Age-associated alterations in thirst and arginine vasopressin in response to a water or sodium load.
There are marked age-associated changes in the regulation of water metabolism. Some authors hold the view that in humans ageing is accompanied by a mild form of diabetes insipidus . Early experimental studies in laboratory rodents tended to support this idea , and the diabetes insipidus was linked to a reduction in the release of arginine vasopressin (AVP) from the posterior pituitary. In addition, there was a decrease in plasma AVP levels in old rats. Conversely, recent studies have not shown a decrease in neurohypophysial function with increasing age .
The evidence for an age-associated difference in the basal plasma AVP of healthy humans is contradictory. Some studies show no change in plasma AVP between young and old men [3-5], although others have found an increase . Old age is also thought to be accompanied by increased osmoreceptor sensitivity . Thus, in one study of elderly people there was a greater release of AVP in response to increasing plasma osmolality , although the age range of the subjects was only 52-66 years. Others  found a diminished AVP response to water deprivation in a much older population (mean age 76 years). A more recent investigation of the response of plasma AVP to hypertonic saline infusion failed to detect a difference between young and old groups . In the light of these contradictory findings further work is necessary to understand age-associated changes in the physiological variables involved in water homoeostasis.
A major element in the preservation of water balance is thirst, and this was not measured in earlier studies [3, 7]. It is a common belief that thirst decreases with age  and this has been reported after water deprivation of healthy, elderly men . These findings were confirmed when old men were studied in the periods immediately following water , or osmotic loads . However, to our knowledge, water homoeostasis has only been examined in small numbers of elderly men [8, 10, 11], whose precise health status was not defined .
Research in our laboratory has confirmed that elderly people are vulnerable to disturbances of hydration. A high plasma osmolality was associated with a marked increase in mortality in long-term-care patients . Others have shown elderly people predisposed to both hypo- and hypernatraemic states with consequent morbidity and mortality . However, because of the contradictions in the published data on water conservation in older people it is impossible to determine whether the changes observed are due to the ageing, or to the age-associated pathology of these subjects. There is a need to clarify whether there are changes in water homoeostasis with age because it is known that age-associated pathology and chronic disability can influence the measurement of age changes . In this study we defined the health status of our elderly subjects using an established protocol, and examined simultaneous changes in thirst, plasma osmolality and AVP during sodium and water loading.
Ten elderly subjects ([greater than] 70 years) were recruited from a panel of people who had previously been examined to define their health status according to set criteria (see Appendix I ). We screened a total of 20 elderly people randomly chosen from this panel. Their plasma and urine osmolality were measured on two consecutive days and their creatinine clearance estimated from a 24-hour urine sample. Four subjects were excluded because their clearance was [less than] 60 ml/min. Ten subjects were randomly chosen from the remainder.
The elderly subjects were compared with ten younger volunteers ([less than] 40 years), who had no history of chronic disease, were free of medication at the time of study and unaware of the aims of the research. The protocol for the study was approved by the Ethical Committee of Salford District Health Authority.
Manipulation of A VP Secretion and Thirst
Pre-experimental conditions: The stimuli used to examine the thirst and AVP response to alterations in plasma osmolality (pOsm) were an oral water load and a hypertonic saline infusion. The order of administration was decided randomly, and at least one week elapsed between studies on each subject. Subjects did not smoke, drink alcohol or take caffeine from 21 h 00 on the night before the study, when 250ml of water was drunk. A light breakfast, with a further 250ml of water, was consumed on the morning of the study. No other fluids were allowed in the 12 hours before each experiment. This method was an attempt to standardize the water status of the subjects as far as possible.
Water loading: Subjects attended the laboratory at 08 h 30, a baseline urine sample was obtained and the volume and osmolality recorded. The subjects were placed in a recumbent position and a venous cannula (21 G, Venflon) inserted into the antecubital fossa. After a further 30 min recumbency two basal blood samples (15 min apart) were taken for haematocrit, plasma sodium, creatinine, urea, osmotic pressure and AVP. Thirst was also assessed (see below).
