1 1962 175 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	
                                                                                                                                                                                   
2 1849  39 EIGHT WEEKS OF PHYSICAL TRAINING DECREASES 2 YEARS OF DNA METHYLATION AGE OF SEDENTARY WOMEN. PURPOSE: THE ACCELERATION OF EPIGENETIC AGE IS A PREDICTOR OF MORTALITY AND CONTRIBUTES TO THE INCREASE IN CHRONIC DISEASES. ADHERENCE TO A HEALTHY LIFESTYLE IS A STRATEGY TO REDUCE EPIGENETIC AGE. THE PRESENT STUDY AIMED TO DETERMINE WHETHER EIGHT WEEKS OF COMBINED (AEROBIC AND STRENGTH) TRAINING (CT) CAN INFLUENCE THE EPIGENETIC AGE OF WOMEN BETWEEN 50 AND 70 YEARS OLD AND THE DIFFERENCES IN SITES AND METHYLATED REGIONS. METHODS: EIGHTEEN WOMEN (AAR(LOW): LOWER AGE ACCELERATION RESIDUAL, N = 10; AAR(HIGH): HIGHER AGE ACCELERATION RESIDUAL, N = 8) PARTICIPATED IN A COMBINED EXERCISE TRAINING PROGRAM (60 MINUTES, 3X A WEEK) FOR EIGHT WEEKS. DNA WAS EXTRACTED FROM WHOLE BLOOD USING THE SALTING OUT TECHNIQUE. DNA METHYLATION WAS PERFORMED USING THE ARRAY TECHNIQUE (ILLUMINA'S INFINIUM METHYLATION BEADCHIP 850K). WE USED THE DNA METHYLATION AGE CALCULATOR PLATFORM TO CALCULATE THE BIOLOGICAL EPIGENETIC AGE. TWO-WAY ANOVA FOLLOWED BY FISHER LSD POSTHOC WAS APPLIED, ADOPTING P < .05. RESULTS: AFTER EIGHT WEEKS OF CT, THERE WERE NO CHANGES TO THE EPIGENETIC AGE ACCELERATION FOR THE AAR(LOW) GROUP (PRE: -2.3 +/- 3.2 TO POST: -2.3 +/- 3.6). HOWEVER, THE AAR(HIGH) GROUP SIGNIFICANTLY DECREASED THE AGE ACCELERATION (PRE: 3.6 +/- 2.6 TO POST: 2.2 +/- 2.7) (GROUP EFFECT, P = .01; TIME EFFECT, P = .31; GROUP VS. TIME EFFECT, P = .005). CONCLUSION: CT FOR EIGHT WEEKS BENEFITS THE EPIGENETIC CLOCK OF WOMEN WITH THE MOST ACCELERATED AGE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
3 4024  40 LUNG ALLOGRAFT EPITHELIUM DNA METHYLATION AGE IS ASSOCIATED WITH GRAFT CHRONOLOGIC AGE AND PRIMARY GRAFT DYSFUNCTION. ADVANCED DONOR AGE IS A RISK FACTOR FOR POOR SURVIVAL FOLLOWING LUNG TRANSPLANTATION. HOWEVER, RECENT WORK IDENTIFYING EPIGENETIC DETERMINANTS OF AGING HAS SHOWN THAT BIOLOGIC AGE MAY NOT ALWAYS REFLECT CHRONOLOGIC AGE AND THAT STRESSORS CAN ACCELERATE BIOLOGIC AGING. WE HYPOTHESIZED THAT LUNG ALLOGRAFTS THAT EXPERIENCED PRIMARY GRAFT DYSFUNCTION (PGD), CHARACTERIZED BY POOR OXYGENATION IN THE FIRST THREE POST-TRANSPLANT DAYS, WOULD HAVE INCREASED BIOLOGIC AGE. WE CULTURED AIRWAY EPITHELIAL CELLS ISOLATED BY TRANSBRONCHIAL BRUSH AT 1-YEAR BRONCHOSCOPIES FROM 13 SUBJECTS WITH SEVERE PGD AND 15 CONTROLS MATCHED ON AGE AND TRANSPLANT INDICATION. WE MEASURED EPIGENETIC AGE USING THE HORVATH EPIGENETIC CLOCK. LINEAR MODELS WERE USED TO DETERMINE THE ASSOCIATION OF AIRWAY EPIGENETIC AGE WITH CHRONOLOGIC AGES AND PGD STATUS, ADJUSTED FOR RECIPIENT PGD RISK FACTORS. SURVIVAL MODELS ASSESSED THE ASSOCIATION WITH CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD) OR DEATH. DISTRIBUTIONS OF PROMOTER METHYLATION WITHIN PATHWAYS WERE COMPARED BETWEEN GROUPS. DNA METHYLTRANSFERASE (DNMT) ACTIVITY WAS QUANTIFIED IN AIRWAY EPITHELIAL CELLS UNDER HYPOXIC OR NORMOXIC CONDITIONS. AIRWAY EPIGENETIC AGE APPEARED YOUNGER BUT WAS STRONGLY ASSOCIATED WITH THE AGE OF THE ALLOGRAFT (SLOPE 0.38 PER YEAR, 95% CI 0.27-0.48). THERE WAS NO CORRELATION BETWEEN EPIGENETIC AGE AND RECIPIENT AGE (P = 0.96). EPIGENETIC AGE WAS 6.5 YEARS GREATER (95% CI 1.7-11.2) IN SUBJECTS WHO HAD EXPERIENCED PGD, AND THIS EFFECT REMAINED SIGNIFICANT AFTER ADJUSTING FOR DONOR AND RECIPIENT CHARACTERISTICS (P = 0.03). EPIGENETIC AGE WAS NOT ASSOCIATED WITH CLAD-FREE SURVIVAL RISK (P = 0.11). ANALYSIS OF DIFFERENTIAL METHYLATION OF PROMOTERS OF KEY BIOLOGIC PATHWAYS REVEALED HYPOMETHYLATION IN REGIONS RELATED TO HYPOXIA, INFLAMMATION, AND METABOLISM-ASSOCIATED PATHWAYS. ACCORDINGLY, AIRWAY EPITHELIAL CELLS CULTURED IN HYPOXIC CONDITIONS SHOWED SUPPRESSED DNMT ACTIVITY. WHILE AIRWAY METHYLATION AGE WAS PRIMARILY DETERMINED BY DONOR CHRONOLOGIC AGE, EARLY INJURY IN THE FORM OF PGD WAS ASSOCIATED WITH INCREASED ALLOGRAFT EPIGENETIC AGE. THESE DATA SHOW HOW PGD MIGHT SUPPRESS KEY PROMOTER METHYLATION RESULTING IN LONG-TERM IMPACTS ON THE ALLOGRAFT.	