1  5679 133 SHORT- AND LONG-TERM HINDLIMB IMMOBILIZATION AND RELOADING: PROFILE OF EPIGENETIC EVENTS IN GASTROCNEMIUS. SKELETAL MUSCLE DYSFUNCTION AND ATROPHY ARE CHARACTERISTIC FEATURES ACCOMPANYING CHRONIC CONDITIONS. EPIGENETIC EVENTS REGULATE MUSCLE MASS AND FUNCTION MAINTENANCE. WE HYPOTHESIZED THAT THE PATTERN OF EPIGENETIC EVENTS (MUSCLE-ENRICHED MICRORNAS AND HISTONE ACETYLATION) AND ACETYLATION OF TRANSCRIPTION FACTORS KNOWN TO SIGNAL MUSCLE WASTING MAY DIFFER BETWEEN EARLY- AND LATE-TIME POINTS IN SKELETAL MUSCLES OF MICE EXPOSED TO HINDLIMB IMMOBILIZATION (I) AND RECOVERY FOLLOWING I. BODY AND MUSCLE WEIGHTS, GRIP STRENGTH, MUSCLE-ENRICHED MICRORNAS, HISTONE DEACETYLASES (HDACS), ACETYLATION OF PROTEINS, HISTONES, AND TRANSCRIPTION FACTORS (TF), MYOGENIC TF FACTORS, AND MUSCLE PHENOTYPE WERE ASSESSED IN GASTROCNEMIUS OF MICE EXPOSED TO PERIODS (1, 2, 3, 7, 15, AND 30 DAYS, I GROUPS) OF HINDLIMB IMMOBILIZATION, AND IN THOSE EXPOSED TO RELOADING FOR DIFFERENT PERIODS OF TIME (1, 3, 7, 15, AND 30 DAYS, R GROUPS) FOLLOWING 7-DAY IMMOBILIZATION. COMPARED TO NON-IMMOBILIZED CONTROLS, MUSCLE WEIGHT, LIMB STRENGTH, MICRORNAS, ESPECIALLY MIR-486, SIRT1 LEVELS, AND SLOW- AND FAST-TWITCH CROSS-SECTIONAL AREAS WERE DECREASED IN MICE OF I GROUPS, WHEREAS PAX7 AND ACETYLATED FOXO1 AND FOXO3 LEVELS WERE INCREASED. MUSCLE RELOADING FOLLOWING SPLINT REMOVAL IMPROVED MUSCLE MASS LOSS, STRENGTH, AND FIBER ATROPHY, BY INCREASING MICRORNAS, PARTICULARLY MIR-486, AND SIRT1 CONTENT, WHILE DECREASING ACETYLATED FOXO1 AND FOXO3 LEVELS. IN THIS MOUSE MODEL OF DISUSE MUSCLE ATROPHY, MUSCLE-ENRICHED MICRORNAS, ESPECIALLY MIR-486, THROUGH PAX7 REGULATION DELAYED MUSCLE CELL DIFFERENTIATION FOLLOWING UNLOADING OF GASTROCNEMIUS MUSCLE. ACETYLATION OF FOXO1 AND 3 SEEMED TO DRIVE MUSCLE MASS LOSS AND ATROPHY, WHILE DEACETYLATION OF THESE FACTORS THROUGH SIRT1 WOULD ENABLE THE MUSCLE FIBERS TO REGENERATE. J. CELL. PHYSIOL. 232: 1415-1427, 2017. (C) 2016 WILEY PERIODICALS, INC.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
2  4912  21 PAIN INTERFERENCE MEDIATES THE ASSOCIATION BETWEEN EPIGENETIC AGING AND GRIP STRENGTH IN MIDDLE TO OLDER AGED MALES AND FEMALES WITH CHRONIC PAIN. INTRODUCTION: CHRONIC PAIN IS ONE OF THE LEADING CAUSES OF DISABILITY THAT MAY ACCELERATE BIOLOGICAL AGING AND REDUCE PHYSICAL FUNCTION. EPIGENETIC CLOCKS PROVIDE AN ESTIMATE OF HOW THE SYSTEM AGES AND CAN PREDICT HEALTH OUTCOMES SUCH AS PHYSICAL FUNCTION. PHYSICAL FUNCTION DECLINES MAY BE ATTRIBUTED TO DECREASES IN MUSCLE QUALITY DUE TO DISUSE THAT CAN BE MEASURED QUICKLY AND NONINVASIVELY USING GRIP STRENGTH. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE ASSOCIATIONS AMONG SELF-REPORTED PAIN, GRIP STRENGTH, AND EPIGENETIC AGING IN THOSE WITH CHRONIC PAIN. METHODS: PARTICIPANTS (57.91 +/- 8.04 YEARS) COMPLETED PAIN QUESTIONNAIRES, A BLOOD DRAW AND HAND GRIP STRENGTH TASK. WE USED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN (DNAMGRIMAGE), AND USED THE SUBSEQUENT DIFFERENCE OF PREDICTED EPIGENETIC AGE FROM CHRONOLOGICAL AGE (DNAMGRIMAGE-DIFFERENCE). RESULTS: EXPLORATORY PATHWAY ANALYSES REVEALED THAT PAIN INTENSITY MEDIATED THE ASSOCIATION BETWEEN DNAMGRIMAGE-DIFFERENCE AND HANDGRIP STRENGTH IN MALES ONLY (BETA = -0.1115; CI [-0.2929, -0.0008]) AND PAIN INTERFERENCE MEDIATED THE ASSOCIATION BETWEEN DNAMGRIMAGE-DIFFERENCE AND HANDGRIP STRENGTH IN MALES BETA = -0.1401; CI [-0.3400, -0.0222]), AND FEMALES (BETA = -0.024; CI [-0.2918, -0.0020]). DISCUSSION: CHRONIC KNEE PAIN MAY ACCELERATE EPIGENETIC AGING PROCESSES THAT MAY INFLUENCE HANDGRIP STRENGTH IN OLDER AGE ADULTS. CHRONIC PAIN COULD BE A SYMPTOM OF THE AGING BODY THUS CONTRIBUTING TO DECLINES IN MUSCULOSKELETAL FUNCTION IN LATER LIFE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3  1963  21 EPIGENETIC AGING MEDIATES THE ASSOCIATION BETWEEN PAIN IMPACT AND BRAIN AGING IN MIDDLE TO OLDER AGE INDIVIDUALS WITH KNEE PAIN. CHRONIC MUSCULOSKELETAL PAIN IS A HEALTH BURDEN THAT MAY ACCELERATE THE AGING PROCESS. ACCELERATED BRAIN AGING AND EPIGENETIC AGING HAVE SEPARATELY BEEN OBSERVED IN THOSE WITH CHRONIC PAIN. HOWEVER, IT IS UNKNOWN WHETHER THESE BIOLOGICAL MARKERS OF AGING ARE ASSOCIATED WITH EACH OTHER IN THOSE WITH CHRONIC PAIN. WE AIMED TO EXPLORE THE ASSOCIATION OF EPIGENETIC AGING AND BRAIN AGING IN MIDDLE-TO-OLDER AGE INDIVIDUALS WITH VARYING DEGREES OF KNEE PAIN. PARTICIPANTS (57.91 +/- 8.04 Y) WITH LOW IMPACT KNEE PAIN (N = 95), HIGH IMPACT KNEE PAIN (N = 53), AND PAIN-FREE CONTROLS (N = 26) COMPLETED SELF-REPORTED PAIN, A BLOOD DRAW, AND AN MRI SCAN. WE USED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN (DNAMGRIMAGE), THE SUBSEQUENT DIFFERENCE OF PREDICTED EPIGENETIC AND BRAIN AGE FROM CHRONOLOGICAL AGE (DNAMGRIMAGE-DIFFERENCE AND BRAIN-PAD, RESPECTIVELY). THERE WAS A SIGNIFICANT MAIN EFFECT FOR PAIN IMPACT GROUP (F (2,167) = 3.847, P = 0.023, ROTATIONAL ENERGY = 1 / 2IOMEGA2 = 0.038, ANCOVA) ON BRAIN-PAD AND DNAMGRIMAGE-DIFFERENCE (F (2,167) = 6.800, P = 0.001, I = MK2 = 0.075, ANCOVA) AFTER CONTROLLING FOR COVARIATES. DNAMGRIMAGE-DIFFERENCE AND BRAIN-PAD WERE MODESTLY CORRELATED (R =0.198; P =0.010). EXPLORATORY ANALYSIS REVEALED THAT DNAMGRIMAGE-DIFFERENCE MEDIATED GCPS PAIN IMPACT, GCPS PAIN SEVERITY, AND PAIN-RELATED DISABILITY SCORES ON BRAIN-PAD. BASED UPON THE CURRENT STUDY FINDINGS, WE SUGGEST THAT PAIN COULD BE A DRIVER FOR ACCELERATED BRAIN AGING VIA EPIGENOME INTERACTIONS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4  