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Chronic pain, perceived stress, and cellular aging : an exploratory study
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 Material Information
Title: Chronic pain, perceived stress, and cellular aging : an exploratory study
Abbreviated Title: Molecular Pain
Physical Description: Archival
Language: English
Creator: Sibille, Kimberly T.
Langaee, Taimour
Burkley, Ben
Gong, Yan
Glover, Toni L.
King, Chris
Riley, Joseph L. III
Leeuwenburgh, Christiaan
Staud, Roland
Bradley, Laurence A.
Fillingim, Roger B.
Publisher: BioMed Central
Publication Date: 2012
 Subjects
Subjects / Keywords: Chronic pain
Perceived stress
Knee osteoarthritis
Telomere length
Cellular aging
 Notes
Abstract: Background: Chronic pain conditions are characterized by significant individual variability complicating the identification of pathophysiological markers. Leukocyte telomere length (TL), a measure of cellular aging, is associated with age-related disease onset, psychosocial stress, and health-related functional decline. Psychosocial stress has been associated with the onset of chronic pain and chronic pain is experienced as a physical and psychosocial stressor. However, the utility of TL as a biological marker reflecting the burden of chronic pain and psychosocial stress has not yet been explored. Findings: The relationship between chronic pain, stress, and TL was analyzed in 36 ethnically diverse, older adults, half of whom reported no chronic pain and the other half had chronic knee osteoarthritis (OA) pain. Subjects completed a physical exam, radiographs, health history, and psychosocial questionnaires. Blood samples were collected and TL was measured by quantitative polymerase chain reaction (qPCR). Four groups were identified characterized by pain status and the Perceived Stress Scale scores: 1) no pain/low stress, 2) no pain/high stress, chronic pain/low stress, and 4) chronic pain/high stress. TL differed between the pain/stress groups (p = 0.01), controlling for relevant covariates. Specifically, the chronic pain/high stress group had significantly shorter TL compared to the no pain/low stress group. Age was negatively correlated with TL, particularly in the chronic pain/ high stress group (p = 0.03). Conclusions: Although preliminary in nature and based on a modest sample size, these findings indicate that cellular aging may be more pronounced in older adults experiencing high levels of perceived stress and chronic pain. Keywords: Chronic pain, Perceived stress, Knee osteoarthritis, Telomere length, Cellular aging
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Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution.
Resource Identifier: doi - 10.1186/1744-8069-8-12
System ID: AA00010465:00001

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Abstract
Background
Chronic pain conditions are characterized by significant individual variability complicating the identification of pathophysiological markers. Leukocyte telomere length (TL), a measure of cellular aging, is associated with age-related disease onset, psychosocial stress, and health-related functional decline. Psychosocial stress has been associated with the onset of chronic pain and chronic pain is experienced as a physical and psychosocial stressor. However, the utility of TL as a biological marker reflecting the burden of chronic pain and psychosocial stress has not yet been explored.
Findings
The relationship between chronic pain, stress, and TL was analyzed in 36 ethnically diverse, older adults, half of whom reported no chronic pain and the other half had chronic knee osteoarthritis (OA) pain. Subjects completed a physical exam, radiographs, health history, and psychosocial questionnaires. Blood samples were collected and TL was measured by quantitative polymerase chain reaction (qPCR). Four groups were identified characterized by pain status and the Perceived Stress Scale scores: 1) no pain/low stress, 2) no pain/high stress, chronic pain/low stress, and 4) chronic pain/high stress. TL differed between the pain/stress groups (p = 0.01), controlling for relevant covariates. Specifically, the chronic pain/high stress group had significantly shorter TL compared to the no pain/low stress group. Age was negatively correlated with TL, particularly in the chronic pain/high stress group (p = 0.03).
Conclusions
Although preliminary in nature and based on a modest sample size, these findings indicate that cellular aging may be more pronounced in older adults experiencing high levels of perceived stress and chronic pain.
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Sibille, Kimberly T
Langaee, Taimour
Burkley, Ben
Gong, Yan
Glover, Toni L
King, Chris
Riley, Joseph L III
Leeuwenburgh, Christiaan
Staud, Roland
Bradley, Laurence A
Fillingim, Roger B
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Molecular Pain. 2012 Feb 12;8(1):12
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p Chronic pain, perceived stress, and cellular aging: an exploratory study
aug
au id A1 ca yes snm Sibillemi Tfnm Kimberlyinsr iid I1 email ksibille@ufl.edu
A2 LangaeeTaimourI2 langaee@cop.ufl.edu
A3 BurkleyBenburkley@cop.ufl.edu
A4 GongYangong@cop.ufl.edu
A5 GloverLToniI3 tglover@ufl.edu
A6 KingChriscking@dental.ufl.edu
A7 RileyLJosephsuf IIIjriley@dental.ufl.edu
A8 LeeuwenburghChristiaanI4 cleeuwen@aging.ufl.edu
A9 StaudRolandstaudr@ufl.edu
A10 BradleyALaurenceI5 braddog@uab.edu
A11 FillingimBRogerI6 rfilling@ufl.edu
insg
ins College of Dentistry, University of Florida, P.O. Box 103628, Gainesville, FL 32610-3628, USA
College of Pharmacy and Center for Pharmacogenomics, University of Florida, Gainesville, USA
College of Dentistry and College of Nursing, University of Florida, Gainesville, USA
College of Medicine, University of Florida, Gainesville, USA
Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, USA
College of Dentistry, University of Florida and North Florida/South Georgia Veterans Health System, Gainesville, USA
source Molecular Pain
issn 1744-8069
pubdate 2012
volume 8
issue 1
fpage 12
url http://www.molecularpain.com/content/8/1/12
xrefbib pubidlist pubid idtype doi 10.1186/1744-8069-8-12pmpid 22325162
history rec date day 25month 8year 2011acc 1222012pub 1222012
cpyrt 2012collab Sibille et al; BioMed Central Ltd.note This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
kwdg
kwd Chronic pain
Perceived stress
Knee osteoarthritis
Telomere length
Cellular aging
abs
sec
st
Abstract
Background
Chronic pain conditions are characterized by significant individual variability complicating the identification of pathophysiological markers. Leukocyte telomere length (TL), a measure of cellular aging, is associated with age-related disease onset, psychosocial stress, and health-related functional decline. Psychosocial stress has been associated with the onset of chronic pain and chronic pain is experienced as a physical and psychosocial stressor. However, the utility of TL as a biological marker reflecting the burden of chronic pain and psychosocial stress has not yet been explored.
