1 1625 198 DNAM-BASED SIGNATURES OF ACCELERATED AGING AND MORTALITY IN BLOOD ARE ASSOCIATED WITH LOW RENAL FUNCTION. BACKGROUND: THE DIFFERENCE BETWEEN AN INDIVIDUAL'S CHRONOLOGICAL AND DNA METHYLATION PREDICTED AGE (DNAMAGE), TERMED DNAMAGE ACCELERATION (DNAMAA), CAN CAPTURE LIFE-LONG ENVIRONMENTAL EXPOSURES AND AGE-RELATED PHYSIOLOGICAL CHANGES REFLECTED IN METHYLATION STATUS. SEVERAL STUDIES HAVE LINKED DNAMAA TO MORBIDITY AND MORTALITY, YET ITS RELATIONSHIP WITH KIDNEY FUNCTION HAS NOT BEEN ASSESSED. WE EVALUATED THE ASSOCIATIONS BETWEEN SEVEN DNAM AGING AND LIFESPAN PREDICTORS (AS WELL AS GRIMAGE COMPONENTS) AND FIVE KIDNEY TRAITS (ESTIMATED GLOMERULAR FILTRATION RATE [EGFR], URINE ALBUMIN-TO-CREATININE RATIO [UACR], SERUM URATE, MICROALBUMINURIA AND CHRONIC KIDNEY DISEASE [CKD]) IN UP TO 9688 EUROPEAN, AFRICAN AMERICAN AND HISPANIC/LATINO INDIVIDUALS FROM SEVEN POPULATION-BASED STUDIES. RESULTS: WE IDENTIFIED 23 SIGNIFICANT ASSOCIATIONS IN OUR LARGE TRANS-ETHNIC META-ANALYSIS (P < 1.43E-03 AND CONSISTENT DIRECTION OF EFFECT ACROSS STUDIES). AGE ACCELERATION MEASURED BY THE EXTRINSIC AND PHENOAGE ESTIMATORS, AS WELL AS ZHANG'S 10-CPG EPIGENETIC MORTALITY RISK SCORE (MRS), WERE ASSOCIATED WITH ALL PARAMETERS OF POOR KIDNEY HEALTH (LOWER EGFR, PREVALENT CKD, HIGHER UACR, MICROALBUMINURIA AND HIGHER SERUM URATE). SIX OF THESE ASSOCIATIONS WERE INDEPENDENTLY OBSERVED IN EUROPEAN AND AFRICAN AMERICAN POPULATIONS. MRS IN PARTICULAR WAS CONSISTENTLY ASSOCIATED WITH EGFR (BETA = - 0.12, 95% CI = [- 0.16, - 0.08] CHANGE IN LOG-TRANSFORMED EGFR PER UNIT INCREASE IN MRS, P = 4.39E-08), PREVALENT CKD (ODDS RATIO (OR) = 1.78 [1.47, 2.16], P = 2.71E-09) AND HIGHER SERUM URATE LEVELS (BETA = 0.12 [0.07, 0.16], P = 2.08E-06). THE "FIRST-GENERATION" CLOCKS (HANNUM, HORVATH) AND GRIMAGE SHOWED DIFFERENT PATTERNS OF ASSOCIATION WITH THE KIDNEY TRAITS. THREE OF THE DNAM-ESTIMATED COMPONENTS OF GRIMAGE, NAMELY ADRENOMEDULLIN, PLASMINOGEN-ACTIVATION INHIBITION 1 AND PACK YEARS, WERE POSITIVELY ASSOCIATED WITH HIGHER UACR, SERUM URATE AND MICROALBUMINURIA. CONCLUSION: DNAMAGE ACCELERATION AND DNAM MORTALITY PREDICTORS ESTIMATED IN WHOLE BLOOD WERE ASSOCIATED WITH MULTIPLE KIDNEY TRAITS, INCLUDING EGFR AND CKD, IN THIS MULTI-ETHNIC STUDY. EPIGENETIC BIOMARKERS WHICH REFLECT THE SYSTEMIC EFFECTS OF AGE-RELATED MECHANISMS SUCH AS IMMUNOSENESCENCE, INFLAMMAGING AND OXIDATIVE STRESS MAY HAVE IMPORTANT MECHANISTIC OR PROGNOSTIC ROLES IN KIDNEY DISEASE. OUR STUDY HIGHLIGHTS NEW FINDINGS LINKING KIDNEY DISEASE TO BIOLOGICAL AGING, AND OPPORTUNITIES WARRANTING FUTURE INVESTIGATION INTO DNA METHYLATION BIOMARKERS FOR PROGNOSTIC OR RISK STRATIFICATION IN KIDNEY DISEASE.	2021	

