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The association between HLA antigens and ageing is not clear. Ageing in women was associated with B40 and DR5 in a recent study, but other studies yielded conflicting results. In none of the studies, however, did the young and elderly samples originate from the same homogeneous population. Homogeneity is dependent on geographic origin. The aim of this study was to investigate whether differences in geographic origin between age groups could explain the age-associated differences in the frequencies of B40 and DR5. The authors used the new design of a 'birth-place-restricted comparison' in which the origin of all subjects was ascertained. The total study population comprised 1010 young women aged 25-40 years and 660 elderly women aged 85 years and older. The 'birth-place-restricted comparison' included 66 young and 285 elderly women from one geographic area (Leiden, the Netherlands). Men were not included because ageing in men was not associated with HLA antigens in a recent study. In the total population, the frequency of B40 in young women of different origin varied between 16 and 28%, and the frequency of DR5 between 11 and 23%. Similar differences were observed in the elderly women. In the 'birth-place-restricted comparison', the frequency of B40 was 15% in the young women and 11% in the elderly women (difference 4%, 95% confidence interval, -5 to 13%). The frequency of DR5 was 20% in the young women, and 28% in the elderly women (difference 8%, 95% confidence interval, -4 to 19%). Thus, marked differences in HLA antigen frequency were found between populations of various geographic origins. Definition and ascertainment of the target population are therefore necessary in genetic studies of ageing. In such a 'birth-place-restricted comparison', the authors confirmed that ageing in women was negatively associated with HLA-B40 and positively associated with HLA-DR5.

The effects of an increased antigen dose on HI, IgG, IgA, and IgM antibody responses to influenza A/Taiwan/1/86 (H1N1) were investigated in 92 elderly nursing-home residents (mean age 81 years) and 104 young subjects (mean age 20 years). At a standard 10-microg dose, HI and IgG titer rises were lower in the elderly. HI titers did not improve at higher vaccine dosages. By contrast, influenza-specific IgG and IgA antibody responses were dose dependent in elderly subjects, but not in young. In the young subjects, IgM antibody responses were dose dependent. The improved antibody responses in the elderly as observed in IgG and IgA were not reflected in the HI response. Therefore, the evaluation of antibody production by HI only may lead to an underestimate of the immune response in elderly people.

Objective: To determine whether the inverse relation between blood pressure and all cause mortality in elderly people over 85 years of age can be explained by adjusting for health status, and to determine whether high blood pressure is a risk factor for mortality when the effects of poor health are accounted for., Design: 5 to 7 year follow up of community residents aged 85 years and older., Setting: Leiden, the Netherlands., Subjects: 835 subjects whose blood pressure was recorded between 1987 and 1989., Main Outcome Measure: All cause mortality., Results: An inverse relation between blood pressure and all cause mortality was observed. For diastolic blood pressure crude 5 year all cause mortality decreased from 88% (52/59) (95% confidence interval 79% to 95%) in those with diastolic blood pressures <65 mm Hg to 59% (27/46) (44% to 72%) in those with diastolic pressures >100 mm Hg. For systolic blood pressure crude 5 year all cause mortality decreased from 85% (95/112) (78% to 91%) in those with systolic pressures <125 mm Hg to 59% (13/22) (38% to 78%) in those with systolic pressures >200 mm Hg. This decrease was no longer significant after adjustment for indicators of poor health. No relation existed between blood pressure and mortality from cardiovascular causes or stroke after adjustment for age and sex, but after adjustment for age, sex, and indicators of poor health there was a positive relation between diastolic blood pressure and mortality from both cardiovascular causes and stroke., Conclusion: The inverse relation between blood pressure and all cause mortality in elderly people over 85 is associated with health status.