Findings
The relationship between chronic pain, stress, and TL was analyzed in 36 ethnically diverse, older adults, half of whom reported no chronic pain and the other half had chronic knee osteoarthritis (OA) pain. Subjects completed a physical exam, radiographs, health history, and psychosocial questionnaires. Blood samples were collected and TL was measured by quantitative polymerase chain reaction (qPCR). Four groups were identified characterized by pain status and the Perceived Stress Scale scores: 1) no pain/low stress, 2) no pain/high stress, chronic pain/low stress, and 4) chronic pain/high stress. TL differed between the pain/stress groups (it p = 0.01), controlling for relevant covariates. Specifically, the chronic pain/high stress group had significantly shorter TL compared to the no pain/low stress group. Age was negatively correlated with TL, particularly in the chronic pain/high stress group (p = 0.03).
Conclusions
Although preliminary in nature and based on a modest sample size, these findings indicate that cellular aging may be more pronounced in older adults experiencing high levels of perceived stress and chronic pain.
bdy
Findings
A recent Institute of Medicine report documents the public health consequences of chronic pain in America with estimates of 116 million adults affected and costs of $635 billion annually abbrgrp
abbr bid B1 1
. One of the challenges illuminated in the report is the difficulty in identifying specific pathophysiological targets due to significant variability in the experience of chronic pain. Consequently, biological markers reflecting the physiological burden of chronic pain on an individual system would offer significant clinical and scientific utility.
Leukocyte telomere length (TL) is a measure of cellular aging and is associated with age-related disease onset, chronic health conditions, psychosocial stress, and mortality
B2 2
B3 3
B4 4
B5 5
. Importantly, recent findings indicate a direct relationship between telomeres and mitochondria, connecting for the first time two major theories of aging
B6 6
. Telomeres are the protective structures at the end of chromosomes comprised of DNA repeat sequences which are reinforced by telomerase activity
B7 7
. Although buffered by telomerase activity, TL decreases over time with cell replication. However, the rate of attrition appears to be influenced by numerous factors including the "biochemical environment" such as oxidative stress, inflammation, and stress hormones
B8 8
B9 9
. Chronic pain represents a physiological stressor often associated with a cascade of negative psychosocial factors
B10 10
. The impact of chronic pain and related psychosocial stress on cellular aging has not yet been explored.
The relationship of chronic pain associated with knee osteoarthritis (OA) and perceived stress on telomere length provides a model for studying cellular aging and chronic pain. We hypothesized that a cumulative effect of "system burden" would be observed such that individuals endorsing chronic pain and high stress would have shorter telomeres than individuals with either chronic pain or high stress, or pain-free individuals with low stress; who would have the longest telomeres of the four groups.
Methods
Thirty six subjects, between the ages of 47 and 75, were included in the analysis. Eighteen subjects presented with current knee pain, endorsed experiencing chronic pain, were confirmed to have radiographic knee osteoarthritic changes
B11 11
, and were without rheumatoid arthritis, heart disease or uncontrolled medical conditions including high blood pressure, diabetes, and gout. The no pain group was comprised of 18 individuals presenting without chronic knee pain or medical comorbidities. The research was conducted on the Clinical Research Unit at the University of Florida (UF). The protocol and procedures were approved by UF's IRB and informed consent was obtained for each participant. Methods described are limited to those relevant to the current analyses.
Subjects completed a health history questionnaire, the Graded Chronic Pain Scale (GCPS)
B12 12
, the Perceived Stress Scale, 10 item (PSS)
B13 13
, the Center for Epidemiologic Studies Depression scale (CES-D)
B14 14
, and a physical exam including knee radiographs. Additionally, duration of knee pain in months was collected. Baseline blood samples were collected and peripheral blood mononuclear cells (PBMCs) were isolated to assess TL. Genomic DNA was extracted from lymphocytes in whole blood using a commercially available kit (Qiagen Flexigene DNA Kit, Qiagen, Valencia, CA). DNA samples were quantified, normalized and plated in 96-well plates. Relative telomere length was measured by quantitative real-time polymerase chain reaction (qPCR). Each qPCR experiment contained telomere primers and β2-globin (control gene) primers
B15 15
.
Telomeres and a single copy gene (β2-globin) were amplified in all the samples in triplicate on each plate. The ΔΔCt method was performed using SDS V.2.1 software from Applied Biosystems. Ct values from each sample were then used to calculate the ratio of telomere to single copy gene (T/S) values using the formula (2 Csub t
sup telomere/2 Ct
β2-globin)-1. Relative T/S values were calculated by the formula 2 -ΔΔCt. Using this formula, we determined the TL of each sample relative to the mean T/S for all samples
15
.
