1  624 122 BIOLOGICAL AGE ACCELERATION AND MOTORIC COGNITIVE RISK SYNDROME. OBJECTIVE: MOTORIC COGNITIVE RISK (MCR) SYNDROME, A PREDEMENTIA SYNDROME CHARACTERIZED BY SLOW GAIT AND SUBJECTIVE COGNITIVE CONCERNS, IS ASSOCIATED WITH MULTIPLE AGE-RELATED RISK FACTORS. WE HYPOTHESIZED THAT MCR IS ASSOCIATED WITH BIOLOGICAL AGE ACCELERATION. WE EXAMINED THE ASSOCIATIONS OF BIOLOGICAL AGE ACCELERATION WITH MCR, AND MORTALITY RISK IN MCR CASES. METHODS: BIOLOGICAL AGE WAS DETERMINED USING PROTEOMIC AND EPIGENETIC CLOCKS IN PARTICIPANTS AGED 65 YEARS AND OLDER IN THE LONGENITY STUDY (N = 700, FEMALES = 57.9%) AND HEALTH AND RETIREMENT STUDY (HRS; N = 1,043, FEMALES = 57.1%) COHORTS. AGE ACCELERATION (AGEACCEL) WAS OPERATIONALLY DEFINED AS THE RESIDUAL FROM REGRESSING PREDICTED BIOLOGICAL AGE (FROM BOTH CLOCKS SEPARATELY) ON CHRONOLOGICAL AGE. ASSOCIATION OF AGEACCEL WITH INCIDENT MCR IN THE OVERALL SAMPLE AS WELL AS WITH MORTALITY RISK IN MCR CASES WAS EXAMINED USING COX MODELS AND REPORTED AS HAZARD RATIOS (HRS). RESULTS: AGEACCEL SCORES DERIVED FROM A PROTEOMIC CLOCK WERE ASSOCIATED WITH PREVALENT MCR (ODDS RATIO ADJUSTED FOR AGE, GENDER, EDUCATION YEARS, AND CHRONIC ILLNESSES [AOR] = 1.36, 95% CONFIDENCE INTERVAL [CI] = 1.09-1.71) AS WELL AS PREDICTED INCIDENT MCR (HR = 1.19, 95% CI = 1.00-1.41) IN THE LONGENITY COHORT. IN HRS, THE ASSOCIATION OF AGEACCEL USING AN EPIGENETIC CLOCK WITH PREVALENT MCR WAS CONFIRMED (AOR = 1.47, 95% CI = 1.16-1.85). PARTICIPANTS WITH MCR AND ACCELERATED AGING (POSITIVE AGEACCEL SCORE) WERE AT THE HIGHEST RISK FOR MORTALITY IN BOTH LONGENITY (HR = 3.38, 95% CI = 2.01-5.69) AND HRS (HR = 2.47, 95% CI = 1.20-5.10). INTERPRETATION: ACCELERATED AGING PREDICTS RISK FOR MCR, AND IS ASSOCIATED WITH HIGHER MORTALITY IN MCR PATIENTS. ANN NEUROL 2023;93:1187-1197.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
2 1645  49 DOES THE EPIGENETIC CLOCK GRIMAGE PREDICT MORTALITY INDEPENDENT OF GENETIC INFLUENCES: AN 18 YEAR FOLLOW-UP STUDY IN OLDER FEMALE TWIN PAIRS. BACKGROUND: EPIGENETIC CLOCKS ARE BASED ON DNA METHYLATION (DNAM). IT HAS BEEN SUGGESTED THAT THESE CLOCKS ARE USEABLE MARKERS OF BIOLOGICAL AGING AND PREMATURE MORTALITY. BECAUSE GENETIC FACTORS EXPLAIN VARIATIONS IN BOTH EPIGENETIC AGING AND MORTALITY, THIS ASSOCIATION COULD ALSO BE EXPLAINED BY SHARED GENETIC FACTORS. WE INVESTIGATED THE INFLUENCE OF GENETIC AND LIFESTYLE FACTORS (SMOKING, ALCOHOL CONSUMPTION, PHYSICAL ACTIVITY, CHRONIC DISEASES, BODY MASS INDEX) AND EDUCATION ON THE ASSOCIATION OF ACCELERATED EPIGENETIC AGING WITH MORTALITY USING A LONGITUDINAL TWIN DESIGN. UTILIZING A PUBLICLY AVAILABLE ONLINE TOOL, WE CALCULATED THE EPIGENETIC AGE USING TWO EPIGENETIC CLOCKS, HORVATH DNAMAGE AND DNAM GRIMAGE, IN 413 FINNISH TWIN SISTERS, AGED 63-76 YEARS, AT THE BEGINNING OF THE 18-YEAR MORTALITY FOLLOW-UP. EPIGENETIC AGE ACCELERATION WAS CALCULATED AS THE RESIDUALS FROM A LINEAR REGRESSION MODEL OF EPIGENETIC AGE ESTIMATED ON CHRONOLOGICAL AGE (AA(HORVATH), AA(GRIMAGE), RESPECTIVELY). COX PROPORTIONAL HAZARD MODELS WERE CONDUCTED FOR INDIVIDUALS AND TWIN PAIRS. RESULTS: THE RESULTS OF THE INDIVIDUAL-BASED ANALYSES SHOWED AN INCREASED MORTALITY HAZARD RATIO (HR) OF 1.31 (CI(95): 1.13-1.53) PER ONE STANDARD DEVIATION (SD) INCREASE IN AA(GRIMAGE). THE RESULTS INDICATED NO SIGNIFICANT ASSOCIATIONS OF AA(HORVATH) WITH MORTALITY. PAIRWISE MORTALITY ANALYSES SHOWED AN HR OF 1.50 (CI(95): 1.02-2.20) PER 1 SD INCREASE IN AA(GRIMAGE). HOWEVER, AFTER ADJUSTING FOR SMOKING, THE HR ATTENUATED SUBSTANTIALLY AND WAS STATISTICALLY NON-SIGNIFICANT (1.29; CI(95): 0.84-1.99). SIMILARLY, IN MULTIVARIABLE ADJUSTED MODELS THE HR (1.42-1.49) WAS NON-SIGNIFICANT. IN AA(HORVATH), THE NON-SIGNIFICANT HRS WERE LOWER AMONG MONOZYGOTIC PAIRS IN COMPARISON TO DIZYGOTIC PAIRS, WHILE IN AA(GRIMAGE) THERE WERE NO SYSTEMATIC DIFFERENCES BY ZYGOSITY. FURTHER, THE PAIRWISE ANALYSIS IN QUARTILES SHOWED THAT THE INCREASED WITHIN PAIR DIFFERENCE IN AA(GRIMAGE) WAS ASSOCIATED WITH A HIGHER ALL-CAUSE MORTALITY RISK. CONCLUSIONS: IN CONCLUSION, THE FINDINGS SUGGEST THAT DNAM GRIMAGE IS A STRONG PREDICTOR OF MORTALITY INDEPENDENT OF GENETIC INFLUENCES. SMOKING, WHICH IS KNOWN TO ALTER DNAM LEVELS AND IS BUILT INTO THE DNAM GRIMAGE ALGORITHM, ATTENUATED THE ASSOCIATION BETWEEN EPIGENETIC AGING AND MORTALITY RISK.	2021	
                                                                                                                                                                                                                                                                                                                           