After 60 min of recumbency a standard water load of 20 ml/kg body weight  was ingested over 40 min. The subjects were encouraged to drink small quantities of fluid at a time, but to maintain continuous drinking during the period of ingestion. There were no reports of discomfort. Every 30 min blood samples for plasma sodium, creatinine, urea, haematocrit and osmotic pressure were taken, and a thirst rating was obtained. Samples for plasma AVP were taken at 60 min intervals during the investigation. Urine samples were collected hourly and the volume and osmotic pressure were determined. The study continued for a total of 6 hours (5 hours after the water load), during which time no other fluids were taken.
Hypertonic saline infusion: The preliminary conditions were identical to the protocol outlined above. Two indwelling cannulas were inserted into the left and right antecubital fossa, one for saline infusion, the other for collection of subsequent blood samples. The two basal blood samples were taken as described above. After 1 h of recumbency, an infusion of hypertonic saline (462 mmol/l) (Infusomat Secura, Braun, Germany) began at a rate of 0.1 ml/min/kg body weight. The osmotic load was continued for 2 hours in a regime similar to that used in a previous study . The measurement of thirst, and the taking of blood and urine samples for assays, was identical to that described in the water-loading experiment. A urine sample was collected at the end of the infusion and its volume and osmotic pressure determined. Oral fluids and food were withheld throughout the infusion, although subjects were informed that they could stop the study at any time.
After cessation of the hypertonic saline infusion each subject drank bottled water at room temperature. The amounts of fluid drunk and thirst ratings were recorded for 2 hours. Measurements of plasma sodium, creatinine, urea, osmotic pressure, haematocrit, and AVP continued at 30 min intervals over this period.
Blood was dispensed from chilled syringes into cold lithium heparin or potassium EDTA tubes, maintained in crushed ice. Samples were processed within 20 min. Plasma was separated from whole blood by centrifuging at 2000 rpm for 10 min at 4 [degrees] C. Glass Pasteur pipettes were used to draw off the plasma and transfer it to appropriate storage vessels. Four millilitres of the plasma treated with potassium EDTA was designated for AVP determination and extracted, lyophilized and stored at -80 [degrees] C as previously described . Lithium heparin treated plasma was used for immediate determination of plasma osmotic pressure, by depression of freezing point (Roebling Osmometer, Camlab, UK). The mean of three measurements was recorded.
Plasma sodium was determined using an atomic absorption spectrophotometer (Philips PU9200, Philips Analytical, Cambridge, UK). The plasma concentrations of creatinine and urea were determined using proprietary test kits.
Plasma vasopressin: Plasma AVP was measured using a sensitive radio-immunoassay previously described . However, the source of the AVP, the radio-labelled AVP and the anti-AVP antibody is now Amersham International (UK). The limit of assay detection was 0.2 pmol/l. The intra-assay coefficient of variation (CV) was between 9.0 (20 pmol/l) and 16.0% (1 pmol/l) and the inter-assay CV was between 5.0% (20 pmol/l) and 16.0% (1 pmol/l) on three separate plasma pools.
Thirst ratings were measured using visual analogue scales (VAS) with the extremes of the 100 mm line labelled 'not at all thirsty' and 'extremely thirsty' . Each scale was presented independently by the same observer. The distance marked on the line was used for the analysis.
The osmotic- and water-loading investigations were analysed separately. Statistical evaluation was by two-factor repeated measures analysis of variance (ANOVA) on the full data sets from each study. The aim was to decide whether there were differences in the measured variables for each age group during the experiment, and if there were differences between the age groups. This analysis also identified interactions in the data (an interaction identifies different responses by the groups during the treatment). Further analysis of the data (between time points within the groups, and between groups at individual time points) was by Tukey's Critical Range Test. The AVP data were not Normally distributed and the appropriate transformation was the inverse of the plasma AVP concentration. One observation from the baseline assessment in the salt-loading study was an outlier for clinical reasons and excluded from the analysis. All computations were by the GLIM statistical computer package .