Independent sample t-tests, ANOVA, and Chi Square or Fisher's Exact tests were implemented for between group comparisons of demographic variables as appropriate. Due to the limited sample size, covariates were selected based on the following criteria: 1) previous association of the measure with TL, 2) association with TL in the current study, 3) not significantly correlated with other covariates, and 4) relevance to the study design. Based on previous findings, potential covariates considered included age, sex, waist/hip ratio (WHR), BMI, annual income, education, exercise frequency, smoking status, and depression. A median PSS split was used to categorize low stress (< 15) and high stress (≥ 15) as previously reported
B16 16
. Four groups were developed based on pain status, no pain or chronic pain, and PSS total scores and were categorized as no pain/low stress (NPLS); no pain/high stress (NPHS); chronic pain/low stress (CPLS); and chronic pain/high stress (CPHS). General Linear Models (GLM) were implemented to analyze TL data. All analyses were completed with IBM SPSS Statistics 19.
Results
Mean duration of knee pain for the chronic pain group was 94.8 ± 93 months (n = 17). TL did not differ between the no pain and chronic pain groups (all p's > 0.10) but did differ between the low stress and high stress groups (p = 0.02) with covariates in the model. Descriptive data by pain/stress group are presented in Table tblr tid T1 1 and Figure figr fid F1 1. TL was correlated with age (r = -0.34, p = 0.04) and WHR (r = -0.33, p = 0.05). Further analysis of age and TL stratified by pain/stress groups revealed a significant correlation only in the CPHS group (r = -0.69, p = 0.03) with non-significant associations in the other three groups (r = -.05/NPLS; -.24/NPHS; -.26/CPLS, p > 0.05). Based on previously described criteria, covariates retained in the multivariate model were age, WHR, and race. Additionally, as a result of a significant interaction between WHR and the pain/stress groups an interaction term was also included in the group comparison analyses. Incorporating age, race, WHR, and WHR*group interaction into the model, TL differed across the pain/stress groups, F (3, 26) = 4.33, p = 0.01, η2 = 0.333 (Figure F2 2). Pairwise comparisons using Least Significant Difference (LSD) indicated NPLS and CPHS group differences (p = 0.02).
tbl Table 1caption Descriptor Variables by Pain and Stress Groups (Means, Standard Deviations, and Percentiles)tblbdy cols 5
r
c left
b Group
No Pain
No Pain
Chronic Pain
Chronic Pain
Low Stress
High Stress
Low Stress
High Stress
(n = 10)
(n = 8)
(n = 8)
(n = 10)
cspan
hr
Age
57.3 ± 6.0
64.2 ± 5.7
57.8 ± 8.4
57.5 ± 7.1
Sexŧ
80% W
75% W
50% W
90% W
20% M
25% M
50% M
10% M
Raceŧ
10% AA
12.5% AA
37.5% AA
50% AA
90% NHW
87.5% NHW
62.5% NHW
50% NHW
WH Ratio
0.82 ± 0.098
0.82 ± 0.104
0.91 ± 0.084
0.81 ± 0.080
PSS*
9.7 ± 2.8
19.2 ± 2.9
9.5 ± 4.3
20.9 ± 6.0
CES-D*
4.0 ± 3.9
7.4 ± 4.8
7.6 ± 4.0
14.9 ± 7.8
tblfn
AA African American; CES-D Center for Epidemiological Studies Depression Scale; M men; NHW non-Hispanic white; PSS Perceived Stress Scale; W women
*Significant at p < 0.005
ŧThough not significant, proportions differ
fig Figure 1GCPS Pain Grade by Pain/Stress Grouptext
GCPS Pain Grade by Pain/Stress Group. NPLS no pain/low stress; NPHS no pain/high stress; CPLS chronic pain/low stress; CPHS chronic pain/high stress GCPS Graded Chronic Pain Scale Grade Classification 12: 0 Pain Free; I Low disability, low intensity; II Low disability, high intensity; III High disability, moderately limiting; IV High disability, severely limiting.
graphic file 1744-8069-8-12-1
Figure 2Relative Telomere Length (Estimated Mean) by Pain/Stress Groups after Adjustments for Age, Race, Waist-Hip Ratio (WHR), and WHR*Group Interaction
Relative Telomere Length (Estimated Mean) by Pain/Stress Groups after Adjustments for Age, Race, Waist-Hip Ratio (WHR), and WHR*Group Interaction. Mean and Standard Error: NPLS no pain/low stress (1.017 ± .007) NPHS no pain/high stress (1.000 ± .008). CPLS chronic pain/low stress (1.001 ± .011). CPHS chronic pain/high stress (.990 ± .008). Covariate values in the model: WHR, race, and age. *Significant at p < 0.05, Least Significant Difference (LSD).
1744-8069-8-12-2
Discussion
This is the first study to assess the relationship of chronic pain and perceived stress with cellular aging. TL has been identified as a cumulative marker of psychosocial stress and chronic disease states
2
B17 17
B18 18
. Findings from the current investigation indicate that individuals endorsing a cumulative and combined burden of chronic pain and high stress have shorter telomeres than individuals without chronic pain and endorsing low levels of stress.
Prior studies have indicated a small and negative correlation between age and TL length
2
B19 19
B20 20
. We also found a small, negative correlation between age and TL across groups which upon further analysis was limited to a strong and significant correlation in the chronic pain/high stress (CPHS) group. These findings suggest that age-related changes in TL may be more pronounced when combined with pain chronicity and high levels of stress and align with 1) patterns previously reported regarding shorter TL in an older group of adults with anxiety disorders compared to similar aged controls
B21 21
and 2) literature indicating stress accelerating the effects of aging and immune vulnerability in older adults
B22 22
.
