1  6018 126 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2  1955  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
3  4249  55 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   525  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5  1780  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6  1956  44 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	
                                                                                                                                                                                                                                      
7   403  65 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	

8  2150  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9  1953  43 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10   173  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
11  6017  43 THE ASSOCIATION OF ACCELERATED EPIGENETIC AGE WITH ALL-CAUSE MORTALITY IN CARDIAC CATHETERIZATION PATIENTS AS MEDIATED BY VASCULAR AND CARDIOMETABOLIC OUTCOMES. BACKGROUND: EPIGENETIC AGE IS A DNA METHYLATION-BASED BIOMARKER OF AGING THAT IS ACCURATE ACROSS THE LIFESPAN AND A RANGE OF CELL TYPES. THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE, TERMED AGE ACCELERATION (AA), IS A STRONG PREDICTOR OF LIFESPAN AND HEALTHSPAN. THE PREDICTIVE CAPABILITIES OF AA FOR ALL-CAUSE MORTALITY HAVE BEEN EVALUATED IN THE GENERAL POPULATION; HOWEVER, ITS UTILITY IS LESS WELL EVALUATED IN THOSE WITH CHRONIC CONDITIONS. ADDITIONALLY, THE PATHOPHYSIOLOGIC PATHWAYS WHEREBY AA PREDICTS MORTALITY ARE UNCLEAR. WE HYPOTHESIZED THAT AA PREDICTS MORTALITY IN INDIVIDUALS WITH UNDERLYING CARDIOVASCULAR DISEASE; AND THE ASSOCIATION BETWEEN AA AND MORTALITY IS MEDIATED, IN PART, BY VASCULAR AND CARDIOMETABOLIC MEASURES. METHODS: WE EVALUATED 562 PARTICIPANTS IN AN URBAN, THREE-COUNTY AREA OF CENTRAL NORTH CAROLINA FROM THE CATHGEN COHORT, ALL OF WHOM RECEIVED A CARDIAC CATHETERIZATION PROCEDURE. WE ANALYZED THREE AA BIOMARKERS, HORVATH EPIGENETIC AGE ACCELERATION (HAA), PHENOTYPIC AGE ACCELERATION (PHENOAA), AND GRIM AGE ACCELERATION (GRIMAA), BY COX REGRESSION MODELS, TO ASSESS WHETHER AAS WERE ASSOCIATED WITH ALL-CAUSE MORTALITY. WE ALSO EVALUATED IF THESE ASSOCIATIONS WERE MEDIATED BY VASCULAR AND CARDIOMETABOLIC OUTCOMES, INCLUDING LEFT VENTRICULAR EJECTION FRACTION (LVEF), BLOOD CHOLESTEROL CONCENTRATIONS, ANGIOPOIETIN-2 (ANG2) PROTEIN CONCENTRATION, PERIPHERAL ARTERY DISEASE, CORONARY ARTERY DISEASE, DIABETES, AND HYPERTENSION. THE TOTAL EFFECT, DIRECT EFFECT, INDIRECT EFFECT, AND PERCENTAGE MEDIATED WERE ESTIMATED USING PATHWAY MEDIATION TESTS WITH A REGRESSION ADJUSTMENT APPROACH. RESULTS: PHENOAA (HR = 1.05, P < 0.0001), GRIMAA (HR = 1.10, P < 0.0001) AND HAA (HR = 1.03, P = 0.01) WERE ALL ASSOCIATED WITH ALL-CAUSE MORTALITY. THE ASSOCIATION