1964  24 EPIGENETIC AGING, KNEE PAIN AND PHYSICAL PERFORMANCE IN COMMUNITY-DWELLING MIDDLE-TO-OLDER AGE ADULTS. KNEE PAIN IS A LEADING CAUSE OF DISABILITY IN THE AGING POPULATION AND MAY INDIRECTLY ACCELERATE BIOLOGICAL AGING PROCESSES. CHRONOLOGICAL AGING INCREASES THE RISK OF DEVELOPING OF KNEE PAIN AND KNEE PAIN REDUCES PHYSICAL FUNCTION; HOWEVER, LIMITED DATA EXIST ON HOW EPIGENETIC AGING, A KNOWN HALLMARK OF BIOLOGICAL AGING SHOWN TO PREDICT HEALTH SPAN AND MORTALITY, MAY INFLUENCE THIS RELATIONSHIP. THE PURPOSE OF THIS STUDY WAS TO EXAMINE WHETHER DECREASED PHYSICAL PERFORMANCE ASSOCIATED WITH KNEE PAIN IS MEDIATED BY MARKERS OF EPIGENETIC AGING. PARTICIPANTS (57.91 +/- 8.04 YEARS) WITH LOW IMPACT KNEE PAIN (N = 95), HIGH IMPACT KNEE PAIN (N = 53) AND PAIN-FREE CONTROLS (N = 26) COMPLETED SELF-REPORTED PAIN, A BLOOD DRAW AND A SHORT PHYSICAL PERFORMANCE BATTERY (SPPB) THAT INCLUDED BALANCE, WALKING, AND SIT TO STAND TASKS. WE EMPLOYED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN AND SHOWN TO PREDICT OVERALL MORTALITY RISK (DNAMGRIMAGE). BOOTSTRAPPED-MEDIATION ANALYSES WERE USED TO DETERMINE ASSOCIATIONS OF DNAMGRIMAGE AND SPPB BETWEEN PAIN GROUPS. THOSE WITH HIGH IMPACT AND LOW IMPACT PAIN HAD A BIOLOGICALLY OLDER EPIGENETIC AGE (5.14Y +/- 5.66 AND 1.32Y +/- 5.41, RESPECTIVELY). HOWEVER, WHILE THERE WERE DIRECT EFFECTS OF PAIN ON OVERALL PHYSICAL PERFORMANCE, THESE WERE NOT EXPLAINED BY EPIGENETIC AGING. EPIGENETIC AGING ONLY MEDIATED THE EFFECT OF PAIN ON BALANCE PERFORMANCE. FUTURE WORK IS NEEDED TO EXAMINE PAIN'S IMPACT ON BIOLOGICAL AGING PROCESSES INCLUDING EPIGENETIC AGING AND ITS ULTIMATE EFFECT ON PHYSICAL FUNCTION MEASURES KNOWN TO PREDICT HEALTH SPAN AND MORTALITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  4047  25 MAIN PATHOGENIC MECHANISMS AND RECENT ADVANCES IN COPD PERIPHERAL SKELETAL MUSCLE WASTING. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A WORLDWIDE PREVALENT RESPIRATORY DISEASE MAINLY CAUSED BY TOBACCO SMOKE EXPOSURE. COPD IS NOW CONSIDERED AS A SYSTEMIC DISEASE WITH SEVERAL COMORBIDITIES. AMONG THEM, SKELETAL MUSCLE DYSFUNCTION AFFECTS AROUND 20% OF COPD PATIENTS AND IS ASSOCIATED WITH HIGHER MORBIDITY AND MORTALITY. ALTHOUGH THE HISTOLOGICAL ALTERATIONS ARE WELL CHARACTERIZED, INCLUDING MYOFIBER ATROPHY, A DECREASED PROPORTION OF SLOW-TWITCH MYOFIBERS, AND A DECREASED CAPILLARIZATION AND OXIDATIVE PHOSPHORYLATION CAPACITY, THE MOLECULAR BASIS FOR MUSCLE ATROPHY IS COMPLEX AND REMAINS PARTLY UNKNOWN. MAJOR DIFFICULTIES LIE IN PATIENT HETEROGENEITY, ACCESSING PATIENTS' SAMPLES, AND COMPLEX MULTIFACTORIAL PROCESS INCLUDING EXTRINSIC MECHANISMS, SUCH AS TOBACCO SMOKE OR DISUSE, AND INTRINSIC MECHANISMS, SUCH