3 1959  40 EPIGENETIC AGING AND HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH SEVERE APLASTIC ANEMIA. CELLULAR AGING IN HEMATOPOIETIC CELL TRANSPLANTATION (HCT) IS IMPORTANT IN THE CONTEXT OF IMMUNE RECONSTITUTION AND AGE-RELATED COMPLICATIONS. RECENTLY, SEVERAL DNA-METHYLATION (DNAM)-BASED BIOMARKERS OF AGING KNOWN AS "EPIGENETIC CLOCKS" HAVE BEEN INTRODUCED AS NOVEL TOOLS TO PREDICT CELLULAR AGE. HERE, WE USED COX PROPORTIONAL HAZARDS MODELS TO ASSESS THE POSSIBLE ASSOCIATIONS OF DONOR PRE-HCT DNAM AGE, AND ITS POST-HCT CHANGES, USING THE RECENTLY PUBLISHED LIFESPAN-ASSOCIATED EPIGENETIC CLOCK KNOWN AS "DNAM-GRIMAGE," WITH OUTCOMES AMONG PATIENTS WITH SEVERE APLASTIC ANEMIA (SAA). THE STUDY INCLUDED 732 SAA PATIENTS FROM THE TRANSPLANT OUTCOMES IN APLASTIC ANEMIA PROJECT, WHO UNDERWENT UNRELATED DONOR HCT AND FOR WHOM A DONOR PRE-HCT BLOOD DNA SAMPLE WAS AVAILABLE; 41 ALSO HAD A POST-HCT SAMPLE COLLECTED AT DAY 100. IN MULTIVARIABLE ANALYSES, WE FOUND SIMILAR ASSOCIATIONS FOR DONOR CHRONOLOGICAL AGE AND PRE-HCT DNAM-GRIMAGE WITH POST-HCT SURVIVAL (HAZARD RATIO [HR] PER DECADE = 1.13; 95% CONFIDENCE INTERVAL [CI], 0.99-1.28; P = .07 AND HR = 1.14; 95% CI, 0.99-1.28; P = .06, RESPECTIVELY). IN DONORS WITH 10+ YEARS OF GRIMAGE ACCELERATION (IE, DEVIATION FROM EXPECTED DNAM AGE FOR CHRONOLOGICAL AGE), ELEVATED RISKS OF CHRONIC GRAFT VERSUS HOST DISEASE (HR = 2.4; 95% CI, 1.21-4.65; P = .01) AND POSSIBLY POST-HCT MORTALITY (HR = 1.79; 95% CI, 0.96-3.33; P = .07) WERE OBSERVED. IN THE SUBSET WITH POST-HCT SAMPLES, WE OBSERVED A SIGNIFICANT INCREASE IN DNAM-GRIMAGE IN THE FIRST 100 DAYS AFTER HCT (MEDIAN CHANGE 12.5 YEARS, RANGE 1.4 TO 26.4). HIGHER DNAM-GRIMAGE AFTER HCT WAS ASSOCIATED WITH INFERIOR SURVIVAL (HR PER YEAR = 1.11; 95% CI, 1.02-1.21; P = .01), PREDOMINANTLY WITHIN THE FIRST YEAR AFTER HCT. THIS STUDY HIGHLIGHTS THE POSSIBLE ROLE CELLULAR AGING MAY PLAY IN HCT OUTCOMES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4 4986  33 PATIENT-REPORTED SYMPTOM OUTCOMES AND MICROSATELLITE INSTABILITY IN PATIENTS WITH METASTATIC COLORECTAL CANCER. BACKGROUND: THE SURVIVAL OF PATIENTS WITH METASTATIC COLORECTAL CANCER (MCRC) IS INFLUENCED BY THE GENETIC AND EPIGENETIC CHANGES THAT MIGHT INFLUENCE THE PATIENT EXPERIENCE OF SYMPTOM BURDEN. UNDERSTANDING THE ASSOCIATION OF MOLECULAR CHANGES WITH THE SYMPTOM BURDEN COULD HELP CLINICIANS GAIN INSIGHT INTO THE MOLECULAR BASIS OF SYMPTOM BURDEN AND IMPROVE TREATMENT TOLERANCE. TO DATE, NO STUDIES HAVE COMPARED THE PATIENT-REPORTED SYMPTOM BURDEN WITH THESE MOLECULAR SUBSETS AMONG PATIENTS WITH MCRC. PATIENTS AND METHODS: WE RECRUITED PATIENTS WITH MCRC THAT WAS REFRACTORY TO >/= 1 LINE OF THERAPY WHO HAD BEEN ENROLLED IN THE ASSESSMENT OF TARGETED THERAPIES AGAINST COLORECTAL CANCER TRIAL AT THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER. ALL PATIENTS COMPLETED A BASELINE GASTROINTESTINAL SYMPTOM INVENTORY (MD ANDERSON SYMPTOM INVENTORY, GASTROINTESTINAL). THE SYMPTOM BURDEN ACROSS KEY DEMOGRAPHIC VARIABLES AND MOLECULAR CHANGES, INCLUDING CRC-ASSOCIATED MUTATIONS, MICROSATELLITE INSTABILITY (MSI) STATUS, AND THE CPG ISLAND METHYLATOR PHENOTYPE (CIMP) WERE COMPARED USING CHI(2) TESTS. ASSOCIATION OF THE SYMPTOM BURDEN WITH OVERALL SURVIVAL WAS EXAMINED USING COX REGRESSION MODELS. RESULTS: PATIENTS WITH AN MSI-HIGH (MSI-H) PHENOTYPE REPORTED GREATER PAIN (ODDS RATIO [OR], 3.06; 95% CONFIDENCE INTERVAL [CI], 1.61-5.84), FATIGUE (OR, 2.78; 95% CI, 1.41-5.49), SLEEP (OR, 2.52; 95% CI, 1.32-4.08); AND DROWSINESS (OR, 2.51; 95% CI, 1.32-4.78) COMPARED WITH MICROSATELLITE STABLE PATIENTS. PATIENTS WITH AN MSI-H PHENOTYPE ALSO HAD GREATER ODDS OF OVERALL SYMPTOM BURDEN (OR, 2.48; 95% CI, 1.29-4.74) COMPARED WITH MICROSATELLITE STABLE PATIENTS. THE CIMP-HIGH PATIENTS EXPERIENCED GREATER ODDS OF PAIN COMPARED WITH THE CIMP-NEGATIVE PATIENTS (OR, 1.72; 95% CI, 1.06-2.80). A GREATER OVERALL SYMPTOM BURDEN WAS ASSOCIATED WITH POOR OVERALL SURVIVAL (HAZARD RATIO, 1.42; 95% CI, 0.98-2.06]), ALTHOUGH THE DIFFERENCE WAS NOT SIGNIFICANT (P = .06). CONCLUSION: CORRELATION OF MSI-H-ASSOCIATED TUMOR FEATURES WITH THE SYMPTOM BURDEN COULD HELP PROVIDE A BETTER UNDERSTANDING OF UNDERLYING MECHANISMS ASSOCIATED WITH OUR FINDINGS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
5 4447  33 MOLECULAR MARKERS OF AGING, EXERCISE CAPACITY, & PHYSICAL ACTIVITY IN COPD. BACKGROUND: EXERCISE CAPACITY (EC) AND PHYSICAL ACTIVITY (PA) ARE INDEPENDENT, POTENTIALLY MODIFIABLE PREDICTORS OF CLINICAL OUTCOMES IN COPD. MOLECULAR MEASURES OF BIOLOGICAL AGE MAY HELP CHARACTERIZE VARIABILITY IN EC AND PA OBSERVED AMONG COPD PATIENTS. METHODS: VETERANS WITH COPD (FEV(1)/FVC<0.7 OR EMPHYSEMA ON CHEST COMPUTED TOMOGRAPHY) ENROLLED IN 2 COHORTS AT VA BOSTON COMPLETED QUESTIONNAIRES, A 6-MIN WALK DISTANCE (6MWD) FOR EC, AND BLOOD COLLECTION AT ENROLLMENT. PA DATA (AVERAGE DAILY STEP COUNT) WAS COLLECTED USING AN HJ-720 ITC PEDOMETER OVER >/=5 DAYS. A SUBSET OF SUBJECTS RETURNED FOR REPEAT ASSESSMENT AFTER 12 WEEKS. DNA METHYLATION DATA WAS GENERATED USING THE HUMANMETHYLATIONEPIC PLATFORM; EPIGENETIC ESTIMATES OF BIOLOGICAL AGE AND AGE ACCELERATION WERE GENERATED USING ESTABLISHED ALGORITHMS. MULTIVARIABLE MODELS EXAMINED THE ASSOCIATIONS BETWEEN BIOLOGICAL AGE, 6MWD, PA AND FUTURE ACUTE EXACERBATIONS (AES), ADJUSTING FOR CHRONOLOGICAL AGE, SEX, RACE, SMOKING STATUS, PACK-YEARS, BODY MASS INDEX, COHORT, AND ESTIMATED CELL COUNTS. RESULTS: SUBJECTS (N = 269) WERE PREDOMINANTLY MALE (98.5%), WHITE (92.9%), AND ELDERLY (70.6 +/- 8.5 YEARS) WITH AVERAGE FEV(1)% OF 57.7 +/- 21.1, 6MWD OF 374.3 +/- 93.5 M, AND DAILY STEPS OF 3043.4 +/- 2374 AT BASELINE. IN ADJUSTED MODELS, MULTIPLE MEASURES OF BASELINE EPIGENETIC AGE AND AGE ACCELERATION WERE INVERSELY ASSOCIATED WITH 6MWD; ONLY GRIMAGE WAS INVERSELY ASSOCIATED WITH PA. LONGITUDINAL CHANGE IN HANNUM-AGE WAS INVERSELY ASSOCIATED WITH CHANGE IN EC AT 12 WEEKS (N = 94). NO MEASURES OF BIOLOGICAL AGE WERE SIGNIFICANTLY ASSOCIATED WITH PROSPECTIVE AES OVER 1.3 +/- 0.3 YEARS. CONCLUSIONS: EPIGENETIC MEASURES OF BIOLOGICAL AGE ARE INDEPENDENT PREDICTORS OF EC AND PA, BUT NOT AES, AMONG INDIVIDUALS WITH COPD.