Endocrinology of Taste with Aging

INTRODUCTION

Taste is one of our five primary senses, along with smell, sight, hearing, and touch. The ability to taste is of upmost importance to our wellbeing and survival; tasting has historically enabled us to detect and consume delicious food (sweet, salty, or savory), while avoiding spoiled and toxic substances (sour or bitter). These five basic tastes –salt, bitter, sour, sweet, and savory (umami) – each has its corresponding taste receptors on taste receptor cells (TRCs) within taste buds.¹ The ability to taste savory and sweet food can also lead us to overindulge, overeat, and become obese. The opposite can occur when the ability to taste is decreased, which can lead to loss of appetite, decrease food consumption, and malnutrition, as can happen with aging. In this review, we will give an overview of taste in humans, covering the prevalence of taste impairment in the general population, underlying physiology of taste, possible endocrine connections, factors that may affect taste, and taste and aging.²

EPIDEMIOLOGY OF TASTE

Epidemiology studies in different populations have shown that taste impairment increases with age.^2,3 Results from the National Health Interview Survey showed that less than 0.1% of individuals in the 18–24 age group (0.07%) reported taste impairment compared to 1.7% in the age group 85 years and older.³ Compelling evidence from human studies found that the detection thresholds of salt, sour, bitter, sweet, and umami are increased in older adults, suggesting the taste perception declines with age.^4,5

The effect of age on taste perception is complex, and the extent and significance of this decline varies between taste modalities, tastants, and research studies. This age-related reduction in the sense of taste (and smell) may, in part, contribute to the prevalence of loss of appetite, anorexia and weight loss in the elderly population; or, in other words, “a tattered coat upon a stick” (William Butler Yeats: Sailing to Byzantium). A key component of this is a loss of the usual hedonic response when eating food, with food becoming more akin to being viewed as simply fuel; therefore, a chore to be accomplished. Thus, the study of age-related changes in taste perception and the hedonic response to food becomes imperative because a better understanding of this topic would help improve the consumption of nutrients and ameliorate the lifestyle-related metabolic disorders in older adults.

PHYSIOLOGY OF TASTE

How do we taste? Taste signaling begins in specialized chemosensory taste receptor cells (TRCs) within taste buds located inside structures called papillae on the tongue. There are three different papillae on the tongue that contain taste buds – fungiform papillae (FP), foliate papillae, and circumvallate papillae (CVP). There is a wide variation in the number of FP across individuals and studies with FP density estimates (FP/cm²) ranging from less than 10/cm² to greater than 200/cm². FP density decreases from apex to mid-region of the tongue.^6,7 In addition, studies with a younger cohort would likely yield a higher count as FP density has been shown to decrease with age both cross-sectionally^8,9 and longitudinally.⁹

Mechanisms of Taste Transduction

As previously mentioned, the sense of taste falls into five main sensory qualities: salty, sour (citrus), bitter (coffee, quinine, strychnine), sweet (sugars, artificial sweeteners), and umami (savory, as in broths and mushrooms). There is growing evidence that fat can also be “tasted” and should be added as a sixth fatty (oleaginous) taste.^10,11 Table 1 illustrates the taste receptor cell (TRC) types and their characteristics within taste buds.

Table 1:

Three types of Taste Receptor Cells

Taste receptor cells	Type I	Type II	Type III
Cell type	50% of the total population	30%	20%
Taste responses	Low salt taste amiloride sensitive response	Sweet, bitter, and umami	Sour response via otopterin 1
Morphology	Spindle shaped with long microvilli (1 – 2mm), no synapses	Long, slender microvilli, no synapses	Single large microvillus, synapses with afferent nerves
Other functions	Support function, ion redistribution, neurotransmitter clearance	High salt taste response?	Probable high salt response?
Marker proteins	GLAST, K+ channel (ROMK), epithelial sodium channels (ENaC)	α-gustducin, PLCβ2, CALHM1, CALHM3, platelet glycoprotein 4 (CD36)	Otopetrin1 (OTOP1), Kir2.1, PDK2L1, SNAP25, 5-HT (serotonin)
GPCRs		T1R2/T1R3 (sweet) + T2Rs (bitter) + T1R1/T1R3 (umami), GPCR120
Hormones + Receptors	Ghrelin, growth hormone secretory receptor (GHSR), oxytocin receptor	CCK, GLP-1, NPY, glucagon, ghrelin, GHSR, VIP, VPACR1, VPACR2, leptin receptor, cannabinoid receptor 1 (CB1)	GLP-1, ghrelin, GHSR
Food source(s)	Salt: NaCL (KCl)	Sweet: Dairy products (lactose), sucrose, glucose, fructose, galactose, maltose, aspartame, Splenda (sucralose) Bitter: Coffee, quinine, broccoli, wine, tea Umami: Savoury food, fermented dairy/meat/fish/chicken broth/mushroom/tomato	Sour: Citric acid, lemons/limes/oranges, cranberries, grapefruits, cherries, vinegar, kimchi, sauerkraut

