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Aging and Secretory Reserve Capacity of Major Salivary Glands
1 University of Michigan School of Dentistry, Department of Cariology, Restorative Sciences, and Endodontics, Ann Arbor; Correspondence: *corresponding author, jonathan.ship{at}nyu.edu
A loss of acinar cells occurs with aging, while salivary production remains age-stable in healthy adults. It is hypothesized that a secretory reserve exists to preserve function despite a loss of acinar cells in normal aging. The purpose of this double-blind, placebo-controlled, crossover study was to determine age-related differences in salivary response to an anti-sialogogue (glycopyrrolate). Thirty-six healthy subjects (18 young - 20-38 yrs; 18 older - 60-77 yrs) received 4.0 µg/kg IV glycopyrrolate. Parotid and submandibular/sublingual saliva samples and xerostomia questionnaire responses were collected. Variables calculated for each subject were: times to initial and maximum suppression and xerostomic complaint; time to recovery; and durations of suppression and complaint. Salivary function was more adversely affected in older persons. There were no consistent age-associated questionnaire response differences. These findings suggest that salivary gland output is more adversely affected by an anti-sialogogue in healthy older vs. younger adults, supporting the secretory reserve hypothesis of salivary function.
Key Words: aging • reserve • saliva • parotid • submandibular/sublingual • xerostomia
Organ reserve is the difference between basal and maximum organ function (Montgomery, 2000), and has been demonstrated in biologic systems such as the heart, lungs, liver, and kidney (Epstein, 1996; Saltzman and Russell, 1998; Schmucker, 1998; Janssens et al., 1999). Gradual loss of reserve capacity is considered normal physiologic aging (Fries, 1980), yet age-related structural changes do not necessarily affect organ function in healthy individuals. Histomorphometric examination of "normal" salivary gland tissue revealed age-associated decreases in the number of acinar cells (Scott et al., 1987), while salivary production remains age-stable in healthy, non-medicated adults (e.g., Ship et al., 1995; Ghezzi et al., 2000). Accordingly, a secretory reserve in salivary glands has been hypothesized to account for loss of cells in normal aging in the presence of preserved functional capacity in older adults (Scott et al., 1987; Baum et al., 1992). Physiologically stressful circumstances (disease, surgery, radiotherapy, pharmacotherapeutics) can strain the reserve capacity, thus hindering its ability to compensate for increased metabolic demand and resulting in compromised function (Evers et al., 1994). Identification of normal physiologic age-associated changes is critical in differentiation between normal functional decline and disease in aging (Fozard et al., 1990). If normal aging and reserve capacity are understood, vulnerable populations at risk for impaired organ function and failure can be identified. Many older adults complain of a dry mouth and experience the deleterious consequences of salivary hypofunction (e.g., Närhi et al., 1999; Thomson et al., 1999). Accordingly, the "normal" aging process has been suggested as an etiological factor for salivary dysfunction (Pedersen et al., 1985; Cowman et al., 1994; Yeh et al., 1998). However, prospective and longitudinal studies demonstrate that salivary gland function is age-stable in healthy adults (e.g., Ship et al., 1995; Ghezzi et al., 2000). Salivary dysfunction in older adults is likely due to systemic diseases, prescription and non-prescription medications, chemotherapy, and head and neck radiation (e.g., Ship et al., 2002). Salivary glands are readily accessible and well-characterized; therefore, they are a useful tool for the study of the normal aging process and the impact of stress (e.g., medication use) on organ reserve and secretory function (Baum et al., 1992). As the number of acinar cells decreases with age, the adverse effects of anticholinergic drugs on salivary output should become more pronounced. However, to our knowledge, no studies have investigated this phenomenon. The purpose of this study was to utilize salivary glands to examine the influence of aging and secretory reserve in an organ system. We assessed the existence of reserve capacity of salivary function in healthy adults by investigating age-related differences in salivary responses following administration of an anticholinergic drug (glycopyrrolate). It was hypothesized that after administration of glycopyrrolate, older adults would experience greater salivary hypofunction compared with younger adults.