We also analysed the relationship between plasma osmolality and thirst (VAS) using all the observations obtained during water loading. An analysis of the relationship between plasma osmolality and 1/AVP used the data obtained during the infusion of hypertonic saline, and excluded those data collected when the subjects were drinking after the infusion. The statistical relationships between plasma osmolality and 1/AVP and thirst were found by multiple linear regression methods. A series of linear models were fitted to the data using the method of maximum likelihood . The models included terms for the effect of the correlation between plasma osmolality and 1/AVP, and VAS, the effect of age grouping (young/old) and the individual effects of each patient.
The results of the various model fits were converted into standard ANOVA tables to find the statistical significance of the effects evaluated. The goodness-of-fit of the models, and the validity of the distributional assumptions made, was tested by constructing half-Normal probability plots from the model residuals and computing the Filliben correlation coefficient. Values of this coefficient over 0.99 suggested an acceptable data fit. If the fit was unacceptable, appropriate Normalizing transformations were sought using the Box-Cox technique .
The ten (six women, four men) health-status-defined elderly subjects had a mean [+ or -] SD (range) age of 72.1 [+ or -] 3.1 (68-79) years, and the ten (four women, six men) young controls 26.8 [+ or -] 4.8 (20-35) years. The preliminary measurement of plasma osmolality showed that the elderly subjects had a significantly higher value than the young (Old: 293 mOsm/kg [SD=4, n = 10]; Young; 288 mOsm/kg [SD = 2, n = 10], p [less than] 0.001, 95% confidence interval (CI) for difference 2 to 7). The mean creatinine clearance for the old group was 81.9 ml/min (SD = 12.0, n = 10) and their mean weight 68.9 kg (SD = 17.6, n = 10). The mean weight of the young group was 70.2 kg (SD = 8.4, n = 10). One elderly subject became ill following the water-loading study day and did not complete the investigation. Data were otherwise complete.
Changes in thirst, AVP and plasma osmolality: Figure 1 shows the changes in thirst, AVP and plasma osmolality after water loading. Two-factor repeated measures ANOVA showed significant differences over time for plasma osmolality (F[11,239] = 27.833; p = [less than] 0.001) and thirst (VAS; F[11,239] = 12.648; p [less than] 0.001). There was no significant difference between the age groups for either of these variables. Further analysis to find differences between individual time points, by Tukey's Critical Range Test, showed a significant fall (p [less than] 0.05) in the plasma osmolality between zero and 1.5 hours. Subsequently, this variable remained below the basal level through to 5 hours in both groups. A similar analysis of thirst showed significant increases in VAS score (p [less than] 0.05) after 5.5 hours in the young, and five hours in the old group.
The relationship between VAS score for thirst and plasma osmolality: It is known that there is a significant relationship between the VAS score for thirst and plasma osmolality. This was confirmed in this study (linear regression model 'best fit' described in Subjects and Methods) in both the young (F[1,108] = 27.945, p = 0.01) and old subjects (F[1,106] = 17.43, p = 0.01). The equations describing the relationship between thirst and plasma osmolality for each subject are given in Appendix II. However, there was no significant difference between the two age groups in the slopes of the linear regression equations (F[1,18] = 0.063; p = 0.9), nor their intercepts (F[1,214] = 0.0192; p = 0.8).
The relationship between plasma AVP and plasma osmolality: The distribution of the AVP data was not statistically Normal and the appropriate Normalizing transformation was the inverse of the plasma AVP concentration. Analysis of the transformed data showed a significant change in 1/AVP during water loading (F[10,158] = 4.775, p [less than] 0.0001), but no difference between the two age groups (F[19,1] = 0.563, p = 0.5). Tukey's Critical Range Test showed a significant fall in plasma AVP from the basal time point (p [less than] 0.05) in the young subjects, after 30 min of drinking and 1.5 and 2.5 h post drinking [ILLUSTRATION FOR FIGURE 1 OMITTED]. In the old group there was a significant fall in plasma AVP (p [less than] 0.05), 1.5 and 2.5 h after drinking the water load [ILLUSTRATION FOR FIGURE 1 OMITTED].
