Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85+ Study.

Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, United Kingdom.
Mechanisms of ageing and development (Impact Factor: 3.51). 06/2012; 133(6):456-66. DOI: 10.1016/j.mad.2012.05.005
Source: PubMed

ABSTRACT Age-related frailty is an increasing societal challenge with growing emphasis on identifying its underlying pathophysiology and prospects for intervention. We report findings from the first comprehensive study of frailty and biomarkers of inflammation, immunosenescence and cellular ageing in the very old. Using cross-sectional data from the Newcastle 85+ Study (n=845, aged 85), frailty was operationalized by the Fried and Rockwood models and biomarker associations explored using regression analysis. We confirmed the importance of inflammatory markers (IL-6, TNF-alpha, CRP, neutrophils) in frailty in the very old, previously established only in younger-old populations. Limited evidence was found for immunosenescence in frailty; although total lymphocyte count was inversely related, no association was found with the immune risk profile and the inverse associations observed with memory/naïve CD8 T and B cell ratios were in the opposite direction to that expected. We found no association with frailty in the very old for CMV sero-positivity, telomere length, markers of oxidative stress or DNA damage and repair. The Fried and Rockwood frailty models measure different albeit overlapping concepts yet biomarker associations were generally consistent between models. Difficulties in operationalizing the Fried model, due to high levels of co-morbidity, limit its utility in the very old.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor necrosis factor (TNF), a potent inflammatory cytokine, and mitochondrial DNA (mtDNA), a product of inflammation-induced tissue damage, increase with age ("inflammaging") and many chronic diseases. Peripheral blood neutrophils, a critical component of innate immunity, have also been shown to be altered with age, and are exceptionally sensitive to external stimuli. Herein, we describe that the phenotype of neutrophils from the advanced-age, frail elderly (ELD) is determined by levels of circulating TNF and mtDNA. Neutrophils from ELD donors are morphologically immature, and have higher levels of intracellular reactive oxygen species (ROS) and expression of the activation markers CD11b and HLA-DR. The frequency of CD11b(++) neutrophils correlated with plasma TNF, and recombinant TNF elevated neutrophil CD11b ex vivo and in vivo. Furthermore, neutrophils from aged TNF-deficient mice expressed CD11b similar to young counterparts. The frequency of HLA-DR(+) neutrophils, on the other hand, positively correlated with circulating mtDNA, which increased neutrophil HLA-DR expression in a dose-dependent manner ex vivo. Cell-surface TLR-9 expression, however, was unaltered on neutrophils from ELD donors. In summary, we provide novel evidence that products of age-related inflammation modulate neutrophil phenotype in vivo. Given this, anti-inflammatory therapies may prove beneficial in improving neutrophil functionality in the elderly. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Molecular Immunology 02/2015; 65(1):148-156. DOI:10.1016/j.molimm.2015.01.015 · 3.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Geriatric patients are highly susceptible to infections. While reduced lymphocyte count has been associated with age, other studies found no change in WBC counts with age. Increased circulating white blood cell (WBC) count has been associated with cardiovascular (CV) diseases and frailty but there are discrepancies. Frailty, geriatric conditions, cardiovascular diseases and WBC count have also been associated with low grade inflammation. Association between geriatric conditions and WBC has been scarcely studied. The aim of the study is to assess the association between WBC and geriatric conditions, CV diseases, and low-grade inflammation.Design, setting, participants, measurementsWe recruited 100 subjects in the general population and hospitalized for chronic medical conditions (age, 23–96 years). We collected information on clinical status (medical history, comorbidities, treatments and geriatric syndromes), biological parameters (hematological tests, cytomegalovirus serology) and cytokine production (basal IL-6). Using stepwise backward multivariate analyses, we defined which set of clinical and biological variables could be predictive of increased total and differential WBC counts.ResultsWe found that low-grade inflammation is independently associated with total WBC, monocyte and neutrophil counts, but not geriatric conditions. CV diseases were the only significant associated factor for high monocyte count.Conclusion In this study, we observed that differential and total WBC counts do not seem to be associated with geriatric conditions but with CV diseases, low-grade inflammation and telomere length
    Experimental Gerontology 11/2014; 61. DOI:10.1016/j.exger.2014.11.016 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: Frailty is a geriatric syndrome characterised by the clinical presentation of identifiable physical alterations such as loss of muscle mass and strength, energy and exercise tolerance, and decreased physiological reserve. Frailty and depressive symptoms are common issues facing older adults and may be associated. It is not clear if the depression facilitates the appearance of frailty syndrome or vice versa or these two coexist independently in the same individuals. Method: We performed searches in several databases (Embase, PubMed, CINAHL, Scopus, and PsycINFO) papers published between November 2003 to February 2014 about frailty syndrome and depression in people aged 65 and older published and the reference lists of from the articles retrieved were pearled in order to identify any which may have been missed in the initial search. Two independent reviewers extracted descriptive information on the prevalence and co-occurrence of frailty and depression in older individuals and of frailty criteria among depressed patients. Results: Depression and frailty occur in a significant proportion of frail older individuals. Common pathophysiological alterations and biomarkers in the two syndromes have been recently described. Conclusion: Studies on the causal relationship between the two syndromes are clearly necessary in the future.
    Aging and Mental Health 10/2014; DOI:10.1080/13607863.2014.967174 · 1.78 Impact Factor

Full-text (2 Sources)

Available from
May 20, 2014