Each TRC within taste buds reacts to a single tastant, although this may not be true for sweet and umami, and each taste bud, regardless of location, has TRCs that are responsive to each of the taste qualities. Still, hormone receptors normally associated with extra-gustatory tissues, and hormones such as CCK,^12,13 ghrelin,¹⁴ GLP-1,^1,15 glucagon,¹⁶ insulin,¹⁷ Neuropeptide Y,¹³ VIP,¹⁸ are produced in taste receptor cells. The hormones expressed in TRCs are reviewed below.

Metabolic Hormones Expressed in Taste Buds

Adenosine Triphosphate (ATP)

The primacy of ATP as a neurotransmitter in taste signal transmission has been firmly established. ATP is released from Type II TRC cells through specialized ‘pores’ connected to large ‘atypical’ mitochondria on the sides of their cells within a few nM of their cell membranes.¹⁹ These Type II TRCs also house the molecular machinery that contains specific receptors for umami, sweet, and bitter signal transduction. Type I and III TRCs are not equipped with the specific machinery for ATP release, although they do contain purinergic receptors on their plasma membranes. Nonetheless, all TRCs contain a range of other neurotransmitters such as serotonin (5HT), acetylcholine (ACH), and gamma-aminobutyric acid (GABA). It is therefore likely that ATP released from the Type II cells is permissive for delivery of neurotransmitters/signaling molecules from the other two TRCs (Type I and Type III) on activation by chemical elements and ions in food, such as NaCl (salty) and hydrogen ions (sour). In addition to the neurotransmitters aforementioned, a whole range of hormones are also synthesized in TRCs where they fine tune taste responses and the integrate information from a complex mix of tastants that is more commonly found in food. Furthermore, there are receptors for hormones not known to be produced in TRCs that are also present on TRCs.

Cholecystokinin (CCK)

CCK is mostly known as a gastrointestinal peptide because the bulk of its secretion into circulation is from enteroendocrine I cells in the proximal portion of the small intestine. CCK was the first hormone, both its mRNA and protein, to be found in TRCs.²⁰ TRCs containing CCK responded via CCK-A receptor activation to exogenous CCK with altered cellular potassium currents and elevated intracellular calcium levels. Additionally, CCK-responsive cells were activated by both bitter tastants and cholinergic stimulation. Subsequent research uncovered that more than half (56%) of the CCK-expressing TRCs also expressed α-gustducin, a molecule in sweet, bitter, and umami responsive TRCs (Table 1) whereas far fewer (15%) co-expressed T1R2 mRNA, a molecule necessary for sweet responsivity, suggesting that CCK is fine-tuning bitter taste-signaling transduction.^12,13,21 Due to the primacy of ATP for taste signal transduction, it is likely that ATP and CCK are co-secreted from a subset Type II cells that contain bitter receptors (T2Rs) and both of them then act on the same gustatory nerves since all CCK receptor-expressing gustatory neurons also express purinergic receptors.²²

Endocannabinoids

Endocannabinoids (ECs) are endogenous lipid-based mediators synthesized from lipid precursors in plasma membranes. There are two such mediators: N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG); and two EC receptors, CB1R and CB2R, both of which are GPCRs.²³ CB1Rs that are present on Type II TRCs and ECs increase gustatory nerve responses to sweeteners while oppose the actions of leptin (see leptin discussion below) without affecting responses to salty, sour, bitter, and umami compounds. Furthermore, the effects of ECs on sweet taste responses are abolished in CB1R knockout mice and are diminished by the administration of CB1 receptor antagonists.²⁴ In obesity, the effects of leptin on suppression of gustatory nerve responses to sweet compounds becomes weakened (likely due to Ob-Rb resistance, see section on Leptin) while the effects of CB1R agonists to increase neuronal responses become more pronounced.²⁵