The relationship between 1/AVP and plasma osmolality was analysed by linear regression models fitted to the data as described above. There was a significant interaction between plasma osmolality and age for 1/AVP (F[1,137] = 8.996; p [less than] 0.001) showing that the relationship between these variables differed between the two age groups. It was possible to fit a linear regression relationship to the data but the correlations were weak and of limited value (Young: r = 0.344, with only 11.8% of the within-subject variation explained; Old: r = 0.253, with only 6.4% of the within subject variation explained). However, the old subjects had a lower plasma AVP than the young subjects for any given plasma osmotic pressure. Furthermore, the rise in plasma AVP with increasing plasma osmotic pressure in the old subjects was lower than in the young individuals. The equations are reproduced in Appendix II.
The elderly subjects excreted less of the water load in the first 2 h (Old: 0.48 [SD = 0.25, n = 9]; Young: 0.82 [SD = 0.15, n = 10] p = 0.003, 95% CI for difference -0.55 to -0.13). This difference had disappeared at 5 h (Old: 0.96 [SD = 0.44, n = 9]; Young: 1.24 [SD = 0.38, n = 10] p = 0.2, 95% CI -0.66 to 0.11). The urine osmolality before the water load was significantly lower in the old group (Old: 511.4 mOsm/kg [SD = 212.4, n = 9]; Young: 776.9 mOsm/kg [SD = 190.0, n = 10] p = 0.02, 95% CI -476 to -55). After the water load the urine osmolality fell to a lower level in the young group (Old: 112.8 mOsm/kg [SD = 29.2, n = 9]; Young: 80.9 mOsm/kg [SD = 14.9, n = 10] p = 0.009, 95% CI 9.5 to 54.3). Plasma osmolality was significantly correlated with serum sodium, log urea, creatinine, and urine volume, but not with haematocrit (data not presented).
Changes in thirst, AVP and plasma osmolality: Changes in AVP, thirst, and plasma osmolality with time are shown for both the young and old subjects [ILLUSTRATION FOR FIGURE 2 OMITTED]. Two-factor repeated measures ANOVA of the complete experimental protocol showed significant time effects for plasma osmolality (F[9,153] = 67.365; p [less than] 0.001), but no difference between the two age groups (F[1,17] = 2.752; p = 0.1). Tukey's Critical Range Test showed significant increases in plasma osmolality (p [less than] 0.05) above the zero hour time point, between 2 and 5 h of the protocol in both age groups.
A two-factor repeated measures ANOVA showed a significant age/time interaction in thirst (F[9,189] = 8.184; p [less than] 0.0001). This finding reveals a significant difference in the way that the young and old age groups recorded their thirst over the time course of the whole experiment [ILLUSTRATION FOR FIGURE 2 OMITTED]. In the young subjects the Tukey Critical Range Test showed a significant increase (p [less than] 0.05) in the thirst score after 1 h. Thirst continued to be raised until the end of the saline infusion and returned to basal values immediately on drinking water after the osmotic load [ILLUSTRATION FOR FIGURE 2 OMITTED]. The old subjects showed a significant increase (p [less than] 0.05) in the VAS score within 30 min of the saline infusion, which then remained elevated throughout the remainder of the protocol [ILLUSTRATION FOR FIGURE 2 OMITTED].
The relationship between VAS score for thirst and plasma osmolality: There was a significant linear relationship between thirst (VAS) and plasma osmolality over the first 3 h of the salt infusion for both the young (F[1,44] = 142.47; p [less than] 0.0001) and old subjects (F[1,49] = 117.42; p [less than] 0.0001), but no significant difference between the age groups (F[1,17] = 1.019; p = 0.3). The relationship for each subject was found initially and the data plotted in Figure 3. Further analysis of the data, by averaging across the subjects within each age group, but considering the subject effect, showed no significant difference between the slopes of the linear regression equations (F[1,93] = 0.0015; p = 0.9), nor the intercepts F[1,97] = 1.6825; p = 0.2). The equations describing the averaged relationships were identical to those found for the individual subjects (without the subject effect) and are given in Appendix II. In the young group the relationship accounted for 70.5% of the variance and in the old 76.4% [ILLUSTRATION FOR FIGURE 3 OMITTED].