2021	
                                                                                                                                                                                                                                                                                                     
4 1964  48 EPIGENETIC AGING, KNEE PAIN AND PHYSICAL PERFORMANCE IN COMMUNITY-DWELLING MIDDLE-TO-OLDER AGE ADULTS. KNEE PAIN IS A LEADING CAUSE OF DISABILITY IN THE AGING POPULATION AND MAY INDIRECTLY ACCELERATE BIOLOGICAL AGING PROCESSES. CHRONOLOGICAL AGING INCREASES THE RISK OF DEVELOPING OF KNEE PAIN AND KNEE PAIN REDUCES PHYSICAL FUNCTION; HOWEVER, LIMITED DATA EXIST ON HOW EPIGENETIC AGING, A KNOWN HALLMARK OF BIOLOGICAL AGING SHOWN TO PREDICT HEALTH SPAN AND MORTALITY, MAY INFLUENCE THIS RELATIONSHIP. THE PURPOSE OF THIS STUDY WAS TO EXAMINE WHETHER DECREASED PHYSICAL PERFORMANCE ASSOCIATED WITH KNEE PAIN IS MEDIATED BY MARKERS OF EPIGENETIC AGING. PARTICIPANTS (57.91 +/- 8.04 YEARS) 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 A SHORT PHYSICAL PERFORMANCE BATTERY (SPPB) THAT INCLUDED BALANCE, WALKING, AND SIT TO STAND TASKS. WE EMPLOYED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN AND SHOWN TO PREDICT OVERALL MORTALITY RISK (DNAMGRIMAGE). BOOTSTRAPPED-MEDIATION ANALYSES WERE USED TO DETERMINE ASSOCIATIONS OF DNAMGRIMAGE AND SPPB BETWEEN PAIN GROUPS. THOSE WITH HIGH IMPACT AND LOW IMPACT PAIN HAD A BIOLOGICALLY OLDER EPIGENETIC AGE (5.14Y +/- 5.66 AND 1.32Y +/- 5.41, RESPECTIVELY). HOWEVER, WHILE THERE WERE DIRECT EFFECTS OF PAIN ON OVERALL PHYSICAL PERFORMANCE, THESE WERE NOT EXPLAINED BY EPIGENETIC AGING. EPIGENETIC AGING ONLY MEDIATED THE EFFECT OF PAIN ON BALANCE PERFORMANCE. FUTURE WORK IS NEEDED TO EXAMINE PAIN'S IMPACT ON BIOLOGICAL AGING PROCESSES INCLUDING EPIGENETIC AGING AND ITS ULTIMATE EFFECT ON PHYSICAL FUNCTION MEASURES KNOWN TO PREDICT HEALTH SPAN AND MORTALITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5  175  30 ACCELERATED AGING WITH HIV BEGINS AT THE TIME OF INITIAL HIV INFECTION. LIVING WITH HIV INFECTION IS ASSOCIATED WITH EARLY ONSET OF AGING-RELATED CHRONIC CONDITIONS, SOMETIMES DESCRIBED AS ACCELERATED AGING. EPIGENETIC DNA METHYLATION PATTERNS CAN EVALUATE ACCELERATION OF BIOLOGICAL AGE RELATIVE TO CHRONOLOGICAL AGE. THE IMPACT OF INITIAL HIV INFECTION ON FIVE EPIGENETIC MEASURES OF AGING WAS EXAMINED BEFORE AND APPROXIMATELY 3 YEARS AFTER HIV INFECTION IN THE SAME INDIVIDUALS (N=102). SIGNIFICANT EPIGENETIC AGE ACCELERATION (MEDIAN 1.9-4.8 YEARS) AND ESTIMATED TELOMERE LENGTH SHORTENING (ALL P</= 0.001) WERE OBSERVED FROM PRE-TO POST-HIV INFECTION, AND REMAINED SIGNIFICANT IN THREE EPIGENETIC MEASURES AFTER CONTROLLING FOR T CELL CHANGES. NO ACCELERATION WAS SEEN IN AGE- AND TIME INTERVAL-MATCHED HIV-UNINFECTED CONTROLS. CHANGES IN GENOME-WIDE CO-METHYLATION CLUSTERS WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INITIAL HIV INFECTION (P</= 2.0 X 10(-4)). THESE LONGITUDINAL OBSERVATIONS CLEARLY DEMONSTRATE AN EARLY AND SUBSTANTIAL IMPACT OF HIV INFECTION ON THE EPIGENETIC AGING PROCESS, AND SUGGEST A ROLE FOR HIV ITSELF IN THE EARLIER ONSET OF CLINICAL AGING.