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date: 03 June 2020

Aging and Olfaction

Summary and Keywords

Decreased ability to smell is common in older persons. Some demonstrable smell loss is present in more than 50% of those 65 to 80 years of age, with up to 10% having no smell at all (anosmia). Over the age of 80, 75% exhibit some loss with up to 20% being totally anosmic. The causes of these decrements appear multifactorial and likely include altered intranasal airflow patterns, cumulative damage to the olfactory receptor cells from viruses and other environmental insults, decrements in mucosal metabolizing enzymes, closure of the cribriform plate foramina through which olfactory receptor cells axons project to the brain, loss of selectivity of receptor cells to odorants, and altered neurotransmission, including that exacerbated in some age-related neurodegenerative diseases.

Keywords: age, olfaction, epithelium, Alzheimer’s disease, Parkinson’s disease, physiology, psychophysics, neurodegeneration

Introduction

Although commonly taken for granted, the ability to smell is critical for safety and quality of life. This unique sensory system largely determines the flavor of foods and beverages and provides an early warning of environmental hazards such as fire, spoiled food, and leaking natural gas. It is used to assess one’s own personal hygiene, as well as that of others, and to confirm the general cleanliness of homes, automobiles, and workplaces. Importantly, this sense is central to the full enjoyment of flowers and nature, as well as perfumes and numerous personal care products.

As we age, decrements occur in our ability to smell. Indeed, some measurable dysfunction is evident in more than 50% of adults 65 to 80 years of age, with up to 10% having no smell at all (anosmia). Over the age of 80 years, 75% of the population exhibits some demonstrable loss of function, with up to 20% being totally anosmic (Doty, 1995). These deficits are easily detected by modern psychophysical, electrophysiological, and psychophysiological olfactory tests.

Despite the fact many elderly persons complain their food does not taste right, flavor perception largely depends on molecules from foodstuffs and drinks reaching the olfactory receptors via the nasal pharynx during deglutition. Thus their “taste” loss largely reflects smell dysfunction. Compromised olfactory function can result in altered food intake and adverse nutritional consequences. In some cases, such loss results in decreased food consumption. In others, it leads to increased consumption of unhealthy junk food. Moreover, the safety consequences of being unable to smell can be quite dramatic. One study found that 45% of older persons are unable to detect odorized natural gas at standard levels of odorization, as compared to only 10% of younger persons (Stevens, Cain, & Weinstein, 1987). Coal-gas poisoning was the cause of ~10% of all accidental domestic deaths in Britain between 1931 and 1956, with most occurring in those older than 60 years of age (Chalke, Dewhurst, & Ward, 1958). Persons with decreased smell function, in general, report having experienced more olfaction-related hazardous events than those with normal smell function, such as ingestion of spoiled food and failure to detect burning food on the stove, fire, or leaking natural gas (Santos, Reiter, DiNardo, & Costanzo, 2004). Recent studies have found that older persons with smell dysfunction have a three-fold increase in the probability of dying over the course of the subsequent half-decade, even after controlling for such confounders as sex, smoking behavior, and a range of health-related diseases (Devanand et al., 2015; Pinto, Wroblewski, Kern, Schumm, & McClintock, 2014).

This article addresses changes that occur in olfaction in the later years of life. The focus is on humans, although animal data are presented when appropriate. An overview of the influences of age on quantitative measures of olfactory function is presented, followed by sections addressing age-related alterations within the nasal cavity, olfactory epithelium, olfactory bulbs, and higher-order olfaction-related brain regions.

Age-Related Olfactory Function

Quantitative testing is essential to accurately establish the influences of age on smell function, since many persons fail to recognize deficits in their ability to smell until formally tested. Modern quantitative tests include (a) psychophysical tests, in which a conscious response is required in response to an odorant; (b) electrophysiological tests, which measure electrical changes within the nose or brain in response to odorants; (c) psychophysiological tests, which largely assess autonomic nervous system responses to odorants; and (d) structural and functional imaging, where changes in the brain can be assessed on the basis of structure size, altered electromagnetic fields, integrity of neural tracts, or brain metabolism in response to an odorant.