The relationship between plasma AVP and plasma osmolality: The AVP data were not Normally distributed and the inverse transformation was applied. An age/time interaction was revealed (F[8,150] = 5.057; p [less than] 0.001), suggesting that the young and old groups regulated their plasma AVP levels differently over the time course of the osmotic load and rehydration protocol. Examination of the AVP levels (presented detransformed in [ILLUSTRATION FOR FIGURE 2 OMITTED]) using Tukey's Critical Range Test showed significant differences in plasma AVP between the age groups at each time point excepting 3 h. The old group started at significantly lower levels and remained at significantly higher levels after drinking. Analysis of the transformed data for each subject showed a significant linear relationship between 1/AVP and plasma osmolality for both the young (F[1,49] = 34.04; p [less than] 0.0001) and the old subjects (F[1,44] = 62.60; p [less than] 0.0001), but no significant age difference (F[1,17] = 0.3435; p = 0.6). The regression curves of these relationships, together with the individual subject values, are plotted in Figure 4.
Further analysis of the data by averaging across the subjects within each age group, but considering the subject effect, showed significant differences between the slopes (F[1,17] = 6.7081; p = 0.02) and the intercepts (F[1,17] = 6.554; p = 0.02) of these two linear regressions [ILLUSTRATION FOR FIGURE 4 OMITTED]. The relationships for each age group are set out in Appendix II. The calculated lines of relationships for each group are plotted also as detransformed values to give a view of AVP against plasma osmolality for the calculated lines only [ILLUSTRATION FOR FIGURE 5 OMITTED]. In the old subjects the basal plasma AVP levels tended to be lower than in the young, but increased more rapidly in response to stimulation.
Fluid ingestion after the osmotic load: There was no difference in the fluid drunk between the two groups following the cessation of the hypertonic saline infusion: young 781 ml (SD = 298, n = 10); old 760 ml (SD = 197, n = 9) (p = 0.9, 95% CI for difference -239 to 268 ml). There were significant falls in VAS, plasma osmolality and AVP (all p [less than] 0.05) after stopping the infusion when compared with the time point immediately before it, but there were no significant differences between the two groups over time (VAS, p = 0.89; AVP, p = 0.9; plasma osmolality, p = 0.9). During the complete osmotic-loading study there were significant correlations between plasma osmolality and serum sodium, haematocrit and urine volume, but not with serum urea (data not presented).
This study showed subtle, age-associated differences in the response of thirst and plasma AVP to water and osmotic loading in young and old health-status-defined subjects. There was no age-associated difference in the relationship between thirst and increasing plasma osmolality. However, there was an age-associated difference in the relationship between plasma AVP and plasma osmolality through the physiological range.
Age-associated changes in thirst: There was no age-associated difference in the overall recording of thirst during the water-loading experiment. This confirms a recent study of thirst in healthy elderly men , showing that after a water load thirst was reduced in both young and old groups. According to Phillips et al. , since plasma AVP fell immediately after drinking only in the young group, the results demonstrate reduced oropharyngeal inhibition of AVP secretion after drinking in healthy elderly men but maintained inhibition of thirst. During the osmotic loading used in the study reported here, a significant difference was detected in the way that the young and old age groups recorded their thirst over the complete time course of the experiment. In the osmotic loading protocol we observed a marked fall in the thirst response of the young subjects after drinking, but not of the old. There was no age-associated difference in the slopes, or intercepts, of the relationship between increasing plasma osmolality and rising thirst scores (in both water loading and during the first 3 hours of osmotic loading). However, we detected change in the thirst response between young and old subjects only when the elderly people were asked to score their thirst response during rapidly changing conditions. There are interesting parallels with studies on temperature regulation where old subjects respond slowly to environmental fluctuations . Thus, this study only partially supports previous reports of a change in thirst with age [8, 10, 11], since we detected an alteration only in the recording of thirst between the two age groups investigated, not in the relationship between rising plasma osmolality and thirst.