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
6  525  34 ASSOCIATIONS OF BODY COMPOSITION AND PHYSICAL ACTIVITY LEVEL WITH MULTIPLE MEASURES OF EPIGENETIC AGE ACCELERATION. EPIGENETIC CLOCKS USE DNA METHYLATION TO ESTIMATE BIOLOGICAL AGE. WHETHER BODY COMPOSITION AND PHYSICAL ACTIVITY ARE ASSOCIATED WITH THESE CLOCKS IS NOT WELL UNDERSTOOD. USING BLOOD SAMPLES COLLECTED AT ENROLLMENT (2003-2009) FROM 2,758 WOMEN IN THE US NATIONWIDE SISTER STUDY, WE CALCULATED 6 EPIGENETIC AGE ACCELERATION METRICS USING 4 EPIGENETIC CLOCKS (HANNUM, HORVATH, PHENOAGE, GRIMAGE). RECREATIONAL PHYSICAL ACTIVITY WAS SELF-REPORTED, AND ADIPOSITY MEASURES WERE ASSESSED BY TRAINED MEDICAL EXAMINERS (BODY MASS INDEX (BMI), WAIST-TO-HIP RATIO (WTH), WAIST CIRCUMFERENCE). IN CROSS-SECTIONAL ANALYSES, ALL ADIPOSITY MEASURES WERE ASSOCIATED WITH EPIGENETIC AGE ACCELERATION. THE STRONGEST ASSOCIATION WAS FOR BMI AND PHENOAGE, A MEASURE OF BIOLOGICAL AGE THAT CORRELATES WITH CHRONIC DISEASE (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 3.15 YEARS, 95% CONFIDENCE INTERVAL (CI): 2.41, 3.90; P FOR TREND < 0.001). IN A MUTUAL-ADJUSTMENT MODEL, BOTH WERE ASSOCIATED WITH PHENOAGE AGE ACCELERATION (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 2.69 YEARS, 95% CI: 1.90, 3.48; P FOR TREND < 0.001; QUARTILE 4 VS.1 WTH, BETA = 1.00 YEARS, 95% CI: 0.34, 1.65; P FOR TREND < 0.008). AFTER ADJUSTMENT, PHYSICAL ACTIVITY WAS ASSOCIATED ONLY WITH GRIMAGE (QUARTILE 4 VS. 1, BETA = -0.42 YEARS, 95% CI: -0.70, -0.14; P FOR TREND = 0.001). PHYSICAL ACTIVITY ATTENUATED THE WAIST CIRCUMFERENCE ASSOCIATIONS WITH PHENOAGE AND GRIMAGE. EXCESS ADIPOSITY WAS ASSOCIATED WITH EPIGENETIC AGE ACCELERATION; PHYSICAL ACTIVITY MIGHT ATTENUATE ASSOCIATIONS WITH WAIST CIRCUMFERENCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7 3687  32 INFLAMMATION-RELATED GENES ARE ASSOCIATED WITH EPIGENETIC AGING IN HIV. CHRONIC INFLAMMATION IS CHARACTERISTIC OF BOTH HIV AND AGING ("INFLAMMAGING") AND MAY CONTRIBUTE TO THE ACCELERATED AGING OBSERVED IN PEOPLE LIVING WITH HIV (PLWH). WE EXAMINED WHETHER THREE INFLAMMATION-RELATED SINGLE-NUCLEOTIDE POLYMORPHISMS (SNPS) WERE RISK FACTORS FOR ACCELERATED AGING AND HIV-ASSOCIATED, NON-AIDS (HANA) CONDITIONS AMONG PLWH. WE EXAMINED 155 POSTMORTEM CASES WITH HIV (MEAN AGE = 47.3, 81% MALE, 68% SELF-REPORTED WHITE) FROM THE NATIONAL NEUROAIDS TISSUE CONSORTIUM WHO HAD PRE-MORTEM NEUROBEHAVIORAL/MEDICAL/VIROLOGIC DATA AND EPIGENOMIC DATA FROM OCCIPITAL CORTEX TISSUE. ACCELERATED AGING WAS MEASURED ACCORDING TO THE EPIGENETIC CLOCK; AN AGING BIOMARKER BASED ON DNA METHYLATION LEVELS. PAST OR CURRENT AGE-ASSOCIATED HANA CONDITIONS INCLUDING CEREBROVASCULAR, LIVER AND KIDNEY DISEASE, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CANCER, AND DIABETES WERE DETERMINED VIA SELF-REPORT. EPIGENETIC AGING Z-SCORES AND LIKELIHOOD OF PAST/CURRENT HANA CONDITIONS WERE COMPARED BETWEEN MAJOR ALLELE HOMOZYGOTES AND MINOR ALLELE CARRIERS FOR EACH SNP (IL-6 - 174G>C, IL-10 - 592C>A, TNF-ALPHA - 308 G>A) SEPARATELY. ANALYSES WERE ADJUSTED FOR RELEVANT DEMOGRAPHIC/CLINICAL FACTORS. EPIGENETIC AGING (E.G., HIGHER Z-SCORES) WAS SIGNIFICANTLY GREATER IN IL-6 C ALLELE CARRIERS (P = .002) AND IL-10 CC HOMOZYGOTES (P = .02) COMPARED TO OTHER GENOTYPE GROUPS. THE LIKELIHOOD OF ANY PAST/CURRENT HANA CONDITION DID NOT DIFFER BY IL-10 GENOTYPE BUT WAS 3.36 TIMES GREATER IN IL-6 C ALLELE CARRIERS VERSUS OTHERS (OR = 3.36, 95%CI = 1.09-10.34, P = .03). TNF-ALPHA GENOTYPE WAS NOT ASSOCIATED WITH EPIGENETIC AGING OR HANA CONDITIONS. IL-6 AND IL-10 SNPS MAY HELP TO IDENTIFY PLWH WHO ARE AT HIGH RISK FOR ACCELERATED AGING. THESE INSIGHTS INTO PATHOPHYSIOLOGICAL PATHWAYS MAY INFORM INTERVENTIONAL APPROACHES TO TREAT RAPID AGING AMONG PLWH.