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6 5757  50 SOCIOECONOMIC STATUS, KNEE PAIN, AND EPIGENETIC AGING IN COMMUNITY-DWELLING MIDDLE-TO-OLDER AGE ADULTS. CHRONIC MUSCULOSKELETAL PAIN IS OFTEN ASSOCIATED WITH LOWER SOCIOECONOMIC STATUS (SES). SES CORRELATES WITH PSYCHOLOGICAL AND ENVIRONMENTAL CONDITIONS THAT COULD CONTRIBUTE TO THE DISPROPORTIONATE BURDEN OF CHRONIC STRESS. CHRONIC STRESS CAN INDUCE CHANGES IN GLOBAL DNA METHYLATION AND GENE EXPRESSION, WHICH INCREASES RISK OF CHRONIC PAIN. WE AIMED TO EXPLORE THE ASSOCIATION OF EPIGENETIC AGING AND SES IN MIDDLE-TO-OLDER AGE INDIVIDUALS WITH VARYING DEGREES OF KNEE PAIN. PARTICIPANTS COMPLETED SELF-REPORTED PAIN, A BLOOD DRAW, AND ANSWERED DEMOGRAPHIC QUESTIONS PERTAINING TO SES. WE USED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN (DNAMGRIMAGE) AND THE SUBSEQUENT DIFFERENCE OF PREDICTED EPIGENETIC AGE (DNAMGRIMAGE-DIFF). OVERALL, THE MEAN DNAMGRIMAGE WAS 60.3 (+/-7.6), AND THE AVERAGE DNAMGRIMAGE-DIFF WAS 2.4 YEARS (+/-5.6 YEARS). THOSE EXPERIENCING HIGH-IMPACT PAIN EARNED LESS INCOME AND HAD LOWER EDUCATION LEVELS COMPARED TO BOTH LOW-IMPACT AND NO PAIN GROUPS. DIFFERENCES IN DNAMGRIMAGE-DIFF ACROSS PAIN GROUPS WERE FOUND, WHEREBY INDIVIDUALS WITH HIGH-IMPACT PAIN HAD ACCELERATED EPIGENETIC AGING ( APPROXIMATELY 5 YEARS) COMPARED TO LOW-IMPACT PAIN AND NO PAIN CONTROL GROUPS (BOTH APPROXIMATELY 1 YEAR). OUR MAIN FINDING WAS THAT EPIGENETIC AGING MEDIATED THE ASSOCIATIONS OF INCOME AND EDUCATION WITH PAIN IMPACT, AS SUCH THE RELATIONSHIP BETWEEN SES AND PAIN OUTCOMES MAY OCCUR THROUGH POTENTIAL INTERACTIONS WITH THE EPIGENOME REFLECTIVE OF ACCELERATED CELLULAR AGING. PERSPECTIVE: SOCIOECONOMIC STATUS (SES) HAS PREVIOUSLY BEEN IMPLICATED IN THE PAIN EXPERIENCE. THE PRESENT MANUSCRIPT AIMS TO PRESENT A POTENTIAL SOCIAL-BIOLOGICAL LINK BETWEEN SES AND PAIN VIA ACCELERATED EPIGENETIC AGING.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7 1957  85 EPIGENETIC AGE PREDICTORS IN COMMUNITY-DWELLING ADULTS WITH HIGH IMPACT KNEE PAIN. GERONTOLOGICAL RESEARCH REVEALS CONSIDERABLE INTERINDIVIDUAL VARIABILITY IN AGING PHENOTYPES, AND EMERGING EVIDENCE SUGGESTS THAT HIGH IMPACT CHRONIC PAIN MAY BE ASSOCIATED WITH VARIOUS ACCELERATED BIOLOGICAL AGING PROCESSES. IN PARTICULAR, EPIGENETIC AGING IS A ROBUST PREDICTOR OF HEALTH-SPAN AND DISABILITY COMPARED TO CHRONOLOGICAL AGE ALONE. THE CURRENT STUDY AIMED TO DETERMINE WHETHER SEVERAL EPIGENETIC AGING BIOMARKERS WERE ASSOCIATED WITH HIGH IMPACT CHRONIC PAIN IN MIDDLE TO OLDER AGE ADULTS (44-78 YEARS OLD). PARTICIPANTS (N = 213) UNDERWENT A BLOOD DRAW, DEMOGRAPHIC, PSYCHOSOCIAL, PAIN AND FUNCTIONAL ASSESSMENTS. WE ESTIMATED FIVE EPIGENETIC CLOCKS AND CALCULATED THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE, WHICH HAS BEEN PREVIOUSLY REPORTED TO PREDICT OVERALL MORTALITY RISK, AS WELL AS INCLUDED ADDITIONAL DERIVED VARIABLES OF EPIGENETIC AGE PREVIOUSLY ASSOCIATED WITH PAIN. THERE WERE SIGNIFICANT DIFFERENCES ACROSS PAIN IMPACT GROUPS IN THREE OUT OF THE FIVE EPIGENETIC CLOCKS EXAMINED (DNAMAGE, DNAMPHENOAGE AND DNAMGRIMAGE), INDICATING THAT PAIN-RELATED DISABILITY DURING THE PAST 6 MONTHS WAS ASSOCIATED WITH MARKERS OF EPIGENETIC AGING. ONLY DNAMPHENOAGE AND DNAMGRIMAGE WERE ASSOCIATED WITH HIGHER KNEE PAIN INTENSITY DURING THE PAST 48 H. FINALLY, PAIN CATASTROPHIZING, DEPRESSIVE SYMPTOMATOLOGY AND MORE NEUROPATHIC PAIN SYMPTOMS WERE SIGNIFICANTLY ASSOCIATED WITH AN OLDER EPIGENOME IN ONLY ONE OF THE FIVE EPIGENETIC CLOCKS (I.E. DNAMGRIMAGE) AFTER CORRECTING FOR MULTIPLE COMPARISONS (CORRECTED P'S < 0.05). GIVEN THE SCANT LITERATURE IN RELATION TO EPIGENETIC AGING AND THE COMPLEX EXPERIENCE OF PAIN, ADDITIONAL RESEARCH IS NEEDED TO UNDERSTAND WHETHER EPIGENETIC AGING MAY HELP IDENTIFY PEOPLE WITH CHRONIC PAIN AT GREATER RISK OF FUNCTIONAL DECLINE AND POORER HEALTH OUTCOMES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8  501  45 ASSOCIATION OF ACCELEROMETER-MEASURED PHYSICAL ACTIVITY AND SEDENTARY TIME WITH EPIGENETIC MARKERS OF