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Inflammation underlying cardiovascular mortality is a late consequence of evolutionary programming ¹

ANITA H. J. VAN DEN BIGGELAAR², ANTON J. M. DE CRAEN, JACOBIJN GUSSEKLOO, TOM W. J. HUIZINGA^*, BASTIAAN T. HEIJMANS, MARIJKE FRÖLICH, TOM B. L. KIRKWOOD and RUDI G. J. WESTENDORP

Department of General Internal Medicine, Section Gerontology and Geriatrics;
^* Department of Reumatology,
Department of Molecular Epidemiology,
Department of Clinical Chemistry, Leiden University Medical Center, Leiden, The Netherlands; and
Institute for Ageing and Health, University of Newcastle, Newcastle upon Tyne, UK

² Correspondence: Department of General Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, C2-R, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands, E-mail:.Biggelaar{at}lumc.nl

SPECIFIC AIMS

With the increase in life expectancy, death from cardiovascular disease has risen greatly. There is increasing evidence that inflammation plays an important role in this process. We tested the hypothesis that cardiovascular mortality in old age is the late consequence of an evolutionary programming for proinflammatory responses. Over 85 years of age, a predisposition to produce high TNF- and low IL-10 innate responses was shown to predict cardiovascular mortality; it was proved in the same study population that this cytokine risk profile is under the control of evolutionary programming.

PRINCIPAL FINDINGS

1. In old age, high TNF- and low IL-10 responses are predictors of cardiovascular death
For a group of 311 Dutch women, aged 85 years, derived from the general population, their capacity to produce the pro- and anti-inflammatory cytokines tumor necrosis factor (TNF-) and interleukin 10 (IL-10) was determined in ex vivo whole blood stimulations with bacterial lipopolysaccharide (LPS). Participants were studied prospectively for death from cardiovascular disease depending on assessed cytokine profiles. During the follow-up period (on average 3 years and 5 months) 93 women died, 42 from cardiovascular causes. Women who died of a cardiovascular event produced significantly higher levels of TNF- to IL-10 (ratio 16.3; 95% CI 14.0–18.9) than the rest of the cohort (ratio 13.1; 95% CI 12.4–13.9) (P=0.018), including women that died of other causes (ratio 12.9; 95% CI 10.7–15.6) and those who did not die during the follow-up (ratio 13.2; 95% CI 12.4–14.0) (P=0.042).

When levels of these antagonistic cytokines were studied simultaneously in a Cox regression model, a high TNF- production capacity was found to be associated with an elevated risk of death from a cardiovascular event, whereas this risk was markedly reduced by an increased capacity to produce IL-10 (Table 1 ). The effect of TNF- and IL-10 on cardiovascular mortality was studied in a separate analysis while adjusting for total cholesterol, high density lipoprotein (HDL)/cholesterol, triglycerides, and diabetes type 2. The effect of the production capacity of these cytokines on death from cardiovascular disease remained unchanged (Table 1) . This means that the antagonistic cytokines TNF- and IL-10 are independent risk factors for cardiovascular morality.

The finding that in old age a strong proinflammatory response, as measured by a capacity to produce high levels of the proinflammatory cytokine TNF- and low levels of the antagonistic cytokine IL-10, predicts cardiovascular death is in accordance with increasing evidence that inflammation contributes to several stages in the development of atherosclerosis, ranging from early formation of the atheroma to the rupture of the "fibrous cap" that protects an atherosclerotic plaque.

2. The association between cardiovascular death and a high TNF-/low IL-10 cytokine profile is genetically determined
The antagonistic pleiotropy theory on the evolution of aging postulates that senescence is the late deleterious effect of genes that are beneficial in early life. Strong proinflammatory and low anti-inflammatory cytokine responses have been found to protect against fatal infections, and associations with genetic variations have been shown. This indicates that evolutionary programming may act via selection on these genetic traits. Providing a genetic explanation for the elevated risk of cardiovascular mortality in elderly people that produce high TNF- and low IL-10 levels would strongly support the postulate that the harmful effect of this cytokine profile in old age is due to an antagonistic pleiotropic effect of aging.

We previously showed that a polymorphism of the IL-10 gene promoter was associated with LPS-induced levels of IL-10. In line with these earlier findings, women who carried the –2849AA genotype (n=21) were found to produce lower levels of IL-10 (mean 495 pg/mL; 95% confidence interval (CI) 349–704) than –2849 AG carriers (n=139) (mean 640 pg/mL, 95% CI 573–715), who in turn produced levels lower than –2849 GG carriers (n=151) (mean 743 pg/mL, 95% CI 684–807) (p_trend=0.009). During follow-up, 29% (6/21) of the –2849 AA carriers died from cardiovascular causes compared with 12% (16/139) of the –2849 AG carriers and 13% (20/151) of the –2849 GG carriers. In Cox regression, this corresponded with –2849-AA carriers having an almost threefold higher risk of death from a cardiovascular event (relative risk is 2.77; 95% CI 1.17–6.60, P=0.021) than 85-year-old women with –2849 AG or –GG genotypes.