AS OXIDATIVE STRESS, HYPOXIA, OR SYSTEMIC INFLAMMATION. MUSCLE WASTING IS ALSO A HIGHLY DYNAMIC PROCESS WHOSE INVESTIGATION IS HAMPERED BY THE DIFFERENTIAL PROTEIN REGULATION ACCORDING TO THE STAGE OF ATROPHY. IN THIS REVIEW, WE REPORT AND DISCUSS RECENT DATA REGARDING THE MOLECULAR ALTERATIONS IN COPD LEADING TO IMPAIRED MUSCLE MASS, INCLUDING INFLAMMATION, HYPOXIA AND HYPERCAPNIA, MITOCHONDRIAL DYSFUNCTION, DIVERSE METABOLIC CHANGES SUCH AS OXIDATIVE AND NITROSATIVE STRESS AND GENETIC AND EPIGENETIC MODIFICATIONS, ALL LEADING TO AN IMPAIRED ANABOLIC/CATABOLIC BALANCE IN THE MYOCYTE. WE RECAPITULATE DATA CONCERNING SKELETAL MUSCLE DYSFUNCTION OBTAINED IN THE DIFFERENT RODENT MODELS OF COPD. FINALLY, WE PROPOSE SEVERAL PATHWAYS THAT SHOULD BE INVESTIGATED IN COPD SKELETAL MUSCLE DYSFUNCTION IN THE FUTURE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6  5757  21 SOCIOECONOMIC STATUS, KNEE PAIN, AND EPIGENETIC AGING IN COMMUNITY-DWELLING MIDDLE-TO-OLDER AGE ADULTS. CHRONIC MUSCULOSKELETAL PAIN IS OFTEN ASSOCIATED WITH LOWER SOCIOECONOMIC STATUS (SES). SES CORRELATES WITH PSYCHOLOGICAL AND ENVIRONMENTAL CONDITIONS THAT COULD CONTRIBUTE TO THE DISPROPORTIONATE BURDEN OF CHRONIC STRESS. CHRONIC STRESS CAN INDUCE CHANGES IN GLOBAL DNA METHYLATION AND GENE EXPRESSION, WHICH INCREASES RISK OF CHRONIC PAIN. WE AIMED TO EXPLORE THE ASSOCIATION OF EPIGENETIC AGING AND SES IN MIDDLE-TO-OLDER AGE INDIVIDUALS WITH VARYING DEGREES OF KNEE PAIN. PARTICIPANTS COMPLETED SELF-REPORTED PAIN, A BLOOD DRAW, AND ANSWERED DEMOGRAPHIC QUESTIONS PERTAINING TO SES. WE USED AN EPIGENETIC CLOCK PREVIOUSLY ASSOCIATED WITH KNEE PAIN (DNAMGRIMAGE) AND THE SUBSEQUENT DIFFERENCE OF PREDICTED EPIGENETIC AGE (DNAMGRIMAGE-DIFF). OVERALL, THE MEAN DNAMGRIMAGE WAS 60.3 (+/-7.6), AND THE AVERAGE DNAMGRIMAGE-DIFF WAS 2.4 YEARS (+/-5.6 YEARS). THOSE EXPERIENCING HIGH-IMPACT PAIN EARNED LESS INCOME AND HAD LOWER EDUCATION LEVELS COMPARED TO BOTH LOW-IMPACT AND NO PAIN GROUPS. DIFFERENCES IN DNAMGRIMAGE-DIFF ACROSS PAIN GROUPS WERE FOUND, WHEREBY INDIVIDUALS WITH HIGH-IMPACT PAIN HAD ACCELERATED EPIGENETIC AGING ( APPROXIMATELY 5 YEARS) COMPARED TO LOW-IMPACT PAIN AND NO PAIN CONTROL GROUPS (BOTH APPROXIMATELY 1 YEAR). OUR MAIN FINDING WAS THAT EPIGENETIC AGING MEDIATED THE ASSOCIATIONS OF INCOME AND EDUCATION WITH PAIN IMPACT, AS SUCH THE RELATIONSHIP BETWEEN SES AND PAIN OUTCOMES MAY OCCUR THROUGH POTENTIAL INTERACTIONS WITH THE EPIGENOME REFLECTIVE OF ACCELERATED CELLULAR AGING. PERSPECTIVE: SOCIOECONOMIC STATUS (SES) HAS PREVIOUSLY BEEN IMPLICATED IN THE PAIN EXPERIENCE. THE PRESENT MANUSCRIPT AIMS TO PRESENT A POTENTIAL SOCIAL-BIOLOGICAL LINK BETWEEN SES AND PAIN VIA ACCELERATED EPIGENETIC AGING.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7   525  20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
