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

Johns Hopkins Medical Institutions, Johns Hopkins University, John R Burton Pavilion, 5505 Hopkins Bayview Circle, Baltimore, MD 21224, USA.
Experimental gerontology (Impact Factor: 3.49). 02/2009; 44(5):350-5. DOI: 10.1016/j.exger.2009.02.004
Source: PubMed


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.

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Available from: Gil Atzmon
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    • "In this context, changes in inflammation and the proinflammatory genes observed in aged subjects in this study may be the result of a favourable reaction helping older people to cope with chronic antigenic stressors. However, the association between IL6R genotype and longevity has not been reported despite strong evidence for association of cardiovascular disease with IL-6 and sIL-6R phenotypes [12]. In agreement with Jylhävä et al. [13], reduced expression of CD40LG in octo/nonagenarians (this study) which functions in full T-cell and B-cell signalling and activation suggests that the aged immune system failed to respond adequately to antigen stimuli. "
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    ABSTRACT: Mechanisms determining both functional rate of decline and the time of onset in aging remain elusive. Studies of the aging process especially those involving the comparison of long-lived individuals and young controls are fairly limited. Therefore, this research aims to determine the differential gene expression profile in related individuals from villages in Pahang, Malaysia. Genome-wide microarray analysis of 18 samples of peripheral blood mononuclear cells (PBMCs) from two groups: octo/nonagenarians (80-99 years old) and their offspring (50.2 ± 4.0 years old) revealed that 477 transcripts were age-induced and 335 transcripts were age-repressed with fold changes ≥1.2 in octo/nonagenarians compared to offspring. Interestingly, changes in gene expression were associated with increased capacity for apoptosis (BAK1), cell cycle regulation (CDKN1B), metabolic process (LRPAP1), insulin action (IGF2R), and increased immune and inflammatory response (IL27RA), whereas response to stress (HSPA8), damage stimulus (XRCC6), and chromatin remodelling (TINF2) pathways were downregulated in octo/nonagenarians. These results suggested that systemic telomere maintenance, metabolism, cell signalling, and redox regulation may be important for individuals to maintain their healthy state with advancing age and that these processes play an important role in the determination of the healthy life-span.
    Full-text · Article · Nov 2013 · Oxidative medicine and cellular longevity
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    • "IL-6 has been implicated in the pathogenesis of many age related diseases and has been shown to be a predictor of all-cause mortality.42, 43 Likewise, low circulating levels of IL-6 are associated with decreased mortality and increased longevity.43–45 In this regard, the low levels of IL-6 seen in cycled mice at one year of age may be indicative of their propensity for increased longevity. "
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    ABSTRACT: Objective With the increasing rates of obesity, many people diet in attempts to lose weight. Since weight loss is seldom maintained in a single effort, weight cycling is a common occurrence. Unfortunately, reports from clinical studies that have attempted to determine the effect of weight cycling on mortality are in disagreement, and to date, no controlled animal study has been performed to assess the impact of weight cycling on longevity. Therefore, our objective was to determine whether weight cycling altered lifespan in mice that experienced repeated weight gain and weight loss throughout their lives. Methods Male C57BL/6J mice were placed on one of three lifelong diets: a low fat (LF) diet, a high fat (HF) diet, or a cycled diet in which the mice alternated between 4 weeks on the LF diet and 4 weeks on the HF diet. Body weight, body composition, several blood parameters and lifespan were assessed. Results Cycling between the HF and LF diet resulted in large fluctuations in body weight and fat mass. These gains and losses corresponded to significant increases and decreases, respectively, in leptin, resistin, GIP, IGF-1, glucose, insulin, and glucose tolerance. Surprisingly, weight cycled mice had no significant difference in lifespan (801±45 days) as compared to LF fed controls (828±74 days), despite being overweight and eating a HF diet for half of their lives. In contrast, the HF fed group experienced a significant decrease in lifespan (544±73days) compared to LF fed controls and cycled mice. Conclusions This is the first controlled mouse study to demonstrate the effect of lifelong weight cycling on longevity. The act of repeatedly gaining and losing weight, in itself, did not decrease lifespan and was more beneficial than remaining obese.
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    • "Likewise, studies on IL-6 genotypes show conflicting results. Some studies show an association between IL-6 variants with increased production of IL-6 by mononuclear blood cells with age [99] [100], but other studies show no link with healthy aging or longevity [101] [102] [103]. Perhaps the most attractive notion for immune gene determinant(s) of longevity stems from the analyses of the human leukocyte histocompatibility antigen (HLA) multigene family because products of this family are central to antigen-specific immunity. "
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    ABSTRACT: Studies comparing chronologically "young" versus "old" humans document age-related decline of classical immunological functions. However, older adults aged ≥65 years have very heterogeneous health phenotypes. A significant number of them are functionally independent and are surviving well into their 8(th)-11(th) decade life, observations indicating that aging or old age is not synonymous with immune incompetence. While there are dramatic age-related changes in the immune system, not all of these changes may be considered detrimental. Here, we review evidences for novel immunologic processes that become elaborated with advancing age that complement preserved classical immune functions and promote immune homeostasis later in life. We propose that elaboration such of late life immunologic properties is indicative of beneficial immune remodeling that is an integral component of successful aging, an emerging physiologic construct associated with similar age-related physiologic adaptations underlying maintenance of physical and cognitive function. We suggest that a systems approach integrating immune, physical, and cognitive functions, rather than a strict immunodeficiency-minded approach, will be key towards innovations in clinical interventions to better promote protective immunity and functional independence among the elderly.
    Full-text · Article · Feb 2012 · Aging and Disease
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