Psychophysical Test Deficits

Numerous types of psychophysical tests, all of which are impacted by age, have been operationally defined. For example, tests of odor detection, recognition, identification, discrimination, memory, hedonics, and suprathreshold perception of intensity have been developed. The results from most such tests are positively correlated with one another (Doty, Smith, McKeown, & Raj, 1994; Koskinen, Vento, Malmberg, & Tuorila, 2004). This suggests that a “general olfactory acuity” factor exists that is conceptually similar to the general intelligence factor proposed for intelligence tests (Doty et al., 1994; Yoshida, 1984). The magnitude of the associations vary, with the size of the correlations between any two tests being dictated in large part by the reliability coefficient of the less reliable test (Doty, McKeown, Lee, & Shaman, 1995). One must keep in mind that the relative influences of age on such tests is unclear, in part because the tests differ in their reliabilities, odorants, nonolfactory task demands, and operational procedures. Nevertheless, regardless of the specific test that is employed, age-related effects are evident (Doty & Kamath, 2014). In general, longer tests are more reliable and hence more sensitive to olfactory deficits (Doty et al., 1995).

The most popular psychophysical olfactory tests are odor identification tests. Their popularity stems from their brevity, sensitivity, reliability, and validity. Some, such as the 40-item University of Pennsylvania Smell Identification Test (UPSIT; Figure 1) and its briefer 3-, 4- and 12-item versions, are commercially available and can be self-administered, minimizing the involvement of test administrators. Such tests typically employ odors familiar to most people. The subject’s task is to identify the odor from a list of written alternatives or, in some cases, pictures reflecting the source of the odor (e.g., a gasoline pump for the odor of gasoline) (Cameron & Doty, 2013; Doty, Shaman, & Dann, 1984; Doty, Marcus, & Lee, 1996; Hummel, Sekinger, Wolf, Pauli, & Kobal, 1997; Kobal et al., 1996; Kobayashi et al., 2006; Krantz et al., 2009; Nordin, Nyroos, Maunuksela, Niskanen, & Tuorila, 2002; Richman, Post, Sheehe, & Wright, 1992). Normative data are available for some tests, allowing the determination of both absolute (e.g., normal or mild, moderate, severe, or total loss) and relative (percentile rank) function, the latter relative to sex- and age-related normative data (Doty, 1995).

The largest age-related deficits in odor identification occur after the age of 65 years. The perception of some odors may decline more than others, although no study has used stimuli that are equated for overall intensity or familiarity, confounding the interpretation of previous findings (Doty & Kamath, 2014). Moreover, most odorants used in such tests are comprised of multiple chemicals and are not standardized across tests. The prototypical age-related decrement observed in odor identification is shown in Figure 2 (Doty, Shaman, Applebaum, et al., 1984).

Aging and Olfaction

Figure 1. The 40-item University of Pennsylvania Smell Identification Test. This test is comprised of four booklets, each containing 10 microencapsulated (“scratch & sniff”) odors that are released by a pencil tip. The examinee is required to provide an answer on each test item (see columns on last page of each booklet) even if no odor is perceived or the perceived odor does not smell like one of the response alternatives (i.e., the test is forced-choice). This test has been administered to hundreds of thousands of subjects and is available in 30 different language versions.

Photograph courtesy of Sensonics International, Haddon Heights, New Jersey, USA. Copyright ©2013 Sensonics International.

Aging and Olfaction

Figure 2. Scores on the UPSIT as a function of age and gender in a large heterogeneous group of subjects. Numbers by data points indicate sample sizes. From Doty, Shaman, Applebaum, et al. (1984), reprinted with permission from the American Association for the Advancement of Science.

Odor threshold tests are designed to estimate the lowest concentration of an odorant that a subject can reliably detect (detection threshold) or recognize (recognition threshold). The concentrations employed in a threshold study typically span a geometric series (e.g., half-log steps) and various psychophysical algorithms have been used to define the threshold estimate (Cain, Gent, Catalanotto, & Goodspeed, 1983; Doty, Shaman, et al., 1984; Doty, McKeown, Lee, & Shaman, 1995; Hummel et al., 1997; Takagi, 1989). Stimuli are presented via devices or instruments reviewed elsewhere (Doty & Laing, 2015).