Ghrelin

The gastrointestinal peptide hormone ghrelin was first identified as a ligand for the growth hormone secretagogue receptor (GHSR).²⁶ Preproghrelin, PC1/3 (enzymes for its post-translational processing to ghrelin), ghrelin, GHSR, and ghrelin-O-acyltransferase (GOAT, the enzyme that activates ghrelin by its acylation) are expressed in all the TRCs of mouse taste buds. Furthermore, GHSR knockout mice display significantly reduced taste responsivity to sour (citric acid) and NaCl tastants.¹⁴

GLP-1 and GLP-2

Preproglucagon is expressed in many tissues throughout the body including TRCs. Post-translational modification from the presence of PC1/3 enzyme in TRCs produces GLP-1 (and GLP-2). Besides mainly regulating blood glucose, GLP-1 also regulates gastric emptying and bowel motility, controls food intake and satiety, and promotes neuronal cell survival. In taste buds, GLP-1 is expressed in two distinct subsets of TRCs: a subset of Type II cells that co-express T1R3 and a population of Type III cells.¹⁵ Sweet stimuli and fatty acid were reported to elicit GLP-1 secretion from TRCs of CVP and FP.^27,28 GLP-1 receptors are expressed on adjacent intragemmal afferent nerve fibers,¹⁵ and GLP-1 receptor knockout mice have dramatically reduced gustatory nerve responses to both nutritive (sucrose) and non-nutritive (sucralose) sweeteners but not to sour or salty tastants, indicating that GLP-1 signaling acts to maintain or enhance sweet taste sensitivity.²⁷ The presence, as well as secretion, of GLP-1 from taste cells highlights an interesting parallel between gustatory and intestinal epithelia.

Insulin

Insulin is primarily secreted from the pancreatic ß cells in the islets of Langerhans. But it is also synthesized and secreted from epithelial cells of the choroid plexus²⁹ and TRCs.¹⁷ All cells of the body express the insulin receptor, including the four types of TRCs.³⁰ In TRCs it would appear to regulate growth and differentiation of the precursor stem cells for TRC replacement. However, the tongue is also a storage site for white adipose tissue where it causes enlargement of the tongue and where it correlates, based on MRI measurements of fat quantity, with episodes of sleep apnea during sleep studies.³¹ In this case, it is possible that insulin derived from taste buds and draining through tongue lymphatics, especially insulin coming from circumvallate where the bulk of the taste buds reside, is involved in regulating lingual adipose deposition. With regards to direct effects of locally produced insulin on taste perception in mice, insulin is reported to affect salt sensitivity through the epithelial sodium channel (ENaC), a receptor for salty taste that is present on the Type I TRC, because insulin increases the open probability of those channels.³² In behavioral preference tests, insulin-treated mice showed significant avoidance of NaCl solutions at lower concentrations than did non-insulin control mice, indicating enhanced sensitivity to NaCl; this effect was abolished by the addition of amiloride, a blocker of the channel, directly to the NaCl solutions. These data would indicate that insulin enhances salt taste sensitivity in mice via amiloride-sensitive, ENaC-expressing, TRCs. Parenthetically, downstream insulin receptor signaling also results in nitric oxide synthesis, especially in vascular epithelium, resulting in vasodilation.³³

Leptin

Leptin, an adipose-derived hormone, plays a key role in energy intake and expenditure due to its involvement in regulation of food intake and appetite, body weight, energy metabolism, and behavior. The db/db mouse, in which the leptin receptor is ineffective due to a naturally occurring genetic mutation, is an animal model for the study of diabetes, obesity, and dyslipidemia.^34,35 Enhanced gustatory neural responses and lower thresholds for sweet taste responses (sucrose, fructose, glucose, maltose) were reported in db/db mice, compared to control mice, as early as only 7 days of age, suggesting that these characteristics are genetically induced by activation of Ob-Rb;^36,37 whereas salt, bitter and sour perceptions were not different.^38,39 In addition, db/db mice showed enhanced responses of the chorda tympani nerve to non-sugar sweeteners such as saccharin.⁴⁰

Similar to its action on pancreatic β-cells and hypothalamic neurons, leptin was found to activate outward K+ currents of TRCs, which hyperpolarizes taste cells.³⁸ The presence of Ob-Rb and STAT3 (signal transducers and activators of transcription-3, involved in the leptin signaling), in a subpopulation of Type II TRCs, confirms potential for involvement of leptin in controlling of sweet taste sensitivity in TRCs.⁴¹ Leptin was shown to suppress sweet taste response directly in T1R3-positive TRCs of mice as well.⁴² These findings suggest that TRCs are peripheral sites of leptin action, suppressing sweet and regulating food intake.