Finally, TL has been negatively associated with perceived stress in 20-50 year old women
2
but not in a group of 50-70 year old men and women
16
. Adjusting for age, race, and WHR, data from the current study indicate that high levels of stress are negatively associated with TL regardless of pain status. Importantly, the association of stress with TL may be modulated by additional factors. For example, Puterman and colleagues
B23 23
reported that exercising at a physical activity level recommended by the Centers for Disease Control appeared to protect women reporting higher levels of perceived stress from TL shortening. In contrast, our study suggests that chronic pain may strengthen the association of stress with reduced TL, because, the shortest telomeres were observed in the presence of chronic pain and high stress.
Although the sample size in the current study is rather small, it is within the range of prior published TL studies of preliminary findings
17
B24 24
B25 25
and in other studies analyzing the lowest and highest tertiles or quartiles of a sample
2
16
23
. More detailed information regarding knee pain duration (beyond 6 months), intensity, and persistence is necessary to better understand pain characteristics that may contribute to telomere shortening. Also, assessment of chronicity and recurrence of mood disorders, in addition to current depressive symptoms would be helpful. These limitations notwithstanding, findings encourage further exploration of the potential utility of TL in improving our understanding of individual differences in the biological consequences of chronic pain conditions. Future studies with a larger sample size will allow for more stringent adjustments for multiple comparisons and further investigation of potentially relevant covariates. Additionally, determining the predictive utility of TL in longitudinal designs would have significant clinical and research value.
Conclusions
Unlike other disease states with documented pathophysiological markers, the biological interface of the experience of chronic pain conditions has been more difficult to measure. Though exploratory, the current findings provide preliminary evidence that chronic pain and psychosocial stress may impose a "burden on the system," accelerating cellular aging.
Abbreviations
CES-D: Center for Epidemiological Studies Depression Scale; CPHS: Chronic pain/high stress; CPLS: Chronic pain/low stress; GCPS: Graded Chronic Pain Scale; NPHS: No pain/high stress; NPLS: No pain/low stress; OA: Osteoarthritis; PBMC: Peripheral blood mononuclear cells; PSS: Perceived Stress Scale; TL: Telomere length; T/S: Telomere to single copy gene; UF: University of Florida; WHR: Waist hip ratio.
Competing interests
Roger Fillingim, Ph.D. is a stockholder in Algynomics.
Authors' contributions
KTS was responsible for study conception and design, data collection, analysis and interpretation of results, and drafting of the manuscript. TL was involved in study conception and design, telomere analysis, and manuscript development and revision. BB was involved in study conception and design, blood sample processing and telomere analysis, and manuscript development and revision. YG contributed to study conception and design, assisted with analysis and interpretation of results, and manuscript development and revision. TLG assisted with parent study conception and design, involved in data collection, and manuscript critique and revision. CK assisted with parent study conception and design, involved in data collection, and manuscript critique and revision. JR contributed to study conception and design, assisted with analysis and interpretation of results, and manuscript critique and revision. CL was involved in study conception and design, assisted with biomarker protocol, and manuscript critique and revision. RS was involved in parent study conception and design, medical oversight of study participants, and manuscript critique and revision. LAB was responsible for parent study conception, design, and acquisition of funding, and manuscript critique and revision. RBF was responsible for current study and parent study conception, design, and acquisition of funding; oversight of data collection, analysis, and interpretation of results; and drafting of the manuscript. All authors reviewed and approved the final manuscript.
bm
ack
Acknowledgements
This work was supported by NIH/NIA grant R01 AG033906, OppNet AG0333906 07S1, UF CTSI grant UL1 RR029890, and American Pain Society Future Leaders in Pain Research grant. Publication of this article was funded in part by the University of Florida Open-Access Publishing Fund.
