1   525 119 ASSOCIATIONS OF BODY COMPOSITION AND PHYSICAL ACTIVITY LEVEL WITH MULTIPLE MEASURES OF EPIGENETIC AGE ACCELERATION. EPIGENETIC CLOCKS USE DNA METHYLATION TO ESTIMATE BIOLOGICAL AGE. WHETHER BODY COMPOSITION AND PHYSICAL ACTIVITY ARE ASSOCIATED WITH THESE CLOCKS IS NOT WELL UNDERSTOOD. USING BLOOD SAMPLES COLLECTED AT ENROLLMENT (2003-2009) FROM 2,758 WOMEN IN THE US NATIONWIDE SISTER STUDY, WE CALCULATED 6 EPIGENETIC AGE ACCELERATION METRICS USING 4 EPIGENETIC CLOCKS (HANNUM, HORVATH, PHENOAGE, GRIMAGE). RECREATIONAL PHYSICAL ACTIVITY WAS SELF-REPORTED, AND ADIPOSITY MEASURES WERE ASSESSED BY TRAINED MEDICAL EXAMINERS (BODY MASS INDEX (BMI), WAIST-TO-HIP RATIO (WTH), WAIST CIRCUMFERENCE). IN CROSS-SECTIONAL ANALYSES, ALL ADIPOSITY MEASURES WERE ASSOCIATED WITH EPIGENETIC AGE ACCELERATION. THE STRONGEST ASSOCIATION WAS FOR BMI AND PHENOAGE, A MEASURE OF BIOLOGICAL AGE THAT CORRELATES WITH CHRONIC DISEASE (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 3.15 YEARS, 95% CONFIDENCE INTERVAL (CI): 2.41, 3.90; P FOR TREND < 0.001). IN A MUTUAL-ADJUSTMENT MODEL, BOTH WERE ASSOCIATED WITH PHENOAGE AGE ACCELERATION (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 2.69 YEARS, 95% CI: 1.90, 3.48; P FOR TREND < 0.001; QUARTILE 4 VS.1 WTH, BETA = 1.00 YEARS, 95% CI: 0.34, 1.65; P FOR TREND < 0.008). AFTER ADJUSTMENT, PHYSICAL ACTIVITY WAS ASSOCIATED ONLY WITH GRIMAGE (QUARTILE 4 VS. 1, BETA = -0.42 YEARS, 95% CI: -0.70, -0.14; P FOR TREND = 0.001). PHYSICAL ACTIVITY ATTENUATED THE WAIST CIRCUMFERENCE ASSOCIATIONS WITH PHENOAGE AND GRIMAGE. EXCESS ADIPOSITY WAS ASSOCIATED WITH EPIGENETIC AGE ACCELERATION; PHYSICAL ACTIVITY MIGHT ATTENUATE ASSOCIATIONS WITH WAIST CIRCUMFERENCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2  6018  38 THE ASSOCIATION OF EPIGENETIC AGE ACCELERATION AND MULTIMORBIDITY AT AGE 90 IN THE WOMEN'S HEALTH INITIATIVE. BACKGROUND: EPIGENETIC AGE ACCELERATION (EAA), A MEASURE OF ACCELERATED BIOLOGICAL AGING, HAS BEEN ASSOCIATED WITH INCREASED RISK OF SEVERAL AGE-RELATED CHRONIC CONDITIONS. THIS IS THE FIRST STUDY TO PROSPECTIVELY EXAMINE THE RELATIONSHIP BETWEEN EAA AND BOTH MULTIMORBIDITY COUNT AND A WEIGHTED MULTIMORBIDITY SCORE AMONG LONG-LIVED POSTMENOPAUSAL WOMEN. METHODS: WE INCLUDED 1,951 WOMEN FROM THE WOMEN'S HEALTH INITIATIVE WHO COULD HAVE SURVIVED TO AGE 90. EAA WAS ESTIMATED USING THE HORVATH PAN-TISSUE, HANNUM, PHENOAGE AND GRIMAGE "CLOCKS." TWELVE CHRONIC CONDITIONS WERE INCLUDED IN THE MULTIMORBIDITY COUNT. THE MULTIMORBIDITY SCORE WAS WEIGHTED FOR EACH MORBIDITY'S RELATIONSHIP WITH MORTALITY IN THE STUDY POPULATION. USING MIXED-EFFECTS POISSON AND LINEAR REGRESSION MODELS THAT INCLUDED BASELINE COVARIATES ASSOCIATED WITH BOTH EAA AND MULTIMORBIDITY, WE ESTIMATED RELATIVE RISKS (RRS) AND 95% CONFIDENCE INTERVALS (CIS) FOR THE RELATIONSHIPS BETWEEN EACH EAA MEASURE AT STUDY BASELINE WITH BOTH MULTIMORBIDITY COUNT AND WEIGHTED MULTIMORBIDITY SCORE AT AGE 90, RESPECTIVELY. RESULTS: FOR EVERY ONE-STANDARD DEVIATION INCREASE IN AGEACCELPHENO, THE RATE OF MULTIMORBIDITY ACCUMULATION INCREASED 6% (RR=1.06; 95% CI=1.01-1.12; P=0.025) AND THE MULTIMORBIDITY SCORE BY 7% (RR=1.07; 95% CI=1.01-1.13; P=0.014) FOR WOMEN WHO SURVIVED TO AGE 90. THE RESULTS FOR A ONE-STANDARD DEVIATION INCREASE IN AGEACCELHORVATH, AGEACCELHANNUM AND AGEACCELGRIM WITH MULTIMORBIDITY ACCUMULATION AND SCORE WERE WEAKER COMPARED TO AGEACCELPHENO, AND THE LATTER TWO DID NOT REACH STATISTICAL SIGNIFICANCE. CONCLUSION: AGEACCELPHENO AND AGEACCELHANNUM MAY PREDICT MULTIMORBIDITY COUNT AND SCORE AT AGE 90 IN OLDER WOMEN AND, THUS, MAY BE USEFUL AS A BIOMARKER PREDICTOR OF MULTIMORBIDITY BURDEN IN THE LAST DECADES OF LIFE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  4249  46 METHYLATION-BASED BIOLOGICAL AGE AND BREAST CANCER RISK. BACKGROUND: AGE IS ONE OF THE STRONGEST PREDICTORS OF CANCER, CHRONIC DISEASE, AND MORTALITY, BUT BIOLOGICAL RESPONSES TO AGING DIFFER AMONG PEOPLE. EPIGENETIC DNA MODIFICATIONS HAVE BEEN USED TO ESTIMATE "BIOLOGICAL AGE," WHICH MAY BE A USEFUL PREDICTOR OF DISEASE RISK. WE TESTED THIS HYPOTHESIS FOR BREAST CANCER. METHODS: USING A CASE-COHORT APPROACH, WE MEASURED BASELINE BLOOD DNA METHYLATION OF 2764 WOMEN ENROLLED IN THE SISTER STUDY, 1566 OF WHOM SUBSEQUENTLY DEVELOPED BREAST CANCER AFTER AN AVERAGE OF 6 YEARS. USING THREE PREVIOUSLY ESTABLISHED METHYLATION-BASED "CLOCKS" (HANNUM, HORVATH, AND LEVINE), WE DEFINED BIOLOGICAL AGE ACCELERATION FOR EACH WOMAN BY COMPARING HER ESTIMATED BIOLOGICAL AGE WITH HER CHRONOLOGICAL AGE. HAZARD RATIOS AND 95% CONFIDENCE INTERVALS FOR BREAST CANCER RISK WERE ESTIMATED USING COX REGRESSION MODELS. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: EACH OF THE THREE CLOCKS SHOWED THAT BIOLOGICAL AGE ACCELERATION WAS STATISTICALLY SIGNIFICANTLY ASSOCIATED WITH INCREASED RISK OF DEVELOPING BREAST CANCER (5-YEAR AGE ACCELERATION, HANNUM'S CLOCK: HAZARD RATIO [HR] = 1.10, 95% CONFIDENCE INTERVAL [CI] = 1.00 TO 1.21, P = .04; HORVATH'S CLOCK: HR = 1.08, 95% CI = 1.00 TO 1.17, P = .04; LEVINE'S CLOCK: HR = 1.15, 95% CI = 1.07 TO 1.23, P < .001). FOR LEVINE'S CLOCK, EACH 5-YEAR ACCELERATION IN BIOLOGICAL AGE CORRESPONDED WITH A 15% INCREASE IN BREAST CANCER RISK. ALTHOUGH BIOLOGICAL AGE MAY ACCELERATE WITH MENOPAUSAL TRANSITION, AGE ACCELERATION IN PREMENOPAUSAL WOMEN INDEPENDENTLY PREDICTED BREAST CANCER. CASE-ONLY ANALYSIS SUGGESTED THAT, AMONG WOMEN WHO DEVELOP BREAST CANCER, INCREASED AGE ACCELERATION IS ASSOCIATED WITH INVASIVE CANCER (ODDS RATIO FOR INVASIVE = 1.09, 95% CI = 0.98 TO 1.22, P = .10). CONCLUSIONS: DNA METHYLATION-BASED MEASURES OF BIOLOGICAL AGE MAY BE IMPORTANT PREDICTORS OF BREAST CANCER RISK.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4   624  34 BIOLOGICAL AGE ACCELERATION AND MOTORIC COGNITIVE RISK SYNDROME. OBJECTIVE: MOTORIC COGNITIVE RISK (MCR) SYNDROME, A PREDEMENTIA SYNDROME CHARACTERIZED BY SLOW GAIT AND SUBJECTIVE COGNITIVE CONCERNS, IS ASSOCIATED WITH MULTIPLE AGE-RELATED RISK FACTORS. WE HYPOTHESIZED THAT MCR IS ASSOCIATED WITH BIOLOGICAL AGE ACCELERATION. WE EXAMINED THE ASSOCIATIONS OF BIOLOGICAL AGE ACCELERATION WITH MCR, AND MORTALITY RISK IN MCR CASES. METHODS: BIOLOGICAL AGE WAS DETERMINED USING PROTEOMIC AND EPIGENETIC CLOCKS IN PARTICIPANTS AGED 65 YEARS AND OLDER IN THE LONGENITY STUDY (N = 700, FEMALES = 57.9%) AND HEALTH AND RETIREMENT STUDY (HRS; N = 1,043, FEMALES = 57.1%) COHORTS. AGE ACCELERATION (AGEACCEL) WAS OPERATIONALLY DEFINED AS THE RESIDUAL FROM REGRESSING PREDICTED BIOLOGICAL AGE (FROM BOTH CLOCKS SEPARATELY) ON CHRONOLOGICAL AGE. ASSOCIATION OF AGEACCEL WITH INCIDENT MCR IN THE OVERALL SAMPLE AS WELL AS WITH MORTALITY RISK IN MCR CASES WAS EXAMINED USING COX MODELS AND REPORTED AS HAZARD RATIOS (HRS). RESULTS: AGEACCEL SCORES DERIVED FROM A PROTEOMIC CLOCK WERE ASSOCIATED WITH PREVALENT MCR (ODDS RATIO ADJUSTED FOR AGE, GENDER, EDUCATION YEARS, AND CHRONIC ILLNESSES [AOR] = 1.36, 95% CONFIDENCE INTERVAL [CI] = 1.09-1.71) AS WELL AS PREDICTED INCIDENT MCR (HR = 1.19, 95% CI = 1.00-1.41) IN THE LONGENITY COHORT. IN HRS, THE ASSOCIATION OF AGEACCEL USING AN EPIGENETIC CLOCK WITH PREVALENT MCR WAS CONFIRMED (AOR = 1.47, 95% CI = 1.16-1.85). PARTICIPANTS WITH MCR AND ACCELERATED AGING (POSITIVE AGEACCEL SCORE) WERE AT THE HIGHEST RISK FOR MORTALITY IN BOTH LONGENITY (HR = 3.38, 95% CI = 2.01-5.69) AND HRS (HR = 2.47, 95% CI = 1.20-5.10). INTERPRETATION: ACCELERATED AGING PREDICTS RISK FOR MCR, AND IS ASSOCIATED WITH HIGHER MORTALITY IN MCR PATIENTS. ANN NEUROL 2023;93:1187-1197.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5   173  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6  1955  41 EPIGENETIC AGE ACCELERATION PREDICTS CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY IN A GERMAN CASE COHORT. BACKGROUND: PREVIOUS STUDIES HAVE DEVELOPED MODELS PREDICTING METHYLATION AGE FROM DNA METHYLATION IN BLOOD AND OTHER TISSUES (EPIGENETIC CLOCK) AND SUGGESTED THE DIFFERENCE BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGES AS A MARKER OF HEALTHY AGING. THE GOAL OF THIS STUDY WAS TO CONFIRM AND EXPAND SUCH OBSERVATIONS BY INVESTIGATING WHETHER DIFFERENT CONCEPTS OF THE EPIGENETIC CLOCKS IN A POPULATION-BASED COHORT ARE ASSOCIATED WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. RESULTS: DNA METHYLATION AGE WAS ESTIMATED IN A COHORT OF 1863 OLDER PEOPLE, AND THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE (DELTAAGE) WAS CALCULATED. A CASE-COHORT DESIGN AND WEIGHTED PROPORTIONAL COX HAZARD MODELS WERE USED TO ESTIMATE ASSOCIATIONS OF DELTAAGE WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. HAZARD RATIOS FOR DELTAAGE (PER 5 YEARS) CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HORVATH WERE 1.23 (95 % CI 1.10-1.38) FOR ALL-CAUSE MORTALITY, 1.22 (95 % CI 1.03-1.45) FOR CANCER MORTALITY, AND 1.19 (95 % CI 0.98-1.43) FOR CARDIOVASCULAR MORTALITY AFTER ADJUSTMENT FOR BATCH EFFECTS, AGE, SEX, EDUCATIONAL LEVEL, HISTORY OF CHRONIC DISEASES, HYPERTENSION, SMOKING STATUS, BODY MASS INDEX, AND LEUCOCYTE DISTRIBUTION. ASSOCIATIONS WERE SIMILAR BUT WEAKER FOR DELTAAGE CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HANNUM. CONCLUSIONS: THESE RESULTS SHOW THAT AGE ACCELERATION IN TERMS OF THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE IS AN INDEPENDENT PREDICTOR OF ALL-CAUSE AND CAUSE-SPECIFIC MORTALITY AND MAY BE USEFUL AS A GENERAL MARKER OF HEALTHY AGING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  1780  36 EDUCATION AND LIFESTYLE FACTORS ARE ASSOCIATED WITH DNA METHYLATION CLOCKS IN OLDER AFRICAN AMERICANS. DNA METHYLATION (DNAM) CLOCKS ARE IMPORTANT BIOMARKERS OF CELLULAR AGING AND ARE ASSOCIATED WITH A VARIETY OF AGE-RELATED CHRONIC DISEASES AND ALL-CAUSE MORTALITY. EXAMINING THE RELATIONSHIP BETWEEN EDUCATION AND LIFESTYLE RISK FACTORS FOR AGE-RELATED DISEASES AND MULTIPLE DNAM CLOCKS CAN INCREASE THE UNDERSTANDING OF HOW RISK FACTORS CONTRIBUTE TO AGING AT THE CELLULAR LEVEL. THIS STUDY EXPLORED THE ASSOCIATION BETWEEN EDUCATION OR LIFESTYLE RISK FACTORS FOR AGE-RELATED DISEASES AND THE ACCELERATION OF FOUR DNAM CLOCKS, INCLUDING INTRINSIC (IEAA) AND EXTRINSIC EPIGENETIC AGE ACCELERATION (EEAA), PHENOAGE ACCELERATION (PHENOAA), AND GRIMAGE ACCELERATION (GRIMAA) IN THE AFRICAN AMERICAN PARTICIPANTS OF THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY. WE PERFORMED BOTH CROSS-SECTIONAL AND LONGITUDINAL ANALYSES. IN CROSS-SECTIONAL ANALYSES, GENDER, EDUCATION, BMI, SMOKING, AND ALCOHOL CONSUMPTION WERE ALL INDEPENDENTLY ASSOCIATED WITH GRIMAA, WHEREAS ONLY SOME OF THEM WERE ASSOCIATED WITH OTHER CLOCKS. THE EFFECT OF SMOKING AND EDUCATION ON GRIMAA VARIED BY GENDER. LONGITUDINAL ANALYSES SUGGEST THAT AGE AND BMI CONTINUED TO INCREASE GRIMAA, AND THAT AGE AND CURRENT SMOKING CONTINUED TO INCREASE PHENOAA AFTER CONTROLLING DNAM CLOCKS AT BASELINE. IN CONCLUSION, EDUCATION AND COMMON LIFESTYLE RISK FACTORS WERE ASSOCIATED WITH MULTIPLE DNAM CLOCKS. HOWEVER, THE ASSOCIATION WITH EACH RISK FACTOR VARIED BY CLOCK, WHICH SUGGESTS THAT DIFFERENT CLOCKS MAY CAPTURE ADVERSE EFFECTS FROM DIFFERENT ENVIRONMENTAL STIMULI.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
9   403  49 ANALYSIS OF EPIGENETIC AGE ACCELERATION AND HEALTHY LONGEVITY AMONG OLDER US WOMEN. IMPORTANCE: ACCELERATED BIOLOGICAL AGING IS ASSOCIATED WITH DECREASED PHYSICAL CAPABILITY AND COGNITIVE FUNCTIONING, WHICH ARE ASSOCIATED WITH INCREASED RISK OF MORBIDITY AND MORTALITY. OBJECTIVE: WE INVESTIGATED ASSOCIATIONS BETWEEN EPIGENETIC AGE ACCELERATION (EAA), A BIOMARKER ASSOCIATED WITH AGING, AND HEALTHY LONGEVITY AMONG OLDER WOMEN. DESIGN, SETTING, AND PARTICIPANTS: THIS COHORT STUDY WAS A SECONDARY ANALYSIS OF PARTICIPANTS IN THE WOMEN'S HEALTH INITIATIVE (WHI) WHO WERE ELIGIBLE TO SURVIVE TO AGE 90 YEARS BY SEPTEMBER 30, 2020. PARTICIPANTS WERE LOCATED IN MULTIPLE CENTERS. THIS STUDY WAS RESTRICTED TO WOMEN WITH GENOME-WIDE DNA METHYLATION DATA, GENERATED FROM BASELINE BLOOD SAMPLES WITHIN 3 WHI ANCILLARY STUDIES. MEDIAN (IQR) FOLLOW-UP TIMES FROM BASELINE WERE 21.6 (19.6-22.9) YEARS AND 21.4 (19.8-22.7) YEARS FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH AND WITHOUT INTACT MOBILITY, RESPECTIVELY, AND 13.2 (8.8-16.7) FOR WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. DATA WERE ANALYZED FROM DECEMBER 2020 TO JULY 2021. EXPOSURES: EAA WAS ESTIMATED USING 4 ESTABLISHED "CLOCKS": HORVATH PANTISSUE, HANNUM, PHENO, AND