The following discussion is restricted to a comparison of the findings produced by the hypertonic saline infusion, which is a well-validated technique for increasing plasma osmolality and stimulating thirst [22-24]. We have found, like others , a straight-line relationship between thirst and plasma osmolality with an x-intercept of around 290 mOsm/kg and a slope of 0.42. In the investigation by Phillips et al.  using this technique the published x-intercept was 261 mOsm/kg for the young subjects and 276 mOsm/kg for the old. The slopes were 2.75 for the young and 1.38 for the old group . These data are different from previously published material for young subjects. In the study reported here there was no difference in the slopes of the relationship between thirst and plasma osmolality for young and old subjects although variation was higher in the former. This may be explained by the more careful screening of the elderly group and their familiarity with scientific studies, although they had no previous experience of these methods. Furthermore, we could not show a difference in the drinking behaviour of the two age groups because almost identical volumes of fluid were drunk by both age groups after the cessation of the infusion. There is doubt in our minds about the precise relationship between VAS and plasma osmolality, particularly when drinking after an osmotic load leads to a prompt drop in VAS score, without a change in plasma osmolality.
Although it is not the only possible explanation for the difference between this investigation and the published literature, the fact that we have used subjects from a panel of elderly people who have been systematically, and repeatedly, screened to remove pathological interference must have a significant bearing. Support for this view can be found in immunogerontology, where the crucial importance of subject selection is recognized, and a standardized protocol devised for the admission of healthy subjects to studies (the SENIEUR protocol ). It has been shown that many age-associated defects in human immune function probably do not arise from immune senescence but are caused by underlying disease . We suggest that the source of the differences between the data presented here, and elsewhere, are in the health status of the subjects and not necessarily to do with age per se.
Age-associated changes in AVP release: We have confirmed the increased osmoreceptor sensitivity observed in other studies of aged subjects. There were significant changes in plasma AVP during both the water and osmotic loading protocols. Most important was the significant time/group interaction showed by the analysis over the whole time of the osmotic loading study. This clearly establishes that plasma AVP responds differently to the increase in plasma osmotic pressure induced by osmotic loading in young and old age groups (see Results section). As described above, we detected an alteration in the levels of plasma AVP between young and old subjects under rapidly changing physiological conditions. Here the elderly subjects drank similar amounts of fluid to the young group, but failed to reduce plasma AVP as rapidly as the young.
The suppression of AVP secretion was investigated by oral water loading. In this study the plasma AVP was identical in the age groups and suppressed after drinking the water load. These data are similar to another study of thirst in healthy elderly men , where after a water load thirst was reduced in both young and old groups but plasma AVP fell immediately after drinking only in the young group . This is in direct contrast to recent findings  where plasma AVP was suppressed in the young group after water loading but was maintained at a higher level than in the elderly subjects throughout the protocol. Although there are flaws in the statistical analysis employed by Faull et al.  the difference in the AVP response after water loading, between the two age groups, is remarkable. There is no simple explanation for the differences between the study of Faull et al.  and others in the literature.
The relationship between plasma osmolality and A VP: The relationship between changing plasma osmolality and AVP was explored in both protocols described here. During water loading there was a significant difference between the age groups over time but the correlations were weak and of limited value. In the osmotic loading study there was a significant age difference in the relationship between increasing plasma osmolality and AVP when the data were analysed for the entire group of subjects. The older subjects started the experiment with lower levels of AVP, and, within the physiological range, the hormonal concentration rose more rapidly in response to plasma osmolality than in the young subjects.