To determine the influence of ageing per se as well as of priming histories on the antibody response to influenza vaccination, haemagglutination inhibition (HI), ELISA IgG, IgA, IgM and neutralizing antibody titres were studied in 43 healthy young subjects (mean age 23 years) and 55 healthy elderly people (mean age 79 years). The HI and ELISA lgG responses to the A/Guizhou/54/89 strain (H3N2) for which both the young and the elderly had similar priming histories were equal. By contrast, the HI and IgG responses to A/Taiwan/1/86 (H1N1), where the priming histories were different, were lower in the elderly (P < 0.05). Influenza-specific IgA responses in the elderly tended to be higher for all vaccine strains. Influenza-specific postvaccination IgM titres were similar or tended to be higher in the elderly. A subgroup of elderly subjects (18%) who did not express HI activity to the A/Taiwan/1/86 (H1N1) vaccine strain, reacted in the HI assay with the closely related A/Singapore/6/86 (H1N1) strain. These elderly people, however, produced lgG antibodies which neutralized A/Taiwan/1/86 virus in vitro. It is concluded that the elderly are capable of mounting antibody responses similar to those observed in the young. Moreover, the observed age-related differences in antibody responses to H1N1 strains are probably not due to ageing of the immune system itself, but are determined by differences in priming histories.

The benefit of annually repeated influenza vaccination on antibody formation is still under debate. In this study the effect of annually repeated influenza vaccination on haemagglutination inhibiting (HI) antibody formation in the elderly is investigated. Between 1990 and 1993 healthy young and elderly, both selected by the SENIEUR protocol, were vaccinated consecutively with commercially available influenza vaccines. The elderly had a lower HI antibody response after one vaccination as compared to the young against the A/Taiwan/1/86 (HINI), B/Yamagata/16/88 and B/Panama/45/90 strains. Annually repeated vaccination did not result in a decrease of the HI antibody titres against the A and B vaccine strains in both age groups. Moreover, the elderly had a significantly higher HI titre against the B strains after the second vaccination as compared to the first, resulting in comparable HI titres for young and elderly. Thus, annually repeated vaccination has a beneficial effect on the antibody titre against influenza virus and can contribute to a better antibody-response in the elderly.

Immunosenescence refers to the influence of aging on the immune system. Numerous problems are encountered in studying this topic, the main one being the influence of concomitant disease. Despite the great efforts that have been devoted to research in this field, the results of studies performed to date have not been convincing and, until now, no sound scientific evidence has emerged to show that immunosenescence is clinically significant. The only possible exceptions to this are the discovery of a selective defect in cell-mediated immunity and the reactivation of varicella zoster virus. Therefore, many more, and better designed, studies will have to be conducted before the full clinical impact of immunosenescence can be delineated.

Objective: The association between Human Leucocyte Antigens (HLA) and aging was investigated. It is possible that HLA antigens are associated with longevity, either indirectly through disease associations or directly through involvement in the aging mechanism., Design: Community-based follow-up study., Setting: Leiden, the Netherlands., Participants: A total of 919 subjects were HLA typed in this community-based study. All subjects were aged 85 and older and were white. Seventy-two percent of the cohort was female., Measurements: Age- and sex-adjusted Mortality Rate Ratios (MRR) were estimated for 79 antigens by the subject-years method. HLA-A, -B and -C typing was performed with the standard NIH lymphocytotoxicity test, HLA-DR and -DQ typing was performed with the two-color fluorescence test. Homozygosity for HLA-A, -B, and -DR was defined as only one detectable antigen at a locus., Results: The mean follow-up period (SD) was 5.0 (0.6) years. At the end of the follow-up, 70% of the subjects had died. The MRR (95% CI) for B60 was 0.96 (0.75-1.23), and for DR11 it was 0.82 (0.66-1.01). For A2 and A26 only, the MRR (95% CI) was significantly different from 1: 0.85 (0.73-0.99), P = .04 and 1.45 (1.06-1.99), P = .02, respectively (P values not corrected for the number of antigens tested). Homozygosity was not associated with mortality., Conclusions: HLA was not associated with mortality after the age of 85. Therefore, direct involvement of HLA in aging is unlikely. We suggest that the findings of previous studies are attributable to methodological shortcomings such as small sample size and differences in genetic background of the subjects.