AGING. INTRODUCTION/PURPOSE: PHYSICAL ACTIVITY MAY INFLUENCE CHRONIC DISEASE RISK, IN PART, THROUGH EPIGENETIC MECHANISMS. PREVIOUS STUDIES HAVE DEMONSTRATED THAT AN ACUTE BOUT OF PHYSICAL ACTIVITY CAN INFLUENCE DNA METHYLATION STATUS. FEW STUDIES HAVE EXPLORED THE RELATIONSHIP BETWEEN HABITUAL, ACCELEROMETER-MEASURED PHYSICAL ACTIVITY OR SEDENTARY TIME WITH EPIGENETIC MARKERS OF AGING. METHODS: WE USED LINEAR REGRESSION TO EXAMINE CROSS-SECTIONAL ASSOCIATIONS OF ACCELEROMETER-MEASURED PHYSICAL ACTIVITY AND SEDENTARY TIME WITH EXTRINSIC AND INTRINSIC EPIGENETIC AGE ACCELERATION (EEAA AND IEAA) MODELS AND GRIMAGE MEASURED FROM BLOOD SAMPLES FROM FRAMINGHAM HEART STUDY PARTICIPANTS WITH ACCELEROMETRY AND DNA METHYLATION DATA ( N = 2435; MEAN AGE, 54.9 +/- 14.3; 46.0% MEN). RESIDUALS OF HANNUM-, HORVATH-, AND GRIMAGE-PREDICTED EPIGENETIC AGE WERE CALCULATED BY REGRESSING EPIGENETIC AGE ON CHRONOLOGICAL AGE. WE TOOK INTO ACCOUNT BLOOD CELL COMPOSITION FOR EEAA, IEAA, AND ADJGRIMAGE. MODERATE TO VIGOROUS PHYSICAL ACTIVITY WAS LOG-TRANSFORMED TO NORMALIZE ITS DISTRIBUTION. ADJUSTMENT MODELS ACCOUNTED FOR FAMILY STRUCTURE, AGE, SEX, SMOKING STATUS, COHORT-LABORATORY INDICATOR, AND ACCELEROMETER WEAR TIME. WE ADDITIONALLY EXPLORED ADJUSTMENT FOR BODY MASS INDEX (BMI). RESULTS: WALKING 1500 MORE STEPS PER DAY OR SPENDING 3 FEWER HOURS SEDENTARY WAS ASSOCIATED WITH >10 MONTHS LOWER GRIMAGE BIOLOGICAL AGE (OR ~1 MONTH LOWER ADJGRIMAGE, AFTER ADJUSTING FOR BLOOD CELLS, P < 0.05). EVERY 5 MIN.D -1 MORE MODERATE TO VIGOROUS PHYSICAL ACTIVITY WAS ASSOCIATED WITH 19-79 D OF LOWER GRIMAGE (4-23 D LOWER USING EEAA OR ADJGRIMAGE, P < 0.01). ADJUSTING FOR BMI ATTENUATED THESE RESULTS, BUT ALL STATISTICALLY SIGNIFICANT ASSOCIATIONS WITH ADJGRIMAGE REMAINED. CONCLUSIONS: GREATER HABITUAL PHYSICAL ACTIVITY AND LOWER SEDENTARY TIME WERE ASSOCIATED WITH LOWER EPIGENETIC AGE, WHICH WAS PARTIALLY EXPLAINED BY BMI. FURTHER RESEARCH SHOULD EXPLORE WHETHER CHANGES IN PHYSICAL ACTIVITY INFLUENCE METHYLATION STATUS AND WHETHER THOSE MODIFICATIONS INFLUENCE CHRONIC DISEASE RISK.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9 4502  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
10 2046  37 EPIGENETIC CLOCK INDICATES ACCELERATED AGING IN GLIAL CELLS OF PROGRESSIVE MULTIPLE SCLEROSIS PATIENTS. BACKGROUND: MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY NEURODEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM (CNS) CHARACTERIZED BY IRREVERSIBLE DISABILITY AT LATER PROGRESSIVE STAGES. A GROWING BODY OF EVIDENCE SUGGESTS THAT DISEASE PROGRESSION DEPENDS ON AGE AND INFLAMMATION WITHIN THE CNS. WE AIMED TO INVESTIGATE EPIGENETIC AGING IN BULK BRAIN TISSUE AND SORTED NUCLEI FROM MS PATIENTS USING DNA METHYLATION-BASED EPIGENETIC CLOCKS. METHODS: WE APPLIED HORVATH'S MULTI-TISSUE AND SHIREBY'S BRAIN-SPECIFIC CORTICAL CLOCK ON BULK BRAIN TISSUE (N = 46), SORTED NEURONAL (N = 54), AND GLIAL NUCLEI (N = 66) FROM POST-MORTEM BRAIN TISSUE OF PROGRESSIVE MS PATIENTS AND CONTROLS. RESULTS: WE FOUND A SIGNIFICANT INCREASE IN AGE ACCELERATION RESIDUALS, CORRESPONDING TO 3.6 YEARS, IN GLIAL CELLS OF MS PATIENTS COMPARED TO CONTROLS (P = 0.0024) USING THE CORTICAL CLOCK, WHICH HELD AFTER ADJUSTMENT FOR COVARIATES (P (ADJ) = 0.0263). THE 4.8-YEAR AGE ACCELERATION FOUND IN MS NEURONS (P = 0.0054) DID NOT WITHSTAND ADJUSTMENT FOR COVARIATES AND NO SIGNIFICANT DIFFERENCE IN AGE ACCELERATION RESIDUALS WAS OBSERVED IN BULK BRAIN TISSUE BETWEEN MS PATIENTS AND CONTROLS. CONCLUSION: WHILE THE FINDINGS WARRANT REPLICATION IN LARGER COHORTS, OUR STUDY SUGGESTS THAT GLIAL CELLS OF PROGRESSIVE MS PATIENTS EXHIBIT ACCELERATED BIOLOGICAL AGING.