In a popular threshold procedure, the first trial occurs at an odorant concentration not discernible from a no-odor blank (Doty & Laing, 2015). On subsequent trials, the concentration is gradually increased until correct performance occurs on five trials in a row at a given concentration. Once this occurs, the next trial is presented at a stimulus concentration level a half-log step lower. From this point on, only one or two trials are presented at a given concentration. If the stimulus is correctly identified on both trials, the next lower concentration is presented. If either of the two trials is incorrect, the next higher concentration is presented. This is continued until a series of seven “up-down reversals” occur, at which time the test is over. The threshold estimate is calculated as the average of the last four of the seven reversal points.

As with odor identification tests, significant age-related alterations are generally observed regardless of the psychophysical paradigm used to establish the threshold (Doty & Kamath, 2014), with somewhat lower thresholds (greater sensitivity) occurring in the healthiest cohorts (Griep et al., 1997). Studies that have explored a spectrum of ages typically report an age-related decrement in sensitivity, that is, elevated thresholds, although such functions depend upon the involved odorant and considerable variation in test scores is present (Deems & Doty, 1987; Venstrom & Amoore, 1968). Depicted in Figure 3 are detection thresholds of 339 subjects for phenyl ethyl alcohol obtained using a single staircase detection threshold paradigm. No significant differences between men and women were found in this study of nonsmoking individuals.

Aging and Olfaction

Figure 3. Phenyl ethyl alcohol thresholds determined using a forced-choice single staircase detection paradigm. Note both the sex and age effects. Reprinted with permission from Deems and Doty (1987).

Odor discrimination tests assess the ability to differentiate among odors of different qualities, for example by identifying an odor that smells different from others within a set of otherwise equivalent odors (Jehl, Royet, & Holley, 1995; Kobal et al., 2000; Weierstall & Pause, 2012). No identification or recognition of the odor is required. In match-to-sample discrimination tests, an odor or set of odors is presented and the subject must match the odor or set of odors to those contained within a larger set of odors. In one test, delay intervals of 10, 30, or 60 seconds are interspersed on different trials between the smelling of an odor and the smelling of inspection odors in an effort to assess short-term odor memory (Bromley & Doty, 1995; Choudhury, Moberg, & Doty, 2003). However, short-term odor memory is rarely impacted by age in healthy persons (Choudhury et al., 2003; Engen, Kuisma, & Eimas, 1973), and the use of familiar odorants confounds true odor memory with semantic memory. Hence, in general, such tests should be considered primarily discrimination tests. The influences of age and sex on test scores from such a test (averaged across statistically nonsignificant delay intervals) is shown in Figure 4.

A more complex test of odor discrimination employs multidimensional scaling. In this procedure, similarities among odorants are established by rating the relative similarity of pairs of odorants. The resultant ratings are subjected to a statistical algorithm that places them in two- or three-dimensional space relative to their perceived similarity (Schiffman & Leffingwell, 1981). Such spaces are markedly influenced by age (Schiffman & Pasternak, 1979).

Aging and Olfaction

Figure 4. Test scores for men and women on a 12-item odor discrimination/memory test as a function of age. Note age-related decline in performance and the fact that women outperform men at all ages. Data are collapsed over 0-, 30-, and 60-sec delay intervals. From Choudhury et al. (2003) with permission.

Copyright ©2003 Oxford University Press.

Suprathreshold intensity of odors is commonly measured using rating scales and other procedures such as assigning numbers to the relative intensity of odorants. Such measures appear to be less sensitive to age than most other olfactory tests (Rovee, Cohen, & Shlapack, 1975). In a study of over 26,000 members of the National Geographic Society, ratings of the intensity of single concentrations of each of six scratch and sniff odorants were made using a 5-point rating scale (Wysocki & Gilbert, 1989). Over the entire age range, a 26% decline in the intensity of the mercaptan, an odorant added as a warning agent to natural gas, was observed. Corresponding percentages for amyl acetate (banana) were 22%, eugenol (clove) 14%, phenyl ethyl alcohol (rose) 13%, androstenone (a putative pheromone) 10%, and Glaxolide (an artificial musk) 3%. Odors with the least decline were rated initially as less intense and typically were more difficult for older persons to identify. This study suggested that, on average, the age-related declines in the ratings began in the 20s for men and in the 40s for women.