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8 4502  39 MORTALITY ASSOCIATIONS WITH DNA METHYLATION-BASED BIOLOGICAL AGING AND PHYSICAL FUNCTIONING MEASURES ACROSS A 20-YEAR FOLLOW-UP PERIOD. BACKGROUND: MEASURES OF BIOLOGICAL AGING RANGE FROM DNA METHYLATION (DNAM)-BASED ESTIMATES TO MEASURES OF PHYSICAL ABILITIES. THE PURPOSE OF THIS STUDY WAS TO COMPARE DNAM- AND PHYSICAL FUNCTIONING-BASED MEASURES OF BIOLOGICAL AGING IN PREDICTING MORTALITY. METHODS: WE STUDIED 63- TO 76-YEAR-OLD WOMEN (N = 395) FROM THE FINNISH TWIN STUDY ON AGING (FITSA). PARTICIPANTS' BIOLOGICAL AGE (EPIGENETIC CLOCKS DNAM GRIMAGE AND DUNEDINPACE) WAS ESTIMATED USING BLOOD DNAM DATA. TESTS OF PHYSICAL FUNCTIONING CONDUCTED UNDER STANDARDIZED LABORATORY CONDITIONS INCLUDED THE TIMED UP AND GO (TUG) TEST AND 10-M WALK TEST. MORTALITY HAZARD RATIOS WERE CALCULATED PER EVERY 1 STANDARD DEVIATION (SD) INCREASE IN THE PREDICTOR. COX REGRESSION MODELS WERE CONDUCTED FOR INDIVIDUALS AND TWIN PAIRS, THE LATTER CONTROLLING FOR UNDERLYING GENETIC EFFECTS. THE MODELS WERE ADJUSTED FOR KNOWN LIFESTYLE PREDICTORS OF MORTALITY. RESULTS: DURING THE FOLLOW-UP PERIOD (MEAN 17.0 YEARS, RANGE 0.2-20.3), 187 PARTICIPANTS DIED. IN BOTH THE INDIVIDUAL-BASED AND PAIRWISE ANALYSES, GRIMAGE AND BOTH FUNCTIONAL BIOMARKERS OF AGING WERE ASSOCIATED WITH MORTALITY INDEPENDENT OF FAMILY RELATEDNESS, CHRONOLOGICAL AGE, PHYSICAL ACTIVITY, BODY MASS INDEX, SMOKING, EDUCATION, OR CHRONIC DISEASES. IN A MODEL INCLUDING BOTH THE DNAM-BASED MEASURES AND FUNCTIONAL BIOMARKERS OF AGING, GRIMAGE AND TUG REMAINED PREDICTIVE. CONCLUSIONS: THE FINDINGS SUGGEST THAT DNAM GRIMAGE AND THE TUG TEST ARE STRONG PREDICTORS OF MORTALITY INDEPENDENT OF EACH OTHERS AND GENETIC INFLUENCES. DNAM-BASED MEASURES AND FUNCTIONAL TESTS CAPTURE DIFFERENT ASPECTS OF THE AGING PROCESS AND THUS COMPLEMENT EACH OTHER AS MEASURES OF BIOLOGICAL AGING IN PREDICTING MORTALITY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9 1963  33 EPIGENETIC AGING MEDIATES THE ASSOCIATION BETWEEN PAIN IMPACT AND BRAIN AGING IN MIDDLE TO OLDER AGE INDIVIDUALS WITH KNEE PAIN. CHRONIC MUSCULOSKELETAL PAIN IS A HEALTH BURDEN THAT MAY ACCELERATE THE AGING PROCESS. ACCELERATED BRAIN AGING AND EPIGENETIC AGING HAVE SEPARATELY BEEN OBSERVED IN THOSE WITH CHRONIC PAIN. HOWEVER, IT IS UNKNOWN WHETHER THESE BIOLOGICAL MARKERS OF AGING ARE ASSOCIATED WITH EACH OTHER IN THOSE WITH CHRONIC PAIN. WE AIMED TO EXPLORE THE ASSOCIATION OF EPIGENETIC AGING AND BRAIN AGING IN MIDDLE-TO-OLDER AGE INDIVIDUALS WITH VARYING DEGREES OF KNEE PAIN. PARTICIPANTS (57.91 +/- 8.04 Y) WITH LOW IMPACT KNEE PAIN (N = 95), HIGH IMPACT KNEE PAIN (N = 53), AND PAIN-FREE CONTROLS (N = 26) COMPLETED SELF-REPORTED PAIN, A BLOOD DRAW, AND AN MRI SCAN. WE USED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN (DNAMGRIMAGE), THE SUBSEQUENT DIFFERENCE OF PREDICTED EPIGENETIC AND BRAIN AGE FROM CHRONOLOGICAL AGE (DNAMGRIMAGE-DIFFERENCE AND BRAIN-PAD, RESPECTIVELY). THERE WAS A SIGNIFICANT MAIN EFFECT FOR PAIN IMPACT GROUP (F (2,167) = 3.847, P = 0.023, ROTATIONAL ENERGY = 1 / 2IOMEGA2 = 0.038, ANCOVA) ON BRAIN-PAD AND DNAMGRIMAGE-DIFFERENCE (F (2,167) = 6.800, P = 0.001, I = MK2 = 0.075, ANCOVA) AFTER CONTROLLING FOR COVARIATES. DNAMGRIMAGE-DIFFERENCE AND BRAIN-PAD WERE MODESTLY CORRELATED (R =0.198; P =0.010). EXPLORATORY ANALYSIS REVEALED THAT DNAMGRIMAGE-DIFFERENCE MEDIATED GCPS PAIN IMPACT, GCPS PAIN SEVERITY, AND PAIN-RELATED DISABILITY SCORES ON BRAIN-PAD. BASED UPON THE CURRENT STUDY FINDINGS, WE SUGGEST THAT PAIN COULD BE A DRIVER FOR ACCELERATED BRAIN AGING VIA EPIGENOME INTERACTIONS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10 5070  30 PHYSICAL ACTIVITY, TELEVISION VIEWING TIME, AND DNA METHYLATION IN PERIPHERAL BLOOD. INTRODUCTION: PHYSICAL ACTIVITY MAY AFFECT HEALTH VIA DNA METHYLATION. THE EPIGENETIC INFLUENCES OF SEDENTARY BEHAVIORS SUCH AS TELEVISION VIEWING ARE UNKNOWN. WE PERFORMED A GENOMEWIDE STUDY OF DNA METHYLATION IN PERIPHERAL BLOOD IN RELATION TO PHYSICAL ACTIVITY AND TELEVISION VIEWING TIME. METHODS: DNA METHYLATION WAS MEASURED USING THE ILLUMINA INFINIUM HUMANMETHYLATION450K BEADCHIP ARRAY IN BLOOD SAMPLES COLLECTED AT BASELINE (N = 5513) AND FOLLOW-UP (N = 1249) FROM PARTICIPANTS IN THE MELBOURNE COLLABORATIVE COHORT STUDY. AT BASELINE, TIMES PER WEEK OF LEISURE-TIME PHYSICAL ACTIVITY WERE SELF-REPORTED. AT FOLLOW-UP, THE INTERNATIONAL PHYSICAL ACTIVITY QUESTIONNAIRE WAS USED TO ASSESS MET-HOURS PER WEEK OF TOTAL AND LEISURE-TIME PHYSICAL ACTIVITY AND HOURS PER DAY OF TELEVISION VIEWING TIME. LINEAR MIXED MODELS WERE USED TO ASSESS ASSOCIATIONS BETWEEN PHYSICAL ACTIVITY AND TELEVISION VIEWING MEASURES AND DNA METHYLATION AT INDIVIDUAL CPG SITES, ADJUSTED FOR POTENTIAL CONFOUNDERS AND BATCH EFFECTS. RESULTS: AT FOLLOW-UP, TOTAL PHYSICAL ACTIVITY WAS ASSOCIATED WITH DNA METHYLATION AT CG10266336 (P = 6.0 X 10), ANNOTATED TO THE SAA2 GENE. WEAKER EVIDENCE OF ASSOCIATIONS (P < 1.0 X 10) WERE OBSERVED FOR AN ADDITIONAL 14 CPG SITES WITH TOTAL PHYSICAL ACTIVITY, FOR 7 CPG SITES WITH LEISURE-TIME PHYSICAL ACTIVITY, AND FOR 9 CPG SITES WITH TELEVISION VIEWING TIME. CHANGES IN LEISURE-TIME PHYSICAL ACTIVITY BETWEEN BASELINE AND FOLLOW-UP WERE ASSOCIATED WITH METHYLATION CHANGES (P < 0.05) AT FOUR OF THE SEVEN CPG SITES WITH WEAKER EVIDENCE OF CROSS-SECTIONAL ASSOCIATIONS WITH LEISURE-TIME PHYSICAL ACTIVITY. CONCLUSION: PHYSICAL ACTIVITY AND TELEVISION VIEWING MAY BE ASSOCIATED WITH BLOOD DNA METHYLATION, A POTENTIAL PATHWAY TO CHRONIC DISEASE DEVELOPMENT. FURTHER RESEARCH USING ACCELEROMETER DATA AND LARGER SAMPLE SIZES IS