Inflammation and stress-related candidate genes, plasma interleukin-6 levels, and longevity in older adults

https://doi.org/10.1016/j.exger.2009.02.004Get rights and content

Abstract

Interleukin-6 (IL-6) is an inflammatory cytokine that influences the development of inflammatory and aging-related disorders and ultimately longevity. In order to study the influence of variants in genes that regulate inflammatory response on IL-6 levels and longevity, we screened a panel of 477 tag SNPs across 87 candidate genes in >5000 older participants from the population-based Cardiovascular Health Study (CHS). Baseline plasma IL-6 concentration was first confirmed as a strong predictor of all-cause mortality. Functional alleles of the IL6R and PARP1 genes were significantly associated with 15%–20% higher baseline IL-6 concentration per copy among CHS European–American (EA) participants (all p < 10−4). In a case/control analysis nested within this EA cohort, the minor allele of PARP1 rs1805415 was nominally associated with decreased longevity (p = 0.001), but there was no evidence of association between IL6R genotype and longevity. The PARP1 rs1805415 – longevity association was subsequently replicated in one of two independent case/control studies. In a pooled analysis of all three studies, the “risk” of longevity associated with the minor allele of PARP1 rs1805415 was 0.79 (95%CI 0.62–1.02; p = 0.07). These findings warrant further study of the potential role of PARP1 genotype in inflammatory and aging-related phenotypes.

Introduction

Aging is associated with low-grade elevation of circulating inflammatory markers (Franceschi et al., 2007, Vasto et al., 2007). Interleukin-6 (IL-6) is a multi-functional inflammatory cytokine that plays an important role in the response to environmental stress and has been implicated in the pathogenesis of many chronic diseases associated with aging (Ershler and Keller, 2000). Increased circulating levels of IL-6 have been associated with the subsequent occurrence of coronary heart disease (Danesh et al., 2008) as well as with physical disability, frailty, increased all-cause and disease-specific mortality and decreased longevity in older adults (Harris et al., 1999, Ferrucci et al., 1999, Volpato et al., 2001, Reuben et al., 2002, Roubenoff et al., 2003, Cohen et al., 2003, Penninx et al., 2004, Störk et al., 2006, Heikkilä et al., 2007). While increased IL-6 levels may signal the occurrence of underlying pathological mechanisms, IL-6 may also contribute directly to a wide variety of chronic degenerative processes, including atherosclerosis (Huber et al., 1999, Ershler and Keller, 2000).

Circulating IL-6 levels (de Maat et al., 2004, de Craen et al., 2005, Dupuis et al., 2005, Su et al., 2008, Wörns et al., 2006) and life span (vB Hjelmborg et al., 2006) are likely heritable traits in older adults, although specific genetic factors responsible for inter-individual differences in IL-6 levels and human longevity are largely unknown. Determination of specific contributing variants to IL-6 and longevity is difficult in part because of the complexity of inflammatory signaling, and because populations studied to date were not recruited for the study of longevity or inflammatory phenotypes. A common promoter variant of the IL6 gene, −174 G/C (rs1800795) was found to be weakly associated with plasma IL-6 levels and CRP levels in older adults, but was not associated with mortality (Walston et al., 2007). In a recent meta-analysis of eight European case-control studies, there was no significant overall difference in IL-6 genotype frequencies between long-lived and controls, though the −174 GG genotype was less common in a subgroup of Italian male centenarians (Di Bona et al., 2009). Given the evidence for genetic influence on IL-6 levels, we hypothesized that polymorphisms in additional inflammation or stress-response genes may account for inter-individual variation in plasma IL-6 concentration and may also contribute to human longevity. In order to test this hypothesis, we designed a candidate gene study that utilized a large cohort study of older adults and two additional nested case-control samples of older adults for validation as described below.

Section snippets

The Cardiovascular Health Study (CHS)

In order to test our hypothesis in the larger candidate gene panel, we utilized stored DNA and previously measured and collected data from CHS. CHS is a prospective, population-based cohort study of 5888 adult men and women 65 y and older recruited from four field centers: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania (Fried et al., 1991). Baseline examination for the original cohort, of whom 4925 or 95% self-identified

Baseline IL-6 levels predict all-cause mortality in CHS

CHS participant baseline characteristics by race are summarized in Table 1. In univariate and multivariable-adjusted regression analyses, older age, male sex, current smoking, higher BMI, alcohol consumption, and prevalent CVD were significantly associated with higher IL-6 (all p < 0.001). When analyzed by quartiles, and adjusted for other risk factors, baseline IL-6 levels were strongly and independently associated with a linear increase in all-cause mortality, as well as mortality due to