Subjects Study participants were 18 young (20-38 yrs; 24.3 ± 3.8, mean ± SD) and 18 older healthy adults (60-77 yrs; 69.9 + 5.1) of middle socio-economic class, diverse racial background, and equally distributed by gender. Each subject was given a complete physical exam and treadmill test. Ineligibility included: (1) evidence of provokable angina or ECG changes during the treadmill test; (2) treatment for systemic diseases; (3) pregnancy; (4) resting ECG abnormality; (5) prescription or non-prescription medication intake associated with salivary hypofunction within 7 days; or (6) history of head and neck radiotherapy or salivary gland hypofunction or disease.
Study Design At the second and third visits, the study protocol was identical with the exception that participants were randomly assigned to receive a 4.0 µg/kg dose of intravenous (IV) glycopyrrolate or IV placebo (5% dextrose in water, D5W), alternately. No statistically significant sequence effect was detected based on the visit order in which drug and placebo were administered. Both subject and examiner were blinded to the drug status of the subject. Participants were not allowed to eat, drink, perform oral hygiene, or smoke 1 hr prior to the study. Upon entry into the study, all participants emptied their bladders and were weighed. Starting at the second hour, subjects received 20 mL of IV D5W each hour. Subjects refrained from exercise or strenuous activity, eating, and wearing removable dental prostheses, but were free to use the bathroom facilities for the six-hour study duration. Continuous ECG monitoring was performed throughout the study so that cardiac changes could be assessed; however, no observable alterations in blood pressure and pulse rates occurred following glycopyrrolate administration. At baseline (collection time #1; CT 1), sitting blood pressure and pulse rate were measured, parotid and submandibular/sublingual saliva samples were collected (see below), a xerostomia questionnaire was administered (see below), and blood was drawn (see below). Following IV administration of 4.0 µg/kg glycopyrrolate or placebo, these measures were collected every 10 min for the first hour (CT 2-6), 15 min for the second hour (CT 7-10), 30 min for the third hour (CT 11-12), and then every hour until the end of the sixth hour (CT 13-16). Following the study, participants emptied their bladders and were weighed. Normal urinary function was demonstrated prior to discharge.
Drug
Parotid and Submandibular/Sublingual Saliva Collection Unstimulated and 2% citrate-stimulated salivary collection methods have been previously described (Ship et al., 1995). Parotid saliva was collected for 2 min with a modified Carlson-Crittenden cup from one gland (Stone Machine Co., Colton, CA, USA), followed by a two-minute collection of submandibular/sublingual saliva by light suction; all samples were collected in pre-weighed plastic graduated conical tubes. Output of saliva was determined gravimetrically and reported as mL/min per gland.
Xerostomic Questionnaire
Blood Collection and Analysis After IV administration, maximum glycopyrrolate concentrations were reached in 10 min, followed by a rapid decrease to a minimal concentration detected after 120 min, and below detectable levels after 240 min. No age- or gender-related differences were detected at any time point.
Statistical Analysis
For each person, lower tolerance limits for SPFR and SSFR were calculated as the value 2.4 standard deviations below the pooled placebo mean for that subject (Fig. 1
The following values were determined:
Eight outcome variables were calculated for each subject from each of the SPFR, SSFR, and 8 VAS values:
Comparisons between the age and gender groups were performed by Wilcoxon Rank Sum tests (outcomes 1-6) and Fischer’s Exact tests (outcomes 7-8). Statistical significance was defined as p < 0.0063 (0.05/8; 8 age group and 8 gender group comparisons for SPFR, SSFR, and xerostomia questions) when Bonferroni adjustment was applied to account for multiple comparisons.
No statistically significant age or gender differences in pooled placebo mean values were demonstrated for SPFR, SSFR, and the xerostomia responses.
For SPFR and SSFR, age and gender comparisons of outcome variables 1-8 were performed. The older group had significantly greater TR and TS (SPFR), shorter TIS (SSFR), and lower MS (SSFR) (Table; Fig. 2
There were no statistically significant gender differences for SPFR and SSFR. The results were not different when age group comparisons were adjusted by gender or when gender comparisons were adjusted by age group (data not shown). There were no significant interactions between age and gender for all comparisons. For xerostomia responses, age and gender comparisons of outcome variables 1-8 were performed. There were no consistent age or gender effects. Of all the xerostomia questions, statistically significant differences were found only for dryness of mouth and throat, where females had greater TR and more persons NR (data not shown). The results were not different when age group comparisons were adjusted by gender or when gender comparisons were adjusted by age group. There were no significant interactions between age and gender for all comparisons (data not shown).