To investigate the effects of the altered composition of the helper T cell compartment in ageing on the humoral response to influenza vaccine, we investigated correlations between helper T cell subsets and anti-influenza antibody responses in 23 JUNIEUR healthy young and 41 SENIEUR healthy elderly subjects. Naive helper T cell numbers (CD4+ CD45RA+) were negatively correlated with antibody production to two of the four strains investigated in JUNIEURS only. By contrast, memory helper T cell numbers (CD4+CD45ROhi) were positively correlated with in vivo IgG antibody titres to three of the four vaccine strains. Age-related differences in the composition of the helper T cell compartment, however, did not explain the lower IgG antibody response that was observed to two of the four vaccine strains examined.

In the elderly, incidence, morbidity, complications, and mortality due to influenza are greatly underestimated. There are several reasons why influenza vaccination is unjustly denied to many elderly. In a number of countries such as the United Kingdom and The Netherlands, health authorities do not recommend to vaccinate all elderly persons above a certain age, and influenza vaccination is offered only to those with conventional risk factors such as cardiac or pulmonary disease. However, conventional risk factors are often not present or are not recognized in the elderly. There now is convincing evidence that age in itself leads to increased vulnerability and thus is a risk factor for influenza and its complications. It no longer seems justified not to vaccinate all elderly, including the healthy, against influenza.

The aim was to investigate the incidence rate of dementia for community residents aged 85 years and over. It was a two wave community study of 224 subjects (community residents including those residing in a nursing home) older than 85 years, restudied 4.1 years after a community prevalence study. A two stage method was used, comprising the mini mental state examination followed in a stratified sample by the geriatric mental state schedule (A3)/AGECAT. Incidence rates were based on person-years at risk. The overall incidence of dementia was 6.9 (95% confidence interval (95% CI) 4.8-9.1) per 100 person-years at risk. The incidence was significantly higher for women than for men; respectively 8.9 (95% CI 5.9-11.9) v 2.7 (95% CI 0.5-4.9) per 100 person-years at risk. In the fastest growing age group seven out of 100 persons develop dementia each year. Women, who constitute two thirds of the oldest old, seem to have a higher risk. Further research is needed into the risk factors for dementia in this age group.

Objective: To determine on what grounds persons over 85 years are or are not vaccinated against influenza., Design: Descriptive., Setting: Gerontological Research Centre and Department of General Practice Medicine, University of Leiden, the Netherlands., Method: A random sample (n = 331) of the general population of Leiden aged 85 years or older and not institutionalized were interviewed. Early in October 1993, 163 interviews were suitable for analysis (response rate 54%). An analysis of non-responders revealed no significant difference as regards gender and housing, but persons aged 90 and older were under-represented. The general practitioners (n = 41) of the 163 elderly persons were interviewed about these persons (response: n = 127; 78%) and about influenza vaccination in general (response: n = 33; 82%)., Results: The vaccination coverage rates were 51% according to the elderly and 56% according to the GPs; those of elderly people with an indication (48% according to themselves and 64% according to the GP) 52% and 67%, respectively. Reasons for elderly people not to accept vaccination were that they considered vaccination unnecessary, that they felt well and wanted to avoid possible adverse effects. A doctor's recommendation to have vaccination done was a positive influence. GPs' motives not to vaccinate were absence of an indication and the elderly person's wish., Conclusion: Only two-thirds of those over 85 not living in a nursing home with an indication for influenza vaccination were indeed vaccinated. Information about the possible damage done by influenza and about the pros and cons of vaccination, together with a doctor's advice to be vaccinated appeared to have a positive effect on the vaccination coverage.

