Journal of Gerontology: MEDICAL SCIENCES Cite journal as: J Gerontol A Biol Sci Med Sci. 2012 June;67A(6):671–676 doi:10.1093/gerona/glr246
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[email protected]. Advance Access published on March 1, 2012
Oxidative Damage, Platelet Activation, and Inflammation to Predict Mobility Disability and Mortality in Older Persons: Results From the Health Aging and Body Composition Study Matteo Cesari,1,2 Stephen B. Kritchevsky,3 Barbara Nicklas,3 Alka M. Kanaya,4 Paola Patrignani,5 Stefania Tacconelli,5 Gregory J. Tranah,6 Gianni Tognoni,7 Tamara B. Harris,8 Raffaele Antonelli Incalzi,9 Anne B. Newman,10 and Marco Pahor2; for the Health ABC study 1Institut du Vieillissement, Université de Toulouse, France. of Aging and Geriatric Research, University of Florida-Institute on Aging, Gainesville. 3Sticht Center on Aging, Wake Forest University-School of Medicine, Gainesville, North Carolina. 4Division of General Internal Medicine, University of California, San Francisco. 5Center of Excellent on Aging, “Gabriele D’Annunzio” University, Chieti, Italy. 6California Pacific Medical Center Research Institute, San Francisco. 7Consorzio Mario Negri Sud, Chieti, Italy. 8Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland. 9Area di Geriatria, Università Campus Bio-Medico, Roma, Italy. 10Department of Epidemiology, University of Pittsburgh, Pennsylvania.
2Department
Address correspondence to Matteo Cesari, MD, PhD, Institut du Vieillissement, Université de Toulouse, 37 Allées Jules Guesde, 31000 Toulouse, France. Email:
[email protected]
Background. Inflammation, oxidative damage, and platelet activation are hypothesized biological mechanisms driving the disablement process. The aim of the present study is to assess whether biomarkers representing these mechanisms predicted major adverse health-related events in older persons. Methods. Data are from 2,234 community-dwelling nondisabled older persons enrolled in the Health Aging and Body Composition study. Biomarkers of lipid peroxidation (ie, urinary levels of 8-iso-prostaglandin F2a), platelet activation (ie, urinary levels of 11-dehydro-thromboxane B2), and inflammation (serum concentrations of interleukin-6) were considered as independent variables of interest and tested in Cox proportional hazard models as predictors of (severe) mobility disability and overall mortality. Results. The sample’s (women 48.0%, whites 64.3%) mean age was 74.6 (SD 2.9) years. During the follow-up (median 11.4 years), 792 (35.5%), 269 (12.0%), and 942 (42.2%) events of mobility disability, severe mobility disability, and mortality occurred, respectively. Only interleukin-6 showed significant independent associations with the onset of all the study outcomes. Higher levels of urinary 8-iso-prostaglandin F2a and 11-dehydro-thromboxane B2 independently predicted increased risk of death (hazard ratio 1.10, 95% confidence interval 1.03–1.19 and hazard ratio 1.14, 95% confidence interval 1.06–1.23, respectively). No significant interactions of gender, race, cardiovascular disease, diabetes, and antiplatelet drugs were detected on the studied relationships. Conclusions. The inflammatory marker interleukin-6 is confirmed to be a robust predictor for the onset of negative health-related events. Participants with higher urinary levels of 8-iso-prostaglandin F2a and 11-dehydro-thromboxane B2 presented a higher mortality risk. Key Words: Oxidative damage—Platelet activation—Inflammation—Disability—Mortality. Received November 30, 2011; Accepted November 30, 2011 Decision Editor: Luigi Ferrucci, MD, PhD
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OBILITY disability is a common early stage of the disablement process in older adults. It predicts major physical disability (1) and mortality (2), and it is associated with poor quality of life (1,3) and with substantial social and health care needs (4). Consequently, prevention of mobility disability represents a high public health priority.