2 4502  54 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
3 2485  50 EPIGENETIC-BASED AGE ACCELERATION IN A REPRESENTATIVE SAMPLE OF OLDER AMERICANS: ASSOCIATIONS WITH AGING-RELATED MORBIDITY AND MORTALITY. BIOMARKERS DEVELOPED FROM DNA METHYLATION (DNAM) DATA ARE OF GROWING INTEREST AS PREDICTORS OF HEALTH OUTCOMES AND MORTALITY IN OLDER POPULATIONS. HOWEVER, IT IS UNKNOWN HOW EPIGENETIC AGING FITS WITHIN THE CONTEXT OF KNOWN SOCIOECONOMIC AND BEHAVIORAL ASSOCIATIONS WITH AGING-RELATED HEALTH OUTCOMES IN A LARGE, POPULATION-BASED, AND DIVERSE SAMPLE. THIS STUDY USES DATA FROM A REPRESENTATIVE, PANEL STUDY OF US OLDER ADULTS TO EXAMINE THE RELATIONSHIP BETWEEN DNAM-BASED AGE ACCELERATION MEASURES IN THE PREDICTION OF CROSS-SECTIONAL AND LONGITUDINAL HEALTH OUTCOMES AND MORTALITY. WE EXAMINE WHETHER RECENT IMPROVEMENTS TO THESE SCORES, USING PRINCIPAL COMPONENT (PC)-BASED MEASURES DESIGNED TO REMOVE SOME OF THE TECHNICAL NOISE AND UNRELIABILITY IN MEASUREMENT, IMPROVE THE PREDICTIVE CAPABILITY OF THESE MEASURES. WE ALSO EXAMINE HOW WELL DNAM-BASED MEASURES PERFORM AGAINST WELL-KNOWN PREDICTORS OF HEALTH OUTCOMES SUCH AS DEMOGRAPHICS, SES, AND HEALTH BEHAVIORS. IN OUR SAMPLE, AGE ACCELERATION CALCULATED USING "SECOND AND THIRD GENERATION CLOCKS," PHENOAGE, GRIMAGE, AND DUNEDINPACE, IS CONSISTENTLY A SIGNIFICANT PREDICTOR OF HEALTH OUTCOMES INCLUDING CROSS-SECTIONAL COGNITIVE DYSFUNCTION, FUNCTIONAL LIMITATIONS AND CHRONIC CONDITIONS ASSESSED 2 Y AFTER DNAM MEASUREMENT, AND 4-Y MORTALITY. PC-BASED EPIGENETIC AGE ACCELERATION MEASURES DO NOT SIGNIFICANTLY CHANGE THE RELATIONSHIP OF DNAM-BASED AGE ACCELERATION MEASURES TO HEALTH OUTCOMES OR MORTALITY COMPARED TO EARLIER VERSIONS OF THESE MEASURES. WHILE THE USEFULNESS OF DNAM-BASED AGE ACCELERATION AS A PREDICTOR OF LATER LIFE HEALTH OUTCOMES IS QUITE CLEAR, OTHER FACTORS SUCH AS DEMOGRAPHICS, SES, MENTAL HEALTH, AND HEALTH BEHAVIORS REMAIN EQUALLY, IF NOT MORE ROBUST, PREDICTORS OF LATER LIFE OUTCOMES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4  177  46 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5  501  56 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6 6017  59 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	
                                               