refgrp Relieving pain in America a blueprint for transforming prevention, care, education, and researchcnm Institute of Medicinepublisher Washington, DC: National Academy of Sciences20111lpage 4Accelerated telomere shortening in response to life stressEpelEBlackburnELinJDhabharFAdlerNMorrowJetal PNAS2004101173121731510.1073/pnas.0407162101pmcid 534658link fulltext 15574496Leukocyte telomere length is associated with cognitive performance in healthy womenValdesAMDearyIJGardnerJKimuraMLuXSpectorTDNeurobiol Aging20103198699210.1016/j.neurobiolaging.2008.07.012287630818718693Accelerated telomere erosion is asociated with a declining immune function of caregivers of Alzheimer's disease patientsDamjanovicAKYangYGlaserRKiecolt-GlaserJKNguyenHLaskowskiBJ Immunol200717942494254226292417785865Accelerated telomere shortening in leukocyte subpopulations of patients with coronary heart disease: role of cytomegalovirus seropositivitySpyridopoulosIHoffmanJAicherABrümmendorfTHDoerrHWZeiherAMCirculation20091201364137210.1161/CIRCULATIONAHA.109.85429919770396Telomere dysfunction induces metabolic and mitochondrial compromiseSahinRCollaSLiesaMMoslehiJMüllerJGuoMNature201147035936510.1038/nature0978721307849Telomeres and telomeraseChanSRBlackburnEHPhilos Trans R Soc Lond200435910912110.1098/rstb.2003.1370Factors impacting human telomere homeostasis and age-related diseaseGilleyDHerbertBSHudaNTanakaHReedTMech Ageing Dev2008129273410.1016/j.mad.2007.10.01018054990Psychological and metabolic stress: a recipe for accelerated cellular aging?EpelEHorm20098722Pain and stress in a systems perspective: Reciprocal neural, endocrine, and immune interactionsChapmanCRTuckettRPSongCWJ Pain2008912214510.1016/j.jpain.2007.09.006227800518088561Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee: Diagnostic and Therapeutic Criteria Committee of the American Rheumatism AssociationAltmanRAschEBlochDArthritis Rheum1986291039104910.1002/art.17802908163741515Grading the severity of chronic painVon KorffMOrmelJKeefeFJDworkinSFPain19925013314910.1016/0304-3959(92)90154-41408309Who's stressed? Distributions of psychological stress in the United States in probability samples from 1983, 2006, and 2009CohenSJanicki-DevertsDJ Applied Social Psychol2010inpress The CES-D scale: A self-report depression scale for research in the general populationRadloffLJ Appl Psychol Meas1977138540110.1177/014662167700100306Telomere measurement by quantitative PCRCawthonRMNucleic Acids Res200230E4710.1093/nar/30.10.e4711530112000852Relationship between physical activity level, telomere length, and telomerase activityLudlowATZimmermanJBWitkowskiSHearnJWHatfieldBDRothSMMed Sci Sports Exerc2008401764177110.1249/MSS.0b013e31817c92aa258141618799986Leukocyte telomere length in major depression: Correlations with chronicity, inflammation and oxidative stress preliminary findingsWolkowitzOMMellonSHEpelELinJDhabharFSSuYPLoS One201163110Telomeres in a life-span perspective: a new "psychobiomarker"?EpelESCurr Dir Psychol Sci20091861010.1111/j.1467-8721.2009.01596.xInvestigation of telomere lengths measurement by quantitative real-time PCR to predict ageHewakapugeSvan OorschotRLewandowskiPBaindur-HudsonSLeg Med20081023624210.1016/j.legalmed.2008.01.007The individual blood cell telomere attrition rate is telomere length dependentNordfjallKSvensonUNorrbackKFAdolfssonRLennerPRoosGPloS Genetics20095e100037510.1371/journal.pgen.1000375263304319214207Childhood adversities are associated with shorter telomere length at adult age both in individuals with an anxiety disorder and controlsKananenLSsurakkaIPirkolaSSuvisaariJLönnqvistJPeltonenLPlosOne20105e10826Stress, age, and immune function: toward a lifespan approachGrahamJEChristianLMKiecolt-GlaserJKJ Beh Med20062938940010.1007/s10865-006-9057-4The power of exercise: buffering the effect of chronic stress on telomere lengthPutermanELinJBlackburnEO'DonovanAAdlerNEpelEPLoS One20105e1083710.1371/journal.pone.0010837287710220520771Pessimism correlates with leukocyte telomere shortness and elevated interleukin-6 in post-menopausal womenO'DonovanALinJDhabharFSWolkowitzOTillieJMBlackburnEBrain Behav Immun20092344644910.1016/j.bbi.2008.11.006271977819111922Childhood maltreatment and telomere shortening: preliminary support for an effect on early stress on cellular agingTyrkaARPriceLHKaoHTPortonBMarsellaSACLBiol Psychiatry20106753153410.1016/j.biopsych.2009.08.014285323819828140