Electrophysiological Test Deficits

Odor-induced electrical responses can be obtained from electrodes placed on the olfactory mucosa (Hosoya & Yashida, 1937; Ottoson, 1956). The responses are proportional to stimulus concentration and are correlated with perceived intensity. However, this measure is impractical in clinical settings since many persons cannot endure electrodes inserted high into the nonanesthetized nose. To date, no human studies have assessed the influences of age on this measure, although murine studies have found an age-related decline in the amplitude of this response (Nakayasu, Kanemura, Hirano, Shimizu, & Tonosaki, 2000). Since the response is larger in some diseases such as schizophrenia in which olfaction is depressed (Turetsky, Hahn, Arnold, & Moberg, 2009) and can be present even after death (Scott & Brierley, 1999), it is not a reliable correlate of smell perception per se.

A more practical electrophysiological procedure is the odor event-related potential, which assesses odor-induced alterations in electrical fields of large populations of cortical neurons (Gevins & Remond, 1987). However, this measure is not detected in many persons with normal olfactory function (Lotsch & Hummel, 2006) and can be confounded by trigeminal signals. Complex stimulus presentation and recording equipment are required to detect and extract the small signals (< 50 μ‎V) from noisy electrical background activity. Delayed latencies and reduced amplitudes of these responses have been found in older subjects (Covington, Geisler, Polich, & Murphy, 1999; Evans, Cui, & Starr, 1995; Hummel, Barz, Pauli, & Kobal, 1998; Morgan & Murphy, 2010; Murphy, Nordin, de Wijk, Cain, & Polich, 1994; Stuck et al., 2006; Thesen & Murphy, 2001).

Psychophysiological Test Deficits

Odors can induce changes in such autonomic nervous system responses as heart rate, blood pressure, respiration, and skin conductance. Such responses, although often sensitive to age, are quite variable, and some are influenced by odorant-induced activation of the nasotrigeminal branch of the trigeminal nerve. A novel psychophysiological test was developed slightly over a decade ago which is sensitive to age-related changes in olfaction (Frank, Dulay, & Gesteland, 2003; Frank, Dulay, Niergarth, & Gesteland, 2004; Frank et al., 2006). In this “Sniff Magnitude Test,” a subject sniffs a canister that, upon initiation of the sniff, releases an unpleasant odor (e.g., 3% methylthiobutyrate) or just air. Individuals with no smell dysfunction immediately stop sniffing the unpleasant odor, whereas those with some or complete loss of function either do not inhibit the sniff or delay its inhibition (Tourbier & Doty, 2007). This test is useful in detecting malingering but is limited in reliability since repeated trials are variable in light of the weariness of normosmic subjects to repeatedly smell obnoxious odors.

Causes of Age-Related Olfactory Dysfunction

Many factors potentially cause age-related decrements in olfactory function, including structural and physiological alterations in the nasal cavity, olfactory epithelium, bulb, and higher brain regions. The degree to which genetics is involved is unclear since, to date, only modest monogenetic effects have been identified. Longitudinal declines in the ability to identify odors are slightly greater for ε‎4-allele carriers than noncarriers (Calhoun-Haney & Murphy, 2005), as well as for those who are homozygous for the val allele of the val66met polymorphism of brain derived neurotrophic factor (Hedner et al., 2010). Gene/environment interactions are likely present. Although low heritability coefficients were noted in a study of 1,222 very old twins and singletons, including 91 centenarians (Doty, Petersen, Mensah, & Christensen, 2011; rs ranging from 0.13 and 0.16), such coefficients are somewhat higher in studies of younger twins (rs as high as 0.78; Gross-Isseroff et al., 1992), suggesting the initial effects of heritability may be swamped by the cumulative environmental insults to the olfactory epithelium or other age-related factors.

Age-Related Changes Within the Nasal Cavity and Olfactory Neuroepithelium

Age-related changes in nasal airflow and nasal secretions can influence the number of odorant molecules that reach the olfactory receptors, which are located in a patch of neuroepithelium in the highest recesses of the nasal cavity. The engorgement of the nasal passages decreases with age, resulting in a lowering of nasal resistance and possibly less shunting of the nasal air steam to the olfactory epithelium (Edelstein, 1996).

The nose itself becomes drier as a result of age-related decline in nasal mucus. Certain nasal diseases, including chronic rhinosinusitis and nasal polyposis, are more common in old age, related, in part, to lessened mucociliary clearance (Cho et al., 2012; Settipane, 1996). Impaired mucociliary function sets the stage for general nasal viral and bacterial infections that may impact olfaction and has been found in about 30% of individuals 60 years of age and older (Sakakura et al., 1983). The nasal epithelium in general undergoes some degree of age-related atrophy, decreased elasticity, and lessened mucosal blood flow, the latter of which is impacted by hormonal and other metabolic factors (Bende, 1983; Somlyo & Somlyo, 1968).

