Approach to define “normal aging” in man. Immune function, serum lipids, lipoproteins and neopterin levels

doi:10.1016/0047-6374(88)90115-7

Mechanisms of Ageing and Development

Volume 46, Issues 1–3, 1988, Pages 67-82

https://doi.org/10.1016/0047-6374(88)90115-7 Get rights and content

Abstract

In 53 healthy women with mean age 25.1 years (age range 21–34 years) and in 51 healthy women with mean age 82.1 years (age range 75–91 years), a panel of immunological and biochemical tests was performed. These test, comprising lymphocyte mitogen responsiveness, phenotyping of lymphocytes, uptake of low density lipoprotein by T cells, serum levels of neopterin, lipids and lipoproteins, as well as routine blood chemistry, were investigated for a possible effect of age and of the classification according to the SENIEUR Protocol of admission criteria by the European Economic Community's Concerted Action Program on Aging (EURAGE). A highly significant effect of age on serum levels of neopterin, lipids and lipoproteins was found. No clear effects, however, of SENIEUR status on these variables was detected. As expected, age had a significant impact on mitogen responsiveness of T cells. Proportional numbers of helper/inducer and cytotoxic/suppressor T cells (as well as antigen density on these cells) were not influenced by age. SENIEUR classification did not affect these immunologic variables. Thus, most of the tested variables that are not included in the SENIEUR admission criteria appear to present information not yet covered by the SENIEUR variables. Various ways for a possible revision or extension of the SENIEUR Protocol are discussed.

References (38)

S. Landahl et al.
Blood components in a 70-year-old population
Clin. Chim. Acta
(1981)
G.J. Ligthart et al.
Admission criteria for immunogerontological studies in man: the SENIEUR PROTOCOL
Mech. Ageing Dev.
(1984)
K.N. Traill et al.
Age-related changes in lymphocyte subset proportions, surface differentiation antigen density and plasma membrane fluidity: Application of the EURAGE SENIEUR PROTOCOL admission criteria
Mech. Ageing Dev.
(1985)
K.N. Traill et al.
Analysis of fluorescent low density lipoprotein uptake by lymphocytes. Paradoxical increase in elderly
Mech. Ageing Dev.
(1987)
W. Barcellini et al.
Heterogeneity of immune responsiveness in healthy elderly subjects
Clin. Immunol. Immunopathol.
(1988)
B. Rivnay et al.
Viscosity of lymphocyte plasma membrane in aging mice and its possible relation to serum cholesterol
Mech. Ageing Dev.
(1979)
B. Rivnay et al.
Correlations between membrane viscosity, serum cholesterol, lymphocyte activation and aging in man
Mech. Ageing Dev.
(1980)
K.N. Traill et al.
Lipids and lymphocyte function
Immunol. Today
(1984)
B. Cinader et al.
Dietary fat alters the fatty acid composition of lymphocyte membranes and the rate at which suppressor capacity is lost
Immunol. Lett.
(1983)
K.N. Traill et al.
Lipid requirement of human T-lymphocytes stimulated with mitogen in serum-free medium. Membrane “fluidity” changes are an artefact of lipid (AL-721) uptake by monocytes
Immunobiology
(1988)

J.A. Cuthbert et al.

Promotion of human T-lymphocyte activation and proliferation by fatty acids in low and high density lipoproteins

J. Biol. Chem.

(1986)

C. Prior et al.

Potential of urinary neopterin excretion in differentiating chronic non-A, non-B hepatitis from fatty liver

Lancet

(1987)

D. Fuchs et al.

Pteridinausscheidung als Marker für alloantigen-induzierte Lymphozytenproliferation

Hoppe-Seyler's Z. Physiol. Chem.

(1982)

C. Huber et al.

Pteridines as a new marker to detect human T cells activated by allogeneic or modified self major histocompatibility complex (MHC) determinants

J. Immunol.

(1983)

C. Huber et al.

Immune response-associated production of neopterin — Release from macrophages primarily under control of interferon gamma

J. Exp. Med.

(1984)

K.N. Traill et al.

Simple method for comparing large numbers of flow cytometry histograms exemplified by analysis of the CD4 (T4) antigen and LDL receptor on human peripheral blood lymphocytes

J. Histochem. Cytochem.

(1986)

E.R. Werner et al.

Determination of neopterin in serum and urine

Clin. Chem.