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SHORTREPORT OpenAccessChronicpain,perceivedstress,andcellularaging: anexploratorystudyKimberlyTSibille1*,TaimourLangaee2,BenBurkley2,YanGong2,ToniLGlover3,ChrisKing1,JosephLRileyIII1, ChristiaanLeeuwenburgh4,RolandStaud4,LaurenceABradley5andRogerBFillingim6AbstractBackground: Chronicpainconditionsarecharacterizedbysignificantindividualvariabilitycomplicatingthe identificationofpathophysiologicalmarkers.Leukocytetelomerelength(TL),ameasureofcellularaging,is associatedwithage-relateddiseaseonset,psychosocialstress,andhealth-relatedfunctionaldecline.Psychosocial stresshasbeenassociatedwiththeonsetofchronicpainandchronicpainisexperiencedasaphysicaland psychosocialstressor.However,theutilityofTLasabiologicalmarkerreflectingtheburdenofchronicpainand psychosocialstresshasnotyetbeenexplored. Findings: Therelationshipbetweenchronicpain,stress,andTLwasanalyzedin36ethnicallydiverse,olderadults, halfofwhomreportednochronicpainandtheotherhalfhadchronickneeosteoarthritis(OA)pain.Subjects completedaphysicalexam,radiographs,healthhistory,andpsychosocialquestionnaires.Bloodsampleswere collectedandTLwasmeasuredbyquantitativepolymerasechainreaction(qPCR).Fourgroupswereidentified characterizedbypainstatusandthePerceivedStressScalescores:1)nopain/lowstress,2)nopain/highstress, chronicpain/lowstress,and4)chronicpain/highstress.TLdifferedbetweenthepain/stressgroups( p =0.01), controllingforrelevantcovariates.Specifically,thechronicpain/highstressgrouphadsignificantlyshorterTL comparedtothenopain/lowstressgroup.AgewasnegativelycorrelatedwithTL,particularlyinthechronicpain/ highstressgroup( p =0.03). Conclusions: Althoughpreliminaryinnatureandbasedonamodestsamplesize,thesefindingsindicatethat cellularagingmaybemorepronouncedinolderadultsexperiencinghighlevelsofperceivedstressandchronic pain. Keywords: Chronicpain,Perceivedstress,Kneeosteoarthritis,Telomerelength,CellularagingFindingsArecentInstituteofMedicinereportdocumentsthe publichealthconsequencesofchronicpaininAmerica withestimatesof116millionadultsaffectedandcosts of$635billionannually[1].Oneofthechallengesilluminatedinthereportisthedifficultyinidentifyingspecificpathophysiologicaltargetsduetosignificant variabilityintheexperienceofchronicpain.Consequently,biologicalmarkersreflectingthephysiological burdenofchronicpainonanindividualsystemwould offersignificantclinicalandscientificutility. Leukocytetelomerelength(TL)isameasureofcellularagingandisassociatedwithage-relateddisease onset,chronichealthconditions,psychosocialstress, andmortality[2-5].Importantly,recentfindingsindicate adirectrelationshipbetweentelomeresandmitochondria,connectingforthefirsttimetwomajortheoriesof aging[6].Telomeresaretheprotectivestructuresatthe endofchromosomescomprisedofDNArepeat sequenceswhicharereinforcedbytelomeraseactivity [7].Althoughbufferedbytelomeraseactivity,TL decreasesovertimewithcellreplication.However,the rateofattritionappearstobeinfluencedbynumerous factorsincludingthe biochemicalenvironment suchas oxidativestress,inflammation,andstresshormones [8,9].Chronicpainrepresentsaphysiologicalstressor *Correspondence:ksibille@ufl.edu1CollegeofDentistry,UniversityofFlorida,P.O.Box103628,Gainesville,FL 32610-3628,USA FulllistofauthorinformationisavailableattheendofthearticleSibille etal MolecularPain 2012, 8 :12 http://www.molecularpain.com/content/8/1/12 MOLECULAR PAIN 2012Sibilleetal;BioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommons AttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductionin anymedium,providedtheoriginalworkisproperlycited.

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oftenassociatedwithacascadeofnegativepsychosocial factors[10].Theimpactofchronicpainandrelatedpsychosocialstressoncellularaginghasnotyetbeen explored. Therelationshipofchronicpainassociatedwithknee osteoarthritis(OA)andperceivedstressontelomere lengthprovidesamodelforstudyingcellularagingand chronicpain.Wehypothesizedthatacumulativeeffect of systemburden wouldbeobservedsuchthatindividualsendorsingchronicpainandhighstresswould haveshortertelomeresthanindividualswitheither chronicpainorhighstress,orpain-freeindividualswith lowstress;whowouldhavethelongesttelomeresofthe fourgroups.MethodsThirtysixsubjects,betweentheagesof47and75,were includedintheanalysis.Eighteensubjectspresented withcurrentkneepain,endorsedexperiencingchronic pain,wereconfirmedtohaveradiographickneeosteoarthriticchanges[11],andwerewithoutrheumatoid arthritis,heartdiseaseoruncontrolledmedicalconditionsincludinghighbloodpre ssure,diabetes,andgout. Thenopaingroupwascomprisedof18individualspresentingwithoutchronickneepainormedicalcomorbidities.TheresearchwasconductedontheClinical ResearchUnitattheUniversityofFlorida(UF).The protocolandprocedureswereapprovedbyUF sIRB andinformedconsentwasobtainedforeachparticipant. Methodsdescribedarelimit edtothoserelevanttothe currentanalyses. Subjectscompletedahealthhistoryquestionnaire,the GradedChronicPainScale(GCPS)[12],thePerceived StressScale,10item(PSS)[13],theCenterforEpidemiologicStudiesDepressionscale(CES-D)[14],anda physicalexamincludingkneeradiographs.Additionally, durationofkneepaininmonthswascollected.Baseline bloodsampleswerecollectedandperipheralblood mononuclearcells(PBMCs)wereisolatedtoassessTL. GenomicDNAwasextractedfromlymphocytesin wholebloodusingacommerciallyavailablekit(Qiagen FlexigeneDNAKit,Qiagen,Valencia,CA).DNAsampleswerequantified,normalizedandplatedin96-well plates.Relativetelomerelengthwasmeasuredbyquantitativereal-timepolymerasechainreaction(qPCR).Each qPCRexperimentcontainedtelomereprimersand b 