WARRANTED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11 5001  31 PERINATAL RISK FACTORS IN TOURETTE'S AND CHRONIC TIC DISORDERS: A TOTAL POPULATION SIBLING COMPARISON STUDY. ADVERSE PERINATAL EVENTS MAY INCREASE THE RISK OF TOURETTE'S AND CHRONIC TIC DISORDERS (TD/CTD), BUT PREVIOUS STUDIES HAVE BEEN UNABLE TO CONTROL FOR UNMEASURED ENVIRONMENTAL AND GENETIC CONFOUNDING. WE AIMED TO PROSPECTIVELY INVESTIGATE POTENTIAL PERINATAL RISK FACTORS FOR TD/CTD, TAKING UNMEASURED FACTORS SHARED BETWEEN FULL SIBLINGS INTO ACCOUNT. A POPULATION-BASED BIRTH COHORT, CONSISTING OF ALL SINGLETONS BORN IN SWEDEN IN 1973-2003, WAS FOLLOWED UNTIL DECEMBER 2013. A TOTAL OF 3 026 861 INDIVIDUALS WERE IDENTIFIED, 5597 OF WHICH HAD A REGISTERED TD/CTD DIAGNOSIS. WE THEN STUDIED DIFFERENTIALLY EXPOSED FULL SIBLINGS FROM 947 942 FAMILIES; OF THESE, 3563 FAMILIES INCLUDED SIBLINGS THAT WERE DISCORDANT FOR TD/CTD. PERINATAL DATA WERE COLLECTED FROM THE MEDICAL BIRTH REGISTER AND TD/CTD DIAGNOSES WERE COLLECTED FROM THE NATIONAL PATIENT REGISTER, USING A PREVIOUSLY VALIDATED ALGORITHM. IN THE FULLY ADJUSTED MODELS, IMPAIRED FETAL GROWTH, PRETERM BIRTH, BREECH PRESENTATION AND CESAREAN SECTION WERE ASSOCIATED WITH A HIGHER RISK OF TD/CTD, LARGELY INDEPENDENT FROM SHARED FAMILY CONFOUNDERS AND MEASURED COVARIATES. MATERNAL SMOKING DURING PREGNANCY WAS ASSOCIATED WITH RISK OF TD/CTD IN A DOSE-RESPONSE MANNER BUT THE ASSOCIATION WAS NO LONGER STATISTICALLY SIGNIFICANT IN THE SIBLING COMPARISON MODELS OR AFTER THE EXCLUSION OF COMORBID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER. A DOSE-RESPONSE RELATIONSHIP BETWEEN THE NUMBER OF ADVERSE PERINATAL EVENTS AND INCREASED RISK FOR TD/CTD WAS ALSO OBSERVED, WITH HAZARD RATIOS RANGING FROM 1.41 (95% CONFIDENCE INTERVAL (CI): 1.33-1.50) FOR ONE EVENT TO 2.42 (95% CI: 1.65-3.53) FOR FIVE OR MORE EVENTS. THESE RESULTS PAVE THE WAY FOR FUTURE GENE BY ENVIRONMENT INTERACTION AND EPIGENETIC STUDIES IN TD/CTD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12 1782  35 EFFECT OF A 3-WEEK MULTIDISCIPLINARY BODY WEIGHT REDUCTION PROGRAM ON THE EPIGENETIC AGE ACCELERATION IN OBESE ADULTS. OBESITY AND AGING SHARE COMMON MOLECULAR AND CELLULAR MECHANISMS UNDERLYING THE PATHOPHYSIOLOGY OF CARDIOVASCULAR DISEASES (CVD), WHICH OCCUR FREQUENTLY IN BOTH CONDITIONS. DNA METHYLATION (DNAM) AGE, A BIOMARKER OF THE EPIGENETIC CLOCK, HAS BEEN PROPOSED AS A MORE ACCURATE PREDICTOR OF BIOLOGICAL AGING THAN CHRONOLOGICAL AGE. A POSITIVE DIFFERENCE BETWEEN AN INDIVIDUAL'S CHRONOLOGICAL AGE AND DNAM AGE IS REFERRED TO AS EPIGENETIC AGE ACCELERATION. THE OBJECTIVE OF THE PRESENT STUDY WAS TO EVALUATE THE EFFECTS OF A 3-WEEK IN-HOSPITAL BODY WEIGHT REDUCTION PROGRAM (BWRP) ON THE EPIGENETIC AGE ACCELERATION, AS WELL AS ON OTHER CARDIOMETABOLIC OUTCOMES, IN A COHORT OF 72 OBESE ADULTS (F/M: 43/29; (CHRONOLOGICAL) AGE: 51.5 +/- 14.5 YRS; BMI: 46.5 +/- 6.3 KG/M2). AT THE END OF THE BWRP, WHEN CONSIDERING THE ENTIRE POPULATION, BMI DECREASED, AND CHANGES IN BODY COMPOSITION WERE OBSERVED. THE BWRP ALSO PRODUCED BENEFICIAL METABOLIC EFFECTS AS DEMONSTRATED BY DECREASES IN GLUCOSE, INSULIN, HOMA-IR, TOTAL CHOLESTEROL, AND LDL CHOLESTEROL. A POST-BWRP IMPROVEMENT IN CARDIOVASCULAR FUNCTION WAS ALSO EVIDENT (I.E., DECREASES IN SYSTOLIC AND DIASTOLIC BLOOD PRESSURES AND HEART RATE). THE BWRP REDUCED SOME MARKERS OF SYSTEMIC INFLAMMATION, PARTICULARLY C-REACTIVE PROTEIN (CRP). FINALLY, VASCULAR AGE (VA) AND FRAMINGHAM RISK SCORE (FRS) WERE REDUCED AFTER THE BWRP. WHEN CONSIDERING THE ENTIRE POPULATION, DNAM AGE AND EPIGENETIC AGE ACCELERATION DID NOT DIFFER AFTER THE BWRP. HOWEVER, WHEN SUBDIVIDING THE POPULATION INTO TWO GROUPS BASED ON EACH SUBJECT'S EPIGENETIC AGE ACCELERATION (I.E., </=0 YRS OR >0 YRS), THE BWRP REDUCED THE EPIGENETIC AGE ACCELERATION ONLY IN OBESE SUBJECTS WITH A VALUE > 0 YRS (THUS BIOLOGICALLY OLDER THAN EXPECTED). AMONG ALL THE SINGLE DEMOGRAPHIC, LIFESTYLE, BIOCHEMICAL, AND CLINICAL CHARACTERISTICS INVESTIGATED, ONLY SOME MARKERS OF SYSTEMIC INFLAMMATION, SUCH AS CRP, WERE ASSOCIATED WITH THE EPIGENETIC AGE ACCELERATION. MOREOVER, CHRONOLOGICAL AGE WAS CORRELATED WITH DNAM AGE AND VA; FINALLY, THERE WAS A CORRELATION BETWEEN DNAM AGE AND VA. IN CONCLUSION, A 3-WEEK BWRP IS CAPABLE OF REDUCING THE EPIGENETIC AGE ACCELERATION IN OBESE ADULTS, BEING THE BWRP-INDUCED REJUVENATION EVIDENT IN SUBJECTS WITH AN EPIGENETIC AGE ACCELERATION > 0 YRS. BASED ON THE BWRP-INDUCED DECREASE IN CRP LEVELS, CHRONIC SYSTEMIC INFLAMMATION SEEMS TO PLAY A ROLE IN MEDIATING OBESITY-RELATED EPIGENETIC REMODELING AND BIOLOGICAL AGING. THUS, DUE TO THE STRONG ASSOCIATION OF CVD RISK WITH THE EPIGENETIC CLOCK AND MORBIDITY/MORTALITY, ANY EFFORT SHOULD BE MADE TO REDUCE THE LOW-GRADE CHRONIC INFLAMMATORY STATE IN OBESITY.	2022	