GRIM. MAIN OUTCOMES AND MEASURES: USING MULTINOMIAL LOGISTIC REGRESSION, ODDS RATIOS (ORS) AND 95% CIS WERE ESTIMATED FOR 3 HEALTHY LONGEVITY OUTCOMES FOR EACH CLOCK: SURVIVAL TO AGE 90 YEARS WITH INTACT MOBILITY, SURVIVAL TO AGE 90 YEARS WITHOUT INTACT MOBILITY, AND NO SURVIVAL TO AGE 90 YEARS. RESULTS: AMONG 1813 WOMEN, THERE WERE 464 WOMEN (MEAN [SD] AGE AT BASELINE, 71.6 [3.5] YEARS) WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTIONING, 420 WOMEN (MEAN [SD] AGE AT BASELINE, 71.3 [3.2] YEARS) WHO SURVIVED TO AGE 90 YEARS WITHOUT INTACT MOBILITY AND COGNITIVE FUNCTIONING, AND 929 WOMEN (MEAN [SD] AGE AT BASELINE, 70.2 [3.4] YEARS) WHO DID NOT SURVIVE TO AGE 90 YEARS. WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION WERE HEALTHIER AT BASELINE COMPARED WITH WOMEN WHO SURVIVED WITHOUT THOSE OUTCOMES OR WHO DID NOT SURVIVE TO AGE 90 YEARS (EG, 143 WOMEN [30.8%] VS 101 WOMEN [24.0%] AND 202 WOMEN [21.7%] WITH 0 CHRONIC CONDITIONS). THE ODDS OF SURVIVING TO AGE 90 YEARS WITH INTACT MOBILITY WERE LOWER FOR EVERY 1 SD INCREASE IN EAA COMPARED WITH THOSE WHO DID NOT SURVIVE TO AGE 90 YEARS AS MEASURED BY AGEACCELHORVATH (OR, 0.82; 95% CI, 0.69-0.96; P = .01), AGEACCELHANNUM (OR, 0.67; 95% CI, 0.56-0.80; P < .001), AGEACCELPHENO (OR, 0.60; 95% CI, 0.51-0.72; P < .001), AND AGEACCELGRIM (OR, 0.68; 95% CI, 0.55-0.84; P < .001). ORS WERE SIMILAR FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION (EG, AGEACCELHORVATH: OR PER 1 SD INCREASE IN EAA, 0.83; 95% CI, 0.71-0.98; P = .03) COMPARED WITH WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. CONCLUSIONS AND RELEVANCE: THESE FINDINGS SUGGEST THAT EAA MAY BE A VALID BIOMARKER ASSOCIATED WITH HEALTHY LONGEVITY AMONG OLDER WOMEN AND MAY BE USED FOR RISK STRATIFICATION AND RISK ESTIMATION OF FUTURE FUNCTIONAL AND COGNITIVE AGING. OUTCOMES SUGGEST THAT FUTURE STUDIES MAY FOCUS ON THE POTENTIAL FOR PUBLIC HEALTH INTERVENTIONS TO COUNTERACT EAA AND ITS ASSOCIATION WITH POOR HEALTH OUTCOMES TO LOWER DISEASE BURDEN WHILE INCREASING LONGEVITY.	2022	

10   648  36 BIRTH WEIGHT AND MATERNAL ENERGY STATUS DURING PREGNANCY AS PREDICTORS OF EPIGENETIC AGE ACCELERATION IN YOUNG ADULTS FROM METROPOLITAN CEBU, PHILIPPINES. EPIGENETIC CLOCKS QUANTIFY REGULAR CHANGES IN DNA METHYLATION THAT OCCUR WITH AGE, OR IN RELATION TO BIOMARKERS OF AGEING, AND ARE STRONG PREDICTORS OF MORBIDITY AND MORTALITY. HERE, WE ASSESS WHETHER MEASURES OF FETAL NUTRITION AND GROWTH THAT PREDICT ADULT CHRONIC DISEASE ALSO PREDICT ACCELERATED BIOLOGICAL AGEING IN YOUNG ADULTHOOD USING A SUITE OF COMMONLY USED EPIGENETIC CLOCKS. DATA COME FROM THE CEBU LONGITUDINAL HEALTH AND NUTRITION SURVEY (CLHNS), A LONG-RUNNING COHORT FOLLOWED SINCE BIRTH IN METROPOLITAN CEBU, PHILIPPINES. PAST WORK HAS SHOWN THAT BIRTH WEIGHT (BW) AND THE MOTHER'S ARM FAT DURING PREGNANCY (A MEASURE OF PREGNANCY ENERGY STATUS) RELATE INVERSELY TO HEALTH OUTCOMES IN THE CLHNS BUT PRIMARILY IN MALES. GENOME-WIDE DNA METHYLATION WAS ASSESSED IN WHOLE BLOOD USING THE INFINIUM EPIC ARRAY. PARTICIPANTS INCLUDED MALES (N=895) AND FEMALES (N=803) MEASURED IN 2005 (20.8-22.5 YEARS). CLOCKS INCLUDED THE HANNUM AND HORVATH CLOCKS TRAINED ON CHRONOLOGICAL AGE, THE DNAMPHENOAGE AND DNAMGRIMAGE CLOCKS TRAINED ON CLINICAL BIOMARKERS, THE DUNEDIN PACE OF AGEING (DUNEDINPACE) CLOCK TRAINED ON LONGITUDINAL CHANGES IN AGEING BIOMARKERS, AND THE DNAMTL CLOCK TRAINED ON LEUKOCYTE TELOMERE LENGTH. IN MALES, LOWER BW PREDICTED ADVANCED BIOLOGICAL AGEING USING THE HANNUM, DNAMPHENOAGE, DUNEDINPOAM, AND DNAMTL CLOCKS. IN CONTRAST, BW DID NOT PREDICT ANY CLOCK IN FEMALE PARTICIPANTS. PARTICIPANTS' MOTHERS' PREGNANCY ARM FAT ONLY PREDICTED DNAMTL IN MALES. THESE FINDINGS SUGGEST THAT EPIGENETIC CLOCKS ARE A USEFUL TOOL FOR GAUGING LONG-TERM OUTCOMES PREDICTED BY FETAL GROWTH, AND ADD TO EXISTING EVIDENCE IN THE CLHNS FOR SEX DIFFERENCES IN THESE RELATIONSHIPS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11  1953  33 EPIGENETIC AGE ACCELERATION AND CHRONIC HEALTH CONDITIONS AMONG ADULT SURVIVORS OF CHILDHOOD CANCER. BACKGROUND: MOUNTING EVIDENCE SUPPORTS THE OCCURRENCE OF ACCELERATING AGING