(1987)

M.B. Brown et al.

The small sample behaviour of some statistics which test the equality of several means

Technometrics

(1974)

H. Levene

Robust tests for equality of variance

Cited by (88)

Ecological, parasitological and individual determinants of plasma neopterin levels in a natural mandrill population
2020, International Journal for Parasitology: Parasites and Wildlife
Citation Excerpt :
First, we showed heightened neopterin concentrations in early and late life – though the latter effect may be weak as it failed to reach significance in adult males and females, likely because few individuals were older than 16 years old. This non-linear, moderate effect of age on plasma neopterin mirrors age-related variation of plasma or urinary neopterin reported by studies in humans (Berdowska and Zwirska-Korczala, 2002; Werner et al., 1987) especially for the age-related neopterin increase in older individuals (Capuron et al., 2014; Diamondstone et al., 1994; Frick et al., 2004; Reibnegger et al., 1988; Schennach et al., 2002; Spencer et al., 2010). Although the immune mechanisms leading to age-related increases in adult neopterin levels are less well documented in non-human primates than in humans, they seem relatively consistent across species and involve an associated increase with age in levels of IFNγ (Messaoudi et al., 2011; Meyer et al., 2012; Müller et al., 2017).
Investigating how individuals adjust their investment into distinct components of the immune system under natural conditions necessitates to develop immune phenotyping tools that reflect the activation of specific immune components that can be measured directly in the field. Here, we examined individual variation of plasma neopterin, a biomarker of Th1 immunity in wild mandrills (Mandrillus sphinx), who are naturally exposed to a suite of parasites, including simian retroviruses and malaria agents. We analyzed a total of 201 plasma samples from 99 individuals and examined the effect of sex, age, social rank, reproductive state and disease status on neopterin levels. We found higher neopterin concentrations in males than females, but were unable to disentangle this effect from possible confounding effects of retroviral infections, which affect nearly all adult males, but hardly any females. We further detected a non-linear age effect with heightened neopterin levels in early and late life. In addition, adult males that harbored very high parasitaemia for Plasmodium gonderi also showed high neopterin levels. There was no effect of social rank in either male or female mandrills, and no effect of female reproductive state. Taken together, these results indicate that plasma neopterin may prove useful to investigate individual variation in investment into specific immune components, as well as to monitor the dynamics of immune responses to naturally occurring diseases that elicit a Th1 immune response.
Cellular immune activation in Sardinian middle-aged, older adults and centenarians
2017, Experimental Gerontology
Citation Excerpt :
In this analysis of Sardinian older adults, the whole group of participants (mean age 85.25 ± 14.20 years) had a median neopterin value of 20.35 (IQR 11.66–32.23) nM. Although slightly greater than the average levels reported by other authors, these values are consistent with the upper limits of normal reported by Reibnegger et al. (1988) (19.0 nM above 75 years). As reported in earlier studies (Diamondstone et al., 1994; Schennach et al., 2002), we also found that plasma neopterin concentrations significantly correlate with age, suggesting increased monocyte/macrophage-mediated immune activation with advancing age.
In addition to viral infections, malignant disorders, autoimmune diseases, and allograft rejection episodes, neopterin increases in older people where it is found to be predictive of overall mortality. Thus, the serum concentrations of this biomarker of systemic immune and inflammation activation, were measured in a small cohort of Sardinian middle-aged, older adults and centenarians. There was a significant positive correlation between neopterin concentrations and age with the subjects in the 95-year-old group with the highest values. Notably, the group of centenarians had neopterin values comparable to those of 80- and 90-year-old groups, and significantly lower than that of 95-year-old group. This suggests a decreased monocyte/macrophage-mediated immune activation and an apparently preserved immune status in centenarians.
Frailty Status in Older Adults Is Related to Alterations in Indoleamine 2,3-Dioxygenase 1 and Guanosine Triphosphate Cyclohydrolase I Enzymatic Pathways
2017, Journal of the American Medical Directors Association
Citation Excerpt :