The olfactory neuroepithelium, which harbors the olfactory receptors, clearly exhibits age-related alterations in its integrity, as evidenced by a decrease in thickness, a change in the pattern and distribution of its constituent cells, a reduction in receptor cell numbers, and a decline in Bowman’s glands, the major source of the overlying mucus. As a result of the decline in Bowman’s gland secretions, one would expect a lowering in odorant-binding proteins that aid in transporting hydrophobic molecules through the mucus to the receptors (Pelosi, 1994). Altered immune factors (Gladysheva, Kukushkina, & Martynova, 1986), growth factors (Federico et al., 1999), biotransformation enzymes, and other agents critical for toxicant metabolism and destruction of viruses and bacteria would also be expected to impact the function and integrity of the olfactory mucosa (Ding & Xie, 2015). Decreased vascularization of this epithelium occurs with age, culminating in a largely avascular epithelium (Naessen, 1971) in which much of the sensory epithelium is replaced with islands of respiratory epithelium (Morrison & Costanzo, 1990; Naessen, 1971; Nakashima, Kimmelman, & Snow, 1984; Paik, Lehman, Seiden, Duncan, & Smith, 1992). This phenomenon is evident in rodents exposed to olfactory toxins such as 3-methyl indole and 3-trifluoromethyl pyridine (Gaskell, Hext, Pigott, Doe, & Hodge, 1990; Peele et al., 1991).

Although the olfactory epithelium has the propensity to regenerate, such regeneration is compromised by age. In the rat, for example, the ratio of dead or dying cells to the number of live receptor cells increases with aging (Mackay-Sim, 2003), suggesting decreased mitotic activity. The degree to which compromise is inherent or dependent upon cumulative damage from environmental insults from viruses, bacteria, and a range of toxins and other xenobiotics is not clear. In contrast to rats reared in a normal laboratory environment, those reared in a pathogen-free environment exhibit no age-related declines in the number of mature olfactory neurons (Loo, Youngentob, Kent, & Schwob, 1996).

Dystrophic neurites and neurofibrillary tangles are found in the olfactory epithelia of healthy older persons, as well as in the epithelia of patients with Alzheimer’s disease (AD) and other neurodegenerative diseases, including those with little olfactory dysfunction (e.g., progressive supranuclear palsy (PSP; Trojanowski, Newman, Hill, & Lee, 1991). Whether these aberrations contribute to age-related olfactory loss is not known.

It is important to point out that the number and size of patent foramina of the cribriform plate decrease with age (Kalmey, Thewissen, & Dluzen, 1998; Krmpotic-Nemanic, 1969), blocking or pinching off the axons of the olfactory receptor cells as they course from the nasal cavity into the brain. In one study, the area of the foramina within the posterior centimeter of the cribriform plate was reduced by 47.3% in men and 28.8% in women over the age of 50 years relative to their younger counterparts (Kalmey et al., 1998).

Age-Related Changes Within the Olfactory Bulb

The olfactory bulb is the first relay station of the olfactory system, receiving the axons of the olfactory receptor cells and, in turn, sending afferents of its major projection cells, the mitral and tufted cells, to the piriform cortex and other central structures. The details of the anatomy and physiology of this relatively complex structure located at the base of the brain are provided elsewhere (Ennis & Holy, 2015). In sum, the direct connection between the olfactory bulb and the olfactory receptor cells provides a gateway for the entrance of viruses and xenobiotics, including nanoparticles, into the brain from the nose. This makes the olfactory bulb a potential target for environmental agents that influence olfaction and perhaps even the genesis of some neurodegenerative diseases (Doty, 2008).