AMONG LONG-TERM SURVIVORS OF CHILDHOOD CANCER. WE AIMED TO INVESTIGATE EPIGENETIC AGE ACCELERATION (EAA) IN SURVIVORS AND EVALUATE ASSOCIATIONS BETWEEN EAA, TREATMENT EXPOSURES, HEALTH BEHAVIORS, AND CHRONIC HEALTH CONDITIONS (CHCS). METHODS: GENOME-WIDE METHYLATION DATA WERE GENERATED WITH INFINIUM EPIC BEADCHIP ON BLOOD-DERIVED DNA FROM 2139 SURVIVORS AND 282 FREQUENCY MATCHED CONTROLS FROM THE ST JUDE LIFETIME COHORT STUDY. EAAS WERE ESTIMATED AS RESIDUALS FROM A LINEAR REGRESSION OF EPIGENETIC AGE (LEVINE'S CLOCK) AGAINST CHRONOLOGICAL AGE. ADJUSTED LEAST SQUARE MEAN (ALSM) OF EAA WAS CALCULATED AND COMPARED BETWEEN SURVIVORS AND CONTROLS, ACROSS TREATMENT EXPOSURES AND HEALTH BEHAVIORS. ASSOCIATIONS OF EAA WITH 20 CLINICALLY ASSESSED CHCS WERE EVALUATED WITH MULTIVARIABLE PIECEWISE-EXPONENTIAL MODELS. ALL STATISTICAL TESTS FOR P VALUES BELOW WERE 2-SIDED. RESULTS: EAA WAS STATISTICALLY SIGNIFICANTLY HIGHER IN SURVIVORS THAN CONTROLS (ALSM = 0.63, 95% CONFIDENCE INTERVAL [CI] = 0.26 TO 1.01 VS -3.61, 95% CI = -4.43 TO 2.80). IN A MULTIVARIABLE MODEL AMONG SURVIVORS, STATISTICALLY SIGNIFICANTLY HIGHER EAA (P < .05) WAS OBSERVED IN THOSE EXPOSED TO CHEST RADIOTHERAPY, ABDOMEN OR PELVIC RADIOTHERAPY, ALKYLATING AGENTS, GLUCOCORTICOIDS, OR EPIPODOPHYLLOTOXINS. COMPARED WITH SURVIVORS WITH FAVORABLE HEALTH BEHAVIORS (ALSM = 0.26, 95% CI=-0.36 TO 0.87), EAA WAS STATISTICALLY SIGNIFICANTLY HIGHER AMONG SURVIVORS WITH INTERMEDIATE (ALSM = 1.07, 95% CI = 0.59 TO 1.54) OR UNFAVORABLE HEALTH BEHAVIORS (ALSM = 1.45, 95% CI = 0.60 TO 2.30). IN TIME-TO-EVENT ANALYSES, STATISTICALLY SIGNIFICANT ASSOCIATIONS WERE IDENTIFIED BETWEEN EAA TERTILES AND INCIDENCE OF 7 CHCS: HYPERTENSION (3RD VS 1ST TERTILE, RELATIVE RATE [RR] = 1.83, 95% CI = 1.17 TO 2.83), MYOCARDIAL INFARCTION (RR = 2.91, 95% CI = 1.27 TO 7.21), OBESITY (RR = 1.39, 95% CI = 1.17 TO 1.66), OBSTRUCTIVE PULMONARY DEFICIT (RR = 1.86, 95% CI = 0.95 TO 3.77), PERIPHERAL MOTOR NEUROPATHY (RR = 2.89, 95% CI = 1.24 TO 6.97), PERIPHERAL SENSORY NEUROPATHY (RR = 2.04, 95% CI = 0.99 TO 4.26), AND PULMONARY DIFFUSION DEFICITS (RR = 2.75, 95% CI = 0.95 TO 7.63). CONCLUSIONS: EAA IS STATISTICALLY SIGNIFICANTLY HIGHER IN SURVIVORS OF CHILDHOOD CANCER THAN IN NONCANCER CONTROLS AND IS ASSOCIATED WITH SPECIFIC TREATMENT EXPOSURES, UNFAVORABLE HEALTH BEHAVIORS, AND PRESENCE OF SPECIFIC CHCS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12  2150  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13  1645  47 DOES THE EPIGENETIC CLOCK GRIMAGE PREDICT MORTALITY INDEPENDENT OF GENETIC INFLUENCES: AN 18 YEAR FOLLOW-UP STUDY IN OLDER FEMALE TWIN PAIRS. BACKGROUND: EPIGENETIC CLOCKS ARE BASED ON DNA METHYLATION (DNAM). IT HAS BEEN SUGGESTED THAT THESE CLOCKS ARE USEABLE MARKERS OF BIOLOGICAL AGING AND PREMATURE MORTALITY. BECAUSE GENETIC FACTORS EXPLAIN VARIATIONS IN BOTH EPIGENETIC AGING AND MORTALITY, THIS ASSOCIATION COULD ALSO BE EXPLAINED BY SHARED GENETIC FACTORS. WE INVESTIGATED THE INFLUENCE OF GENETIC AND LIFESTYLE FACTORS (SMOKING, ALCOHOL CONSUMPTION, PHYSICAL ACTIVITY, CHRONIC DISEASES, BODY MASS INDEX) AND EDUCATION ON THE ASSOCIATION OF ACCELERATED EPIGENETIC AGING WITH MORTALITY USING A LONGITUDINAL TWIN DESIGN. UTILIZING A PUBLICLY AVAILABLE ONLINE TOOL, WE CALCULATED THE EPIGENETIC AGE USING TWO EPIGENETIC CLOCKS, HORVATH DNAMAGE AND DNAM GRIMAGE, IN 413 FINNISH TWIN SISTERS, AGED 63-76 YEARS, AT THE BEGINNING OF THE 18-YEAR MORTALITY FOLLOW-UP. EPIGENETIC AGE ACCELERATION WAS CALCULATED AS THE RESIDUALS FROM A LINEAR REGRESSION MODEL OF EPIGENETIC AGE ESTIMATED ON CHRONOLOGICAL AGE (AA(HORVATH), AA(GRIMAGE), RESPECTIVELY). COX PROPORTIONAL HAZARD MODELS WERE CONDUCTED FOR INDIVIDUALS AND TWIN PAIRS. RESULTS: THE RESULTS OF THE INDIVIDUAL-BASED ANALYSES SHOWED AN INCREASED MORTALITY HAZARD RATIO (HR) OF 1.31 (CI(95): 1.13-1.53) PER ONE STANDARD DEVIATION (SD) INCREASE IN AA(GRIMAGE). THE RESULTS INDICATED NO SIGNIFICANT ASSOCIATIONS OF AA(HORVATH) WITH MORTALITY. PAIRWISE MORTALITY ANALYSES SHOWED AN HR OF 1.50 (CI(95): 1.02-2.20) PER 1 SD INCREASE IN AA(GRIMAGE). HOWEVER, AFTER ADJUSTING FOR SMOKING, THE HR ATTENUATED