7 5395  60 REDUCED EPIGENETIC AGE IN OLDER ADULTS WITH HIGH SENSE OF PURPOSE IN LIFE. PSYCHOSOCIAL RISK FACTORS HAVE BEEN LINKED WITH ACCELERATED EPIGENETIC AGING, BUT LITTLE IS KNOWN ABOUT WHETHER PSYCHOSOCIAL RESILIENCE FACTORS (EG, SENSE OF PURPOSE IN LIFE) MIGHT REDUCE EPIGENETIC AGE ACCELERATION. IN THIS STUDY, WE TESTED IF OLDER ADULTS WHO EXPERIENCE HIGH LEVELS OF PURPOSE MIGHT SHOW REDUCED EPIGENETIC AGE ACCELERATION. WE EVALUATED THE RELATIONSHIP BETWEEN PURPOSE AND EPIGENETIC AGE ACCELERATION AS MEASURED BY 13 DNA METHYLATION (DNAM) "EPIGENETIC CLOCKS" ASSESSED IN 1 572 OLDER ADULTS FROM THE HEALTH AND RETIREMENT STUDY (MEAN AGE 70 YEARS). WE QUANTIFIED THE TOTAL ASSOCIATION BETWEEN PURPOSE AND DNAM AGE ACCELERATION AS WELL AS THE EXTENT TO WHICH THAT TOTAL ASSOCIATION MIGHT BE ATTRIBUTABLE TO DEMOGRAPHIC FACTORS, CHRONIC DISEASE, OTHER PSYCHOSOCIAL VARIABLES (EG, POSITIVE AFFECT), AND HEALTH-RELATED BEHAVIORS (HEAVY DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BODY MASS INDEX [BMI]). PURPOSE IN LIFE WAS ASSOCIATED WITH REDUCED EPIGENETIC AGE ACCELERATION ACROSS 4 "SECOND-GENERATION" DNAM CLOCKS OPTIMIZED FOR PREDICTING HEALTH AND LONGEVITY (FALSE DISCOVERY RATE [FDR] Q < 0.0001: PHENOAGE, GRIMAGE, ZHANG EPIGENETIC MORTALITY INDEX; FDR Q < 0.05: DUNEDINPOAM). THESE ASSOCIATIONS WERE INDEPENDENT OF DEMOGRAPHIC AND PSYCHOSOCIAL FACTORS, BUT SUBSTANTIALLY ATTENUATED AFTER ADJUSTING FOR HEALTH-RELATED BEHAVIORS (DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BMI). PURPOSE SHOWED NO SIGNIFICANT ASSOCIATION WITH 9 "FIRST-GENERATION" DNAM EPIGENETIC CLOCKS TRAINED ON CHRONOLOGICAL AGE. OLDER ADULTS WITH GREATER PURPOSE IN LIFE SHOW "YOUNGER" DNAM EPIGENETIC AGE ACCELERATION. THESE RESULTS MAY BE DUE IN PART TO ASSOCIATED DIFFERENCES IN HEALTH-RELATED BEHAVIORS. RESULTS SUGGEST NEW OPPORTUNITIES TO REDUCE BIOLOGICAL AGE ACCELERATION BY ENHANCING PURPOSE AND ITS BEHAVIORAL SEQUELAE IN LATE ADULTHOOD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8  173  49 ACCELERATED AGING IN BIPOLAR DISORDERS: AN EXPLORATORY STUDY OF SIX EPIGENETIC CLOCKS. BIPOLAR DISORDER (BD) IS A CHRONIC AND SEVERE PSYCHIATRIC DISORDER ASSOCIATED WITH SIGNIFICANT MEDICAL MORBIDITY AND REDUCED LIFE EXPECTANCY. IN THIS STUDY, WE ASSESSED ACCELERATED EPIGENETIC AGING IN INDIVIDUALS WITH BD USING VARIOUS DNA METHYLATION (DNAM)-BASED MARKERS. FOR THIS PURPOSE, WE USED FIVE EPIGENETIC CLOCKS (HORVATH, HANNUM, EN, PHENOAGE, AND GRIMAGE) AND A DNAM-BASED TELOMERE LENGTH CLOCK (DNAMTL). DNAM PROFILES WERE OBTAINED USING INFINIUM METHYLATIONEPIC ARRAYS FROM WHOLE-BLOOD SAMPLES OF 184 INDIVIDUALS WITH BD. WE ALSO ESTIMATED BLOOD CELL COUNTS BASED ON DNAM LEVELS FOR ADJUSTMENT. SIGNIFICANT CORRELATIONS BETWEEN CHRONOLOGICAL AGE AND EACH EPIGENETIC AGE ESTIMATED USING THE SIX DIFFERENT CLOCKS WERE OBSERVED. FOLLOWING ADJUSTMENT FOR BLOOD CELL COUNTS, WE FOUND THAT THE SIX EPIGENETIC AGEACCELS (AGE ACCELERATIONS) WERE SIGNIFICANTLY ASSOCIATED WITH THE BODY MASS INDEX. GRIMAGE AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH MALE SEX, SMOKING STATUS AND CHILDHOOD MALTREATMENT. DNAMTL AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH SMOKING STATUS. OVERALL, THIS STUDY SHOWED THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS IN BD. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS OF POTENTIAL DETERMINANTS OF AN ACCELERATED EPIGENETIC AGING IN BD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9 3568  46 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
10  816  48 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
11 4024  49 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	
                                                                                                                                                                                                                                                                                                                                                  
12  175  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
13 6508  44 TRAJECTORIES OF INFLAMMATORY BIOMARKERS OVER THE EIGHTH DECADE AND THEIR ASSOCIATIONS WITH IMMUNE CELL PROFILES AND EPIGENETIC AGEING. BACKGROUND: EPIGENETIC AGE ACCELERATION (AN OLDER METHYLATION AGE COMPARED TO CHRONOLOGICAL AGE) CORRELATES STRONGLY WITH VARIOUS AGE-RELATED MORBIDITIES AND MORTALITY. CHRONIC SYSTEMIC INFLAMMATION IS THOUGHT TO BE A HALLMARK OF AGEING, BUT THE RELATIONSHIP BETWEEN AN INCREASED EPIGENETIC AGE AND THIS LIKELY KEY PHENOTYPE OF AGEING HAS NOT YET BEEN EXTENSIVELY INVESTIGATED. METHODS: WE MODELLED THE TRAJECTORIES OF THE INFLAMMATORY BIOMARKERS C-REACTIVE PROTEIN (CRP; MEASURED USING BOTH A HIGH- AND LOW-SENSITIVITY ASSAY) AND INTERLEUKIN-6 (IL-6) OVER THE EIGHTH DECADE IN THE LOTHIAN BIRTH COHORT 1936. USING LINEAR MIXED MODELS, WE INVESTIGATED THE ASSOCIATION BETWEEN CRP AND IMMUNE CELL PROFILES IMPUTED FROM THE METHYLATION DATA AND EXAMINED THE CROSS-SECTIONAL AND LONGITUDINAL ASSOCIATION BETWEEN THE INFLAMMATORY BIOMARKERS AND TWO MEASURES OF EPIGENETIC AGE ACCELERATION, DERIVED FROM THE HORVATH AND HANNUM EPIGENETIC CLOCKS. RESULTS: WE FOUND THAT LOW-SENSITIVITY CRP DECLINED, HIGH-SENSITIVITY CRP DID NOT CHANGE, AND IL-6 INCREASED OVER TIME WITHIN THE COHORT. CRP LEVELS INVERSELY ASSOCIATED WITH CD8+T CELLS AND CD4+T CELLS AND POSITIVELY ASSOCIATED WITH SENESCENT CD8+T CELLS, PLASMABLASTS AND GRANULOCYTES. CROSS-SECTIONALLY, THE HANNUM, BUT NOT THE HORVATH, MEASURE OF AGE ACCELERATION WAS POSITIVELY ASSOCIATED WITH EACH OF THE INFLAMMATORY BIOMARKERS, INCLUDING A RESTRICTED MEASURE OF CRP (</= 10 MG/L) LIKELY REFLECTING LEVELS RELEVANT TO CHRONIC INFLAMMATION. CONCLUSIONS: WE FOUND A DIVERGENT RELATIONSHIP BETWEEN