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11 6017  46 THE ASSOCIATION OF ACCELERATED EPIGENETIC AGE WITH ALL-CAUSE MORTALITY IN CARDIAC CATHETERIZATION PATIENTS AS MEDIATED BY VASCULAR AND CARDIOMETABOLIC OUTCOMES. BACKGROUND: EPIGENETIC AGE IS A DNA METHYLATION-BASED BIOMARKER OF AGING THAT IS ACCURATE ACROSS THE LIFESPAN AND A RANGE OF CELL TYPES. THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE, TERMED AGE ACCELERATION (AA), IS A STRONG PREDICTOR OF LIFESPAN AND HEALTHSPAN. THE PREDICTIVE CAPABILITIES OF AA FOR ALL-CAUSE MORTALITY HAVE BEEN EVALUATED IN THE GENERAL POPULATION; HOWEVER, ITS UTILITY IS LESS WELL EVALUATED IN THOSE WITH CHRONIC CONDITIONS. ADDITIONALLY, THE PATHOPHYSIOLOGIC PATHWAYS WHEREBY AA PREDICTS MORTALITY ARE UNCLEAR. WE HYPOTHESIZED THAT AA PREDICTS MORTALITY IN INDIVIDUALS WITH UNDERLYING CARDIOVASCULAR DISEASE; AND THE ASSOCIATION BETWEEN AA AND MORTALITY IS MEDIATED, IN PART, BY VASCULAR AND CARDIOMETABOLIC MEASURES. METHODS: WE EVALUATED 562 PARTICIPANTS IN AN URBAN, THREE-COUNTY AREA OF CENTRAL NORTH CAROLINA FROM THE CATHGEN COHORT, ALL OF WHOM RECEIVED A CARDIAC CATHETERIZATION PROCEDURE. WE ANALYZED THREE AA BIOMARKERS, HORVATH EPIGENETIC AGE ACCELERATION (HAA), PHENOTYPIC AGE ACCELERATION (PHENOAA), AND GRIM AGE ACCELERATION (GRIMAA), BY COX REGRESSION MODELS, TO ASSESS WHETHER AAS WERE ASSOCIATED WITH ALL-CAUSE MORTALITY. WE ALSO EVALUATED IF THESE ASSOCIATIONS WERE MEDIATED BY VASCULAR AND CARDIOMETABOLIC OUTCOMES, INCLUDING LEFT VENTRICULAR EJECTION FRACTION (LVEF), BLOOD CHOLESTEROL CONCENTRATIONS, ANGIOPOIETIN-2 (ANG2) PROTEIN CONCENTRATION, PERIPHERAL ARTERY DISEASE, CORONARY ARTERY DISEASE, DIABETES, AND HYPERTENSION. THE TOTAL EFFECT, DIRECT EFFECT, INDIRECT EFFECT, AND PERCENTAGE MEDIATED WERE ESTIMATED USING PATHWAY MEDIATION TESTS WITH A REGRESSION ADJUSTMENT APPROACH. RESULTS: PHENOAA (HR = 1.05, P < 0.0001), GRIMAA (HR = 1.10, P < 0.0001) AND HAA (HR = 1.03, P = 0.01) WERE ALL ASSOCIATED WITH ALL-CAUSE MORTALITY. THE ASSOCIATION OF MORTALITY AND PHENOAA WAS PARTIALLY MEDIATED BY ANG2, A MARKER OF VASCULAR FUNCTION (19.8%, P = 0.016), AND BY DIABETES (8.2%, P = 0.043). THE GRIMAA-MORTALITY ASSOCIATION WAS MEDIATED BY ANG2 (12.3%, P = 0.014), AND SHOWED WEAKER EVIDENCE FOR MEDIATION BY LVEF (5.3%, P = 0.065). CONCLUSIONS: EPIGENETIC AGE ACCELERATION REMAINS STRONGLY PREDICTIVE OF MORTALITY EVEN IN INDIVIDUALS ALREADY BURDENED WITH CARDIOVASCULAR DISEASE. MORTALITY ASSOCIATIONS WERE MEDIATED BY ANG2, WHICH REGULATES ENDOTHELIAL PERMEABILITY AND ANGIOGENIC FUNCTIONS, SUGGESTING THAT SPECIFIC VASCULAR PATHOPHYSIOLOGY MAY LINK ACCELERATED EPIGENETIC AGING WITH INCREASED MORTALITY RISKS.	2022	

12  177  31 ACCELERATED EPIGENETIC AGING AND INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) IN PATIENTS WITH CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY A REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). THIS FAILURE CAN BE RELATED TO A PHENOTYPE OF ACCELERATED AGING. IN THIS WORK, WE CONSIDERED 76 PATIENTS WITH END-STAGE RENAL DISEASE (ESRD) AND 83 HEALTHY CONTROLS. WE CONCOMITANTLY EVALUATED FOR THE FIRST TIME TWO MEASURES THAT CAN BE INFORMATIVE OF THE RATE OF AGING, I.E., WHOLE BLOOD DNA METHYLATION USING THE ILLUMINA INFINIUM EPIC ARRAY AND PLASMA LEVELS OF A SELECTION OF INFLAMMATORY/IMMUNOLOGICAL PROTEINS USING MULTIPLEX IMMUNOASSAYS. FIRST OF ALL, WE DEMONSTRATED ACCELERATED AGING IN TERMS OF THE MOST COMMON EPIGENETIC AGE ESTIMATORS IN CKD PATIENTS. MOREOVER, WE DEVELOPED A NEW CLOCK/PREDICTOR OF AGE BASED ON THE INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) AND IDENTIFIED THE INFLAMMATORY/IMMUNOLOGICAL BIOMARKERS DIFFERENTIALLY EXPRESSED BETWEEN CASES AND CONTROLS. IPAGE APPEARED TO BE MORE SENSITIVE THAN EPIGENETIC CLOCKS IN QUANTIFYING THE ACCELERATED AGING PHENOTYPE OF ESRD PATIENTS. INTERESTINGLY, WE DID NOT FIND ANY CORRELATION BETWEEN THE AGE ACCELERATION EVALUATED ACCORDING TO