SUBSTANTIALLY AND WAS STATISTICALLY NON-SIGNIFICANT (1.29; CI(95): 0.84-1.99). SIMILARLY, IN MULTIVARIABLE ADJUSTED MODELS THE HR (1.42-1.49) WAS NON-SIGNIFICANT. IN AA(HORVATH), THE NON-SIGNIFICANT HRS WERE LOWER AMONG MONOZYGOTIC PAIRS IN COMPARISON TO DIZYGOTIC PAIRS, WHILE IN AA(GRIMAGE) THERE WERE NO SYSTEMATIC DIFFERENCES BY ZYGOSITY. FURTHER, THE PAIRWISE ANALYSIS IN QUARTILES SHOWED THAT THE INCREASED WITHIN PAIR DIFFERENCE IN AA(GRIMAGE) WAS ASSOCIATED WITH A HIGHER ALL-CAUSE MORTALITY RISK. CONCLUSIONS: IN CONCLUSION, THE FINDINGS SUGGEST THAT DNAM GRIMAGE IS A STRONG PREDICTOR OF MORTALITY INDEPENDENT OF GENETIC INFLUENCES. SMOKING, WHICH IS KNOWN TO ALTER DNAM LEVELS AND IS BUILT INTO THE DNAM GRIMAGE ALGORITHM, ATTENUATED THE ASSOCIATION BETWEEN EPIGENETIC AGING AND MORTALITY RISK.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  1956  37 EPIGENETIC AGE IN PERIPHERAL BLOOD AMONG CHILDREN, ADOLESCENT, AND ADULT SURVIVORS OF CHILDHOOD CANCER. IMPORTANCE: CERTAIN CANCER THERAPIES ARE RISK FACTORS FOR EPIGENETIC AGE ACCELERATION (EAA) AMONG SURVIVORS OF CHILDHOOD CANCER, AND EAA IS ASSOCIATED WITH CHRONIC HEALTH CONDITIONS (CHCS). HOWEVER, SMALL NUMBERS OF YOUNGER SURVIVORS (AGED <20 YEARS) PREVIOUSLY EVALUATED HAVE LIMITED THE ABILITY TO CALCULATE EAA AMONG THIS AGE GROUP. OBJECTIVE: TO EVALUATE THE CHANGE RATE OF EPIGENETIC AGE (EA) AND EAA IN YOUNGER COMPARED WITH OLDER SURVIVORS AND THE POSSIBLE ASSOCIATION OF EAA WITH EARLY-ONSET OBESITY (AGED <20 YEARS), SEVERITY/BURDEN OF CHCS, AND LATE MORTALITY (>5 YEARS FROM CANCER DIAGNOSIS). DESIGN, SETTING, AND PARTICIPANTS: STUDY PARTICIPANTS WERE FROM THE ST JUDE LIFETIME COHORT, INITIATED IN 2007 WITH ONGOING FOLLOW-UP. THE PRESENT STUDY WAS CONDUCTED FROM APRIL 17, 2022, TO MARCH 23, 2023. SURVIVORS IN THIS COHORT OF EUROPEAN ANCESTRY WITH DNA METHYLATION DATA WERE INCLUDED. CROSS-SECTIONAL ANNUAL CHANGES IN EA AND EAA WERE COMPARED ACROSS 5 DIFFERENT CHRONOLOGIC AGE GROUPS: AGE 0 TO 9 (CHILDREN), 10 TO 19 (ADOLESCENTS), 20 TO 34 (YOUNGER ADULTS), 35 TO 49 (MIDDLE-AGED ADULTS), AND GREATER THAN OR EQUAL TO 50 (OLDER ADULTS) YEARS. LOGISTIC REGRESSION EVALUATED THE ASSOCIATION BETWEEN EAA AND EARLY-ONSET OBESITY OR SEVERITY/BURDEN OF CHCS. COX PROPORTIONAL HAZARDS REGRESSION ASSESSED THE ASSOCIATION BETWEEN EAA AND LATE MORTALITY. MAIN OUTCOMES AND MEASURES: EARLY-ONSET OBESITY, SEVERITY/BURDEN OF CHCS (GRADED USING THE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (GRADE 1, MILD; 2, MODERATE; 3, SEVERE/DISABLING; 4, LIFE-THREATENING) AND WERE COMBINED INTO HIGH VS LOW SEVERITY/BURDEN BASED ON FREQUENCY AND GRADE), AND LATE MORTALITY WERE THE OUTCOMES BASED ON FOLLOW-UP UNTIL APRIL 2020. EXPANDED DNA METHYLATION PROFILING INCREASED THE NUMBER OF SURVIVORS YOUNGER THAN 20 YEARS (N = 690). EPIGENETIC AGE WAS CALCULATED PRIMARILY USING THE LEVINE CLOCK, AND EAA WAS DERIVED FROM LEAST SQUARES REGRESSION OF EA AGAINST CHRONOLOGIC AGE AND WAS STANDARDIZED TO A Z SCORE (LEVINE EEA). RESULTS: AMONG 2846 PARTICIPANTS (MEDIAN AGE, 30.3 [IQR, 9.3-41.5] YEARS; 53% MALES), THE CROSS-SECTIONAL ANNUAL CHANGE IN EA_LEVINE WAS HIGHER IN CHILDREN (1.63 YEARS) AND ADOLESCENTS (1.14 YEARS), AND THE ADJUSTED LEAST-SQUARES MEAN OF LEVINE EEA WAS LOWER IN CHILDREN (-0.22 YEARS) AND OLDER ADULTS (-1.70 YEARS). EACH 1-SD INCREASE IN LEVINE EEA WAS ASSOCIATED WITH INCREASED RISK OF DEVELOPING EARLY-ONSET OBESITY (ODDS RATIO [OR], 1.46; 95% CI, 1.19-1.78), HIGH SEVERITY/BURDEN OF CHCS (OR, 1.13; 95% CI, 1.03-1.24), AND LATE MORTALITY (HAZARD RATIO, 1.75; 95% CI, 1.35-2.26). CONCLUSIONS AND RELEVANCE: THE FINDINGS OF THIS STUDY SUGGEST THAT EAA MEASURED IN CHILDREN AND ADOLESCENT SURVIVORS OF CHILDHOOD CANCER IS ASSOCIATED WITH EARLY-ONSET OBESITY, SEVERITY/BURDEN OF ALL CHCS, AND LATE MORTALITY. EVALUATING EAA MAY HELP IDENTIFY SURVIVORS OF CHILDHOOD CANCER AT INCREASED RISK FOR EARLY-ONSET OBESITY, MORBIDITY IN GENERAL, AND MORTALITY.	2023	
                                                                                                                                                                                                                                     
