ARTICLE
Introduction
Circulating levels of proinflammatory and anti-inflammatory cytokines
are influenced by aging. The purpose of the present summary is to discuss
how chronic, low-grade increases in systemic tumour necrosis factor-a
(TNF-a) or interleukin-6 (IL-6) levels are related to morbidity and mortality
in elderly populations.
Pro- and anti-inflammatory
cytokines
TNF-a and IL-6 are both multifunctional cytokines with important regulatory
roles in immune processes, the coagulation system, and the metabolism
of fat, proteins, carbohydrates, and bones [1, 2]. TNF-a is a proinflammatory
cytokine and constitutes a direct and important stimulator of IL-6 production.
IL-6 has been categorized as both a pro-inflammatory, as well as an anti-inflammatory
cytokine, but the present view is that it has predominantly anti-inflammatory
and immunosuppressive roles. Thus, IL-6 inhibits the transcription of
the TNF gene, induces the release of glucocorticoids, and stimulates the
production of anti-inflammatory cytokines [3]. In epidemiological studies,
the strong link between TNF-a and IL-6 often makes it difficult to separate
their biological effects from each other, although their roles in inflammatory
processes are reversible.
Aging and inflammatory cytokines
Circulating levels of TNF-a, IL-6, natural cytokine antagonists and
acute phase proteins increase with aging [4]. TNF-a was correlated with
IL-6, circulating TNF receptors, and C reactive protein (CRP) in 126 centenarians
[4], indicating an interrelated activation of the entire inflammatory
cascade in the very old. The age-related increases in inflammatory markers
are only 2-4 fold compared to concentrations observed in young healthy
controls. However, although these increases are minute, as compared to
levels observed during acute infections, this chronic low-grade inflammatory
activity is of clinical importance in elderly populations [5].
Cytokines and morbidity
in elderly populations
Inflammation is a characteristic part of the neuropathology in Alzheimer's
disease and in atherosclerotic lesions. High plasma levels of TNF-a are
independently associated with Alzheimer's disease and atherosclerosis
in centenarians [4]. Although a linear relationship was found between
TNF-a and IL-6, similar associations were not found for IL-6, indicating
that systemic TNF-a had a direct role in the pathogenesis of dementia
and cardiovascular diseases (CVD) in the very old. The association between
circulating TNF-a and the prevalence of CVD was confirmed in a cohort
of 130, 80-year-old people [6] and moreover, TNF-a predicted insulin resistance
with advancing age [7]. Most immunogerontological studies have focused
on IL-6, which has turned out to be a very strong predictor for the risk
of developing CVD and type 2 diabetes mellitus [1]. However, IL-6
may partly act as a bystander phenomenon to TNF-a in some studies, e.g.
experimental studies suggest that TNF-a, but not IL-6, has a mechanistic
role in insulin resistance [8, 9]. Furthermore, it is unclear if increased
circulating levels of cytokines cause age-associated diseases or if it
reflects the sum of ongoing pathological processes.
Cytokines are associated
with mortality independently of co-morbidity
If cytokines cause age-related mortality, it is to be expected that
cytokines are predictors of mortality, independently of co-morbidity.
In contrast, if cytokines are markers of disease states, it is to be expected
that the hazard function will be severely affected when adjusting for
the prevalence of co-morbidity in elderly populations. High plasma levels
of TNF-a, but not IL-6, were associated with mortality independently of
the prevalence of dementia and CVD in a Cox regression analysis of 126 centenarians
(Bruunsgaard et al., unpublished data). In contrast, IL-6 was associated
with mortality in a study of 675 healthy older persons with or without
CVD, and similar results were found for cardiovascular and non-cardiovascular
causes of death [10]. IL-6 levels could have reflected a bystander phenomenon
to TNF-a in the latter study, considering the close link between the two
cytokines. However, in a study of 333, healthy, 80-year-old people, circulating
levels of TNF-a in men and low-grade increases in IL-6, in both sexes,
were independently of each other associated with all-cause mortality in
the following 7 years, indicating different biological effects of
the two cytokines (Bruunsgaard et al., unpublished data). Associations
between the two cytokines and mortality were also independent of classical
risk markers and co-morbidity in this study. Accordingly, these studies
together show that low-grade increases in circulating cytokines are strong,
independent risk factors of morbidity and mortality in old populations.