This investigation demonstrated that major salivary gland output in healthy older adults is more adversely affected by an anticholinergic drug than that in younger adults. A salivary gland secretory reserve has been proposed to explain the loss of cells in normal aging (Scott et al., 1987) in the presence of preserved functional capacity in older adults (Ship and Baum, 1990; Ship et al., 1995; Ghezzi et al., 2000). In normal circumstances, lack of secretory reserve in older adults would not cause impaired function. However, conditions that adversely affect salivary function (i.e., anticholinergic medications) would cause greater impairment in an older compared with a younger person (Baum et al., 1992). A gradual loss of reserve capacity has been considered "normal" physiologic aging. In health, reserve capacity permits homeostasis to occur by using a fraction of total organ functional capacity (DiGiovanna, 1994). Cardiopulmonary, hepatic, and renal reserves are reduced in the elderly, but do not necessarily impair organ function in healthy older persons. Adequate functional capacity can be maintained in the presence of non-pathologic, "normal" aging changes, but these organs are vulnerable to external insults (Fozard et al., 1990; Baum et al., 1992). Physiologically stressful circumstances (e.g., disease, surgery, pharmacotherapeutics) strain the reserve capacity, thus hindering its ability to compensate for increased metabolic demand, resulting in compromised function (Evers et al., 1994). With increased susceptibility to acute and chronic stress, functional decline occurs more quickly and recovery takes longer in the older population. Salivary glands are ideal for demonstrating organ reserve capacity, since these exocrine glands are readily accessible, well-characterized, and reflect many systemic conditions (e.g., poorly controlled diabetes, HIV immunosuppression) (e.g., Atkinson and Wu, 1994). In juxtaposition to the flow rate findings, the magnitude of xerostomic complaints was not significantly different between the age groups, thus corroborating previous studies that reported fewer complaints of xerostomia in older adults after dehydration (Ship and Fischer, 1997). This may represent a significant problem for older adults, since they may experience impairments in the ability to respond to acute and chronic insults to salivary function. Further research is needed to determine whether lost reserve capacity results from "normal" aging in healthy persons or aging in the presence of pathoses. In addition, determination of possible alterations in the muscarinic receptor function in salivary glands of elderly people, as demonstrated in animal models (Maki et al., 1989; Olsen et al., 1997), needs to be investigated. However, results from this and previous studies utilizing healthy adults across the human lifespan (Epstein, 1996; Saltzman and Russell, 1998; Schmucker, 1998; Janssens et al., 1999) suggest that diminished reserve capacity is an age-dependent event.
The authors are grateful for research support from the following sources: the National Institute of Dental and Craniofacial Research (NIH, K23 DE00427), the University of Michigan General Clinical Research Center (M01-RR00042), the University of Michigan Office of the Vice President for Research, the University of Michigan Faculty Training Project in Geriatric Medicine and Dentistry (DHHS, HRSA #D31 AH90005), the American Association for Dental Research Student Research Fellowship, and the University of Michigan School of Dentistry Student Research Program (NIDCR Training Grant DE07101). The authors also thank Maryam Beyramian, DDS (University of Michigan School of Dentistry), Claudia Cotca, MPH (University of Michigan School of Dentistry), Michaela Goodson, BDS, MFDS RCS(Eng) (University of Newcastle upon Tyne), Puravi Patel, DDS (Private Practice; Sayville, NY), Elisa Rosier, BS (Wayne State University), Laura Walsh, MSBS, DDS (University of Michigan School of Dentistry), and Kazuhiro Shimoyama, DDS, PhD (Tokyo Medical and Dental University) for contributions to data collection. The authors are grateful to Leslie Lange, PhD (Wake Forest University School of Medicine), Satishchandra Pai, BDS, MDS, MPH, MIS (Columbia University School of Dental and Oral Surgery), John Preisser, PhD (University of North Carolina School of Public Health), and M. Anthony Schork, PhD (University of Michigan School of Public Health) for contributions to data analysis. Received for publication October 17, 2002. Revision received July 3, 2003. Accepted for publication July 25, 2003.
Journal of Dental Research, Vol. 82, No. 10,
844-848 (2003) This article has been cited by other articles:
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