Discusssion

Our results confirm that higher circulating IL-6 levels strongly predict future mortality in a large community-based sample of older EA and AA adults from CHS. By screening a panel of inflammation and stress-response candidate genes, we demonstrate that SNPs tagging common functional polymorphisms of IL6R and PARP1 are associated with circulating IL-6 levels among European–American CHS participants. Though no SNPs contained within our candidate gene panel reached the experiment-wide

Acknowledgments

This study was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-55222, N01 HC-15103, N01-HC-75150, N01-HC-45133, Grant No. U01 HL080295 from the National Heart, Lung, and Blood Institute, U19 AG023122 from the National Institute on Aging Longevity Consortium and P30 AG021334 from the National Institute on Aging Claude D. Pepper Older Americans Independence Centers, and grants R01 AG027236 (Dr. Walston), R01 HL-071862 (Dr Reiner), R01 HL077449 (Dr. Tracy), P01

References (54)

  • D.G. Ives et al.

    Surveillance and ascertainment of cardiovascular events. The Cardiovascular Health Study

    Ann. Epidemiol.

    (1995)
  • D. Reich et al.

    Health, Aging and Body Composition (Health ABC) Study. Admixture mapping of an allele affecting interleukin 6 soluble receptor and interleukin 6 levels

    Am. J. Hum. Genet.

    (2007)
  • A.P. Reiner et al.

    Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study

    Am. J. Hum. Genet.

    (2005)
  • A.P. Reiner et al.

    Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein

    Am. J. Hum. Genet.

    (2008)
  • P.M. Ridker et al.

    Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women’s Genome Health Study

    Am. J. Hum. Genet.

    (2008)
  • R. Roubenoff et al.

    Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study

    Am. J. Med.

    (2003)
  • S. Störk et al.

    Prediction of mortality risk in the elderly

    Am. J. Med.

    (2006)
  • S. Su et al.

    Genetic and environmental influences on systemic markers of inflammation in middle-aged male twins

    Atherosclerosis

    (2008)
  • S. Vasto et al.

    Inflammatory networks in ageing, age-related diseases and longevity

    Mech. Ageing Dev.

    (2007)
  • X.G. Wang et al.

    PARP1 Val762Ala polymorphism reduces enzymatic activity

    Biochem. Biophys. Res. Commun.

    (2007)
  • G. Atzmon et al.

    Adiponectin levels and genotype: a potential regulator of life span in humans

    J. Gerontol. A Biol. Sci. Med. Sci.

    (2008)
  • G. Atzmon et al.

    Lipoprotein genotype and conserved pathway for exceptional longevity in humans

    PLoS Biol.

    (2006)
  • N. Barzilai et al.

    Unique lipoprotein phenotype and genotype associated with exceptional longevity

    JAMA

    (2003)
  • S. Beneke et al.

    Poly(ADP-ribosyl)ation in mammalian ageing

    Nucleic Acids Res.

    (2007)
  • A. Csiszar et al.

    Inflammation and endothelial dysfunction during aging: role of NF-{kappa}B

    J. Appl. Physiol.

    (2008)
  • S.R. Cummings et al.

    Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group

    N. Engl. J. Med.

    (1995)
  • M. Cushman et al.

    Laboratory methods and quality assurance in the Cardiovascular Health Study

    Clin. Chem.

    (1995)
  • Cited by (44)

    • Frailty Worsens Antidepressant Treatment Outcomes in Late Life Depression

      2021, American Journal of Geriatric Psychiatry
      Citation Excerpt :

      Targeting dopaminergic availability in adults with LLD and slowed motor speed with carbidopa/levodopa results in increased motor speed and decreased depressive symptoms after only 3 weeks of treatment.35 Finally, inflammation also increases with age and is associated with increased frailty and specific frailty deficits in both human36 and animal models.37,38 Inflammation is more prevalent in adults with major depressive disorders and incurs increased treatment resistance to some antidepressant medications.39

    • The gut microbiome and frailty

      2020, Translational Research
      Citation Excerpt :

      Markers of inflammation increase with age. Heightened inflammation has been significantly associated with a range of prevalent and incident age-associated disease conditions.98–104 Heightened inflammation also has been strongly associated with premature mortality in aging populations.98,102,103

    • Using sweat to measure cytokines in older adults compared to younger adults: A pilot study

      2018, Journal of Immunological Methods
      Citation Excerpt :

      Although not significant in this small sample, the increased IL-6: IL-10 ratio in older adults could indicate a change in the inflammatory response system itself where IL-10, which down regulates pro-inflammatory cytokines including IL-6, is no longer as responsive to increases in pro-inflammation in older adults. A higher pro-inflammatory state has long been considered an important consideration in aging research (Leng et al., 2007; Walston et al., 2006; Walston et al., 2009). A higher pro-inflammatory state has also been associated with an increase in chronic disease count (Puzianowska-Kuźnicka et al., 2016), which may explain why the outlier in the older adult group had lower cytokine levels compared to her peers.

    View all citing articles on Scopus
    View full text