Neuropeptide Y

Neuropeptide Y (NPY) is a neuropeptide possessing structural similarities to peptide YY (PYY) that is secreted from enteroendocrine L cells of the gut,⁴³ and pancreatic polypeptide (PP) that is secreted from PP cells in islets of Langerhans. NPY is one of the most potent orexigenic peptides known and is found mostly in the hypothalamus within the arcuate nucleus. NPY is expressed in a subset of TRCs where its expression overlaps almost 100% with either CCK- or VIP-positive TRCs, although the total number of NPY-positive cells is less than those for CCK and VIP combined.²⁰ Pharmacological evidence strongly suggests that the modulatory effect of NPY upon gustation is mediated by activation of the NPY-1 receptor (NPY-1R) subtype. However, the exact functional role of NPY in gustation has yet to be determined.

Oxytocin

Oxytocin, a neuropeptide hormone best known for its role in lactation, is primarily synthesized in magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus. With respect to feeding behavior, oxytocin regulates the intake of sweet-containing food, as well as NaCl.⁴⁴ Oxytocin knockout mice overconsume solutions of saccharin and sucrose, but have a normal appetite for lipid emulsions.⁴⁵ The oxytocin receptor, but not oxytocin peptide itself, is expressed in a subset of TRCs, and oxytocin was found to increase intracellular calcium in those cells that was readily inhibited by the addition of an oxytocin receptor antagonist.⁴⁶ These findings therefore suggest that peripheral taste organs may be an important locus for the oxytocin-mediated regulation of food ingestion.

Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP), the 28-amino-acid peptide first isolated from pig small intestine, has a diverse range of effects: it increases vasodilatation and reduces arterial blood pressure (hence its name); it causes smooth muscle relaxation; and, in the gut, it stimulates electrolyte secretion.⁴⁷ VIP demonstrates a widespread cellular distribution and has also been identified in taste cells in rat, hamster, carp, and human tongue.^1,48 Our recent work delineated the location and potential functional role of VIP in taste buds by demonstrating the co-expression of VIP with α-gustducin (which is involved in bitter, umami, and sweet transduction cascades) and T1R2 (a sweet taste receptor subunit).¹⁸ Our recent study also deepens the understanding of the VIP’s role in taste perception and regulation of energy homeostasis. Interestingly, we found reduced leptin receptor and increased GLP-1 expression in TRCs of VIP knockout mice that presented altered taste perception of sweet, bitter, and sour stimuli, indicating the potential interactions between VIP, GLP-1, and the leptin receptor.¹⁸

FACTORS THAT AFFECT TASTE

Anatomical factors

There are many factors that may affect taste. The muscle of the tongue is innervated by the hypoglossal nerve.⁴⁹ In addition, special viscero-sensory (gustatory) nerves, chorda tympani and greater petrosal nerve (branches of three cranial nerves), transmit taste information from taste buds.⁴⁹ The lingual artery provides most of the blood supply to the tongue.⁴⁹ Declines in the health of these systems due to aging or disease could contribute to the deterioration in taste function.⁵⁰ For example, some subjects with taste dysfunction were found to have flat and irregular FP with poor blood vessel flow.⁵¹ Diseases with abnormal neurotrophic support, such as in Alzheimer’s and Huntington’s diseases, exhibit taste dysfunction.⁵² Among 750 patients who were seen at the University of Pennsylvania Smell and Taste Center between 1980 to 1986, 8.7% reported loss of taste only, 57.7% loss of both taste and smell, 20.4% with loss of smell only, and the rest with other primary complaints.⁵³ In this group of patients who sought treatment at a specialized clinical center, the three most common causes of loss of taste are head trauma, upper respiratory infection, and nasal sinus disease.⁵³