THE EPIGENETIC CLOCKS AND IPAGE IN EITHER THE ESRD GROUP OR THE CONTROL GROUP. ON THE WHOLE, OUR DATA SHOW A CONSISTENT ACCELERATED AGING PHENOTYPE IN ESRD PATIENTS, WHICH IS BETTER APPRECIATED BY QUANTIFYING THE UNDERLYING INFLAMMATORY PROCESSES (INFLAMMAGING) BY IPAGE THAN BY USING EPIGENETIC CLOCKS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13 1952  29 EPIGENETIC AGE ACCELERATION AMONG SURVIVORS OF PEDIATRIC MEDULLOBLASTOMA AND PRIMITIVE NEUROECTODERMAL TUMOR. SURVIVORS OF CHILDHOOD CENTRAL NERVOUS SYSTEM (CNS) TUMORS EXPERIENCE EARLY-ONSET AGING-RELATED PHENOTYPES. DNA METHYLATION (DNAM) AGE IS AN EMERGING EPIGENETIC BIOMARKER OF PHYSIOLOGIC AGE AND MAY BE PREDICTIVE OF CHRONIC HEALTH CONDITIONS IN LONG-TERM SURVIVORS. THIS REPORT DESCRIBES THE COURSE OF EPIGENETIC AGE ACCELERATION USING POST-DIAGNOSIS BLOOD SAMPLES (MEDIAN: 3.9 YEARS POST-DIAGNOSIS; RANGE: 0.04-15.96) FROM 83 SURVIVORS OF PEDIATRIC CNS TUMORS. EPIGENETIC AGE ACCELERATION WAS DETECTED IN 72% OF PATIENTS, WITH AN AVERAGE DIFFERENCE BETWEEN CHRONOLOGIC AND DNAM AGE OF 2.58 YEARS (95% CI: 1.75-3.41, P < 0.001). TIME FROM DIAGNOSIS TO SAMPLE COLLECTION CORRELATED WITH THE MAGNITUDE OF EPIGENETIC AGE ACCELERATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
14  816  42 CHARACTERISATION OF AN INFLAMMATION-RELATED EPIGENETIC SCORE AND ITS ASSOCIATION WITH COGNITIVE ABILITY. BACKGROUND: CHRONIC SYSTEMIC INFLAMMATION HAS BEEN ASSOCIATED WITH INCIDENT DEMENTIA, BUT ITS ASSOCIATION WITH AGE-RELATED COGNITIVE DECLINE IS LESS CLEAR. THE ACUTE RESPONSES OF MANY INFLAMMATORY BIOMARKERS MEAN THEY MAY PROVIDE AN UNRELIABLE PICTURE OF THE CHRONICITY OF INFLAMMATION. RECENTLY, A LARGE-SCALE EPIGENOME-WIDE ASSOCIATION STUDY IDENTIFIED DNA METHYLATION CORRELATES OF C-REACTIVE PROTEIN (CRP)-A WIDELY USED ACUTE-PHASE INFLAMMATORY BIOMARKER. DNA METHYLATION IS THOUGHT TO BE RELATIVELY STABLE IN THE SHORT TERM, MARKING IT AS A POTENTIALLY USEFUL SIGNATURE OF EXPOSURE. METHODS: WE UTILISE A DNA METHYLATION-BASED SCORE FOR CRP AND INVESTIGATE ITS TRAJECTORIES WITH AGE, AND ASSOCIATIONS WITH COGNITIVE ABILITY IN COMPARISON WITH SERUM CRP AND A GENETIC CRP SCORE IN A LONGITUDINAL STUDY OF OLDER ADULTS (N = 889) AND A LARGE, CROSS-SECTIONAL COHORT (N = 7028). RESULTS: WE IDENTIFIED NO HOMOGENEOUS TRAJECTORIES OF SERUM CRP WITH AGE ACROSS THE COHORTS, WHEREAS THE EPIGENETIC CRP SCORE WAS CONSISTENTLY FOUND TO INCREASE WITH AGE (STANDARDISED BETA = 0.07 AND 0.01) AND TO DO SO MORE RAPIDLY IN MALES COMPARED TO FEMALES. ADDITIONALLY, THE EPIGENETIC CRP SCORE HAD HIGHER TEST-RETEST RELIABILITY COMPARED TO SERUM CRP, INDICATING ITS ENHANCED TEMPORAL STABILITY. HIGHER SERUM CRP WAS NOT FOUND TO BE ASSOCIATED WITH POORER COGNITIVE ABILITY (STANDARDISED BETA = - 0.08 AND - 0.05); HOWEVER, A CONSISTENT NEGATIVE ASSOCIATION WAS IDENTIFIED BETWEEN COGNITIVE ABILITY AND THE EPIGENETIC CRP SCORE IN BOTH COHORTS (STANDARDISED BETA = - 0.15 AND - 0.08). CONCLUSIONS: AN EPIGENETIC PROXY OF CRP MAY PROVIDE A MORE RELIABLE SIGNATURE OF CHRONIC INFLAMMATION, ALLOWING FOR MORE ACCURATE STRATIFICATION OF INDIVIDUALS, AND THUS CLEARER INFERENCE OF ASSOCIATIONS WITH INCIDENT HEALTH OUTCOMES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15 1537  27 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16 3914  40 LIFETIME STRESS ACCELERATES EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT: RELEVANCE OF GLUCOCORTICOID SIGNALING. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ACCELERATED AGING AND INCREASED RISK FOR AGING-RELATED DISEASES, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNCLEAR. RESULTS: WE EXAMINED THE EFFECT OF LIFETIME STRESSORS ON A DNA METHYLATION-BASED AGE PREDICTOR, EPIGENETIC CLOCK. AFTER CONTROLLING FOR BLOOD CELL-TYPE COMPOSITION AND LIFESTYLE PARAMETERS, CUMULATIVE LIFETIME STRESS, BUT NOT CHILDHOOD MALTREATMENT OR CURRENT STRESS ALONE, PREDICTED ACCELERATED EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT (N = 392). THIS EFFECT WAS PRIMARILY DRIVEN BY PERSONAL LIFE STRESSORS, WAS MORE PRONOUNCED WITH ADVANCING AGE, AND WAS BLUNTED IN INDIVIDUALS WITH HIGHER CHILDHOOD ABUSE EXPOSURE. HYPOTHESIZING THAT THESE EPIGENETIC EFFECTS COULD BE MEDIATED BY GLUCOCORTICOID SIGNALING, WE FOUND THAT A HIGH NUMBER (N = 85) OF EPIGENETIC CLOCK CPG SITES WERE LOCATED WITHIN GLUCOCORTICOID RESPONSE ELEMENTS. WE FURTHER EXAMINED THE FUNCTIONAL EFFECTS OF GLUCOCORTICOIDS ON EPIGENETIC CLOCK CPGS IN AN INDEPENDENT SAMPLE WITH GENOME-WIDE DNA METHYLATION (N = 124) AND GENE EXPRESSION DATA (N = 297) BEFORE AND AFTER EXPOSURE TO THE GLUCOCORTICOID RECEPTOR AGONIST DEXAMETHASONE. DEXAMETHASONE INDUCED DYNAMIC CHANGES IN METHYLATION IN 31.2 % (110/353) OF THESE CPGS AND TRANSCRIPTION IN 81.7 % (139/170) OF GENES NEIGHBORING EPIGENETIC CLOCK CPGS. DISEASE ENRICHMENT ANALYSIS OF THESE DEXAMETHASONE-REGULATED GENES SHOWED ENRICHED ASSOCIATION FOR AGING-RELATED DISEASES, INCLUDING CORONARY ARTERY DISEASE, ARTERIOSCLEROSIS, AND LEUKEMIAS. CONCLUSIONS: CUMULATIVE LIFETIME STRESS MAY ACCELERATE EPIGENETIC AGING, AN EFFECT THAT COULD BE DRIVEN BY GLUCOCORTICOID-INDUCED EPIGENETIC CHANGES. THESE FINDINGS CONTRIBUTE TO OUR UNDERSTANDING OF MECHANISMS LINKING CHRONIC STRESS WITH ACCELERATED AGING AND HEIGHTENED DISEASE RISK.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17 3568  29 IMPACT OF INFLAMMATION ON EPIGENETIC DNA METHYLATION - A NOVEL RISK FACTOR FOR CARDIOVASCULAR DISEASE? OBJECTIVE: THE LIFESPAN OF DIALYSIS PATIENTS IS AS SHORT AS IN PATIENTS WITH METASTATIC CANCER DISEASE, MAINLY DUE TO CARDIOVASCULAR DISEASE (CVD). DNA METHYLATION IS AN IMPORTANT CELLULAR MECHANISM MODULATING GENE EXPRESSION ASSOCIATED WITH AGEING, INFLAMMATION AND ATHEROSCLEROTIC PROCESSES. DESIGN: DNA METHYLATION WAS ANALYSED IN PERIPHERAL BLOOD LEUCOCYTES FROM THREE DIFFERENT GROUPS OF CHRONIC KIDNEY DISEASE (CKD) POPULATIONS (37 CKD STAGES 3 AND 4 PATIENTS, 98 CKD STAGE 5 PATIENTS AND 20 PREVALENT HAEMODIALYSIS PATIENTS). THIRTY-SIX HEALTHY SUBJECTS SERVED AS CONTROLS. CLINICAL CHARACTERISTICS (DIABETES MELLITUS, NUTRITIONAL STATUS AND PRESENCE OF CLINICAL CVD), INFLAMMATION AND OXIDATIVE STRESS BIOMARKERS, HOMOCYSTEINE AND GLOBAL DNA METHYLATION IN PERIPHERAL BLOOD LEUCOCYTES (DEFINED AS HPAII/MSPI RATIO BY THE LUMINOMETRIC METHYLATION ASSAY METHOD) WERE EVALUATED. CKD STAGE 5 PATIENTS (N=98) STARTING DIALYSIS TREATMENT WERE FOLLOWED FOR A PERIOD OF 36 +/- 2 MONTHS. RESULTS: INFLAMED PATIENTS HAD LOWER RATIOS OF HPAII/MSPI, INDICATING GLOBAL DNA HYPERMETHYLATION. ANALYSIS BY THE COX REGRESSION MODEL DEMONSTRATED THAT DNA HYPERMETHYLATION (HPAII/MSPI RATIO <MEDIAN) WAS SIGNIFICANTLY ASSOCIATED WITH BOTH ALL-CAUSE (RR 5.0; 95% CI: 1.7-14.8; P<0.01) AND CARDIOVASCULAR (RR 13.9; 95% CI: 1.8-109.3; P<0.05) MORTALITY, EVEN FOLLOWING THE ADJUSTMENT FOR AGE, CVD, DIABETES MELLITUS AND INFLAMMATION. CONCLUSION: THE PRESENT STUDY DEMONSTRATES THAT GLOBAL DNA HYPERMETHYLATION IS ASSOCIATED WITH INFLAMMATION AND INCREASED MORTALITY IN CKD.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