In this study we examined the Normality of the distribution of our data before carrying out a statistical analysis. The AVP data were not Normally distributed and required an inverse transformation before parametric statistics could be used. Linear regression methods were then used to determine the relationship between 1/AVP and plasma osmolality. In this investigation the relationship between AVP and plasma osmolality is curvilinear. This agrees with other studies in the literature [27, 28]. Other reports [3, 29-31] have employed linear regression analysis in their studies of the relationship between AVP and plasma osmolality, however, none of them has reported checking the Normality of the distribution of their AVP data. In the earliest study  (to our knowledge) it was argued that when plasma osmolality fell below a 'threshold' level of between 275 and 280 mOsm/kg, plasma AVP was 'uniformly suppressed, allowing maximum water diuresis. Above this 'set point', plasma AVP rises sharply in direct proportion with plasma osmolality, and the slope of the regression line describing this relationship provides a measure of the sensitivity of the system. A least-squares analysis of the relationship between plasma osmolality and AVP was made  on all values of plasma osmolality greater than 280 mOsm/kg, although the data presented show many low AVP values occurring below 280 mOsm/kg. Clearly, the idea of a set point is convenient since a straightforward switching mechanism for AVP release in response to increasing levels of plasma osmolality can be postulated. However, in our view the curvilinear relationship makes fewer assumptions about such a mechanism. Despite debate in the literature there has been no clear resolution of this issue .
The effect of age on neurohypophysial responsiveness to an osmotic load was first investigated on a group of subjects drawn from the Baltimore longitudinal study of ageing . The sex of the subjects was not stated, and the mean age of the old group was 59 years (range 52-66 years) compared with 37 years for the young (range 22-48 years). A heightened AVP response to increasing plasma osmolality was reported  in the older group, but this is difficult to interpret as an ageing change given the ages of the subjects. Their results were, apparently, confirmed in a much older group . However, no raw data were presented  and the line of relationship between AVP and plasma osmolality in the young group had a slope of only 0.06, much less than previous studies [3, 16]. Furthermore, the slope of the relationship in the elderly subjects (0.23)  was similar to that found in studies of young volunteers . A more recent investigation failed to establish relationships between either plasma sodium and AVP, or plasma osmolality and AVP, because of poor correlations in these variables in many elderly subjects . A further assumption is that any increase in plasma hormone concentrations is due to increased secretion. There is evidence that there is a decrease in clearance of AVP from the plasma , though others have reported no change in the half-life .
Functional changes in the kidney: Our data suggest that the elderly have functional changes in the kidney since there was a delay in the excretion of the water load. This could be due to a lower glomerular filtration rate, or a reduction in the sensitivity of the kidney to AVP stimulation . These data must be interpreted with caution since there were differences in the initial urine osmolalities, despite attempts to standardize fluid intake in the pre-experimental period. The same comment applies to other studies. In the investigation reported by Phillips et al. , the initial mean urine osmolality before fluid deprivation was over 900 mOsm/kg in the young compared with 700 mOsm/kg in the old group. Similarly, Faull et al.  recorded an initial mean urine osmolality after fluid deprivation of 842 mOsm/kg in the young compared with 508 mOsm/kg in the old group, but failed to report the basal levels of plasma or urine osmolality before the start of the experiment. It is therefore difficult to assess any age differences in the response of the kidneys to water loading.
We have shown that in carefully screened elderly subjects, corresponding to those undergoing 'successful ageing' , the 'threshold' detection of thirst does not decline with age. However, thirst is a complex mechanism and will require subtle experimental approaches to unravel its intricacies. The data that we have supports to some extent the proposal that thirst deficits in elderly people may result from changes with age in the more poorly defined pathways that bring thirst to the attention . However, the increase of plasma AVP in response to raising plasma osmolality is significantly greater. The results support previous studies to a certain extent, however, the difference between this investigation and others emphasizes the importance of subject selection.
The authors are grateful for the generous support of the Violet M. Richards Charity for financial support of this project. The study could not have been carried out without the generous help of Professor Michael Horan who carried out the initial screening of the defined-health-status elderly subjects. Finally, we thank Yvonne Davidson and Andrew Fotheringham for their excellent technical work during this study.