Smoking/Alcohol

There are many other factors that have been associated with altered taste. Smokers, for example, have been shown to have higher electrogustatory thresholds and lower taste sensitivity than non-smokers.⁵⁴ Smoking is also associated with lower FP density as well.^8,55 Heavy alcohol consumption has also been associated with impaired taste and decreased FP density.^8,56

Endocrine systems

An altered endocrine system has also been associated with altered taste. In humans, increased circulating aldosterone concentrations were associated with reduced taste perception for sodium chloride.⁵⁷ Primary hypothyroidism and subclinical hypothyroidism have both been associated with altered bitter taste.^58,59 Taste impairment improved after treatment of subclinical and clinical hypothyroidism.^58,59 Interestingly, Type II taste receptors (TAS2Rs) which are activated by bitter tastants, are expressed on human thyrocytes, and T2S2Rs coupled the detection of bitter tastants to changes in the function of thyrocytes and production of triiodothyronine and thyroxine from thyrocytes.⁶⁰ Taste hedonic and intensity ratings followed a cyclic pattern in alignment with different phases of the menstrual cycle with perceived intensity peaking in the mid-luteal phase.⁶¹

Obesity

Overweight and obesity statuses are associated with both higher electrogustometry (EGM) and taste thresholds.^54,62 In addition, in the Beaver Dam Offspring Study of 1918 participants, those with above-average taste intensities for salt, sour, and bitter were associated with higher five-year change in BMI.⁶³ Obesity is associated with a loss of FP possibly mediated through inflammation.⁶⁴ Rodents fed with a high fat diet became obese and had a lower FP density; this association appeared to be mediated via inflammation, specifically TNF-alpha.⁶⁵ Individuals prone to obesity may have a heightened hedonic response to unhealthy foods such as sweet, salty, and energy dense foods.^54,62,63,66

Sex differences

There are reported differences in taste sensitivity between women and men with women having higher taste sensitivity and more supertasters.^67–69 The etiology of the sex differences is not clear. One possibility is that women have a greater FP density than men.^8,9,70 The sex hormones estrogen and progesterone may play a role as evidenced by changes in taste intensity and hedonic preferences in pregnancy, such as an increase in bitter intensity.⁷¹ Sex steroid hormones have been shown to affect gustatory processing at the levels of the taste receptor, peripheral nerve, and the central nervous system, with receptors for sex hormones prominently present in several nuclei associated with central gustatory pathways.

Race differences

Racial differences have been reported in taste sensitivity where non-Hispanic Black populations have been noted to have a higher prevalence of taste impairment,⁷² but have rated taste sensations higher.⁷³ Proposed mechanisms for these variabilities include genetic distinctions such as differences in the frequency distribution and functional variants of TAS2R16 and TAS2R38 haplotypes.⁷⁴

Medications

Finally, many medications are well known to affect taste. Box 1 provides a list of over 250 different medications that have been shown to affect taste. It is important for patients and health care providers to be cognizant of the possible taste-altering effect of medications because dysgeusia may lead to malnutrition and other health problems. The elderly are more likely to be taking multiple medications in their daily regime.

Box 1: List of medications associated with altered taste.

