Frailty has a stronger association with inflammation than age in older veterans

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Abstract

Background

Upregulation of pro-inflammatory cytokines has not only been associated with increased morbidity and mortality in older adults but also has been linked to frailty. In the current study we aimed to compare the relative relationship of age and frailty on inflammation and thrombosis in older veterans.

Results

We analyzed 117 subjects (age range 62–95 years; median 81) divided into 3 cohorts: non-frail, pre-frail and frail based on the Fried phenotype of frailty. Serum inflammatory markers were determined using commercially available ELISA kits. Frail and pre-frail (PF) subjects had higher levels than non-frail (NF) subjects of IL-6 (NF vs. PF: p = 0.002; NF vs. F: p < 0.001), TNFR1 (NF vs. F: p = 0.012), TNFRII (NF vs. F: 0.002; NF vs. PF: p = 0.005) and inflammatory index: = 0.333*log(IL-6) + 0.666*log(sTNFR1) (NF vs. F: p = 0.009; NF vs. PF: p < 0.001). Frailty status explained a greater percent of variability in markers of inflammation than age: IL-6 (12 % vs. 0.3 %), TNFR1 (5 % vs. 4 %), TNFR2 (11 % vs. 6 %), inflammatory index (16 % vs. 8 %). Aging was significantly associated with higher fibrinogen ( p = 0.04) and D-dimer levels ( p = 0.01) but only among NF subjects.

Conclusion

In conclusion, these data suggest that among older veterans, frailty status has a stronger association with inflammation and the inflammatory index than age does. Larger studies, in more diverse populations are needed to confirm these findings.

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Most cited references 25

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Inflamm-aging. An evolutionary perspective on immunosenescence.

C Franceschi, M BonaFe, S Valensin … (2000)

In this paper we extend the "network theory of aging," and we argue that a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status are major characteristics of the aging process. This phenomenon, which we will refer to as "inflamm-aging," is provoked by a continuous antigenic load and stress. On the basis of evolutionary studies, we also argue that the immune and the stress responses are equivalent and that antigens are nothing other than particular types of stressors. We also propose to return macrophage to its rightful place as central actor not only in the inflammatory response and immunity, but also in the stress response. The rate of reaching the threshold of proinflammatory status over which diseases/disabilities ensue and the individual capacity to cope with and adapt to stressors are assumed to be complex traits with a genetic component. Finally, we argue that the persistence of inflammatory stimuli over time represents the biologic background (first hit) favoring the susceptibility to age-related diseases/disabilities. A second hit (absence of robust gene variants and/or presence of frail gene variants) is likely necessary to develop overt organ-specific age-related diseases having an inflammatory pathogenesis, such as atherosclerosis, Alzheimer's disease, osteoporosis, and diabetes. Following this perspective, several paradoxes of healthy centenarians (increase of plasma levels of inflammatory cytokines, acute phase proteins, and coagulation factors) are illustrated and explained. In conclusion, the beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.

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William Ershler, Evan Keller (2000)

Interleukin-6 (IL-6) is a proinflammatory cytokine that is normally tightly regulated and expressed at low levels, except during infection, trauma, or other stress. Among several factors that down-regulate IL-6 gene expression are estrogen and testosterone. After menopause or andropause, IL-6 levels are elevated, even in the absence of infection, trauma, or stress. IL-6 is a potent mediator of inflammatory processes, and it has been proposed that the age-associated increase in IL-6 accounts for certain of the phenotypic changes of advanced age, particularly those that resemble chronic inflammatory disease [decreased lean body mass, osteopenia, low-grade anemia, decreased serum albumin and cholesterol, and increased inflammatory proteins such as C-reactive protein (CRP) and serum amyloid A]. Furthermore, the age-associated rise in IL-6 has been linked to lymphoproliferative disorders, multiple myeloma, osteoporosis, and Alzheimer's disease. This overview discusses the data relating IL-6 to age-associated diseases and to frailty. Like the syndrome of inappropriate antidiuretic hormone, it is possible that certain clinically important late-life changes are due to an inappropriate presence of IL-6.