Consistent with the assumption that the two cytokines are separately associated
with mortality due to points of distinction in their biological effects,
several risk factors are indeed affected differently by TNF-a and IL-6
(Figure 1) [1, 2]. Thus, both cytokines induce dyslipidaemia, but only
TNF-a affects the function of endothelial cells and increases their expression
of adhesion molecules. Furthermore, TNF-a, but not IL-6, inhibits insulin
receptor activity, and induces down-regulation of insulin receptors in
experimental studies as already stated. IL-6 per se promotes procoagulant
changes including fibrinogen production and aggregation of platelets.
Furthermore, circulating levels of IL-6 may represent a better marker
of the sum of ongoing inflammation in the body than systemic levels of
TNF-a, because locally produced TNF-a does not escape to the circulation
although it induces a strong, systemic IL-6 response. IL-6, together with
TNF-a stimulates the production of CRP, which has been associated with
thromboembolic events, and with mortality in elderly populations [10].
However, the latter association might simply reflect activities of TNF-a
or IL-6 because IL-6 is a better predictor of mortality than CRP [10].
Different biological effects of the two cytokines, together with the different
prevalence of co-morbidity could also explain why TNF-a, but not IL-6,
is associated with mortality in centenarians, whereas IL-6 is the strongest
predictor of mortality in octogenarians. For instance, high circulating
levels of IL-6 may represent a bystander phenomenon to the increased systemic
levels of TNF-a, to a greater extent in centenarians than in octogenarians,
e.g. systemic levels of TNF-a explained 20 % of the variability
in IL-6 in centenarians but only 8 % in octogenarians (Bruunsgaard
et al., unpublished data). Such a scenario could result from a
high mortality among octogenarians with a systemic anti-inflammatory profile,
due to local inflammatory processes or to a genetic disposition and, thus,
a selection of individuals without this risk profile for longevity. On
the other hand, the anti-inflammatory response may be insufficient to
counteract the detrimental effects of the systemic proinflammatory activity
in centenarians with high circulating levels of TNF-a.
What is the triggering signal for age-related
increases in systemic levels of cytokines ?
Considering that low-grade increases in circulating pro- and anti-inflammatory
cytokines seem to induce age-related morbidity, it is important to isolate
the triggering factors in order to improve health in elderly populations.
Actually, a wide range of factors affect and modulate the production of
TNF-a and IL-6 including smoking, obesity, infections, the age-related
decline in sex hormones, trauma, exercise, and polymorphisms in the promoter
genes. To our knowledge, no studies have determined the balance between
the contribution of life style factors versus genetic programming.
CONCLUSION
Concluding remarks
Aging is associated with chronic, low-grade increases in circulating
levels of TNF-a and IL-6, which are both associated with mortality, independently
of co-morbidity in different elderly populations. Furthermore, in relatively
healthy octogenarians, TNF-a and IL-6 were associated with life style
factors but not with chronic diseases (Bruunsgaard et al., unpublished
data). This strongly suggests that cytokines cause age-related pathology
instead of being a reflection of the diseases present, although co-morbidity
may contribute to high levels. The production of TNF-a and IL-6 is very
closely linked and, accordingly, it is sometimes difficult to distinguish
between their effects in epidemiological studies. Despite this, TNF-a
and IL-6 seem to have separate effects on morbidity and mortality in old
populations. Thus, low-grade increases in TNF-a and IL-6 represent independent
links between life style factors and genetic programming on one hand and
age-related risk factors, inflammatory diseases and mortality on the other.
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