The oxidative damage due to the excess of free radicals is thought to play an important role in the onset of mobility limitation, disability, and mortality. Although available evidence is particularly focused on protein oxidation (5,6), previous reports (7) and the age-related increase of lipid peroxidation levels (8,9) may well justify the evaluation of 671
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this pathway as determinant of negative health-related events in older persons. Oxidative damage (especially lipid peroxidation) is closely associated with platelet activation (10) and inflammation (11), and an interaction among these three pathways might generate the vicious cycle determining the pathophysiological modifications typical of the aging process (10,12–15). Furthermore, oxidative damage, platelet activation, and inflammation are involved in subclinical (eg, sarcopenia, obesity, insulin resistance, atherogenesis) and clinical (eg, cardiovascular disease, diabetes, cancer) conditions, each of which also represents a risk factor for disability and mortality (16). In the present study, we hypothesize that oxidative damage (in particular, lipid peroxidation), platelet activation, and inflammation are all independently associated with the onset of major health-related events in older persons. Thus, we performed longitudinal analyses in a large sample of community-dwelling older persons aimed at evaluating the predictive value of lipid peroxidation (assessed by measuring its systemic biomarker, ie, urinary excretion of 8-isoprostaglandin [PG] F2a, 8-iso-PGF2a [17]), platelet activation (by measuring its systemic biomarker, ie, urinary concentrations of 11-dehydro-thromboxane [TX] B2, 11-dehydroTXB2 [18]), and inflammation (ie, serum concentrations of interleukin-6 [IL-6]) biomarkers for incident mobility disability and mortality. Methods
Study Sample The Health Aging and Body Composition (Health ABC) study is an on-going prospective cohort study investigating changes in body composition and weight-related health conditions in well-functioning older persons. Health ABC study recruited 3,075 community-dwelling black and white men and women, aged 70–79 years, from April 1997 to June 1998. White participants were randomly selected from a sample of Medicare beneficiaries residing in the areas surrounding Pittsburgh, PA, and Memphis, TN. All black participants were potentially eligible. Subjects were considered eligible if they reported no difficulty walking a quarter mile, climbing 10 steps, or performing basic activities of daily living; were free of life-threatening illness; planned to remain in the geographic area for at least 3 years and were not enrolled in lifestyle intervention trials. The key components of Health ABC include a baseline exam, annual follow-up clinical exams for 6 years with additional examinations in Years 8, 10, and 11, and phone contacts every 6 months to identify major health events and document functional status between clinic visits. In addition, the study collects and abstracts medical records of all hospitalizations (≥24 hours) and adjudicates the occurrence of targeted health events including all deaths. Interviews with proxies are conducted when the participant cannot answer for himself. The primary measures were repeated during each annual clinic visit. The Health ABC research proposal
and informed consent forms have been approved by the Institutional Review Boards at the University of Tennessee and at the University of Pittsburgh. The baseline for the present analyses is the second visit (or first annual follow-up) for the Health ABC study (1998– 1999) due to the availability of the biological specimens (urine and serum samples) for the assessment of the three biomarkers of interest. From the original Health ABC study sample (n = 3,075), we excluded 32 participants who had died during the first year, 648 who developed mobility disability before our analytical baseline, and 111 who had inadequate or missing biological specimens. Thus, the present analyses are based on 2,234 Health ABC participants. Excluded participants were older, more likely to be women, and had a higher prevalence of all the clinical conditions compared with those included in these analyses. Biomarkers The 8-iso-PGF2a is a member of a family of PG isomers called F2-isoprostanes. In contrast to classic PGs, formed through an enzymatic action of the PG H synthase from arachidonic acid, F2-isoprostanes result from a free radical– catalyzed mechanism (19,20). The formation of isoprostanes in lipid bilayers may contribute to alterations in fluidity and integrity of cellular membranes (17). The 11-dehydro-TXB2 is a biologically inactive major enzymatic metabolite of TXB2, the chemically stable and biologically inactive hydration product of TXA2 (a derivative of PG endoperoxide metabolism with receptor-mediated effects on platelet function) (18). Thus, urinary excretion of 8-iso-PGF2a and 11-dehydro-TXB2 provide reliable noninvasive indexes of lipid peroxidation and platelet activation in vivo, respectively. Urinary levels of 8-iso-PGF2a and 11-dehydro-TXB2 were measured by previously described radioimmunoassay methods (18,21) at the Laboratory of Clinical Pharmacology of Eicosanoids and Pharmacodynamic located in the Center of Excellence on Aging at the “Gabriele D’Annnunzio” University Foundation (Chieti, Italy). Measurements of urinary eicosanoid metabolites by radioimmunoassay methods have been validated with different antisera and by comparison with gas chromatography-mass spectrometry, as previously described (18,21). The intraassay and interassay coefficients of variation for the 8-iso-PGF2a were 2.0% and 2.9% at the lowest level of standard (2 pg/mL) and 3.7% and 10.8% at the highest level of standard (250 pg/mL), respectively. Both urinary levels of 8-iso-PGF2a and 11-dehydro-TXB2 were adjusted for urinary creatinine in all analyses. Serum IL-6 concentrations were measured in duplicate using a high-sensitivity Quantikine enzyme-linked immunosorbent assay kit (R&D Systems, Minneapolis, MN). The assay has a sensitivity of 1 per day Body mass index (kg/m2) Physical activity (kcal/week) Cardiovascular disease Diabetes Osteoarthritis Peripheral artery disease Cerebrovascular disease Cancer Pulmonary disease Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Statins Corticosteroids Antihypertensive drugs Nonsteroidal anti-inflammatory drugs Antiplatelet drugs Interleukin-6 (pg/mL) 8-iso-prostaglandin F2a (pg/mg urinary creatinine) 11-dehydro-thromboxane B2 (pg/mg urinary creatinine)
74.6 ± 2.9 48.0 64.3 50.4 45.0 46.5 8.5 47.3 21.1 23.5 8.1 26.8 ± 4.4 568.3 (125.9–1456.0) 15.8 12.7 15.5 3.8 6.1 21.6 3.3 133.1 ± 20.3 70.3 ± 11.7 15.7 4.5 53.6 17.7 37.8 2.22 (1.43–3.68) 720. 99 (467.67–1051.28) 248.68 (119.41–522.02)
concentrations of 8-iso-PGF2a and 11-dehydro-TXB2 were associated with an increased risk of death (Model 2 adjustment: HR 1.10, 95% CI 1.03–1.19, and HR 1.14, 95% CI 1.06–1.23, respectively). When the three biomarkers of interest were simultaneously included in the fully-adjusted models (Model 3 adjustment), IL-6 was confirmed to be the biomarker most strongly associated with all the study outcomes, although significant relationships of 8-iso-PGF2a and 11-dehydro-TXB2 with mortality were maintained (p values