13 3574  29 IMPACT OF METHIONINE SYNTHASE REDUCTASE POLYMORPHISMS IN CHRONIC MYELOID LEUKEMIA PATIENTS. INTRODUCTION: METABOLISM METHIONINE AND OF FOLATE PLAY A VITAL FUNCTION IN CELLULAR METHYLATION REACTIONS, DNA SYNTHESIS AND EPIGENETIC PROCESS.HOWEVER, POLYMORPHISMS OF METHIONINE HAVE RECEIVED MUCH ATTENTION IN RECENT MEDICAL GENETICS RESEARCH. OBJECTIVES: TO ASCERTAIN WHETHER THE COMMON POLYMORPHISMS OF THE MTRR (METHIONINE SYNTHASE REDUCTASE) A66G GENE COULD PLAY A ROLE IN AFFECTING SUSCEPTIBILITY TO CHRONIC MYELOID LEUKEMIA (CML) IN SUDANESE INDIVIDUALS. METHODS: IN A CASE-CONTROLLED STUDY, WE EXTRACTED AND ANALYZED DNA FROM 200 CML PATIENTS AND 100 HEALTHY CONTROL SUBJECTS BY THE PCR-RFLP METHOD. RESULTS: WE FOUND NO SIGNIFICANT DIFFERENCE IN AGE ORGENDER BETWEEN THE PATIENT GROUP AND CONTROLS. THE MTRR A66G GENOTYPES WERE DISTRIBUTED BASED ON THE HARDY-WEINBERG EQUILIBRIUM (P > 0.05). THE VARIATION OF MTRR A66G WAS LESS SIGNIFICANTLY FREQUENT IN CASES WITH CML (68.35%) THAN IN CONTROLS (87%) (OR = 0.146, 95% CI = 0.162-0.662, P < 0.002). ADDITIONALLY, AG AND GG GENOTYPES AND G ALLELE WERE REDUCING THE CML RISK (ODDS RATIO [OR] = 0.365; 95% CI [0.179-0.746]; P = 0.006; OR = 0.292; 95% CI [0.145-0.590]; P = 0.001 AND OR = 0.146; 95% CI [0.162-0.662]; P = 0.002 AND OR = 2.0; 95% CI [1.3853-2.817]; RESPECTIVELY, (P = 0.000)). CONCLUSIONS: OUR DATA DEMONSTRATED THAT HETEROZYGOUS AND HOMOZYGOUS MUTANT GENOTYPES OF MTRR POLYMORPHISMS WERE ASSOCIATED WITH DECREASED RISK OF DEVELOPING CML IN THE SUDANESE POPULATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
14 1351  37 DETERMINATION OF SALIVA EPIGENETIC AGE IN INFANCY, AND ITS ASSOCIATION WITH PARENTAL SOCIO-ECONOMIC CHARACTERISTICS AND PREGNANCY OUTCOMES. EPIGENETIC AGE ACCELERATION (AA) HAS BEEN ASSOCIATED WITH ADVERSE ENVIRONMENTAL EXPOSURES AND MANY CHRONIC CONDITIONS. WE ESTIMATED, IN THE NINFEA BIRTH COHORT, INFANT SALIVA EPIGENETIC AGE, AND INVESTIGATED WHETHER PARENTAL SOCIO-ECONOMIC POSITION (SEP) AND PREGNANCY OUTCOMES ARE ASSOCIATED WITH INFANT EPIGENETIC AA. A TOTAL OF 139 SALIVA SAMPLES COLLECTED AT ON AVERAGE 10.8 (RANGE 7-17) MONTHS WERE USED TO ESTIMATE HORVATH'S DNA METHYLATION AGE. EPIGENETIC AA WAS DEFINED AS THE RESIDUAL FROM A LINEAR REGRESSION OF EPIGENETIC AGE ON CHRONOLOGICAL AGE. LINEAR REGRESSION MODELS WERE USED TO TEST THE ASSOCIATIONS OF PARENTAL SEP AND PREGNANCY OUTCOMES WITH SALIVA EPIGENETIC AA. A MODERATE POSITIVE ASSOCIATION WAS FOUND BETWEEN DNA METHYLATION AGE AND CHRONOLOGICAL AGE, WITH THE MEDIAN ABSOLUTE DIFFERENCE OF 6.8 MONTHS (STANDARD DEVIATION [SD] 3.9). THE EVIDENCE OF THE ASSOCIATION BETWEEN THE INDICATORS OF LOW SEP AND EPIGENETIC AA WAS WEAK; INFANTS BORN TO UNEMPLOYED MOTHERS OR WITH LOW EDUCATION HAD ON AVERAGE 1 MONTH HIGHER EPIGENETIC AGE THAN INFANTS OF MOTHERS WITH HIGH EDUCATION AND EMPLOYMENT (COEFFICIENT 0.78 MONTHS, 95% CONFIDENCE INTERVALS [CIS]: -0.79 TO 2.34 FOR LOW/MEDIUM EDUCATION; 0.96, 95% CI: -1.81 TO 3.73 FOR UNEMPLOYMENT). THERE WAS NO EVIDENCE FOR ASSOCIATION OF GESTATIONAL AGE, BIRTHWEIGHT OR CAESAREAN SECTION WITH INFANT EPIGENETIC AA. USING THE HORVATH'S METHOD, DNA METHYLATION AGE CAN BE FAIRLY ACCURATELY PREDICTED FROM SALIVA SAMPLES ALREADY IN THE FIRST MONTHS OF LIFE. THIS STUDY DID NOT REVEAL CLEAR ASSOCIATIONS BETWEEN EITHER PREGNANCY OUTCOMES OR PARENTAL SOCIO-ECONOMIC CHARACTERISTICS AND INFANT SALIVA EPIGENETIC AA.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15 1962  39 EPIGENETIC AGING IS ASSOCIATED WITH CLINICAL AND EXPERIMENTAL PAIN IN COMMUNITY-DWELLING OLDER ADULTS. GERONTOLOGICAL RESEARCH REVEALS CONSIDERABLE INTERINDIVIDUAL VARIABILITY IN AGING PHENOTYPES, WHICH HAS MOTIVATED RESEARCH EFFORTS TO IDENTIFY "AGING BIOMARKERS." AGING BIOMARKERS ARE USED TO CALCULATE BIOLOGICAL AGE, WHICH ARE BETTER PREDICTORS OF DISEASE RISK AND RESIDUAL LIFESPAN WHEN COMPARED TO CHRONOLOGICAL AGE ALONE. EMERGING EVIDENCE USING THE EPIGENETIC CLOCK AS AN AGING BIOMARKER SUPPORTS HIGHLY RELIABLE INDIVIDUALIZED PREDICTIONS ABOUT FUTURE HEALTH. THIS STUDY AIMED TO DETERMINE WHETHER AN EPIGENETIC AGING BIOMARKER WAS ASSOCIATED WITH CHRONIC PAIN IN OLDER ADULTS (60-83 YEARS OLD). A SUBSET OF PARTICIPANTS (N = 29) IN THE NEUROMODULATORY EXAMINATION OF PAIN AND MOBILITY ACROSS THE LIFESPAN STUDY UNDERWENT A BLOOD DRAW, DEMOGRAPHIC, PSYCHOLOGICAL, COGNITIVE, AND PAIN ASSESSMENTS. WE ESTIMATED HORVATH'S EPIGENETIC CLOCK AND CALCULATED THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE THAT HAS BEEN PREVIOUSLY REPORTED TO PREDICT OVERALL MORTALITY RISK. OLDER INDIVIDUALS WITHOUT CHRONIC PAIN (N = 9) HAD SIGNIFICANTLY "YOUNGER" EPIGENETIC AGE COMPARED TO THOSE WITH CHRONIC PAIN (N = 20, P < 0.05). OLDER EPIGENETIC AGE WAS ASSOCIATED WITH GREATER PAIN DURING DAILY ACTIVITIES (R = 0.494, P = 0.010) AND ANATOMICAL PAIN SITES (R = 0.741, P < 0.001) BUT NOT PAIN FREQUENCY/DURATION. AN OLDER EPIGENETIC AGE WAS ALSO ASSOCIATED WITH HIGHER VIBRATORY DETECTION THRESHOLDS (R = 0.490, P = 0.021), HEAT PAIN THRESHOLDS (R = -0.478, P = 0.028), AND PRESSURE PAIN THRESHOLDS AT THE TRAPEZIUS (R = -0.571, P = 0.006) BUT NOT THERMAL DETECTION, PRESSURE PAIN AT THE QUADRICEPS OR PAIN INHIBITION (P'S > 0.05). EPIGENETIC AGING WAS ASSOCIATED WITH GREATER EMOTIONAL STABILITY (R = -0.461, P = 0.027), CONSCIENTIOUSNESS (R = -0.549, P = 0.007), AND LOWER EXTRAVERSION (R = 0.414, P = 0.049) BUT NOT DEPRESSION OR AFFECT (P'S > 0.05). EPIGENETIC AGING WAS ALSO ASSOCIATED WITH LOWER EPISODIC (R = -0.698, P = 0.001) AND WORKING MEMORY (R = -0.760, P < 0.001). OUR FINDINGS SUGGEST THAT CHRONIC PAIN IS ASSOCIATED WITH ACCELERATED EPIGENETIC AGING IN HEALTHY, COMMUNITY-DWELLING OLDER INDIVIDUALS, AND FUTURE STUDIES WITH LARGER SAMPLES ARE NEEDED TO CONFIRM OUR FINDINGS. AN AGING BIOMARKER SUCH AS THE EPIGENETIC CLOCK MAY HELP IDENTIFY PEOPLE WITH CHRONIC PAIN AT GREATER RISK OF FUNCTIONAL DECLINE AND POORER HEALTH OUTCOMES.	