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Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.

Jeremy Walston, Mary Ann McBurnie, Anne Newman … (2002)

The biological basis of frailty has been difficult to establish owing to the lack of a standard definition, its complexity, and its frequent coexistence with illness. To establish the biological correlates of frailty in the presence and absence of concurrent cardiovascular disease and diabetes mellitus. Participants were 4735 community-dwelling adults 65 years and older. Frail, intermediate, and nonfrail subjects were identified by a validated screening tool and exclusion criteria. Bivariate relationships between frailty level and physiological measures were evaluated by Pearson chi2 tests for categorical variables and analysis of variance F tests for continuous variables. Multinomial logistic regression was performed to evaluate multivariable relationships between frailty status and physiological measures. Of 4735 Cardiovascular Health Study participants, 299 (6.3%) were identified as frail, 2147 (45.3%) as intermediate, and 2289 (48.3%) as not frail. Frail vs nonfrail participants had increased mean +/- SD levels of C-reactive protein (5.5 +/- 9.8 vs 2.7 +/- 4.0 mg/L), factor VIII (13 790 +/- 4480 vs 11 860 +/- 3460 mg/dL), and, in a smaller subset, D dimer (647 +/- 1033 vs 224 +/- 258 ng/mL) (P< or =.001 for all, chi2 test for trend). These differences persisted when individuals with cardiovascular disease and diabetes were excluded and after adjustment for age, sex, and race. These findings support the hypothesis that there is a specific physiological basis to the geriatric syndrome of frailty that is characterized in part by increased inflammation and elevated markers of blood clotting and that these physiological differences persist when those with diabetes and cardiovascular disease are excluded.

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Author and article information

Contributors

P. Van Epps: puja.vanepps@va.gov

D. Oswald: dmo25@case.edu

P. A. Higgins: patricia.higgins@va.gov

T. R. Hornick: Thomas.hornick@case.edu

H. Aung: hxa11@case.edu

R. E. Banks: Richard.banks2@va.gov

B. M. Wilson: Brigid.wilson@va.gov

C. Burant: cxb43@case.edu

S. Graventstein: Stefan.gravenstein@uhhospitals.org

D. H. Canaday: dxc44@case.edu

Journal

Journal ID (nlm-ta): Immun Ageing

Journal ID (iso-abbrev): Immun Ageing

Title: Immunity & Ageing : I & A

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-4933

Publication date (Electronic): 19 October 2016

Publication date PMC-release: 19 October 2016

Publication date Collection: 2016

Volume: 13

Electronic Location Identifier: 27

Affiliations

[1 ]Geriatric Research, Education, and Clinical Center, Louis Stokes Cleveland VA Medical Center, Cleveland, OH USA

[2 ]Division of Infectious Disease, Case Western Reserve University, Cleveland, OH USA

[3 ]Division of Geriatrics, Department of Medicine, Case Western Reserve University, Cleveland, OH USA

[4 ]School of Nursing, Case Western Reserve University, Cleveland, OH USA

Article

Publisher ID: 82

DOI: 10.1186/s12979-016-0082-z

PMC ID: 5069820

PubMed ID: 27777599

SO-VID: 4d70aed5-96d0-4a86-b840-2fbba96d6530

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 21 July 2016

Date accepted : 10 October 2016

Funding

Funded by: VA Merit Review

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: RO1 AI108972

Award Recipient : D. H. Canaday

Funded by: Sanofi Pasteur

Custom metadata

ScienceOpen disciplines: Immunology

Keywords: inflammatory index,cytokines,functional decline and coagulation

Data availability:

ScienceOpen disciplines: Immunology

Keywords: inflammatory index, cytokines, functional decline and coagulation

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