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I. Davies*, P. A. O'Neill, J. Catania University of Manchester, Department of Geriatric Medicine, University Research and Teaching Building, Withington Hospital, Nell Lane, Manchester, M20 8LR
K. A. McLean Department of Geriatric Medicine
D. Bennett, Department of Medical Statistics,
Withington Hospital, Nell Lane, Manchester, M20 8LR
Address correspondence to Dr I. Davies, University of Manchester, School of Biological Sciences, 1.124 Stopford Building, Oxford Road, Manchester, M13 9PT
Received in revised form 17 July 1994
Appendix I. The Senieur Protocol
This protocol was developed by a working party of the European Economic Community (EURAGE-Concerted Action Programme on Aging) . This is a brief overview of the detailed questionnaire. In the absence of a full array of reference values for the older age groups some arbitrary limits have to be used.
(a) The age, sex, ethinic group, body weight, height, pregnancies, major surgery, blood transfusions, use of drugs, smoking, drinking, eating habits, profession, living conditions, and activities of daily living are recorded.
(b) The subjects are given a full physical examination (including chest radiography) and a basic clinical chemical investigation, which is followed up after 2 weeks
These are grouped under three headings:
Clinical information: Detailed attention is paid to problems of the immune system: Exclusion occurs if there is evidence for infection within the preceding 6-week period, any inflammatory process, or past or present malignancy or lymphoproliferative disorders. Other conditions which may affect the immune system, including significant arteriosclerosis, cardiac insufficiency, hypertension, alcoholism and drug abuse, dementia and malnutrition (Quetelet index) are also taken into account.
Laboratory data: Exclusion occurs if the subject is outside age-dependent reference ranges for ESR, haemoglobin, mean corpuscular volume, white cell count and differential, urea, alkaline phosphatase, aspartate transaminase, glucose, protein electrophoresis and urine analysis. Abnormal chest radiograph and/or electrocardiogram also leads to exclusion.
Pharmacological interference: All subjects must be free from drugs at the time of study and must not be taking prescribed medication on a regular basis.
The relationship between VAS score for thirst and plasma osmolality
The equations describing the relationship between thirst and plasma osmolality for each subject are given below:
VAS = -57.18 + (Subject effect) + 0.1999 [multiply by] pOsm
(SE = 10.95) (SE = 0.03782)
VAS = -57.31 + (Subject effect) + 0.2086 [multiply by] pOsm
(SE = 14.43) (SE = 0.04996)
The relationship between plasma AVP and plasma osmolality
The equations describing the relationship between 1/AVP and plasma osmolality are reproduced below:
1/AVP = 2.302 + (Subject effect) - 0.007113 [multiply by] pOsm
(SE = 0.6830) (SE = 0.0024)
1/AVP = 2.013 + (Subject effect) - 0.00496 [multiply by] pOsm
(SE = 0.6642) (SE = 0.0023)
The relationship between VAS score for thirst and plasma osmolality
The equations describing the averaged relationships between VAS score and plasma osmolality were identical to those found for the individual subjects (i.e. without the subject effect) and are given below:
VAS = - 120.44+ 0.4178 [multiply by] pOsm
(SE = 1.66) (SE=0.09114)
VAS = -122.50 + 0.4199 [multiply by] pOsm
(SE = 1.14) (SE = 0.03846)
The relationship between plasma AVP and plasma osmolality
The relationships for each age group are set out below:
1/AVP = 3.166 - (0.00953 [multiply by] pOsm)
(SE = 0.592) (SE = 0.0019l)
1/AVP = 6.452 - (0.02041 [multiply by] pOsm)
(SE = 1.12) (SE = 0.00381)
In the young subjects the relationship accounted for a smaller amount of the variance (59%), with greater between-subject variation, whereas in the old the relationship explained 40.96% of the variance.
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|Author:||Davies, Ioan; O'Neill, Paul A.; McLean, Kathleen A.; Catania, James; Bennett, Derek|
|Publication:||Age and Ageing|
|Date:||Mar 1, 1995|
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