INFLAMMATION AND IMMUNE SYSTEM PARAMETERS IN OLDER AGE. WE ADDITIONALLY REPORT THE HANNUM MEASURE OF EPIGENETIC AGE ACCELERATION ASSOCIATED WITH AN ELEVATED INFLAMMATORY PROFILE CROSS-SECTIONALLY, BUT NOT LONGITUDINALLY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14 1962  55 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	
                                                                                                                                                                                                                                
15 2150  55 EPIGENETIC MEASURES OF AGEING PREDICT THE PREVALENCE AND INCIDENCE OF LEADING CAUSES OF DEATH AND DISEASE BURDEN. BACKGROUND: INDIVIDUALS OF THE SAME CHRONOLOGICAL AGE DISPLAY DIFFERENT RATES OF BIOLOGICAL AGEING. A NUMBER OF MEASURES OF BIOLOGICAL AGE HAVE BEEN PROPOSED WHICH HARNESS AGE-RELATED CHANGES IN DNA METHYLATION PROFILES. THESE MEASURES INCLUDE FIVE 'EPIGENETIC CLOCKS' WHICH PROVIDE AN INDEX OF HOW MUCH AN INDIVIDUAL'S BIOLOGICAL AGE DIFFERS FROM THEIR CHRONOLOGICAL AGE AT THE TIME OF MEASUREMENT. THE FIVE CLOCKS ENCOMPASS METHYLATION-BASED PREDICTORS OF CHRONOLOGICAL AGE (HORVATHAGE, HANNUMAGE), ALL-CAUSE MORTALITY (DNAM PHENOAGE, DNAM GRIMAGE) AND TELOMERE LENGTH (DNAM TELOMERE LENGTH). A SIXTH EPIGENETIC MEASURE OF AGEING DIFFERS FROM THESE CLOCKS IN THAT IT ACTS AS A SPEEDOMETER PROVIDING A SINGLE TIME-POINT MEASUREMENT OF THE PACE OF AN INDIVIDUAL'S BIOLOGICAL AGEING. THIS MEASURE OF AGEING IS TERMED DUNEDINPOAM. IN THIS STUDY, WE TEST THE ASSOCIATION BETWEEN THESE SIX EPIGENETIC MEASURES OF AGEING AND THE PREVALENCE AND INCIDENCE OF THE LEADING CAUSES OF DISEASE BURDEN AND MORTALITY IN HIGH-INCOME COUNTRIES (N </= 9537, GENERATION SCOTLAND: SCOTTISH FAMILY HEALTH STUDY). RESULTS: DNAM GRIMAGE PREDICTED INCIDENCE OF CLINICALLY DIAGNOSED CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), TYPE 2 DIABETES AND ISCHEMIC HEART DISEASE AFTER 13 YEARS OF FOLLOW-UP (HAZARD RATIOS = 2.22, 1.52 AND 1.41, RESPECTIVELY). DUNEDINPOAM PREDICTED THE INCIDENCE OF COPD AND LUNG CANCER (HAZARD RATIOS = 2.02 AND 1.45, RESPECTIVELY). DNAM PHENOAGE PREDICTED INCIDENCE OF TYPE 2 DIABETES (HAZARD RATIO = 1.54). DNAM TELOMERE LENGTH ASSOCIATED WITH THE INCIDENCE OF ISCHEMIC HEART DISEASE (HAZARD RATIO = 0.80). DNAM GRIMAGE ASSOCIATED WITH ALL-CAUSE MORTALITY, THE PREVALENCE OF COPD AND SPIROMETRY MEASURES AT THE STUDY BASELINE. THESE ASSOCIATIONS WERE PRESENT AFTER ADJUSTING FOR POSSIBLE CONFOUNDING RISK FACTORS INCLUDING ALCOHOL CONSUMPTION, BODY MASS INDEX, DEPRIVATION, EDUCATION AND TOBACCO SMOKING AND SURPASSED STRINGENT BONFERRONI-CORRECTED SIGNIFICANCE THRESHOLDS. CONCLUSIONS: OUR DATA SUGGEST THAT EPIGENETIC MEASURES OF AGEING MAY HAVE UTILITY IN CLINICAL SETTINGS TO COMPLEMENT GOLD-STANDARD METHODS FOR DISEASE ASSESSMENT AND MANAGEMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                       