The objective of this study was to describe over time the course of cognitive function of elderly without cognitive impairment and of elderly with different stages of impairment, and to assess if the change in cognitive function was dependent on the initial level of function. The Mini-Mental State Examination (MMSE) was used at two time points. The first assessment (MMSE-1) was part of a community-based study and was obtained from 871 subjects. For the second assessment (MMSE-2) a sample of 166 subjects was drawn from the subjects alive at follow-up who had an MMSE-1 score. This sample was stratified by MMSE-1 score to avoid oversampling of subjects with high MMSE-1 scores. A second MMSE score was obtained from 134 elderly, whereas 18 subjects refused participation and 14 subjects were not traceable. The median age at first assessment was 89 years (25th percentile 87, 75th percentile 92), the mean follow-up period (S.D.) was 3.3 (0.5) years. The median change in MMSE score was minus 4 points (95% confidence interval (CI) -7 to -2) and the slope of the regression line of MMSE-2 on MMSE-1 was 1.1 (95% CI 0.9-1.3). It is likely that the slope was underestimated due to a floor effect, regression to the mean and missing observations. However, the probability of decline decreased if MMSE-1 was higher. Nevertheless, the probability ranged from 27 to 59% for subjects with the highest MMSE-1 scores aged 85 and 95 years respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives: To study the prevalences of musculoskeletal disorders and disability in the elderly, and the relationship between them., Methods: A community sample of 73 females and 32 males aged 85 and over underwent a standardised examination at home. Musculoskeletal disorders were classified according to published clinical criteria. The relative effects on disability (a walking distance of < 500 m or dependency in activities of daily living (ADL)) of musculoskeletal disorders and comorbidity were analysed by logistic regression., Results: Musculoskeletal pain was reported by 57% of those interviewed. A major restriction of joint movement range was frequent in the shoulder but uncommon in other joints. A shoulder disorder was found in 27% of subjects, rheumatoid arthritis in 1% and osteoarthritis (OA) of the hand, hip, and knee in five, seven, and 18% of subjects, respectively. Disability was frequent: a walking distance of < 500 m was found in 60% and ADL dependency in 40% of the group. Factors related to one or both of these disability measures included female gender, hip and knee OA, impaired vision, cognitive impairment and neurological disease., Conclusion: Musculoskeletal pain and disorders, in addition to disability were frequent in this very elderly population. However, as a cause of disability, other disorders were at least as important as musculoskeletal disorders.

To assess the impact of institutionalization on sleep/wake characteristics of elderly people, we compared subjective (study I: n = 160) and objective (study II: n = 30) sleep/wake measures of non-demented institutionalized subjects and age-matched non-institutionalized controls. We also evaluated the prevalence and causes of various sleep disturbances. The three living conditions, i.e. independently living (IL), service home (SH) and nursing home (NH) were respectively assumed to have minimal, moderate and maximal effects upon the timing, the amount and the quality of the sleep/wake behaviour of the persons involved. Study I showed that a higher level of institutionalization was significantly (p < 0.05) associated with phase-advanced sleep/wake patterns, increased amounts of time spent in bed during the 24-hour period and increased usage of prescribed sedative-hypnotic drugs. Poor sleep quality and disturbed sleep onset occurred significantly mostly in the SH group. No differences between groups were demonstrated with respect to the prevalence of disturbed sleep maintenance, parasomnias and difficulty with awakening and their possible causes, except for environmental noise which was exclusively reported by institutionalized subjects. No differences between groups for any of the objective measures were found (study II). Overall, our findings are in line with previous findings on this topic, although the observed high rate of poor sleep quality and sleep disturbances and their associated causes as observed in institutionalized subjects also occurs in an age-matched non-institutionalized population.