Hence, the possible disturbance of the mentioned immune stimulation-related enzymatic pathways was analyzed in the present work in a population of Spanish older adults, classified according to their frailty status following the 5 phenotypic criteria proposed by Fried et al.11 Although concentrations of the immune biomarkers assessed in this work were previously reported in populations or subpopulations of older adults,53–58 frailty status of the participants in these studies was not determined; at most some reports specified they were “healthy.” Thus, it was necessary to establish reference ranges of these biomarkers specifically in the group of robust older adults (ie, in the absence of frailty).
Frailty is a multidimensional syndrome correlated to the loss of homeostasis and increased vulnerability to stressors, which is associated with increase in the risk of disability, comorbidity, hospitalization, and death in the elderly. It is based on the interplay of physiological, psychological, social, and environmental factors.
Because aging involves a detrimental immune response, this work aimed to assess the possible role of chronic low-grade immune stimulation on frailty status in the elderly.
Biomarkers involved in indoleamine 2,3-dioxygenase 1 and guanosine triphosphate cyclohydrolase I enzymatic pathways (namely neopterin, tryptophan, kynurenine, phenylalanine, tyrosine, and nitrite) were analyzed in a population of Spanish older adults aged 65 years and above, and their relationships with frailty status were evaluated.
Significant increases in neopterin levels, kynurenine/tryptophan ratio, and phenylalanine/tyrosine ratio, and significant decreases in tryptophan, nitrite and tyrosine concentrations in frail individuals compared with nonfrail persons were obtained. Significant correlations were also observed between immune biomarkers, indicating they change in parallel, thus, pointing to interrelated causes. Besides, reference ranges for a number of immune biomarkers in the population of robust older adults were established for the first time.
Results obtained in the present study are consistent with the idea that frailty status in the elderly is associated with an additional degree of immune stimulation, manifested in a more intense disturbance of indoleamine 2,3-dioxygenase 1 and guanosine triphosphate cyclohydrolase I pathways than in nonfrail or prefrail older adults.
Regular consumption of black tea increases circulating kynurenine concentrations: A randomized controlled trial
2015, BBA Clinical
Citation Excerpt :
Given the close crosstalk between metabolism and immune response, also these associations indicate an individual's immune status. An association of neopterin levels with age and immune status has been documented earlier [31] In conclusion, our study shows that black tea consumption is associated with an increased kynurenine production in individuals with no major illnesses and having normal to mildly elevated systolic blood pressure.
Circulating neopterin and the ratio of kynurenine to tryptophan (KYN/TRP) concentrations are biomarkers of immune activation that have been linked to cardiovascular and total mortality. Several in vitro studies indicated that tea flavonoids and other antioxidants can modulate tryptophan breakdown rates and neopterin production in immune cells. We aimed to assess the effects of regular black tea consumption on tryptophan and neopterin metabolisms in vivo.
Participants were healthy individuals, with no major illnesses and having normal to mildly elevated systolic blood pressure. They were randomly assigned to consume 3 cups/day of either powdered black tea solids (tea; n = 45) or a flavonoid-free caffeine-matched beverage (control; n = 49). Serum concentrations of tryptophan, kynurenine and neopterin were assessed at baseline and again at 3 and 6 months after daily ingestion of the respective beverage.
Regular consumption of tea over 6 months, compared to control, did not significantly alter neopterin (p = 0.13) or tryptophan (p = 0.85) concentrations, but did result in significantly higher kynurenine (p = 0.016) and KYN/TRP (p = 0.012). Relative to the control group, in the tea group kynurenine and KYN/TRP increased during the treatment period by 0.28 μmol/L (95% CI: − 0.04, 0.60) and 3.2 μmol/mmol (95% CI: − 1.6, 8.0), respectively at 3 months, and by 0.48 μmol/L (95% CI: 0.16, 0.80) and 7.5 μmol/mmol (95% CI: 2.5, 12.5), respectively at 6 months.
Increased circulation of kynurenine and KYN/TRP following regular black tea consumption may indicate enhanced tryptophan breakdown, possibly due to immune activation-induced tryptophan degrading enzyme indoleamine 2,3-dioxygenase.
The influence of black tea consumption on biomarkers of immune system activation could relate to its general health benefits. Data suggests that the net effect strongly depends on the individual immune state, being stimulatory in healthy individuals, while acting more immune dampening in situations with an inflammatory background.