2globin(controlgene)primers[15]. Telomeresandasinglecopygene( b 2-globin)were amplifiedinallthesamplesintriplicateoneachplate. The CtmethodwasperformedusingSDSV.2.1softwarefromAppliedBiosystems.Ctvaluesfromeach samplewerethenusedtocalculatetheratiooftelomere tosinglecopygene(T/S)valuesusingtheformula(2 Ct telomere/2Ct b 2-globin)-1.RelativeT/Svalueswere calculatedbytheformula2Ct.Usingthisformula,we determinedtheTLofeachsamplerelativetothemean T/Sforallsamples[15]. Independentsamplet-tests,ANOVA,andChiSquare orFisher sExacttestswereimplementedforbetween groupcomparisonsofdemogr aphicvariablesasappropriate.Duetothelimitedsamplesize,covariateswere selectedbasedonthefollowingcriteria:1)previous associationofthemeasurewithTL,2)associationwith TLinthecurrentstudy,3)notsignificantlycorrelated withothercovariates,and4)relevancetothestudy design.Basedonpreviousfindings,potentialcovariates consideredincludedage,sex,waist/hipratio(WHR), BMI,annualincome,education,exercisefrequency, smokingstatus,anddepression.AmedianPSSsplitwas usedtocategorizelowstress(<15)andhighstress( 15)aspreviouslyreported[16].Fourgroupsweredevelopedbasedonpainstatus,nopainorchronicpain,and PSStotalscoresandwerecategorizedasnopain/low stress(NPLS);nopain/hi ghstress(NPHS);chronic pain/lowstress(CPLS);andc hronicpain/highstress (CPHS).GeneralLinearModels(GLM)wereimplementedtoanalyzeTLdata.Allanalyseswerecompleted withIBMSPSSStatistics19.ResultsMeandurationofkneepainforthechronicpaingroup was94.893months(n=17).TLdidnotdiffer betweenthenopainandchronicpaingroups(all p s> 0.10)butdiddifferbetweenthelowstressandhigh stressgroups(p =0.02)withcovariatesinthemodel. Descriptivedatabypain/stressgrouparepresentedin Table1andFigure1.TLwascorrelatedwithage(r= -0.34, p =0.04)andWHR(r=-0.33, p =0.05).Further analysisofageandTLstratifiedbypain/stressgroups Table1DescriptorVariablesbyPainandStressGroups (Means,StandardDeviations,andPercentiles)GroupNoPainNoPainChronicPainChronicPain LowStressHighStressLowStressHighStress (n=10)(n=8)(n=8)(n=10) Age57.36.064.25.757.88.457.57.1 Sex80%W75%W50%W90%W 20%M25%M50%M10%M Race10%AA12.5%AA37.5%AA50%AA 90%NHW87.5%NHW62.5%NHW50%NHW WHRatio0.820.0980.820.1040.910.0840.810.080 PSS*9.72.819.22.99.54.320.96.0 CES-D*4.03.97.44.87.64.014.97.8AA AfricanAmerican; CES-D CenterforEpidemiologicalStudiesDepression Scale; M men; NHW non-Hispanicwhite; PSS PerceivedStressScale; W women *Significantat p <0.005Thoughnotsignificant,proportionsdifferSibille etal MolecularPain 2012, 8 :12 http://www.molecularpain.com/content/8/1/12 Page2of5

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revealedasignificantcorrelationonlyintheCPHS group(r=-0.69, p =0.03)withnon-significantassociationsintheotherthreegr oups(r=-.05/NPLS;-.24/ NPHS;-.26/CPLS, p >0.05).Basedonpreviously describedcriteria,covariatesretainedinthemultivariate modelwereage,WHR,andrace.Additionally,asa resultofasignificantinteractionbetweenWHRandthe pain/stressgroupsaninteractiontermwasalsoincluded inthegroupcomparisonanalyses.Incorporatingage, race,WHR,andWHR*groupinteractionintothemodel, TLdifferedacrossthepain/stressgroups,F(3,26)= 4.33, p =0.01, h2=0.333(Figure2).PairwisecomparisonsusingLeastSignificantDifference(LSD)indicated NPLSandCPHSgroupdifferences( p =0.02).DiscussionThisisthefirststudytoassesstherelationshipof chronicpainandperceivedstresswithcellularaging.TL hasbeenidentifiedasacumulativemarkerofpsychosocialstressandchronicdiseasestates[2,17,18].Findings fromthecurrentinvestigationindicatethatindividuals endorsingacumulativeandcombinedburdenofchronic painandhighstresshaveshortertelomeresthanindividualswithoutchronicpainandendorsinglowlevelsof stress. PriorstudieshaveindicatedasmallandnegativecorrelationbetweenageandTL length[2,19,20].Wealso foundasmall,negativecorrelationbetweenageandTL acrossgroupswhichuponfurtheranalysiswaslimited toastrongandsignificantcorrelationinthechronic pain/highstress(CPHS)group.Thesefindingssuggest thatage-relatedchangesinTLmaybemorepronouncedwhencombinedwithpainchronicityandhigh levelsofstressandalignwith1)patternspreviously reportedregardingshorterTLinanoldergroupof adultswithanxietydisorderscomparedtosimilaraged controls[21]and2)literatureindicatingstressacceleratingtheeffectsofagingandimmunevulnerabilityin olderadults[22]. Finally,TLhasbeennegativelyassociatedwithperceivedstressin20-50yearoldwomen[2]butnotina groupof50-70yearoldmenandwomen[16].Adjusting forage,race,andWHR,datafromthecurrentstudy indicatethathighlevelsofstressarenegativelyassociatedwithTLregardlessofpainstatus.Importantly, theassociationofstresswithTLmaybemodulatedby additionalfactors.Forexa mple,Putermanandcolleagues[23]reportedthatexercisingataphysicalactivity levelrecommendedbytheCentersforDiseaseControl appearedtoprotectwomenreportinghigherlevelsof perceivedstressfromTLshortening.Incontrast,our studysuggeststhatchronicpainmaystrengthenthe associationofstresswithreducedTL,because,the shortesttelomereswereobservedinthepresenceof chronicpainandhighstress. Althoughthesamplesizeinthecurrentstudyis rathersmall,itiswithintherangeofpriorpublishedTL studiesofpreliminaryfindings[17,24,25]andinother studiesanalyzingthelowestandhighesttertilesorquartilesofasample[2,16,23].Moredetailedinformation 4 6 00 5 2 4 1 00 2 3 00 22 000 4 N PLS N PHS CPLS CPHS0 I II III IV0 I II III IV0 I II III IV0 I II III IV GCPS Pain GradeFrequency Figure1 GCPSPainGradebyPain/StressGroup.NPLS-nopain/lowstress;NPHS-nopain/highstress;CPLS-chronicpain/lowstress;CPHS -chronicpain/highstressGCPS-GradedChronicPainScaleGradeClassification[12]:0-PainFree;I-Lowdisability,lowintensity;II-Low disability,highintensity;III-Highdisability,moderatelylimiting;IV-Highdisability,severelylimiting. Sibille etal MolecularPain 2012, 8 :12 http://www.molecularpain.com/content/8/1/12 Page3of5