The influence of ageing on phenotype and function of CD4+ T cells was studied by comparing young (19-28 years of age) and aged (75-84 years of age) donors that were selected using the SENIEUR protocol to exclude underlying disease. An age-related increase was observed in the relative number of memory cells, not only on the basis of a decreased CD45RA and increased CD45RO expression, but also on the basis of a decrease in the fraction of CD27+CD4+ T cells. Our observation that the absolute number of CD45RO+CD4+ T cells was increased, while absolute numbers of CD27-CD4+ T cells remained unchanged in aged donors, indicates that the latter subset does not merely reflect the size of the CD45RO+CD4+ T cell pool. The increased fraction of memory cells in the aged was functionally reflected in an increased IL-4 production and T cell proliferation, when cells were activated with the combination of anti-CD2 and anti-CD28, whereas IL-2 production was comparable between both groups. No differences were observed with respect to proliferative T cell responses or IL-2 production using plate-bound anti-CD3 or phytohaemagglutinin (PHA). The observation that IL-4 production correlated with the fraction of memory cells in young donors but not in aged donors suggests different functional characteristics of this subset in aged donors.

Objective: To measure the influence of age on measures of nocturnal activity and immobility in 100 healthy subjects aged 50 to 98 years., Design: Cross-sectional study., Setting: Urban population in Leiden. Recordings were performed at home while the subjects maintained their habitual 24-hour pattern of activities., Participants: 100 subjects without a history of major medical disorders and a normal neurological examination and performance-oriented assessment of gait (Tinetti)., Measurements: Motor activity was recorded during six successive nights with a wrist-worn activity monitor. The occurrence of supra-threshold motor activity was recorded over 15-second epochs. A questionnaire was used to evaluate sleep habits and the occurrence of sleep disturbances. Four mean measures reflecting activity or immobility during the nocturnal period were calculated for each subject., Results: Only one out of four measures, (ie, the nocturnal proportion of time with movement, increased with age for females. For males, no age effects emerged. The mean duration of nocturnal immobility periods was higher in females than in males. Also, for females, the use of hypnotics increased with successive decades. Sex and the use of hypnotics were significantly related to the mean duration of immobility periods., Conclusion: If care is taken not to confound aging with illness, measures of nocturnal activity and immobility reveal only marginal effects of aging.

To investigate the effects of age and antigen dose (10, 20, 60 micrograms) on the immunoglobulin (sub) class distribution following influenza vaccination, antibody responses in 79 elderly nursing home residents were compared with the responses in 100 young subjects. At a 10 micrograms dose the IgM, IgG3 and IgA1 responses were comparable in both age groups, whereas the IgG, IgG1 and haemagglutination inhibition (HI) responses were twofold lower in the elderly. A 20 micrograms dose increased the IgG, IgG1 and HI levels in the elderly to the levels in the young and the IgA1 to significantly higher levels. A 60 micrograms dose increased antibody levels in the young, but did not further increase the response in the elderly. The 20 micrograms dose might represent a higher level of protection in the elderly.

Several arguments support the idea of a link between longevity and heredity, both in experimental animals and in the human species. In mice, genes in the major histocompatibility complex (MHC) are associated with a significant effect on life span. Results of analogous studies in man are confusing and contradictory. We have therefore investigated the question of an association of the human leucocyte antigen (HLA) and longevity in a large and ethnically homogeneous population. Our study population consisted of all 964 available inhabitants aged 85 years and over in the Dutch community of Leiden (pop. 104,000). Our control group comprised 2444 young inhabitants, aged 20-35 years, with an identical ethnic and demographic background. In addition, control groups of different age-brackets from the same region were used. Two antigens differed in frequency: HLA-B40 was lower and HLA-DR5 was higher in the group of 85 years and over, as compared to the control group, aged 20-35 years. Both differences were more evident in females. No major disease associations with HLA-B40 or HLA-DR5 have been reported. It is unlikely that these results are a chance observation: the overall similarity of the HLA pattern of the old and young age groups is a confirmation of their identical ethnic and demographic background and the changes as observed in the different age-groups were gradual. The biological meaning of these results is still unclear.