18 2627  38 EPIGENOME-WIDE ASSOCIATION STUDY OF ADIPOSITY AND FUTURE RISK OF OBESITY-RELATED DISEASES. BACKGROUND: OBESITY IS AN ESTABLISHED RISK FACTOR FOR SEVERAL COMMON CHRONIC DISEASES SUCH AS BREAST AND COLORECTAL CANCER, METABOLIC AND CARDIOVASCULAR DISEASES; HOWEVER, THE BIOLOGICAL BASIS FOR THESE RELATIONSHIPS IS NOT FULLY UNDERSTOOD. TO EXPLORE THE ASSOCIATION OF OBESITY WITH THESE CONDITIONS, WE INVESTIGATED PERIPHERAL BLOOD LEUCOCYTE (PBL) DNA METHYLATION MARKERS FOR ADIPOSITY AND THEIR CONTRIBUTION TO RISK OF INCIDENT BREAST AND COLORECTAL CANCER AND MYOCARDIAL INFARCTION. METHODS: DNA METHYLATION PROFILES (ILLUMINA INFINIUM((R)) HUMANMETHYLATION450 BEADCHIP) FROM 1941 INDIVIDUALS FROM FOUR POPULATION-BASED EUROPEAN COHORTS WERE ANALYSED IN RELATION TO BODY MASS INDEX, WAIST CIRCUMFERENCE, WAIST-HIP AND WAIST-HEIGHT RATIO WITHIN A META-ANALYTICAL FRAMEWORK. IN A SUBSET OF THESE INDIVIDUALS, DATA ON GENOME-WIDE GENE EXPRESSION LEVEL, BIOMARKERS OF GLUCOSE AND LIPID METABOLISM WERE ALSO AVAILABLE. VALIDATION OF METHYLATION MARKERS ASSOCIATED WITH ALL ADIPOSITY MEASURES WAS PERFORMED IN 358 INDIVIDUALS. FINALLY, WE INVESTIGATED THE ASSOCIATION OF OBESITY-RELATED METHYLATION MARKS WITH BREAST, COLORECTAL CANCER AND MYOCARDIAL INFARCTION WITHIN RELEVANT SUBSETS OF THE DISCOVERY POPULATION. RESULTS: WE IDENTIFIED 40 CPG LOCI WITH METHYLATION LEVELS ASSOCIATED WITH AT LEAST ONE ADIPOSITY MEASURE. OF THESE, ONE CPG LOCUS (CG06500161) IN ABCG1 WAS ASSOCIATED WITH ALL FOUR ADIPOSITY MEASURES (P = 9.07X10(-)(8) TO 3.27X10(-18)) AND LOWER TRANSCRIPTIONAL ACTIVITY OF THE FULL-LENGTH ISOFORM OF ABCG1 (P = 6.00X10(-7)), HIGHER TRIGLYCERIDE LEVELS (P = 5.37X10(-)(9)) AND HIGHER TRIGLYCERIDES-TO-HDL CHOLESTEROL RATIO (P = 1.03X10(-10)). OF THE 40 INFORMATIVE AND OBESITY-RELATED CPG LOCI, TWO (IN IL2RB AND FGF18) WERE SIGNIFICANTLY ASSOCIATED WITH COLORECTAL CANCER (INVERSELY, P < 1.6X10(-3)) AND ONE INTERGENIC LOCUS ON CHROMOSOME 1 WAS INVERSELY ASSOCIATED WITH MYOCARDIAL INFARCTION (P < 1.25X10(-3)), INDEPENDENTLY OF OBESITY AND ESTABLISHED RISK FACTORS. CONCLUSION: OUR RESULTS SUGGEST THAT EPIGENETIC CHANGES, IN PARTICULAR ALTERED DNA METHYLATION PATTERNS, MAY BE AN INTERMEDIATE BIOMARKER AT THE INTERSECTION OF OBESITY AND OBESITY-RELATED DISEASES, AND COULD OFFER CLUES AS TO UNDERLYING BIOLOGICAL MECHANISMS.	2018	
                                                                                                                                                                                                                                                                                                        
19 1351  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20 1607  28 DNA METHYLATION, COLON CANCER AND MEDITERRANEAN DIET: RESULTS FROM THE EPIC-ITALY COHORT. THE BIOLOGICAL MECHANISMS THROUGH WHICH ADHERENCE TO MEDITERRANEAN DIET (MD) PROTECTS AGAINST COLON CANCER (CC) ARE POORLY UNDERSTOOD. EVIDENCE SUGGESTS THAT CHRONIC INFLAMMATION MAY BE IMPLICATED IN THE PATHWAY. BOTH DIET AND CC ARE RELATED TO EPIGENETIC REGULATION. WE PERFORMED A NESTED CASE-CONTROL STUDY ON 161 PAIRS FROM THE ITALIAN COMPONENT OF THE EUROPEAN PROSPECTIVE INVESTIGATION INTO CANCER AND NUTRITION (EPIC) COHORT, IN WHICH WE LOOKED FOR THE METHYLATION SIGNALS IN DNA EXTRACTED FROM LEUCOCYTES ASSOCIATED WITH BOTH CC AND MD IN 995 CPGS LOCATED IN 48 INFLAMMATION GENES. THE DNA METHYLATION SIGNALS DETECTED IN THIS ANALYSIS WERE VALIDATED IN A SUBGROUP OF 47 CASE-CONTROL PAIRS AND FURTHER REPLICATED (WHERE VALIDATED) IN 95 NEW PAIRS BY MEANS OF PYROSEQUENCING. AMONG THE CPG SITES SELECTED A-PRIORI IN INFLAMMATION-RELATED GENES, SEVEN CPG SITES WERE FOUND TO BE ASSOCIATED WITH CC STATUS AND WITH MD, IN LINE WITH ITS PROTECTIVE EFFECT. ONLY TWO CPG SITES (CG17968347-SERPINE1 AND CG20674490-RUNX3) WERE VALIDATED USING BISULPHITE PYROSEQUENCING AND, AFTER REPLICATION, WE FOUND THAT DNA METHYLATION OF CG20674490-RUNX3 MAY BE A POTENTIAL MOLECULAR MEDIATOR EXPLAINING THE PROTECTIVE EFFECT OF MD ON CC ONSET. THE USE OF A 'MEET-IN-THE-MIDDLE' APPROACH TO IDENTIFY THE OVERLAP BETWEEN EXPOSURE AND PREDICTIVE MARKERS OF DISEASE IS INNOVATIVE IN STUDIES ON THE RELATIONSHIP BETWEEN DIET AND CANCER, IN WHICH EXPOSURE ASSESSMENT IS DIFFICULT AND THE MECHANISMS THROUGH WHICH THE NUTRIENTS EXERT THEIR PROTECTIVE EFFECT IS LARGELY UNKNOWN.	2019