15  2044  36 EPIGENETIC CLOCK ANALYSIS OF BLOOD SAMPLES IN DRUG-NAIVE FIRST-EPISODE SCHIZOPHRENIA PATIENTS. BACKGROUND: SCHIZOPHRENIA (SCZ) IS A SEVERE AND CHRONIC PSYCHIATRIC DISORDER WITH PREMATURE AGE-RELATED PHYSIOLOGICAL CHANGES. HOWEVER, NUMEROUS PREVIOUS STUDIES EXAMINED THE EPIGENETIC AGE ACCELERATION IN SCZ PATIENTS AND YIELDED INCONCLUSIVE RESULTS. IN THIS STUDY, WE PROPOSE TO EXPLORE THE EPIGENETIC AGE ACCELERATION IN DRUG-NAIVE FIRST-EPISODE SCZ (FSCZ) PATIENTS AND INVESTIGATE WHETHER EPIGENETIC AGE ACCELERATION IS ASSOCIATED WITH ANTIPSYCHOTIC TREATMENT, PSYCHOTIC SYMPTOMS, COGNITION, AND SUBCORTICAL VOLUMES. METHODS: WE ASSESSED THE EPIGENETIC AGE IN 38 DRUG-NAIVE FSCZ PATIENTS AND 38 HEALTHY CONTROLS BY USING THREE INDEPENDENT CLOCKS, INCLUDING HORVATH, HANNUM AND LEVINE ALGORITHMS. THE EPIGENETIC AGE MEASUREMENTS IN SCZ PATIENTS WERE REPEATED AFTER RECEIVING 8 WEEKS RISPERIDONE MONOTHERAPY. RESULTS: OUR FINDINGS SHOWED SIGNIFICANTLY POSITIVE CORRELATIONS BETWEEN EPIGENETIC AGES ASSESSED BY THREE CLOCKS AND CHRONOLOGICAL AGE IN BOTH FSCZ PATIENTS AND HEALTHY CONTROLS. COMPARED WITH HEALTHY CONTROLS, DRUG-NAIVE FSCZ PATIENTS HAVE A SIGNIFICANT EPIGENETIC AGE DECELERATION IN HORVATH CLOCK (P = 0.01), BUT NOT IN HANNUM CLOCK (P = 0.07) AND LEVINE CLOCK (P = 0.43). THE EPIGENETIC AGES OF HANNUM CLOCK (P = 0.002) AND LEVINE CLOCK (P = 0.01) WERE SIGNIFICANTLY ACCELERATED IN SCZ PATIENTS AFTER 8-WEEK RISPERIDONE TREATMENT. HOWEVER, NO SIGNIFICANT ASSOCIATIONS BETWEEN EPIGENETIC AGE ACCELERATION AND PSYCHOTIC SYMPTOMS, COGNITIVE FUNCTION, AS WELL AS SUBCORTICAL VOLUMES WERE OBSERVED IN FSCZ PATIENTS. CONCLUSION: THESE RESULTS DEMONSTRATE THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
16  3579  41 IMPACT OF PATERNAL EDUCATION ON EPIGENETIC AGEING IN ADOLESCENCE AND MID-ADULTHOOD: A MULTI-COHORT STUDY IN THE USA AND MEXICO. BACKGROUND: BOTH PARENTAL AND NEIGHBOURHOOD SOCIO-ECONOMIC STATUS (SES) ARE LINKED TO POORER HEALTH INDEPENDENTLY OF PERSONAL SES MEASURES, BUT THE BIOLOGICAL MECHANISMS ARE UNCLEAR. OUR OBJECTIVE WAS TO EXAMINE THESE INFLUENCES VIA EPIGENETIC AGE ACCELERATION (EAA)-THE DISCREPANCY BETWEEN CHRONOLOGICAL AND EPIGENETIC AGES. METHODS: WE EXAMINED THREE USA-BASED [CORONARY ARTERY RISK DISEASE IN ADULTS (CARDIA) STUDY, FRAGILE FAMILIES AND CHILD WELLBEING STUDY (FFCWS) AND PROGRAMMING RESEARCH IN OBESITY, GROWTH, ENVIRONMENT AND SOCIAL STRESSORS (PROGRESS)] AND ONE MEXICO-BASED (PROJECT VIVA) COHORT. DNA METHYLATION WAS MEASURED USING ILLUMINA ARRAYS, PERSONAL/PARENTAL SES BY QUESTIONNAIRE AND NEIGHBOURHOOD DISADVANTAGE FROM GEOCODED ADDRESS. IN CARDIA, WE EXAMINED THE MOST STRONGLY ASSOCIATED PERSONAL, PARENTAL AND NEIGHBOURHOOD SES MEASURES WITH EAA (HANNUM'S METHOD) AT STUDY YEARS 15 AND 20 SEPARATELY AND COMBINED USING A GENERALIZED ESTIMATING EQUATION (GEE) AND COMPARED WITH OTHER EAA MEASURES (HORVATH'S EAA, PHENOAGE AND GRIMAGE CALCULATORS, AND DUNEDINPOAM). RESULTS: EAA WAS ASSOCIATED WITH PATERNAL EDUCATION IN CARDIA [GEES: BETASOME COLLEGE = -1.01 YEARS (-1.91, -0.11) AND BETA<HIGH SCHOOL = 1.05 (0.09, 2.01) VS COLLEGE GRADUATES] AND FFCWS [GEES: BETA<HIGH SCHOOL = 0.62 (0.00, 1.24)]. WE FOUND STRONGER ASSOCIATIONS FOR SOME PATERNAL EDUCATION CATEGORIES AMONG WHITE ADULTS (FOR GEE, BETASOME COLLEGE = -1.39 (-2.41, -0.38)], MEN (BETASOME COLLEGE = -1.76 (-3.16, -0.35)] AND WOMEN [BETA<HIGH SCHOOL = 1.77 (0.42, 3.11)]. CONCLUSIONS: THESE FINDINGS SUGGEST THAT EAA CAPTURES EPIGENETIC IMPACTS OF PATERNAL EDUCATION INDEPENDENTLY OF PERSONAL SES LATER IN LIFE. LONGITUDINAL STUDIES SHOULD EXPLORE THESE ASSOCIATIONS AT DIFFERENT LIFE STAGES AND LINK THEM TO HEALTH OUTCOMES. EAA COULD BE A USEFUL BIOMARKER OF SES-ASSOCIATED HEALTH AND PROVIDE IMPORTANT INSIGHT INTO THE PATHOGENESIS AND PREVENTION OF CHRONIC DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17  1625  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18  3637  30 INCREASED EPIGENETIC AGE ACCELERATION IN THE HIDRADENITIS SUPPURATIVA SKIN. EPIGENETIC (OR DNA METHYLATION) AGE IS CALCULATED BASED ON METHYLATION OF CERTAIN CYTOSINE-GUANINE (CPG) REPEATS, AND IT CAN ACCURATELY ESTIMATE ONE'S CHRONOLOGIC AGE. IMPORTANTLY, EPIGENETIC AGE ACCELERATION (EAA) IS HIGHLY PREDICTIVE OF AGE-ASSOCIATED MORBIDITY AND ALL-CAUSE MORTALITY. HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH SIGNIFICANT SYSTEMIC DISEASE BURDEN. HERE, WE PERFORMED A PILOT STUDY TO CALCULATE EAA FROM FORMALIN-FIXED PARAFFIN-EMBEDDED SKIN SAMPLES USING ILLUMINA INFINIUM METHYLATIONEPIC BEADCHIP ARRAYS. OUR RESULTS DEMONSTRATED NO SIGNIFICANT DIFFERENCE IN INTRINSIC EAA AMONG HS COMPARED TO CONTROLS (- 1.00 YEARS, P-VALUE = 0.52), SIGNIFICANT INCREASES IN BOTH EXTRINSIC EAA (13.72 YEARS, P-VALUE < 0.001) AND PHENOAGE ACCELERATION (7.72 YEARS, P-VALUE = 0.003), AND A SIGNIFICANT DECREASE IN GRIMAGE ACCELERATION (- 5.14 YEARS, P-VALUE < 0.001). OUR FINDINGS SUGGEST THAT THE ACCELERATION OF EPIGENETIC AGE IN THE HS SKIN MAY BE ASSOCIATED WITH EXTRINSIC IMMUNE-RELATED CHANGES AND CAN POTENTIALLY SERVE AS A BIOMARKER OF THE PRESENT AND/OR FUTURE DISEASE BURDEN IN HS PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19  1746  33 EARLY LIFE ADVERSITY, PUBERTAL TIMING, AND EPIGENETIC AGE ACCELERATION IN ADULTHOOD. BACKGROUND: GIVEN ASSOCIATIONS LINKING EARLY LIFE ADVERSITY, PUBERTAL TIMING, AND BIOLOGICAL AGING, WE EXAMINED THE DIRECT AND INDIRECT EFFECTS OF EARLY LIFE TRAUMA ON ADULT BIOLOGICAL AGING (VIA AGE OF MENARCHE). METHODS: PARTICIPANTS WERE PREMENOPAUSAL WOMEN (N = 183). PATH MODELS EVALUATED WHETHER EARLY LIFE TRAUMA PREDICTED EARLY PUBERTAL TIMING AND THEREBY, ADULT EPIGENETIC AGE ACCELERATION (INDEXED VIA FOUR EPIGENETIC CLOCKS: HORVATH DNAM AGE, HANNUM DNAM AGE, DNAM PHENOAGE, AND DNAM GRIMAGE). SECONDARY ANALYSES EXPLORED THE EFFECTS OF TYPE OF TRAUMA (ABUSE AND NEGLECT) AND ADULT CHRONIC STRESS STATUS (CAREGIVER OF CHILD WITH AUTISM AND NON-CAREGIVER). RESULTS: EARLY LIFE TRAUMA AND EARLIER AGE AT MENARCHE INDEPENDENTLY PREDICTED ACCELERATED AGING BASED ON ONE OF THE FOUR EPIGENETIC CLOCKS, DNAM GRIMAGE, THOUGH EARLY LIFE TRAUMA WAS NOT ASSOCIATED WITH AGE OF MENARCHE. CHILDHOOD ABUSE, BUT NOT NEGLECT, PREDICTED FASTER EPIGENETIC AGING; RESULTS DID NOT DIFFER BY CHRONIC STRESS STATUS. CONCLUSIONS: EARLY TRAUMA AND EARLY MENARCHE APPEAR TO EXERT INDEPENDENT EFFECTS ON DNAM GRIMAGE, WHICH HAS BEEN SHOWN TO BE THE STRONGEST EPIGENETIC PREDICTOR OF MORTALITY RISK. THIS STUDY IDENTIFIES A POTENTIAL CORRELATE OR DETERMINANT OF ACCELERATED EPIGENETIC AGING-MENARCHEAL AGE. FUTURE RESEARCH SHOULD ADDRESS THE LIMITATIONS OF THIS STUDY BY USING RACIALLY DIVERSE SAMPLES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20   176  36 ACCELERATED DNA METHYLATION AGE AND MEDICATION USE AMONG AFRICAN AMERICANS. DNA METHYLATION AGE ACCELERATION, THE DISCREPANCY BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE, IS ASSOCIATED WITH MORTALITY AND CHRONIC DISEASES, INCLUDING DIABETES, HYPERTENSION, AND HYPERLIPIDEMIA. IN THIS STUDY, WE INVESTIGATE WHETHER MEDICATIONS COMMONLY USED TO TREAT THESE DISEASES IN 15 DRUG CATEGORIES ARE ASSOCIATED WITH FOUR EPIGENETIC AGE ACCELERATION MEASURES: HORVATHAGE ACCELERATION (HORVATHAA), HANNUMAGE ACCELERATION (HANNUMAA), PHENOAGE ACCELERATION, AND GRIMAGE ACCELERATION (GRIMAA) USING CROSS-SECTIONAL (PHASE 1, N=1,100) AND LONGITUDINAL (PHASES 1 AND 2, N=266) DATA FROM AFRICAN AMERICANS IN THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY (GENOA) STUDY. IN CROSS-SECTIONAL ANALYSES, THE USE OF CALCIUM CHANNEL BLOCKERS WAS ASSOCIATED WITH 1.27 YEARS LOWER HANNUMAA AFTER ADJUSTING FOR COVARIATES INCLUDING HYPERTENSION (P=0.001). LONGITUDINAL ANALYSES SHOWED THAT, COMPARED TO THOSE WHO NEVER USED ANTIHYPERTENSIVES, THOSE WHO STARTED TO TAKE ANTIHYPERTENSIVES AFTER PHASE 1 HAD A 0.97-YEAR DECREASE IN GRIMAA (P=0.007). IN ADDITION, COMPARED TO THOSE WHO NEVER USED NSAID ANALGESICS, THOSE WHO STARTED TO TAKE THEM AFTER PHASE 1 HAD A 2.61-YEAR INCREASE IN HORVATHAA (P=0.0005). OUR STUDY DEMONSTRATES THAT THREE COMMONLY USED MEDICATIONS ARE ASSOCIATED WITH DNAM AGE ACCELERATION IN AFRICAN AMERICANS AND SHEDS LIGHT ON THE POTENTIAL EPIGENETIC EFFECTS OF PHARMACEUTICALS ON AGING AT THE CELLULAR LEVEL.	2021