Acarbose78

ACE Inhibitors (drug class)79

Acetaminophen78

Acetazolamide78–81

Acyclovir78,80,82

Afatinib83

Albuterol78,79

Aldesleukin83

Alendronate78

Allopurinol78,79

Alprazolam78,80

Amantadine80

Amiloride78–80

Amiodarone78,80

Amitriptyline78,80

Amlodipine besylate78

Amoxicillin78,84

Amphetamine79,80

Amphotericin B79

Ampicillin80,82

Amrinone79

Anastrozole83

Anticholinergics80

Aspirin78,79

Atorvastatin78,80

Atovaquone82

Atropine sulfate78

Auranofin79,80

Auranofin83

Azelastine84

Azithromycin80

Aztreonam79

Baclofen78,80

Beclomethasone80,84

Benazepril79

Benztropine78

Bepridil80

β-lactam antibiotics (drug class)79

Betaxolol80

Bevacizumab + interferon-alpha84

Bisphosphonates (drug class)79

Bitolterol80

Bleomycin79

Bosutinib83

Bretylium79

Bromocriptine78

Budesonide80,83

Buspirone78,80

Busulfan78

Cabozantinib83

Calcitonin78

Candesartan85,86

Capecitabine83

Captopril78–80,84

Carbamazepine78–80

Carbimazole80

Carboplatin/Cisplatin78–80

Cefamandole79

Cefpirome79

Celecoxib78

Cephalosporin antibiotics (drug class)78

Cetirizine78

Chlorhexidine79

Chlorphenamine80

Chlorthalidone87

Choline magnesium trisalicylate79

Ciprofloxacin79,80,84

Clarithromycin80,84

Clidinium78

Clomipramine78,80

Clozapine80

Colchicine80

Crizotinib83

Cyclophosphamide80,84

Dantrolene80

Dapsone82

Dasatinib83

Deferoxamine79

Desipramine80

Dexamethasone80

Dexamphetamine80

Diazoxide78,79

Diclofenac82

Dicyclomine78,79

Dihydroergotamine mesilate80

Diltiazem79,80

Dipyridamole78,79

Disulfiram79

Docetaxel84

Donepezil78

Dorzolamide timolol78,88

Doxepin78,80

Doxorubicin79,80

Duloxetine89

Enalapril78–80

Enoxacin80,82

Eplerenone90

Eprosartan90

Esmolol79

Eszopiclone80

Ethacrynic acid90,91

Ethambutol79,80,82

Ethionamide79

Ethylenediaminetetraacetic acid79

Etidronate78,79

Everolimus83

Famotidine78,79

Fenfluramine78

Fenoprofen82

Fentanyl78

Filgrastim79

Flecainide78

Flosequinan79

Fluconazole78

Flunisolide79 80

Fluorouracil78–80

Fluoxetine78,79

Flurazepam78–80

Fluticasone propionate80

Fluvastatin78,80

Fluvoxamine78

Fosinopril79

Furosemide87,90,92,93

Ganciclovir78,80

Gemfibrozil78

Glyburide78

Glycopyrrolate79

Gold78 80

Granisetron78

Griseofulvin78,80

Guanfacine79

Hydralazine79

Hydrochlorothiazide78–80

Hydrocortisone79

Hydroxychloroquine78

Ibuprofen79,82

Imipramine80

Indomethacin78

Interferon (α & γ)79,80,84

Iodide 13184

Iodine79

Isotretinoin78,79

Isradipine91

Ketoprofen82

Ketorolac79

Labetalol79,90,91

Lansoprazole84

Levamisole79,80

Levodopa78–80

Levofloxacin i/inhalation solution84

Levothyroxine59,80,92

Lifitegrast84

Lincomycin79

Lisinopril79

Lithium79 80

Lomefloxacin HCl79,82

Loratadine80

Losartan78–80,85

Lovastatin79,80

Loxapine84

MAP 0004 (orally inhaled dihydroergotamine)84

Methimazole78,79

Methotrexate79,80

Methylphenidate80

Metolazone90

Metronidazole79,80,84

Miconazole (oral)83

Midodrine93

Minoxidil78

Moexipril79,90

Nabumetone82

Naproxen79

Naratriptan78,80

Necitumumab83

Nicotine79,80

Nifedipine78–80 91

Nilotinib83

Niridazole79

Nisoldipine80

Nitroglycerin79,80

Nortriptyline78,80,84

Ofloxacin78–80,82

Olanzapine78

Omeprazole78,79,84

Opiates (drug class)79

Oseltamivir80

Paclitaxel + Pazopanib84

Palbociclib83

Pamidronate78

Pancrelipase80

Panobinostat83

Paroxetine79

Paxlovid94

Penicillamine78–80

Pentamidine78–80,82,95

Pentazocine78,79

Pentoxifylline78

Pergolide78,79

Perindopril78,90

Phenytoin78,80

Phytonadione78

Pilocarpine78

Pirbuterol80

Pirodavir80

Pivaloyloxymethyl butyrate84

Podophyllum resin84

Potassium Iodide78

Pravastatin80

Procainamide78

Propafenone79,80

Propantheline78

Propranolol78–80

Propylthiouracil78–80

Pseudoephedrine80

Pyrimethamine78,82

Quinapril79

Quinidine78

Ramipril79

Ranitidine78,84

Rifabutin78 79

Ritonavir78

Rivastigmine78

Rizatriptan80

Selegiline79

Sodium phenylbutyrate83

Sorafenib83,84

Spironolactone78–80

Sulfamethoxazole80,82

Sulfasalazine79,83

Sulindac82

Sumatriptan79,80,84

Sunitinib84

Tegafur80,83

Temsirolimus83,84

Teprotumumab96,97

Terbinafine79,80

Tetracycline79,80,82

Thiamazole80

Ticarcillin80

Tinidazole84

Tocainide79,80

Topiramate78,80

Tranylcypromine79

Trastuzumab83,98

Triamterene90,92

Triazolam79

Trifluoperazine80

Valsartan85

Vandetanib83

Venlafaxine78

Vincristine80

Vismodegib83,84

Zalcitabine80

Zolpidem 80

TASTE AND AGING