Association of detectable cytomegalovirus (CMV) DNA in monocytes rather than positive CMV IgG serology with elevated neopterin levels in community-dwelling older adults
2011, Experimental Gerontology
Citation Excerpt :
Neopterin, whose production is primarily induced by IFN-γ stimulation, is a well established immune activation marker produced by monocytes and macrophages. Serum neopterin levels increase with age (Fuchs, 2008; Spencer et al., 2010; Reibnegger et al., 1988; Frick et al., 2004; Solichova et al., 2001). Our results are consistent with previously reported neopterin levels of 9 nM or higher in persons over 75 years of age (Fuchs, 2008; Spencer et al., 2010).
In immunocompetent persons, cytomegalovirus (CMV) is thought to persist primarily in monocytes and myeloid progenitor cells, establishing a chronic infection. In older adults, chronic CMV infection is typically diagnosed by a positive IgG serology. While many studies have shown CMV-specific T-cell expansion in CMV seropositive older individuals, significant heterogeneity has also been observed in this elderly population. In a study of 71 community-dwelling older adults, we assessed CMV viral DNA in peripheral monocytes by nested PCR and compared the relationships of detectable CMV DNA and IgG serology with serum levels of neopterin, a marker for monocyte/macrophage-mediated immune activation. The results showed that 52 (73.2%) participants were CMV seropositive, of whom 30 (57.5%) had detectable CMV DNA. CMV seropositive and seronegative participants did not differ in their neopterin levels, but individuals with detectable CMV DNA had higher neopterin than those without (10.6 ± 4.4 vs 8.0 ± 1.9 nM, respectively, p < .0001) adjusting for demographic and clinical covariates and interferon (IFN)-γ levels. In addition, there was no association between IgG titers and neopterin. These findings suggest that detection of CMV viral DNA in monocytes may be an informative tool to evaluate chronic CMV infection and its potential role in monocyte/macrophage-mediated immune activation in the elderly.
Serum neopterin levels in patients with brucellosis
2005, Journal of Infection
The aim of this study was to evaluate the importance of neopterin levels in brucellosis and its alterations with treatment.
Thirty patients who had positive clinical findings, Brucella standard tube agglutination tests and/or positive blood culture were included in the study. The control group was composed of 30 healthy subjects. Neopterin (NPT) levels were measured by ELISA according to the protocol of manufacturer.
Mean NPT levels were 54.15±33.7 nmol/l in study groups and 8.75±2.48 nmol/l in controls (P<0.001). It was determined that NPT levels measured at the time of admission of the patients had a linear correlation between the duration of complaint (r=0.560, P=0.001). While the mean NPT levels in patients with complaints of over 30 days were 79.07±34.9 nmol/l and it was 39.71±23.4 nmol/l in the patients with complaints of less than or equal to 30 days (P=0.002). NPT values measured after treatment (20.48±25.6) was determined lower by statistical means than the values measured before treatment (54.15±33.7, P=0.0001). The NPT levels of patients with positive blood culture (75.56±33.6) were higher than those of with negative blood cultures (32.72±15.2, P=0.001).
It was concluded that the NPT levels were higher in patients with brucellosis. In addition, it was found that the levels of NPT were higher in non-responding patients than responded to the brucellosis treatment. It was thought that monitoring NPT levels could be useful for the extent and activity of the disease.

View all citing articles on Scopus

View full text

Approach to define “normal aging” in man. Immune function, serum lipids, lipoproteins and neopterin levels

Abstract

Clin. Chim. Acta

Mech. Ageing Dev.

Mech. Ageing Dev.

Mech. Ageing Dev.

Clin. Immunol. Immunopathol.

Mech. Ageing Dev.

Mech. Ageing Dev.

Immunol. Today

Immunol. Lett.

Immunobiology

J. Biol. Chem.

Lancet

Pteridinausscheidung als Marker für alloantigen-induzierte Lymphozytenproliferation

Hoppe-Seyler's Z. Physiol. Chem.

Pteridines as a new marker to detect human T cells activated by allogeneic or modified self major histocompatibility complex (MHC) determinants

J. Immunol.

Immune response-associated production of neopterin — Release from macrophages primarily under control of interferon gamma

J. Exp. Med.

Simple method for comparing large numbers of flow cytometry histograms exemplified by analysis of the CD4 (T4) antigen and LDL receptor on human peripheral blood lymphocytes

J. Histochem. Cytochem.

Determination of neopterin in serum and urine

Clin. Chem.

The small sample behaviour of some statistics which test the equality of several means

Technometrics

Robust tests for equality of variance