16 1271  46 CYTOSINE METHYLATION PREDICTS RENAL FUNCTION DECLINE IN AMERICAN INDIANS. DIABETIC NEPHROPATHY ACCOUNTS FOR MOST OF THE EXCESS MORTALITY IN INDIVIDUALS WITH DIABETES, BUT THE MOLECULAR MECHANISMS BY WHICH NEPHROPATHY DEVELOPS ARE LARGELY UNKNOWN. HERE WE TESTED CYTOSINE METHYLATION LEVELS AT 397,063 GENOMIC CPG SITES FOR ASSOCIATION WITH DECLINE IN THE ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) OVER A SIX YEAR PERIOD IN 181 DIABETIC PIMA INDIANS. METHYLATION LEVELS AT 77 SITES SHOWED SIGNIFICANT ASSOCIATION WITH EGFR DECLINE AFTER CORRECTION FOR MULTIPLE COMPARISONS. A MODEL INCLUDING METHYLATION LEVEL AT TWO PROBES (CG25799291 AND CG22253401) IMPROVED PREDICTION OF EGFR DECLINE IN ADDITION TO BASELINE EGFR AND THE ALBUMIN TO CREATININE RATIO WITH THE PERCENT OF VARIANCE EXPLAINED SIGNIFICANTLY IMPROVING FROM 23.1% TO 42.2%. CG22253401 WAS ALSO SIGNIFICANTLY ASSOCIATED WITH EGFR DECLINE IN A CASE-CONTROL STUDY DERIVED FROM THE CHRONIC RENAL INSUFFICIENCY COHORT. PROBES AT WHICH METHYLATION SIGNIFICANTLY ASSOCIATED WITH EGFR DECLINE WERE LOCALIZED TO GENE REGULATORY REGIONS AND ENRICHED FOR GENES WITH METABOLIC FUNCTIONS AND APOPTOSIS. THREE OF THE 77 PROBES THAT WERE ASSOCIATED WITH EGFR DECLINE IN BLOOD SAMPLES SHOWED DIRECTIONALLY CONSISTENT AND SIGNIFICANT ASSOCIATION WITH FIBROSIS IN MICRODISSECTED HUMAN KIDNEY TISSUE, AFTER CORRECTION FOR MULTIPLE COMPARISONS. THUS, CYTOSINE METHYLATION LEVELS MAY PROVIDE BIOMARKERS OF DISEASE PROGRESSION IN DIABETIC NEPHROPATHY AND EPIGENETIC VARIATIONS CONTRIBUTE TO THE DEVELOPMENT OF DIABETIC KIDNEY DISEASE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17 1849  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18 6080  52 THE EFFECT OF DNA METHYLATION IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC KIDNEY DISEASE IN THE GENERAL POPULATION: AN EPIGENOME-WIDE ASSOCIATION STUDY USING THE KOREAN GENOME AND EPIDEMIOLOGY STUDY DATABASE. BACKGROUND: ALTHOUGH KNOWLEDGE OF THE GENETIC FACTORS INFLUENCING KIDNEY DISEASE IS INCREASING, EPIGENETIC PROFILES, WHICH ARE ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), HAVE NOT BEEN FULLY ELUCIDATED. WE SOUGHT TO IDENTIFY THE DNA METHYLATION STATUS OF CPG SITES ASSOCIATED WITH REDUCED KIDNEY FUNCTION AND EXAMINE WHETHER THE IDENTIFIED CPG SITES ARE ASSOCIATED WITH CKD DEVELOPMENT. METHOD: WE ANALYZED DNA METHYLATION PATTERNS OF 440 PARTICIPANTS IN THE KOREAN GENOME AND