OF MORTALITY AND PHENOAA WAS PARTIALLY MEDIATED BY ANG2, A MARKER OF VASCULAR FUNCTION (19.8%, P = 0.016), AND BY DIABETES (8.2%, P = 0.043). THE GRIMAA-MORTALITY ASSOCIATION WAS MEDIATED BY ANG2 (12.3%, P = 0.014), AND SHOWED WEAKER EVIDENCE FOR MEDIATION BY LVEF (5.3%, P = 0.065). CONCLUSIONS: EPIGENETIC AGE ACCELERATION REMAINS STRONGLY PREDICTIVE OF MORTALITY EVEN IN INDIVIDUALS ALREADY BURDENED WITH CARDIOVASCULAR DISEASE. MORTALITY ASSOCIATIONS WERE MEDIATED BY ANG2, WHICH REGULATES ENDOTHELIAL PERMEABILITY AND ANGIOGENIC FUNCTIONS, SUGGESTING THAT SPECIFIC VASCULAR PATHOPHYSIOLOGY MAY LINK ACCELERATED EPIGENETIC AGING WITH INCREASED MORTALITY RISKS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12  4502  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13   176  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
14  3637  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15   713  39 CADMIUM EXPOSURE AND AGE-ASSOCIATED DNA METHYLATION CHANGES IN NON-SMOKING WOMEN FROM NORTHERN THAILAND. DNA METHYLATION CHANGES WITH AGE, AND MAY SERVE AS A BIOMARKER OF AGING. CADMIUM (CD) MODIFIES CELLULAR PROCESSES THAT PROMOTE AGING AND DISRUPTS METHYLATION GLOBALLY. WHETHER CD MODIFIES AGING PROCESSES BY INFLUENCING ESTABLISHMENT OF AGE-ASSOCIATED METHYLATION MARKS IS CURRENTLY UNKNOWN. IN THIS PILOT STUDY, WE CHARACTERIZED METHYLATION PROFILES IN > 450 000 CPG SITES IN 40 NON-SMOKING WOMEN (AGE 40-80) DIFFERENTIALLY EXPOSED TO ENVIRONMENTAL CD FROM THAILAND. BASED ON SPECIFIC GRAVITY ADJUSTED URINARY CD, WE CLASSIFIED THEM AS HIGH (HE) AND LOW (LE) EXPOSED AND AGE-MATCHED WITHIN 5 YEARS. URINARY CD WAS DEFINED AS BELOW 2 MICROG/L IN THE LE GROUP. WE PREDICTED EPIGENETIC AGE (DNAM-AGE) USING TWO PUBLISHED METHODS BY HORVATH AND HANNUM AND EXAMINED THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGIC AGE (DELTAAGE). WE ASSESSED DIFFERENCES BY CD EXPOSURE USING LINEAR MIXED MODELS ADJUSTED FOR ESTIMATED WHITE BLOOD CELL PROPORTIONS, BMI, AND URINARY CREATININE. WE IDENTIFIED 213 AGE-ASSOCIATED CPG SITES IN OUR POPULATION (P < 10(-4)). COUNTERINTUITIVELY, THE MEAN DELTAAGE WAS SMALLER IN HE VS. LE (HANNUM: 3.6 VS. 7.6 YEARS, P = 0.0093; HORVATH: 2.4 VS. 4.5 YEARS, P = 0.1308). THE CD EXPOSED GROUP WAS ASSOCIATED WITH CHANGES IN METHYLATION (P < 0.05) AT 12, 8, AND 20 AGE-ASSOCIATED SITES IDENTIFIED IN OUR POPULATION, HANNUM, AND HORVATH. FROM THE RESULTS OF THIS PILOT STUDY, ELEVATED CD EXPOSURE IS ASSOCIATED WITH METHYLATION CHANGES AT AGE-ASSOCIATED SITES AND SMALLER DIFFERENCES BETWEEN DNAM-AGE AND CHRONOLOGIC AGE, IN CONTRAST TO EXPECTED AGE-ACCELERATING EFFECTS. CD MAY MODIFY EPIGENETIC AGING, AND BIOMARKERS OF AGING WARRANT FURTHER INVESTIGATION WHEN EXAMINING CD AND ITS RELATIONSHIP WITH CHRONIC DISEASE AND MORTALITY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16   