Elsevier

Experimental Gerontology

Volume 42, Issue 8, August 2007, Pages 753-761
Experimental Gerontology

No Immune Risk Profile among individuals who reach 100 years of age: Findings from the Swedish NONA immune longitudinal study

https://doi.org/10.1016/j.exger.2007.05.001Get rights and content

Abstract

In the present NONA immune longitudinal study, we investigate the previously identified Immune Risk Profile (IRP), defined by an inverted CD4/CD8 ratio and associated with persistent cytomegalovirus infection and increased numbers of CD8+CD28− cells, relative 6-year survival and age in NONA individuals. These subjects have now reached age 92, 96, and for the first time in this study, 100 years at follow-up. A 55 year old middle-aged group was used for comparison. Immunological monitoring included the analysis of numbers of lymphocytes and neutrophils, the T-cell subsets CD3+CD4+, CD3+CD8+, CD8+CD28+, CD8+CD28−, and the CD4/CD8 ratio. Longitudinal data were analysed by multivariate analyses of variance (MANOVA) from four measurement occasions at 2-year inter-intervals. One-way ANOVA was used for cross-sectional comparisons at baseline and the 6-year follow-up. The results confirmed the importance of the IRP as a major predictor of mortality in this population of very old. Moreover, the results suggested that survival to the age of 100 years is associated with selection of individuals with an “inverted” IRP that was stable across time, i.e., maintenance of a high CD4/CD8 ratio and low numbers of CD8+CD28− cells. The results underlines the importance of a longitudinal study design in dissecting immune parameters predictive of survival and show for the first time that centenarian status is associated with avoidance of the IRP over at least the previous 6 years and probably throughout life.

Introduction

Throughout the 20th century, a remarkable increase in mean lifespan and possibly also maximum longevity has taken place in humans. A substantial number of centenarians reached the age of 110 already in the 1960s in larger European countries (Jeune, 2002). Centenarians today have experienced major improvements in their overall health and living conditions, for example a decline in mortality due to cardiovascular diseases at younger ages. The increased numbers of centenarians in recent decades is mainly due to a dramatic decline in the mortality rate among those above 80-years of age (Jeune, 2002). The rate of mortality due to cardiovascular disease or cancer increases with age from middle age up to about 80 year old and levels off thereafter, whereas the mortality due to infectious disease continue to accelerate also in very late life (reviewed in Pawelec et al., 2006). The ageing human body is less able to cope with infectious disease probably due to changes in innate and especially adaptive immunity (Delarosa et al., 2006, Solana et al., 2006). The immune system may thus be considered decisive for successful ageing and longevity in humans. The present NONA immune longitudinal study examines age-related changes relative to survival across a 6-year follow-up period among very old individuals.

There is considerable evidence of age-associated changes in immune capabilities resulting in increased morbidity and mortality due to altered function of the adaptive immune system (Wayne et al., 1990). An Immune Risk Profile (IRP), consisting of high CD8, low CD4 numbers, and poor proliferative response to Con A, was initially identified in the Swedish OCTO immune longitudinal study using a cluster analysis approach (Ferguson et al., 1995). Subsequent work indicated that the IRP could be defined using only the inverted CD4/CD8 ratio, since this sole marker is significantly associated with the IRP (Wikby et al., 1998). More recent investigations have extended these results to show that cytomegalovirus (CMV) infection has a major impact on the IRP and may in fact be the major driving force behind the accumulation of many of the CD8+CD28− effector cell expansions observed (Olsson et al., 2000; Reker-Hadrup et al., 2006).

Findings in the Swedish OCTO immune longitudinal study provided the basis for the subsequent ongoing NONA immune longitudinal study of very old individuals investigated independently of health status at baseline ages 86, 90, and 94 years old. Follow-ups were performed at three occasions after 2, 4, and 6 years (Wikby et al., 2002). Importantly, it was found that the IRP was largely independent of disease status in this sample in which three quarters of the individuals met criteria for compromised health and only 9% conformed to the SENIEUR inclusion criteria for excellent health at baseline (Nilsson et al., 2003).

The aim of the present data analysis at the 6-year follow-up of the NONA immune longitudinal follow-up was to examine the relative importance of the IRP relative to mortality and age. Considering that the oldest cohort had now become centenarians, commonly taken as a paradigm for “successfully ageing”, we addressed the question of weather the “successfully aged” are exceptional in their avoidance of the IRP and show here that the centenarians never entered this at-risk category.

Section snippets

Subjects

The NONA immune sample was recruited from participants in the NONA longitudinal study, in which a population-based sample of oldest-old individuals are investigated with a broad-based battery of tests for health and biobehavioral functioning. The NONA sample was drawn in the municipality of Jönköping, located in South-Central Sweden.

The sampling frame of the NONA study was based on available census information in September 1999 by means of which a non-proportional sampling procedure was

Neutrophils, lymphocytes and T-cell subsets by age groups

The numbers of neutrophils, lymphocytes, T-cells and subsets and the CD4/CD8 ratio were compared between the age groups 55, 92, 96, and 100 years old by one-way ANOVA. At baseline there were significant overall between group differences for the numbers of CD8+CD28− (p < 0.01) and CD8+CD28+ (p < 0.05) with higher numbers of CD8+CD28− and lower numbers of CD8+CD28+ T-cells in the very old compared with the middle-aged. There were no significant differences between the age groups in very old

Discussion

This study used a longitudinal design that permitted an examination of age-related changes in a population based sample of very old Swedish people.

The initial cross-sectional analysis of data at baseline and the 6-year follow-up demonstrated differences between the very old and middle-aged for the CD8+CD28+ and CD8+CD28− T-cell subsets on both occasions, confirming a loss of CD28 expression with increased age and seen previously in our own and other studies (reviewed in Effros, 2004). At 6-year

Acknowledgements

The authors acknowledge the considerable support of the EU project “T cell immunity and ageing”, T-CIA, contract no. (QLK6-CT-2001-02283), Futurum – the academy of healthcare, County Council, Jönköping and the Medical Research Council of South-east Sweden for funding of this project. We also acknowledge Länssjukhuset Ryhov for provision of laboratory resources for completion of the studies. We are indebted to our co-worker Per-Erik Evrin and would particularly like to thank the nursing staff

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