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: 3.4). 06/2012; 133(6):456-66. DOI: 10.1016/j.mad.2012.05.005
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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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Available from: Carmen Martin-Ruiz, Jan 30, 2014
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    • "However, the use of molecular and cellular biomarkers has a great potential of anticipating , at preclinical stages, the recognition of frail individuals and improving outcomes by means of prevention and intervention programs . Several investigators noted an association between frailty and immunological system alterations, including inmunosenescence and inflammation markers (Collerton et al., 2012). Analysis of immunological changes, such as alterations in lymphocyte subsets, during senescence may provide useful markers for frailty and associated pathologies. "
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    ABSTRACT: Age-related frailty is characterized by increased vulnerability to stress due to decline in homeostatic reserve, which results in increased risk of adverse health outcomes including disability, hospitalization, and death. The relationship between frailty and immunological system alterations is well established. Thus, analysis of immunological changes, such as alterations in lymphocyte subsets, during senescence may provide useful markers for frailty and associated pathologies. Since reference ranges currently used for lymphocyte subsets do not specifically differentiate the elderly group, the aim of this study was to (1) establish reference ranges in nonfrail elderly individuals and (2) assess the evolution of these parameters with age. Further, the influence of other physiological and lifestyle factors was also evaluated. The study was performed on 144 elderly individuals (aged 65–95) from Galicia (in northwestern Spain). Percentages of lymphocyte subpopulations (CD3+ T lymphocytes, CD4+ T-helper lymphocytes, CD8+ T-cytotoxic lymphocytes, CD19+ B lymphocytes, and CD56+16+ natural killer cells) were analyzed in peripheral blood by flow cytometry, and reference ranges were calculated. The individual status as nonfrail or prefrail did not markedly affect the immunological parameters, but an apparent influence of age was obtained for %CD3+, %CD4+, and %CD19+ cells, all of which fell with increasing age. Women showed higher levels of %CD19+ lymphocytes. No significant influence of smoking habits, physical activity, or drinking alcohol or caffeine beverages was observed. The results obtained may serve as a basis to establish comparisons between frail and nonfrail elderly individuals, in order to determine the usefulness of lymphocyte subsets as immunological biomarkers of frailty.
    Journal of Toxicology and Environmental Health Part A 07/2015; 78(13-14):790-804. DOI:10.1080/15287394.2015.1051170 · 2.35 Impact Factor
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    • "However, the lack of a significant association between T/S values and measures of frailty is in keeping with previous reports on the topic (Woo et al., 2008; Collerton et al., 2012). Similar to the present study, PBMC telomere length was indeed unrelated to either PF (Collerton et al., 2012) or the FI (Woo et al., 2008; Collerton et al., 2012). As previously reasoned with regard to muscle function, it is conceivable that the " snapshot " assessment of a single biological marker may not be sufficient at capturing a complex, multidimensional syndrome, such as frailty. "
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    ABSTRACT: Background: Telomere shortening in peripheral blood mononuclear cells (PBMCs) has been associated with biological age and several chronic degenerative diseases. However, the relationship between telomere length and sarcopenia, a hallmark of the aging process, is unknown. The aim of the present study was therefore to determine whether PBMC telomeres obtained from sarcopenic older persons were shorter relative to non-sarcopenic peers. We further explored if PBMC telomere length was associated with frailty, a major clinical correlate of sarcopenia. Methods: Analyses were conducted in 142 persons aged ≥65 years referred to a geriatric outpatient clinic (University Hospital). The presence of sarcopenia was established according to the European Working Group on Sarcopenia in Older People criteria, with bioelectrical impedance analysis used for muscle mass estimation. The frailty status was determined by both the Fried’s criteria (physical frailty, PF) and a modified Rockwood’s frailty index (FI). Telomere length was measured in PBMCs by quantitative real-time polymerase chain reaction according to the telomere/single-copy gene ratio (T/S) method. Results: Among 142 outpatients (mean age 75.0 ± 6.5 years, 59.2% women), sarcopenia was diagnosed in 23 individuals (19.3%). The PF phenotype was detected in 74 participants (52.1%). The average FI score was 0.46 ± 0.17. PBMC telomeres were shorter in sarcopenic subjects (T/S = 0.21; 95% CI: 0.18–0.24) relative to non-sarcopenic individuals (T/S = 0.26; 95% CI: 0.24–0.28; p = 0.01), independent of age, gender, smoking habit, or comorbidity. No significant associations were determined between telomere length and either PF or the FI. Conclusion: PBMC telomere length, expressed as T/S values, is shorter in older outpatients with sarcopenia. The cross-sectional assessment of PBMC telomere length is not sufficient at capturing the complex, multidimensional syndrome of frailty.
    Frontiers in Aging Neuroscience 08/2014; 6(233). DOI:10.3389/fnagi.2014.00233 · 4.00 Impact Factor
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    • "However, immune phenotypes in this group have not been well characterized, as most immunosenescence studies have excluded the nursing home elderly [10]. Three studies have investigated the immune phenotype of peripheral blood mononuclear cells (PBMCs) in the nursing home elderly [3,11,12]; two of these reports contained an elderly population composed of community dwelling and nursing home elderly and did not report specifically on the latter group [11,12], whereas the other study enrolled exclusively nursing home elderly [3]. The overall observations from these studies concluded that the nursing home elderly displayed immunosenescent phenotypes similar to the community dwelling elderly. "
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    ABSTRACT: To describe T-cell and natural killer (NK) cell phenotypes within nursing home elderly. Nursing home elderly were recruited from four nursing homes in Hamilton, Ontario between September 2010 and December 2011. Healthy adults were recruited from McMaster University between September 2011 and December 2011. Nursing home elderly >=65 years were eligible; those on immunosuppressive medications were excluded. Healthy adults >=18-64 years were eligible. CD8+ and CD4+ T-cells% and their subsets, T-regs% and NK cell subset% were compared between the nursing home elderly and healthy adults. 262 nursing home elderly were enrolled; median age 87 years and 81% were female. 16 healthy adults were enrolled; median age 31 and 50% were female. There was no significant difference between CD8+ T-cell% in nursing home and healthy adults (median 17.1 versus 18.0, p = 0.56), however there were fewer naive CD8 + T-cell% (median 0.9 versus 5.2, p < 0.001), more terminally differentiated CD8 + T-cell% (median 7.3 versus 4.1, p = 0.004) and more senescent T-cell% (median 5.3 versus 3.1, p = 0.04) in the nursing home elderly. There were more CD4+ T-cell% in the nursing home elderly compared to healthy adults (median 45.5 versus 37.1, p = 0.001). Nursing home elderly had a higher CD4+/CD8+ ratio than healthy adults (2.6 versus 1.9, p = 0.048), higher T-reg% (median 1.8 versus 0.8, p < 0.001) and increased mature NK cell% (median 12.1 versus 5.4, p = 0.001) compared to healthy adults. Differences in naive CD8+ T-cells, terminally differentiated and senescent CD8+ T-cells, T-regs and NK cell subsets were similar to studies involving community dwelling elderly. In contrast, the CD4+/CD8+ ratio was higher in nursing home elderly.
    BMC Geriatrics 04/2014; 14(1):50. DOI:10.1186/1471-2318-14-50 · 1.68 Impact Factor
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