EPIDEMIOLOGY STUDY (KOGES) WITH ESTIMATED GLOMERULAR FILTRATION RATES (EGFRS) >/= 60 ML/MIN/1.73 M(2) AT BASELINE. CKD DEVELOPMENT WAS DEFINED AS A DECREASE IN THE EGFR OF <60 AT ANY TIME DURING AN 8-YEAR FOLLOW-UP PERIOD ("CKD PREDICTION" ANALYSIS). IN ADDITION, AMONG THE 440 PARTICIPANTS, 49 PARTICIPANTS WHO UNDERWENT A SECOND METHYLATION PROFILING WERE ASSESSED FOR AN ASSOCIATION BETWEEN A DECLINE IN KIDNEY FUNCTION AND CHANGES IN THE DEGREE OF METHYLATION OF CPG SITES DURING THE 8 YEARS ("KIDNEY FUNCTION SLOPE" ANALYSIS). RESULTS: IN THE CKD PREDICTION ANALYSIS, METHYLATION PROFILES OF A TOTAL OF 403,129 CPG SITES WERE EVALUATED AT BASELINE IN 440 PARTICIPANTS, AND INCREASED AND DECREASED METHYLATION OF 268 AND 189 CPG SITES, RESPECTIVELY, WERE SIGNIFICANTLY CORRELATED WITH THE DEVELOPMENT OF CKD IN MULTIVARIABLE LOGISTIC REGRESSION. DURING KIDNEY FUNCTION SLOPE ANALYSIS USING FOLLOW-UP METHYLATION PROFILES OF 49 PARTICIPANTS, THE PERCENT METHYLATION CHANGES IN 913 CPG SITES SHOWED A LINEAR RELATIONSHIP WITH THE PERCENT CHANGE IN EGFR DURING 8 YEARS. DURING FUNCTIONAL ENRICHMENT ANALYSES FOR SIGNIFICANT CPG SITES FOUND IN THE CKD PREDICTION AND KIDNEY FUNCTION SLOPE ANALYSES, WE FOUND THAT THOSE CPG SITES REPRESENTED MAPK, PI3K/AKT, AND RAP1 PATHWAYS. IN ADDITION, THREE CPG SITES FROM THREE GENES, NPHS2, CHCHD4, AND AHR, WERE FOUND TO BE SIGNIFICANT IN THE CKD PREDICTION ANALYSIS AND RELATED TO A DECLINE IN KIDNEY FUNCTION. CONCLUSION: IT IS SUGGESTED THAT DNA METHYLATION ON SPECIFIC GENES IS ASSOCIATED WITH THE DEVELOPMENT OF CKD AND THE DETERIORATION OF KIDNEY FUNCTION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                 
19 1512  53 DNA METHYLATION AND PROTEIN MARKERS OF CHRONIC INFLAMMATION AND THEIR ASSOCIATIONS WITH BRAIN AND COGNITIVE AGING. BACKGROUND AND OBJECTIVES: TO INVESTIGATE CHRONIC INFLAMMATION IN RELATION TO COGNITIVE AGING BY COMPARISON OF AN EPIGENETIC AND SERUM BIOMARKER OF C-REACTIVE PROTEIN AND THEIR ASSOCIATIONS WITH NEUROIMAGING AND COGNITIVE OUTCOMES. METHODS: AT BASELINE, PARTICIPANTS (N = 521) WERE COGNITIVELY NORMAL, AROUND 73 YEARS OF AGE (MEAN 72.4, SD 0.716), AND HAD INFLAMMATION, VASCULAR RISK (CARDIOVASCULAR DISEASE HISTORY, HYPERTENSION, DIABETES, SMOKING, ALCOHOL CONSUMPTION, BODY MASS INDEX), AND NEUROIMAGING (STRUCTURAL AND DIFFUSION MRI) DATA AVAILABLE. BASELINE INFLAMMATORY STATUS WAS QUANTIFIED BY A TRADITIONAL MEASURE OF PERIPHERAL INFLAMMATION-SERUM C-REACTIVE PROTEIN (CRP)-AND AN EPIGENETIC MEASURE (DNA METHYLATION [DNAM] SIGNATURE OF CRP). LINEAR MODELS WERE USED TO EXAMINE THE INFLAMMATION-BRAIN HEALTH ASSOCIATIONS; MEDIATION ANALYSES WERE PERFORMED TO INTERROGATE THE RELATIONSHIP