have begun to focus on identifying growth factors and hormonal signals that play important roles in both development and regeneration of the olfactory pathway. One of these is retinoic acid (the active form of vitamin A), which plays a key role in embryonic development of the olfactory system (75), promoting regeneration after injury (76) and improving specific aspects of memory formation that are affected by aging and used in odor-mediated learning (77). We do not yet know, however, whether poor vitamin A status or the dysfunction of retinol-regulated pathways contributes to age-related olfactory loss. Only one study has attempted to reverse age-related olfactory impairment. In this study, caffeine administered 30 minutes before testing improved the performance of aged rats in olfactory discrimination and social recognition tasks. This result was due at least in part to the ability of caffeine to block adenosine A2A receptors, which are present in several regions along the olfactory pathway and other brain areas involved in performing these tasks (78). The multiple effects of caffeine make it difficult to determine whether the results reported were due to olfactory-specific actions or to more general attentional and motor effects caused by the activity of caffeine in other parts of the central nervous system. Intriguing data have been published suggesting that odor exposure can increase the longevity of ORNs (79). The efficacy of this approach to prevent or reverse age-related olfactory deficits has not yet been examined, but making a conscious effort to expose our noses to a variety of scents throughout life may be the best approach to ensure that we can continue to enjoy the full spectrum of our aromatic world as we age.

February 8, 2006
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Cytokine profile in human olfactory cleft mucus and associated changes in olfactory function.
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