Age-related decrements in the volume of the olfactory bulbs from older persons have been reported via magnetic resonance imaging (MRI; Buschhuter et al., 2008; Yousem, Geckle, Bilker, & Doty, 1998). Conceivably, such decrements reflect the lack of trophic input secondary to damage to the olfactory receptors (Hinds & McNelly, 1981), although numerous disorders are associated with decreased olfactory bulb volumes. These include acute depression, cigarette smoking, chronic sinusitis, epilepsy, head trauma, multiple sclerosis, polyposis, schizophrenia, and smell loss secondary to prior upper respiratory infections (Doty & Kamath, 2014). The volume decrements are not absolute in all cases. For example, in rhinosinusitis, olfactory bulb volumes return to normal following successful treatment of the inflammatory problem (Gudziol et al., 2009). In rodents, intrabulbar circuitry recovers from the impact of naris occlusion after reinstatement of the nasal patency (Cummings & Belluscio, 2010).

The olfactory bulb is damaged early in the AD process, although there is some, albeit controversial, evidence that disrupted connections between the olfactory cortex and the hippocampus predate the involvement of the olfactory bulb pathology (Braak et al., 1996). That said, age-related increases in neurofibrillary tangles have been observed in the olfactory bulbs of nondemented older persons. For example, one autopsy study found such tangles in 35.3% of the olfactory bulbs of 133 individuals ranging from 40 to 91 years (mean = 64.3 years), only one of whom had dementia (Kishikawa, Iseki, Nishimura, Sekine, & Fujii, 1990). When the analysis was confined to only those over the age of 50, this percentage increased to 40.5%. Most of the neurofibrillary tangles were found in the anterior olfactory nucleus, although some were found in mitral and tufted cells. Interestingly, similar olfactory bulb pathology was present at autopsy in young persons who had lived in areas of high pollution, apparently in relation to nanoparticles that enter the bulbs via the olfactory fila (Calderon-Garciduenas et al., 2010). The olfactory bulb is one of two brain regions that are the first to show alpha-synuclein pathology associated with Parkinson’s disease (PD), another disease that typically occurs in later life (Braak et al., 1996).

Age-Related Changes Within Higher-Order Olfactory System Structures

Among the age-related changes in olfaction-related central nervous system structures beyond the olfactory bulb and tract are decreased volumes of the hippocampus, amygdala, piriform cortex, anterior olfactory nucleus, and frontal poles. In one study of nondemented subjects aged 51 to 77 years, UPSIT scores were significantly correlated with the volume of the right amygdala and bilaterally with the volume of gray matter in the perirhinal and entorhinal cortices (Segura et al., 2013). UPSIT scores were also correlated with cortical thickness in the postcentral gyrus and with fractional anisotropy and mean diffusivity levels in the splenum of the corpus callosum and the superior longitudinal fasciculi.

Several autopsy studies have noted correlations between premortem olfactory test scores and postmortem abnormal deposits of tau and α‎-synuclein (key pathologic markers of several neurodegenerative diseases) in central brain structures of older nondemented persons. This suggests that age-related alterations in olfaction may reflect “preclinical” or “presymptomatic” neurodegenerative disease. For example, in one study of 122 nondemented individuals, inverse correlations were found between scores on the 12-item version of the UPSIT obtained before death and the postmortem density of neurofibrillary tangles in the entorhinal cortex, the CA1 subfield of the hippocampus, and the subiculum (Wilson, Arnold, Schneider, Tang, & Bennett, 2007). This same group found similar correlations between premortem olfactory test scores and postmortem measures of Lewy bodies within limbic and cortical brain regions (Wilson et al., 2011).

Anosmia, a condition common in older persons, has been associated with significant changes in cortical gray matter. For example, Bitter and associates (2010), using MRI and voxel-based morphometry, found anosmia to be related to widespread changes in gray matter within the piriform cortex, insular, orbitofrontal, medial, and dorsolateral prefrontal cortices, as well as in the hippocampus, parahippocampal gyrus, supramarginal gyrus, nucleus accumbens, and subcallosal gyrus. This work implies that smell loss that is common in the elderly is associated with gray matter structural losses throughout large regions of the brain.

Aging and Olfaction

Figure 5. Olfactory fMRI activation maps from 11 younger (mean age = 23.9 years) and 8 older (right; mean age = 66.4 years) persons to lavender and spearmint odors. Note greater activation in the younger subjects. Reproduced with permission from Wang, Eslinger, Smith, and Yang (2005).