2019	
                                                                                                                                                                                                                                                                                                                                
16 3310  34 HIGHER ORDER GENES INTERACTION IN DNA REPAIR AND CYTOKINE GENES POLYMORPHISM AND RISK TO LUNG CANCER IN NORTH INDIANS. CONTEXT: LUNG CANCER PATHOLOGICAL PROCESS INVOLVES CUMULATIVE EFFECTS EXERTED BY GENE POLYMORPHISM(S), EPIGENETIC MODIFICATIONS, AND ALTERATIONS IN DNA REPAIR MACHINERY. FURTHER, DNA DAMAGE DUE TO OXIDATIVE STRESS, CHRONIC INFLAMMATION, AND THE INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS IS ALSO AN ETIOLOGIC MILIEU OF THIS MALIGNANT DISEASE. AIMS: THE PRESENT STUDY AIMS TO ASSESS THE PROGNOSTIC VALUE OF DNA REPAIR, CYTOKINES, AND GST GENE POLYMORPHISM IN LUNG CANCER PATIENTS WHO HAD NOT RECEIVED ANY NEOADJUVANT THERAPY. MATERIALS AND METHODS: IN THIS CASE-CONTROL STUDY, 127 CASES AND 120 CONTROLS WERE ENROLLED. DNA FROM THE BLOOD SAMPLES OF BOTH PATIENTS AND CONTROLS WAS USED TO GENOTYPE XRCC1ARG399GLN, XPDLYS751GLN, AND INTERLEUKIN-1 (IL-1BETA) GENES BY POLYMERASE CHAIN REACTION (PCR)-RESTRICTION FRAGMENT LENGTH POLYMORPHISM METHOD, WHEREAS MULTIPLEX PCR WAS PERFORMED TO GENOTYPE GSTT1 AND GSTM1. RESULTS: BINARY LOGISTIC REGRESSION ANALYSIS SHOWED THAT XRCC1ARG399GLN-MUTANT GENOTYPE (GLN/GLN, ODDS RATIO [OR] = 4.6, 95% CONFIDENCE INTERVAL [CI]: 2.2-9.6) AND GSTT1 NULL (OR = 2.7, 95% CI: 1.6-4.5) WERE LINKED TO CANCER SUSCEPTIBILITY. GENERALIZED MULTIDIMENSIONAL REDUCTION ANALYSIS OF HIGHER ORDER GENE-GENE INTERACTION USING CROSS-VALIDATION TESTING (CVT) ACCURACY SHOWED THAT GSTT1 (CVT 0.62, P = 0.001), XPD751 AND IL-1BETA (CVT 0.6, P = 0.001), AND XRCC1399, XPD751, AND INTERLEUKIN-1 RECEPTOR ANTAGONISTS (IL-1RN) (CVT 0.98, P = 0.001) WERE SINGLE-, TWO-, AND THREE-FACTOR BEST MODEL PREDICTED, RESPECTIVELY, FOR LUNG CANCER RISK. CLASSIFICATION AND REGRESSION TREE ANALYSIS RESULTS SHOWED THAT TERMINAL NODES WHICH CONTAIN XRCC1399-MUTANT GENOTYPE (AA) HAD INCREASED THE RISK TO LUNG CANCER. CONCLUSION: THE PRESENT STUDY DEMONSTRATED THAT XRCC1399 (GLN/GLN), GSTT1, AND IL-1RN ALLELE I, I/II SERVED AS THE RISK GENOTYPES. THESE GENES COULD SERVE AS THE BIOMARKERS TO PREDICT LUNG CANCER RISK.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17 2390  31 EPIGENETIC REPRESSION OF CCDC37 AND MAP1B LINKS CHRONIC OBSTRUCTIVE PULMONARY DISEASE TO LUNG CANCER. INTRODUCTION: LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) SHARE ENVIRONMENTAL RISK FACTORS. COPD ALSO INCREASES THE RISK OF LUNG CANCER; HOWEVER, THE MOLECULAR MECHANISMS ARE UNCLEAR. METHODS: AN EPIGENOME-WIDE ASSOCIATION STUDY OF LUNG TUMORS AND CANCER-FREE LUNG TISSUE (CFLT) PAIRS FROM NON-SMALL-CELL LUNG CANCER CASES WITH (N = 18) OR WITHOUT (N = 17) COPD WAS CONDUCTED USING THE HUMANMETHYLATION450 BEADCHIP (HM450K). COPD-ASSOCIATED METHYLATION OF TOP-RANKED GENES WAS CONFIRMED IN A LARGER SAMPLE SET, INDEPENDENTLY VALIDATED, AND THEIR POTENTIAL AS SPUTUM-BASED BIOMARKERS WAS INVESTIGATED. RESULTS: METHYLATION OF CCDC37 AND MAP1B WAS MORE PREVALENT IN LUNG TUMORS FROM COPD THAN NON-COPD CASES [54 OF 71 (76%) VERSUS 20 OF 46 (43%), P = 0.0013] AND [48 OF 71 (68%) VERSUS 17 OF 46 (37%), P = 0.0035], RESPECTIVELY, AFTER ADJUSTMENT FOR AGE, SEX, SMOKING STATUS, AND TUMOR HISTOLOGY. HM450K PROBES ACROSS CCDC37 AND MAP1B PROMOTERS SHOWED HIGHER METHYLATION IN TUMORS THAN CFLT WITH THE HIGHEST METHYLATION SEEN IN TUMORS FROM COPD CASES (P < 0.05). THESE RESULTS WERE INDEPENDENTLY VALIDATED USING THE CANCER GENOME ATLAS DATA. CCDC37 METHYLATION WAS MORE PREVALENT IN SPUTUM FROM COPD THAN NON-COPD SMOKERS (P < 0.005) FROM TWO COHORTS. CCDC37 AND MAP1B EXPRESSION WAS DRAMATICALLY REPRESSED IN TUMORS AND CFLT FROM COPD THAN NON-COPD CASES, P LESS THAN 0.02. CONCLUSIONS: THE REDUCED EXPRESSION OF CCDC37 AND MAP1B ASSOCIATED WITH COPD LIKELY PREDISPOSES THESE GENES TO METHYLATION THAT IN TURN, MAY CONTRIBUTE TO LUNG CANCER.