Natural killer cells can phenotypically be identified as CD16 positive with a specific monoclonal antibody (B73.1 = Leu-11c) by either immunofluorescence microscopy or by flow cytometry. The standard procedure in flow cytometry is to set a window or gate around the so called lymphocytic population, based on scatter characteristics. In this paper we demonstrate that a substantial part of the NK cell population is situated outside this gate in the total mononuclear cell population. We therefore recommend that the number of CD16+ cells is determined in the total mononuclear cell population. However, in the total mononuclear cell population, a group of dimly CD16 positive cells, probably monocytes, interferes with a clear separation of cells with a positive and negative fluorescence. We describe two methods to overcome this problem.

Prolonging life only makes sense if quality of life is maintained. In biomedical terms this means that life extension should not be accomplished at the cost of an increase of morbidity and dependence. The survival curve must maintain its rectangular shape and compression of morbidity should be sought for. Ageing is not synonymous with disease, and a healthy old age certainly is possible. Many disorders of old age are a result of extrinsic, avoidable factors such as drinking, smoking, eating habits, and inactivity. Prevention must begin in youth. This is the price to be paid by the individual. The medical and scientific community should increase its efforts to develop health care for the aged and increase investments in the study of the ageing process itself. Society as a whole can give support by funding the development of geriatrics and gerontology, and by improving the position and the acceptance of the elderly in daily life.

Disease is frequent in ageing, and the many conflicting results in studies of the ageing process can be due to the presence of factors such as underlying disease or the use of medication. For immunogerontology, a solution to this problem was initiated in 1984 by a working party of EURAGE, the European Community's Concerted Action Programme on Ageing and Diseases. A protocol defining strict admission criteria to studies of ageing, the SENIEUR protocol, was elaborated. This protocol intends to limit the influence of disease and/or medication and to standardize admission criteria to immunogerontological studies. In subjects fulfilling the SENIEUR criteria, we found less immunological defects with ageing than generally stated. This could mean that many studies performed in not-optimally healthy subjects describe defects that are not a consequence of the ageing process, but could be a result of underlying disease or of the influence of medication. For lymphocyte subsets, certain changes are only found in the comparison of SENIEUR groups of young and aged, while other changes are only found when non-healthy groups are compared. The occurrence of monoclonal gammopathies and autoantibodies was increased in ageing, but was also influenced by health status. Experience of other groups, and the objections against the protocol are discussed.

To determine the incidence of monoclonal gammopathies (MG) in relation to the aging process as such, and to evaluate the influence of disease on the occurrence of MG, we studied 439 elderly subjects aged 75-84 years. These individuals were categorized into 4 groups on the basis of their health status. There was a group of "optimally healthy" elderly, a group of "apparently healthy" residents of homes for the aged, a group of geriatric outpatients and a group of randomly chosen inpatients from a general hospital. Whereas no MG were detected in a control group of healthy young subjects aged 25-34 years, the frequency of MG in the aged groups ranged from 11% in the "optimally healthy" aged group to 38% in the inpatients group. In a tentative classification according to possible cause, most of the MG belonged to the pathogenetic category of immunodeficiency. There was a clear association of the occurrence of monoclonal gammopathies of this category with the health status.

Immunogerontological studies in man have often led to conflicting results. One of the main reasons is the selection of the subjects to be studied. Admission criteria such as "apparently healthy" or "without overt disease" seem insufficient to exclude underlying disease which might influence the immune system and thereby the results. In an attempt to solve this problem, the SENIEUR protocol described in this paper was developed by a working party in the framework of the EURAGE Concerted Action Programme on Ageing of the European Community. This protocol establishes strict admission criteria for immunogerontological studies in man based on clinical information and laboratory data, and it sets limits to pharmacological interference. The use of this protocol will lead to standardization between centers and also to a closer study of the influence of age as such on the immune system. These findings in the immunologically "optimally aged" can also serve as reference values for immunogerontological studies in subjects who do not meet the SENIEUR criteria. In this way the use of this protocol can contribute to the dissection of the influence of disease versus ageing on the immune system.