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regardingkneepainduration(beyond6months),intensity,andpersistenceisnecessarytobetterunderstand paincharacteristicsthatmaycontributetotelomere shortening.Also,assessmentofchronicityandrecurrenceofmooddisorders,inadditiontocurrentdepressivesymptomswouldbehelpful.Theselimitations notwithstanding,findingsencouragefurtherexploration ofthepotentialutilityofTLinimprovingourunderstandingofindividualdiffer encesinthebiologicalconsequencesofchronicpainconditions.Futurestudies withalargersamplesizewillallowformorestringent adjustmentsformultiplecomparisonsandfurtherinvestigationofpotentiallyrelevantcovariates.Additionally, determiningthepredictiveutilityofTLinlongitudinal designswouldhavesignificantclinicalandresearch value.ConclusionsUnlikeotherdiseasestateswithdocumentedpathophysiologicalmarkers,thebiologicalinterfaceoftheexperienceofchronicpainconditionshasbeenmoredifficult tomeasure.Thoughexploratory,thecurrentfindings providepreliminaryevidencethatchronicpainandpsychosocialstressmayimposea burdenonthesystem, acceleratingcellularaging.Abbreviations CES-D:CenterforEpidemiologicalStudiesDepressionScale;CPHS:Chronic pain/highstress;CPLS:Chronicpain/lowstress;GCPS:GradedChronicPain Scale;NPHS:Nopain/highstress;NPLS:Nopain/lowstress;OA: Osteoarthritis;PBMC:Peripheralbloodmononuclearcells;PSS:Perceived StressScale;TL:Telomerelength;T/S:Telomeretosinglecopygene;UF: UniversityofFlorida;WHR:Waisthipratio. Acknowledgements ThisworkwassupportedbyNIH/NIAgrantR01AG033906,OppNet AG033390607S1,UFCTSIgrantUL1RR029890,andAmericanPainSociety FutureLeadersinPainResearchgrant.Publicationofthisarticlewasfunded inpartbytheUniversityofFloridaOpen-AccessPublishingFund. Authordetails1CollegeofDentistry,UniversityofFlorida,P.O.Box103628,Gainesville,FL 32610-3628,USA.2CollegeofPharmacyandCenterforPharmacogenomics, UniversityofFlorida,Gainesville,USA.3CollegeofDentistryandCollegeof Nursing,UniversityofFlorida,Gainesville,USA.4CollegeofMedicine, UniversityofFlorida,Gainesville,USA.5DivisionofClinicalImmunologyand Rheumatology,UniversityofAlabamaatBirmingham,Birmingham,USA.6CollegeofDentistry,UniversityofFloridaandNorthFlorida/SouthGeorgia VeteransHealthSystem,Gainesville,USA. Authors contributions KTSwasresponsibleforstudyconceptionanddesign,datacollection, analysisandinterpretationofresults,anddraftingofthemanuscript.TLwas involvedinstudyconceptionanddesign,telomereanalysis,andmanuscript developmentandrevision.BBwasinvolvedinstudyconceptionanddesign, bloodsampleprocessingandtelomereanalysis,andmanuscript developmentandrevision.YGcontributedtostudyconceptionanddesign, assistedwithanalysisandinterpretationofresults,andmanuscript developmentandrevision.TLGassistedwithparentstudyconceptionand design,involvedindatacollection,andmanuscriptcritiqueandrevision.CK assistedwithparentstudyconceptionanddesign,involvedindata collection,andmanuscriptcritiqueandrevision.JRcontributedtostudy conceptionanddesign,assistedwithanalysisandinterpretationofresults, andmanuscriptcritiqueandrevision.CLwasinvolvedinstudyconception anddesign,assistedwithbiomarkerprotocol,andmanuscriptcritiqueand revision.RSwasinvolvedinparentstudyconceptionanddesign,medical oversightofstudyparticipants,andmanuscriptcritiqueandrevision.LAB wasresponsibleforparentstudyconception,design,andacquisitionof funding,andmanuscriptcritiqueandrevision.RBFwasresponsiblefor currentstudyandparentstudyconception,design,andacquisitionof funding;oversightofdatacollection,analysis,andinterpretationofresults; anddraftingofthemanuscript.Allauthorsreviewedandapprovedthefinal manuscript. Competinginterests RogerFillingim,Ph.D.isastockholderinAlgynomics. 0.97 0.98 0.99 1 1.01 1.02 1.03 NPLS NPHS CPLS CPHS**Relative Telomere Length Figure2 RelativeTelomereLength(EstimatedMean)byPain/StressGroupsafterAdjustmentsforAge,Race,Waist-HipRatio(WHR), andWHR*GroupInteraction .MeanandStandardError:NPLS-nopain/lowstress(1.017.007)NPHS-nopain/highstress(1.000.008). CPLS-chronicpain/lowstress(1.001.011).CPHS-chronicpain/highstress(.990.008).Covariatevaluesinthemodel:WHR,race,andage. *Significantat p <0.05,LeastSignificantDifference(LSD). Sibille etal MolecularPain 2012, 8 :12 http://www.molecularpain.com/content/8/1/12 Page4of5

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