In a pioneering functional MRI (fMRI) study, odors were found to activate fewer voxels in older than in younger persons within the right inferior frontal and left and right superior frontal and perisylvian regions of the brain (Yousem et al., 1999). Another group noted less fMRI odor-induced activation in older than in younger persons during an odor discrimination task in a region within the left orbital pole (Suzuki et al., 2001). Others have found that older subjects exhibit less odor-induced activation than younger subjects within a broad array of central olfactory structures (Figure 5), with the greatest effects occurring in right-side primary olfactory structures, notably the amygdala and the piriform and periamygdaloid cortices (Wang, Eslinger, Smith, & Yang, 2005). Wong, Muller, Kuwabara, Studenski, and Bohnen (2010) found that a measure of nigrostriatal denervation in healthy older persons, as determined by positron emission tomography (PET) imaging of the brain dopamine transporter, was significantly correlated with UPSIT scores, suggesting that age-related declines in nigrostriatal function might be associated in some way with age-related losses in smell ability.

In a recent study, the 12-item version of the UPSIT was administered to 829 cognitively normal subjects (Vassilaki et al., 2017). The subjects underwent MRI assessment to assess hippocampal volumes and cortical thickness in regions known to be decreased in AD, as well as PET scanning to assess amyloid accumulation employing 11C-Pittsburgh compound B and brain hypometabolism using 18fluorodeoxyglucose. Lower olfactory test scores were associated with increased amyloid accumulation and with reductions in cortical thickness and hippocampal volumes. The authors concluded that “odor identification may be a noninvasive, inexpensive marker for risk stratification, for identifying participants at the preclinical stage of AD who may be at risk for cognitive impairment and eligible for inclusion in AD prevention clinical trials” (p. 871).

Neurochemical Changes in the Brain

Age-related changes occur, often beginning before the age of 60 years, in numerous enzyme, neurotransmitter, and neuromodulator systems of brain regions related to smell function. These include most if not all neurotransmitter and neuromodulator systems, including GABA, acetylcholine, norepinephrine, and dopamine (Selkoe & Kosik, 1984). Such changes likely predate the appearance of the neuropathology and cognitive and motor phenotypes of AD and PD. Conceivably such changes decrease the threshold for adverse influences from neural insults, mutations, and other age-related deleterious factors and might be a key substrate for the development of “preclinical” stages of such diseases. These neurochemical changes may be most salient within limbic structures associated with olfaction (Strong, 1998). Imaging studies suggest that binding sites for a number of neurotransmitters are significantly decreased in the brains of older persons (Dewey et al., 1990; Rosier et al., 1996; Volkow et al., 2000).

As noted elsewhere (Doty, 2017), one neurotransmitter that appears to be intimately involved in age-related modulation of olfactory function is acetylcholine. The biogenic amine impacts all sectors of the central olfactory system via its projections from cell bodies located the medial septum, the nucleus basalis of Meynert, and the horizontal and vertical diagonal band of Broca (Schliebs & Arendt, 2011). Acetylcholine modulates neural activity within the olfactory bulb and inhibits activity of microglial cells involved in immune responses to brain damage and the invasion of foreign agents (Doty, 2012). When such inhibition is released, secretion of inflammatory mediators and other factors can occur that, if left unchecked, can damage neurons and other cells (Lalancette-Hebert, Phaneuf, Soucy, Weng, & Kriz, 2009; Tang et al., 2007). Interestingly, the relative amount of damage to basal forebrain cholinergic structures appears to be correlated with the degree of olfactory dysfunction among a number of neurodegenerative diseases (Doty, 2017). Such diseases include AD, PD, Down syndrome, Parkinson-dementia complex of Guam, Korsakoff syndrome, amyotrophic lateral sclerosis, vascular dementia, schizophrenia, and PSP.

Conclusions

Functional and pathophysiological changes occur in the aging human olfactory system. This article addressed the influences of age on modern tests of olfactory function, as well as alterations in number anatomical and physiological factors that appear to contribute to age-related olfactory deficits. Multiple factors were explored, including physical changes in the anatomy of the nose that impact airflow to the receptors, increased propensity for nasal disease in later life, cumulative damage to the olfactory epithelium from environmental insults, decreases in protective metabolizing enzymes within the olfactory mucosa, ossification of the foramina of the cribriform plate through which olfactory receptor axons reach the brain, changes in central neurotransmitter and neuromodulator systems, and neuropathological processes related to age-related diseases such as AD and PD. The relative importance of each of these factors is presently unknown and probably varies considerable among members of the older population.

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