Analysis of the subpopulations of mononuclear cells in human blood in ageing has revealed a striking increase in the number of null cells, defined as non-T, non-B, non-monocyte cells, and a decrease in the number of T and B cells. By using recently developed monoclonal antibodies against natural killer cells in combination with T-cell markers in two-wavelength immunofluorescence, we were able to define 13 subpopulations of mononuclear cells and compare them in two groups of persons, respectively aged 25-34 and 75-84 years, all fulfilling the stringent admission criteria for immunogerontological studies described in the SENIEUR protocol, and thus all to be considered as optimally healthy and immunologically uncompromised. We found that the increased null cell population in the aged is a result of an increase in the numbers of NK cells, mostly the CD16+Leu7+ subset. The number of CD8+ suppressor/cytotoxic cells is decreased. This is due to a decrease of the number of CD8+Leu7- cells. All NK and T-cell subsets bearing the Leu7 antigen, namely CD16+ Leu7+, CD4+Leu7+ and CD8+Leu7+, are increased. These changes can be due to defects of the ageing immune system, but they can also represent the optimal state of the immune system in the healthy aged and may be linked to survival. These values can be used as reference values for the 75-84 years age group and serve to monitor attempts to reconstitute the immune defects in ageing.

Study of the immune system in ageing has yielded conflicting results. These controversies are mainly due to the selection of the subjects studied. We investigated the mononuclear cell subpopulations in the peripheral blood of subjects fulfilling strict admission criteria meant to exclude persons with diseases that influence the immune system. These criteria are described in the SENIEUR protocol devised by a working group in the framework of EURAGE, the Concerted Action Programme on Ageing of the European Community. We compared two groups of volunteers aged 25-34 years, and 75-84 years. Mononuclear cells were investigated by two-wavelength immunofluorescence combined with phase-contrast microscopy. We found a striking increase in the number of 'null' cells (non-T, non-B, non-monocyte) in the blood of the aged persons. The number of T cells was decreased, especially in the suppressor/cytotoxic subset. The number of B cells was slightly, but significantly, decreased; the number of monocytes did not change. The changes in these cell populations may be related to functional changes, and their quantification could be used to monitor attempts to reconstitute the immune defects in ageing. These findings can also serve as reference values in the study of aged persons not fulfilling the SENIEUR criteria, which, in turn, can contribute to the dissection of the influence of disease versus age on the immune system.

We studied natural killer (NK) cell subsets and NK function in young (25-35 years) and aged (75-84 years) persons by means of the single-cell assay. The subjects admitted to the study all fulfilled the SENIEUR health criteria in order to avoid confounding factors such as underlying disease or the influence of medication. We found no significant difference in the NK function between healthy young and aged persons on a per cell basis. A new application of the two-wavelength immunofluorescence technique during the single cell assay made it possible to define the phenotypes of the conjugate-forming cells responsible for the natural killer function. Most of the conjugate-forming cells were CD 16-positive, and half of these were also positive for Leu 7. The CD 16 antigen disappeared from the cell surface during the effector:target interaction. T-cell markers were found on some of the conjugate-forming cells but not on the strongly bound effector cells. The NK cell function was directly proportional to the number of NK (CD 16) cells in the peripheral blood.

Pharmacokinetics of nisoldipine and the drug's effects on blood pressure and heart rate were investigated in healthy young (20 to 23 years of age), middle-aged (49 to 57 years of age), and elderly (75 to 84 years of age) subjects after single-dose and short-term multiple-dose oral administration (10 mg twice daily). No age-dependent differences in pharmacokinetic parameters were observed. Decreases in blood pressure were comparable in the three groups, but reflex tachycardia was less pronounced in the elderly subjects. Side effects mainly occurred on the first day of drug administration. Dose adaptation of nisoldipine does not seem to be necessary in elderly subjects.