624  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17  6314  37 THE RELATIONSHIP BETWEEN THE EPIGENETIC AGING BIOMARKER "GRIMAGE" AND LUNG FUNCTION IN BOTH THE AIRWAY AND BLOOD OF PEOPLE LIVING WITH HIV: AN OBSERVATIONAL COHORT STUDY. BACKGROUND: AGE-RELATED COMORBIDITIES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE COMMON IN PEOPLE LIVING WITH HUMAN IMMUNODEFICIENCY VIRUS (PLWH). WE INVESTIGATED THE RELATIONSHIP BETWEEN COPD AND THE EPIGENETIC AGE OF THE AIRWAY EPITHELIUM AND PERIPHERAL BLOOD OF PLWH. METHODS: AIRWAY EPITHELIAL BRUSHINGS FROM 34 PLWH ENROLLED IN THE ST. PAUL'S HOSPITAL HIV BRONCHOSCOPY COHORT AND PERIPHERAL BLOOD FROM 378 PLWH ENROLLED IN THE STRATEGIC TIMING OF ANTIRETROVIRAL TREATMENT (START) STUDY WERE PROFILED FOR DNA METHYLATION. THE DNA METHYLATION BIOMARKER OF AGE AND HEALTHSPAN, GRIMAGE, WAS CALCULATED IN BOTH TISSUE COMPARTMENTS. WE TESTED THE ASSOCIATION OF GRIMAGE WITH COPD IN THE AIRWAY EPITHELIUM AND AIRFLOW OBSTRUCTION AS DEFINED BY AN FEV(1)/FVC<0.70, AND FEV(1) DECLINE OVER 6 YEARS IN BLOOD. FINDINGS: THE AIRWAY EPITHELIUM OF PLWH WITH COPD WAS ASSOCIATED WITH GREATER GRIMAGE RESIDUALS COMPARED TO PLWH WITHOUT COPD (BETA=3.18, 95%CI=1.06-5.31, P=0.005). IN BLOOD, FEV(1)/FVC<LLN WAS ASSOCIATED WITH GREATER GRIMAGE RESIDUALS (BETA=1.74, 95%CI=0.37-3.24, P=0.019). FEV(1) DECLINE WAS INVERSELY CORRELATED WITH GRIMAGE RESIDUALS IN BLOOD (R=-0.13, P=0.012). PLWH WHO HAD NORMAL LUNG FUNCTION BUT WHO SUBSEQUENTLY DEVELOPED AN FEV(1)/FVC<0.70 OVER THE COURSE OF 6 YEARS HAD HIGHER GRIMAGE RESIDUALS AT BASELINE (BETA=2.33, 95%CI=0.23-4.44, P=0.031). INTERPRETATION: GRIMAGE MAY REFLECT LUNG AND SYSTEMIC EPIGENETIC CHANGES THAT OCCUR WITH ADVANCED AIRFLOW OBSTRUCTION AND MAY HELP TO IDENTIFY PLWH WITH A HIGHER RISK OF DEVELOPING COPD. FUNDING: CANADIAN INSTITUTES OF HEALTH RESEARCH AND THE BRITISH COLUMBIA LUNG ASSOCIATION. THE START SUBSTUDY WAS FUNDED BY NIH GRANTS: UM1-AI068641, UM1-AI120197, AND RO1HL096453.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18   178  39 ACCELERATED EPIGENETIC AGING AS A RISK FACTOR FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND DECREASED LUNG FUNCTION IN TWO PROSPECTIVE COHORT STUDIES. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A FREQUENT DIAGNOSIS IN OLDER INDIVIDUALS AND CONTRIBUTOR TO GLOBAL MORBIDITY AND MORTALITY. GIVEN THE LINK BETWEEN LUNG DISEASE AND AGING, WE NEED TO UNDERSTAND HOW MOLECULAR INDICATORS OF AGING RELATE TO LUNG FUNCTION AND DISEASE. USING DATA FROM THE POPULATION-BASED KORA (COOPERATIVE HEALTH RESEARCH IN THE REGION OF AUGSBURG) SURVEYS, WE ASSOCIATED BASELINE EPIGENETIC (DNA METHYLATION) AGE ACCELERATION WITH INCIDENT COPD AND LUNG FUNCTION. MODELS WERE ADJUSTED FOR AGE, SEX, SMOKING, HEIGHT, WEIGHT, AND BASELINE LUNG DISEASE AS APPROPRIATE. ASSOCIATIONS WERE REPLICATED IN THE