Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85+ Study.
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.
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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
Article: No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: an investigation of the impact of frailty upon treatment effect in the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over[Show abstract] [Hide abstract]
ABSTRACT: Treatment for hypertension with antihypertensive medication has been shown to reduce stroke, cardiovascular events, and mortality in older adults, but there is concern that such treatment may not be appropriate in frailer older adults. To investigate whether there is an interaction between effect of treatment for hypertension and frailty in older adults, we calculated the frailty index (FI) for all available participants from the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over, and obtained frailty adjusted estimates of the effect of treatment with antihypertensive medication on risk of stroke, cardiovascular events, and mortality. Participants in HYVET were randomised 1:1 to active treatment with indapamide sustained release 1.5 mg ± perindopril 2 to 4 mg or to matching placebo. Data relating to blood pressure, comorbidities, cognitive function, depression, and quality of life were collected at entry into the study and at subsequent follow-up visits. The FI was calculated at entry, based on 60 potential deficits. The distribution of FI was similar to that seen in population studies of adults aged 80 years and above (median FI, 0.17; IQR, 0.11-0.24). Cox regression was used to assess the impact of FI at entry to the study on subsequent risk of stroke, total mortality, and cardiovascular events. Models were stratified by region of recruitment and adjusted for sex and age at entry. Extending these models to include a term for a possible interaction between treatment for hypertension and FI provided a formula for the treatment effect as a function of FI. For all three models, the point estimates of the hazard ratios for the treatment effect decreased as FI increased, although to varying degrees and with varying certainty. We found no evidence of an interaction between effect of treatment for hypertension and frailty as measured by the FI. Both the frailer and the fitter older adults with hypertension appeared to gain from treatment. Further work to examine whether antihypertensive treatment modifies frailty as measured by the FI should be explored. ClinicalTrials.gov NCT00122811 (July 2005).BMC Medicine 04/2015; 13(1):78. DOI:10.1186/s12916-015-0328-1 · 7.28 Impact Factor
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ABSTRACT: Whereas physical impairment is the main hallmark of frailty, evidence suggests that other dimensions, such as psychological, cognitive and social factors also contribute to this multidimensional condition. Cognition is now considered a relevant domain of frailty. Cognitive and physical frailty interact: cognitive problems and dementia are more prevalent in physically frail individuals, and those with cognitive impairment are more prone to become frail. Disentangling the relationship between cognition and frailty may lead to new intervention strategies for the prevention and treatment of both conditions. Both frailty and cognitive decline share common potential mechanisms. This review examines the relationship between frailty and cognitive decline and explores the role of vascular changes, hormones, vitamin D, inflammation, insulin resistance, and nutrition in the development of physical frailty and cognitive problems, as potential underlying mechanisms behind this link. Dual tasking studies may be a useful way to explore and understand the relation between cognitive and physical frailty. Further studies are needed to elucidate this complex relation to improve the outcomes of frailty.The Journal of Nutrition Health and Aging 01/2015; 19(3):276-83. DOI:10.1007/s12603-014-0535-z · 2.66 Impact Factor