The aging process is a gradual, continuous process, wherein multiple changes occur at various rates, including loss of homeostasis and reserve over time. This includes reduced appreciation for food and its contents. FP density has been shown to be associated with taste intensity.^6,75 The decreasing sensitivity to taste with age may be due to anatomical changes in the tongue (the primary organ) such as reductions in numbers of both papillae and taste buds within each taste papillae during aging. In addition, vessel density at the tip of the tongue decreased significantly in older men and women compared to a younger population.⁷⁶ It is also possible that there is microvascular damage within the tongue vessels that interrupts nutrients being supplied to taste buds; however, this has not been studied. There are likely to be alterations in the sensory nerve endings of the three CN nerves in the taste papillae/taste buds. And finally, the perception of food in the primary gustatory cortex may be altered. Investigations of animal models have also demonstrated that taste sensitivities decline with age and are accompanied by a delayed stem cell renewal that would prevent replenishment of taste receptor cells when they undergo apoptosis. Highly vacuolated cytoplasm has been noted in the taste receptor cells of taste buds.

Furthermore, our recent study demonstrated a significant reduction in taste bud size and numbers of taste receptor cells per bud accompanied by altered sweet taste responsivity in older mice compared with younger ones⁷⁷. In humans, we, along with others, have shown that FP density decreases with age both cross-sectionally^8,9 and longitudinally.⁹

Since several hormones play important roles in modulating taste responsiveness via autocrine, paracrine, or endocrine mechanisms; these hormones within taste buds may change in accordance with taste alterations. We have previously shown that the metabolic hormones GLP-1, ghrelin as well as the sweet taste receptor subunit T1R3, protein gene product 9.5, and sonic hedgehog (necessary for stem cell differentiation) are significantly decreased in taste buds of the older rodents: all of these factors combined, if also the case in humans, are likely to be involved in altered taste perception at the primary site as aging marches on.

SUMMARY

The ability to taste is paramount to our wellbeing and existence – detect and consume delicious and nutritious foods while avoiding spoiled and poisonous ingredients. Taste has been known to decrease with aging but the determinants behind this decline are not well understood. Recent advances in our understanding of the molecular mechanisms of TRCs have shed light on this organ in a fascinating way. The unexpected findings of endocrine hormones in TRCs point towards taste buds being endocrine organs. Further studies are needed to possibly help us treat the decline in taste with aging in the future.

Key Points:

• Taste impairment increases with age

• Endocrine hormones are present in taste receptor cells within taste buds

• Many medications have been associated with taste impairment—common medications include: ACE Inhibitors (captopril, perindopril, moexipril, enalapril); Antibiotics (amoxicillin, ampicillin, ciprofloxacin, metronidazole, azithromycin); Anxiolytics (alprazolam, buspirone, flurazepam); ARBs (candesartan, losartan, valsartan); Chemotherapy drugs; Diuretics (furosemide, hydrochlorothiazide); Beta blockers (propranolol, labetalol); Lipid lowering agents (atorvastatin, lovastatin); Thyroid medications (levothyroxine, methimazole, propylthiouracil)

Synopsis:

Taste is one of our five primary senses, and taste impairment has been shown to increase with aging. The ability to taste allows us to enjoy the food we eat and to avoid foods that are potentially spoiled or poisonous. Recent advances in our understanding of the molecular mechanisms of taste receptor cells located within taste buds help us decipher how taste works. The discoveries of ‘classic’ endocrine hormones in taste receptor cells point towards taste buds being actual endocrine organs. A better understanding of how taste work may help in reversing taste impairment associated with aging.

CLINICS CARE POINTS.

• Ask about alteration in taste during routine doctor visit with an older adult

• Take a detailed medical history to identify possible reversible causes of dysgeusia or ageusia such as hypothyroidism

• Review medications in patients reporting dysgeusia or ageusia