NORMATIVE AGING STUDY. OF 770 KORA PARTICIPANTS, 131 DEVELOPED INCIDENT COPD OVER 7 YEARS. BASELINE ACCELERATED EPIGENETIC AGING WAS SIGNIFICANTLY ASSOCIATED WITH INCIDENT COPD. THE CHANGE IN AGE ACCELERATION (FOLLOW-UP - BASELINE) WAS MORE STRONGLY ASSOCIATED WITH COPD THAN BASELINE AGING ALONE. THE ASSOCIATION BETWEEN THE CHANGE IN AGE ACCELERATION BETWEEN BASELINE AND FOLLOW-UP AND INCIDENT COPD REPLICATED IN THE NORMATIVE AGING STUDY. ASSOCIATIONS WITH SPIROMETRIC LUNG FUNCTION PARAMETERS WERE WEAKER THAN THOSE WITH COPD, BUT A META-ANALYSIS OF BOTH COHORTS PROVIDE SUGGESTIVE EVIDENCE OF ASSOCIATIONS. ACCELERATED EPIGENETIC AGING, BOTH BASELINE MEASURES AND CHANGES OVER TIME, MAY BE A RISK FACTOR FOR COPD AND REDUCED LUNG FUNCTION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19  1514  44 DNA METHYLATION AND THE EPIGENETIC CLOCK IN RELATION TO PHYSICAL FRAILTY IN OLDER PEOPLE: THE LOTHIAN BIRTH COHORT 1936. BACKGROUND: THE BIOLOGICAL MECHANISMS UNDERLYING FRAILTY IN OLDER PEOPLE ARE POORLY UNDERSTOOD. THERE IS SOME EVIDENCE TO SUGGEST THAT DNA METHYLATION PATTERNS MAY BE ALTERED IN FRAIL INDIVIDUALS. METHODS: PARTICIPANTS WERE 791 PEOPLE AGED 70 YEARS FROM THE LOTHIAN BIRTH COHORT 1936. DNA METHYLATION WAS MEASURED IN WHOLE BLOOD. BIOLOGICAL AGE WAS ESTIMATED USING TWO MEASURES OF DNA METHYLATION-BASED AGE ACCELERATION-EXTRINSIC AND INTRINSIC EPIGENETIC AGE ACCELERATION. WE CARRIED OUT AN EPIGENOME-WIDE ASSOCIATION STUDY OF PHYSICAL FRAILTY, AS DEFINED BY THE FRIED PHENOTYPE. MULTINOMIAL LOGISTIC REGRESSION WAS USED TO CALCULATE RELATIVE RISK RATIOS FOR BEING PHYSICALLY FRAIL OR PRE-FRAIL ACCORDING TO EPIGENETIC AGE ACCELERATION. RESULTS: THERE WAS A SINGLE SIGNIFICANT (P = 1.16 X 10-7) ASSOCIATION IN THE EPIGENOME-WIDE ASSOCIATION STUDY COMPARING FRAIL VERSUS NOT FRAIL. THE SAME CPG WAS NOT SIGNIFICANT WHEN COMPARING PRE-FRAIL VERSUS NOT FRAIL. GREATER EXTRINSIC EPIGENETIC AGE ACCELERATION WAS ASSOCIATED WITH AN INCREASED RISK OF BEING PHYSICALLY FRAIL, BUT NOT OF BEING PRE-FRAIL. FOR A YEAR INCREASE IN EXTRINSIC EPIGENETIC AGE ACCELERATION, AGE- AND SEX-ADJUSTED RELATIVE RISK RATIOS (95% CI) FOR BEING PHYSICALLY FRAIL OR PRE-FRAIL WERE 1.06 (1.02, 1.10) AND 1.02 (1.00, 1.04), RESPECTIVELY. AFTER FURTHER ADJUSTMENT FOR SMOKING AND CHRONIC DISEASE, THE ASSOCIATION WITH PHYSICAL FRAILTY REMAINED SIGNIFICANT. INTRINSIC EPIGENETIC AGE ACCELERATION WAS NOT ASSOCIATED WITH PHYSICAL FRAILTY STATUS. CONCLUSIONS: PEOPLE WHO ARE BIOLOGICALLY OLDER, AS INDEXED BY GREATER EXTRINSIC EPIGENETIC AGE ACCELERATION, ARE MORE LIKELY TO BE PHYSICALLY FRAIL. FUTURE RESEARCH WILL NEED TO INVESTIGATE WHETHER EPIGENETIC AGE ACCELERATION PLAYS A CAUSAL ROLE IN THE ONSET OF PHYSICAL FRAILTY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
20   501  40 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