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18  181  28 ACCELERATED EPIGENETIC AGING MEDIATES THE ASSOCIATION BETWEEN VITAMIN D LEVELS AND KNEE PAIN IN COMMUNITY-DWELLING INDIVIDUALS. OBJECTIVES: TO EXAMINE THE RELATIONSHIP BETWEEN VITAMIN D STATUS AND PAIN INTENSITY AND DISABILITY IN INDIVIDUALS WITH AND WITHOUT KNEE PAIN, AND TO EXAMINE THE ROLE OF EPIGENETICS IN THIS RELATIONSHIP. DESIGN: CROSS-SECTIONAL ANALYSIS OF DATA FROM THE UPLOAD-2 STUDY (UNDERSTANDING PAIN AND LIMITATIONS IN OSTEOARTHRITIC DISEASE-2). PARTICIPANTS: 189 INDIVIDUALS AGED 45-65 YEARS AND OLDER. MEASUREMENTS: SERUM VITAMIN D LEVELS, PAIN RELATED INTERFERENCE AND CHARACTERISTIC PAIN INTENSITY MEASURES, AND THE EPIGENETIC CLOCK GRIMAGE DERIVED FROM BLOOD ANALYSES. RESULTS: LOWER VITAMIN D WAS ASSOCIATED WITH ADVANCED EPIGENETIC AGING (AGEACCELGRIM), GREATER PAIN AND DISABILITY AND THAT (AGEACCELGRIM) MEDIATED THE RELATIONSHIP BETWEEN VITAMIN D STATUS AND SELF-REPORTED PAIN (AB = -0.0799; CI [-0.1492, -0.0237]) AND DISABILITY (AB = -0.0669; CI [-0.1365, -0.0149]) OUTCOMES. CONCLUSION: THESE DATA SUPPORT THE NOTION THAT LIFESTYLE FACTORS SUCH AS NUTRITION STATUS PLAY A KEY ROLE IN AGING PROCESS, AS WELL AS THE DEVELOPMENT AND MAINTENANCE OF AGE-RELATED DISEASES SUCH AS PAIN. MODIFYING NUTRITION STATUS COULD HELP PROMOTE HEALTHY AGING AND REDUCE PAIN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19 4912  35 PAIN INTERFERENCE MEDIATES THE ASSOCIATION BETWEEN EPIGENETIC AGING AND GRIP STRENGTH IN MIDDLE TO OLDER AGED MALES AND FEMALES WITH CHRONIC PAIN. INTRODUCTION: CHRONIC PAIN IS ONE OF THE LEADING CAUSES OF DISABILITY THAT MAY ACCELERATE BIOLOGICAL AGING AND REDUCE PHYSICAL FUNCTION. EPIGENETIC CLOCKS PROVIDE AN ESTIMATE OF HOW THE SYSTEM AGES AND CAN PREDICT HEALTH OUTCOMES SUCH AS PHYSICAL FUNCTION. PHYSICAL FUNCTION DECLINES MAY BE ATTRIBUTED TO DECREASES IN MUSCLE QUALITY DUE TO DISUSE THAT CAN BE MEASURED QUICKLY AND NONINVASIVELY USING GRIP STRENGTH. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE ASSOCIATIONS AMONG SELF-REPORTED PAIN, GRIP STRENGTH, AND EPIGENETIC AGING IN THOSE WITH CHRONIC PAIN. METHODS: PARTICIPANTS (57.91 +/- 8.04 YEARS) COMPLETED PAIN QUESTIONNAIRES, A BLOOD DRAW AND HAND GRIP STRENGTH TASK. WE USED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN (DNAMGRIMAGE), AND USED THE SUBSEQUENT DIFFERENCE OF PREDICTED EPIGENETIC AGE FROM CHRONOLOGICAL AGE (DNAMGRIMAGE-DIFFERENCE). RESULTS: EXPLORATORY PATHWAY ANALYSES REVEALED THAT PAIN INTENSITY MEDIATED THE ASSOCIATION BETWEEN DNAMGRIMAGE-DIFFERENCE AND HANDGRIP STRENGTH IN MALES ONLY (BETA = -0.1115; CI [-0.2929, -0.0008]) AND PAIN INTERFERENCE MEDIATED THE ASSOCIATION BETWEEN DNAMGRIMAGE-DIFFERENCE AND HANDGRIP STRENGTH IN MALES BETA = -0.1401; CI [-0.3400, -0.0222]), AND FEMALES (BETA = -0.024; CI [-0.2918, -0.0020]). DISCUSSION: CHRONIC KNEE PAIN MAY ACCELERATE EPIGENETIC AGING PROCESSES THAT MAY INFLUENCE HANDGRIP STRENGTH IN OLDER AGE ADULTS. CHRONIC PAIN COULD BE A SYMPTOM OF THE AGING BODY THUS CONTRIBUTING TO DECLINES IN MUSCULOSKELETAL FUNCTION IN LATER LIFE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20 3162  27 GREATER STRESS AND TRAUMA MEDIATE RACE-RELATED DIFFERENCES IN EPIGENETIC AGE BETWEEN BLACK AND WHITE YOUNG ADULTS IN A COMMUNITY SAMPLE. BLACK AMERICANS SUFFER LOWER LIFE EXPECTANCY AND SHOW SIGNS OF ACCELERATED AGING COMPARED TO OTHER AMERICANS. WHILE PREVIOUS STUDIES OBSERVE THESE DIFFERENCES IN CHILDREN AND POPULATIONS WITH CHRONIC ILLNESS, WHETHER THESE PATHOLOGIC PROCESSES EXIST OR HOW THESE PATHOLOGIC PROCESSES PROGRESS HAS YET TO BE EXPLORED PRIOR TO THE ONSET OF SIGNIFICANT CHRONIC ILLNESS, WITHIN A YOUNG ADULT POPULATION. THEREFORE, WE INVESTIGATED RACE-RELATED DIFFERENCES IN EPIGENETIC AGE IN A CROSS-SECTIONAL SAMPLE OF YOUNG PUTATIVELY HEALTHY ADULTS AND ASSESSED WHETHER LIFETIME STRESS AND/OR TRAUMA MEDIATE THOSE DIFFERENCES. BIOLOGICAL AND PSYCHOLOGICAL DATA WERE COLLECTED FROM SELF-REPORTED HEALTHY ADULT VOLUNTEERS WITHIN THE LOCAL NEW HAVEN AREA (399 VOLUNTEERS, 19.8% BLACK, MEAN AGE: 29.28). STRESS AND TRAUMA DATA WAS COLLECTED USING THE CUMULATIVE ADVERSITY INVENTORY (CAI) INTERVIEW, WHICH ASSESSED SPECIFIC TYPES OF STRESSORS, INCLUDING MAJOR LIFE EVENTS, TRAUMATIC EVENTS, WORK, FINANCIAL, RELATIONSHIP AND CHRONIC STRESSORS CUMULATIVELY OVER TIME. GRIMAGE ACCELERATION (GAA), DETERMINED FROM WHOLE BLOOD COLLECTED FROM PARTICIPANTS, MEASURED EPIGENETIC AGE. IN ORDER TO UNDERSTAND THE IMPACT OF STRESS AND TRAUMA ON GAA, EXPLORATORY MEDIATION ANALYSES WERE THEN USED. WE FOUND CUMULATIVE STRESSORS ACROSS ALL TYPES OF EVENTS (MEAN DIFFERENCE OF 6.9 P = 2.14E-4) AND GAA (BETA = 2.29 YEARS [1.57-3.01, P = 9.70E-10] FOR RACE, PARTIAL ETA(2) = 0.091, MODEL ADJUSTED R(2) = 0.242) WERE SIGNIFICANTLY GREATER IN BLACK COMPARED TO WHITE PARTICIPANTS. CRITICALLY, CAI TOTAL SCORE (PROPORTION MEDIATED: 0.185 [0.073-0.34, P = 6E-4]) SIGNIFICANTLY MEDIATED THE RELATIONSHIP BETWEEN RACE AND GAA. FURTHER ANALYSIS ATTRIBUTED THIS DIFFERENCE TO MORE TRAUMATIC EVENTS, PARTICULARLY ASSAULTIVE TRAUMAS AND DEATH OF LOVED ONES. OUR RESULTS SUGGEST THAT, PRIOR TO DEVELOPMENT OF SIGNIFICANT CHRONIC DISEASE, BLACK INDIVIDUALS HAVE INCREASED EPIGENETIC AGE COMPARED TO WHITE PARTICIPANTS AND THAT INCREASED CUMULATIVE STRESS AND TRAUMATIC EVENTS MAY CONTRIBUTE SIGNIFICANTLY TO THIS EPIGENETIC AGING DIFFERENCE.	2023