This genetic association provides strong evidence for the hypothesis that the harmful effect of strong proinflammatory and low anti-inflammatory responses in old age is an antagonistic pleiotropic effect of aging.

3. Reproductive success, which is studied as a readout of evolutionary programming, is associated with a high TNF- and a genetically determined low IL-10 production capacity
The antagonistic pleiotropy theory is based on the assumption that aging results from an evolutionary selection for genes that promote early survival. We showed that a production capacity of high TNF- and low IL-10 predicts resistance to fatal meningococcal disease in young age, which implies that this cytokine profile is under the control of evolutionary programming. Moreover, we have demonstrated that a high TNF- and low IL-10 cytokine profile is inversely associated with reproductive success, which is in line with the hypothesis that early survival trades off with fertility. Thus, evolutionary programming can be deduced from reproductive success. To confirm that in our study population the association of cardiovascular mortality and a high TNF- and low IL-10 production capacity is due to a late effect of evolutionary imprinting, the women were studied retrospectively for reproductive success.

Thirty-two women (10%) were found to have remained childless. Among the 279 who had children, the mean number of life births (parity) was 3 (3.3; 95% CI 3.1–3.5), with a maximum of 11. The association between LPS-induced levels of TNF- to IL-10 and reproductive success was studied by modeling in Cox regression the age at which a mother had her first child. We adjusted for the age a woman got married, since women with children were found to have married at a significantly younger age than those without children. A higher IL-10 production capacity was found to be associated with an increased chance of reproductive success; the reverse was found for TNF- (Table 2 ).

We then studied the association of reproductive success dependent on genetic variation of the IL-10 promoter gene. Consistent with an earlier study, 12.5% of the childless women (4/32) were found to carry the –2849 AA genotype against 6% of the women with children (17/269). The –2849 AG and GG genotype were found in 53% (17/32) and 34% (11/32) of the childless women against 44% (122/279) and 50% (140/279) of the reproductive successful women, respectively. In Cox regression, this corresponded with carriers of the –2849 AA genotype having half the chance of reproductive success (RR=0.54; 95% CI 0.33–0.90, P=0.018) as women with the –2849 GG genotype; this was reduced by 23% for carriers of the –2849 AG allele (RR=0.77; 95% CI 0.61–0.99, P=0.040).

These findings confirm that, within our population, reproductive success is associated with genetically determined high TNF- and a low IL-10 production capacity, which we propose provides evidence that this cytokine profile is likely under the control of evolutionary programming.

CONCLUSIONS AND SIGNIFICANCE

In this study, we show that consistent with the antagonistic pleiotropy theory on aging, cardiovascular death is the late consequence of an evolutionary selection for proinflammatory genes that increase resistance to infectious diseases. The hypothesis that a genetic predisposition for strong proinflammatory responses underlies cardiovascular disease in old age is in line with indications that inflammation plays a prominent role in the onset of cardiovascular disease.

Evolutionary programming in our ancestral environment is associated with a positive selection for genes coding for strong proinflammatory but low anti-inflammatory responses (Fig. 1 ). However, once reproductive age has been reached and prolonged survival no longer adds to the maintenance of (human) kind, the force of natural selection is assumed to decline. According to the antagonistic pleiotropy theory of Williams, this is explained by the deleterious late-life effect of genes that have beneficial early life effects. In this study we provide evidence that the capacity to produce pro- and anti-inflammatory responses is consistent with this idea and may explain the high prevalence of cardiovascular disease in prosperous societies where life expectancy has increased greatly.

View larger version (50K): [in this window] [in a new window]   Figure 1. Schematic diagram showing the assumed antagonistic pleiotropic effect of proinflammatory and anti-inflammatory immune responses with aging. In early life, high proinflammatory and low anti-inflammatory responses are beneficial by increasing the probability to survive fatal infections; after reproductive age, when the force of evolutionary pressure declines, these responses become harmful and increase the risk to die of degenerative, inflammatory diseases. The positive effects of proinflammatory resistance genes may still be present in populations living under adverse conditions, but not in modern Western populations. On the contrary, the late negative effects of proinflammatory genes are predominantly recognizable in affluent societies, where the majority of the people are able to survive to mid-age.

We propose that understanding when protective immune responses turn harmful with aging is of high interest and importance, especially in less-developed parts of the world where selection for strong proinflammatory responses is still present, but where with the increase in life expectancy an epidemic of cardiovascular diseases is emerging.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-1162fje;

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