BETWEEN CHRONIC INFLAMMATION, BRAIN STRUCTURE, AND COGNITIVE FUNCTIONING. RESULTS: WE DEMONSTRATE THAT DNAM CRP SHOWS SIGNIFICANTLY (ON AVERAGE 6.4-FOLD) STRONGER ASSOCIATIONS WITH BRAIN HEALTH OUTCOMES THAN SERUM CRP. DNAM CRP IS ASSOCIATED WITH TOTAL BRAIN VOLUME (BETA = -0.197, 95% CONFIDENCE INTERVAL [CI] -0.28 TO -0.12, P (FDR) = 8.42 X 10(-6)), GRAY MATTER VOLUME (BETA = -0.200, 95% CI -0.28 TO -0.12, P (FDR) = 1.66 X 10(-5)), AND WHITE MATTER VOLUME (BETA = -0.150, 95% CI -0.23 TO -0.07, P (FDR) = 0.001) AND REGIONAL BRAIN ATROPHY. WE ALSO FIND THAT DNAM CRP HAS AN INVERSE ASSOCIATION WITH GLOBAL AND DOMAIN-SPECIFIC (SPEED, VISUOSPATIAL, AND MEMORY) COGNITIVE FUNCTIONING AND THAT BRAIN STRUCTURE PARTIALLY MEDIATES THIS CRP-COGNITIVE ASSOCIATION (UP TO 29.7%), DEPENDENT ON LIFESTYLE AND HEALTH FACTORS. DISCUSSION: THESE RESULTS SUPPORT THE HYPOTHESIS THAT CHRONIC INFLAMMATION MAY CONTRIBUTE TO NEURODEGENERATIVE BRAIN CHANGES THAT UNDERLIE DIFFERENCES IN COGNITIVE ABILITY IN LATER LIFE AND HIGHLIGHT THE POTENTIAL OF DNAM PROXIES FOR INDEXING CHRONIC INFLAMMATORY STATUS. CLASSIFICATION OF EVIDENCE: THIS STUDY PROVIDES CLASS II EVIDENCE THAT A DNAM SIGNATURE OF CRP LEVELS IS MORE STRONGLY ASSOCIATED WITH BRAIN HEALTH OUTCOMES THAN SERUM CRP LEVELS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                             
20 5884  44 SYSTEMIC INFLAMMATION AND BIOLOGICAL AGING IN THE HEALTH AND RETIREMENT STUDY. CHRONIC, LOW-LEVEL SYSTEMIC INFLAMMATION ASSOCIATED WITH AGING, OR INFLAMMAGING, IS A RISK FACTOR FOR SEVERAL CHRONIC DISEASES AND MORTALITY. USING DATA FROM THE HEALTH AND RETIREMENT STUDY, WE GENERATED A CONTINUOUS LATENT VARIABLE FOR SYSTEMIC INFLAMMATION FROM SEVEN MEASURED INDICATORS OF INFLAMMATION AND EXAMINED ASSOCIATIONS WITH ANOTHER BIOMARKER OF BIOLOGICAL AGING, DNA METHYLATION AGE ACCELERATION MEASURED BY EPIGENETIC CLOCKS, AND 4-YEAR MORTALITY (N = 3,113). WE FOUND THAT GREATER SYSTEMIC INFLAMMATION WAS POSITIVELY ASSOCIATED WITH DNA METHYLATION AGE ACCELERATION FOR 10 OF THE 13 EPIGENETIC CLOCKS, AFTER ADJUSTMENT FOR SOCIODEMOGRAPHICS AND CHRONIC DISEASE RISK FACTORS. THE LATENT VARIABLE FOR SYSTEMIC INFLAMMATION WAS ASSOCIATED WITH 4-YEAR MORTALITY INDEPENDENT OF DNA METHYLATION AGE ACCELERATION AND WAS A BETTER PREDICTOR OF 4-YEAR MORTALITY THAN ANY OF THE EPIGENETIC CLOCKS EXAMINED, AS WELL AS MORTALITY RISK FACTORS, INCLUDING OBESITY AND MULTIMORBIDITY. INFLAMMAGING AND DNA METHYLATION AGE ACCELERATION MAY REPRESENT DIFFERENT BIOLOGICAL PROCESSES CONTRIBUTING TO MORTALITY RISK. LEVERAGING MULTIPLE MEASURED INFLAMMATION MARKERS TO CAPTURE INFLAMMAGING IS IMPORTANT FOR BIOLOGY OF AGING RESEARCH.	2023