8   648  17 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9  4502  22 MORTALITY ASSOCIATIONS WITH DNA METHYLATION-BASED BIOLOGICAL AGING AND PHYSICAL FUNCTIONING MEASURES ACROSS A 20-YEAR FOLLOW-UP PERIOD. BACKGROUND: MEASURES OF BIOLOGICAL AGING RANGE FROM DNA METHYLATION (DNAM)-BASED ESTIMATES TO MEASURES OF PHYSICAL ABILITIES. THE PURPOSE OF THIS STUDY WAS TO COMPARE DNAM- AND PHYSICAL FUNCTIONING-BASED MEASURES OF BIOLOGICAL AGING IN PREDICTING MORTALITY. METHODS: WE STUDIED 63- TO 76-YEAR-OLD WOMEN (N = 395) FROM THE FINNISH TWIN STUDY ON AGING (FITSA). PARTICIPANTS' BIOLOGICAL AGE (EPIGENETIC CLOCKS DNAM GRIMAGE AND DUNEDINPACE) WAS ESTIMATED USING BLOOD DNAM DATA. TESTS OF PHYSICAL FUNCTIONING CONDUCTED UNDER STANDARDIZED LABORATORY CONDITIONS INCLUDED THE TIMED UP AND GO (TUG) TEST AND 10-M WALK TEST. MORTALITY HAZARD RATIOS WERE CALCULATED PER EVERY 1 STANDARD DEVIATION (SD) INCREASE IN THE PREDICTOR. COX REGRESSION MODELS WERE CONDUCTED FOR INDIVIDUALS AND TWIN PAIRS, THE LATTER CONTROLLING FOR UNDERLYING GENETIC EFFECTS. THE MODELS WERE ADJUSTED FOR KNOWN LIFESTYLE PREDICTORS OF MORTALITY. RESULTS: DURING THE FOLLOW-UP PERIOD (MEAN 17.0 YEARS, RANGE 0.2-20.3), 187 PARTICIPANTS DIED. IN BOTH THE INDIVIDUAL-BASED AND PAIRWISE ANALYSES, GRIMAGE AND BOTH FUNCTIONAL BIOMARKERS OF AGING WERE ASSOCIATED WITH MORTALITY INDEPENDENT OF FAMILY RELATEDNESS, CHRONOLOGICAL AGE, PHYSICAL ACTIVITY, BODY MASS INDEX, SMOKING, EDUCATION, OR CHRONIC DISEASES. IN A MODEL INCLUDING BOTH THE DNAM-BASED MEASURES AND FUNCTIONAL BIOMARKERS OF AGING, GRIMAGE AND TUG REMAINED PREDICTIVE. CONCLUSIONS: THE FINDINGS SUGGEST THAT DNAM GRIMAGE AND THE TUG TEST ARE STRONG PREDICTORS OF MORTALITY INDEPENDENT OF EACH OTHERS AND GENETIC INFLUENCES. DNAM-BASED MEASURES AND FUNCTIONAL TESTS CAPTURE DIFFERENT ASPECTS OF THE AGING PROCESS AND THUS COMPLEMENT EACH OTHER AS MEASURES OF BIOLOGICAL AGING IN PREDICTING MORTALITY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10  5334  43 QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EPIGENETIC PROFILE IN ADVANCED COPD. EPIGENETIC MECHANISMS REGULATE MUSCLE MASS AND FUNCTION IN MODELS OF MUSCLE DYSFUNCTION AND ATROPHY. WE ASSESSED WHETHER QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EXPRESSION PROFILE OF EPIGENETIC EVENTS IN PATIENTS WITH ADVANCED COPD (CHRONIC OBSTRUCTIVE PULMONARY DISEASE). IN VASTUS LATERALIS (VL) OF SEDENTARY SEVERE COPD PATIENTS (N=41), WHO WERE FURTHER SUBDIVIDED INTO THOSE WITH (N=25) AND WITHOUT (N=16) MUSCLE WEAKNESS AND HEALTHY CONTROLS (N=19), EXPRESSION OF MUSCLE-ENRICHED MIRNAS, HISTONE ACETYLTRANSFERASES (HATS) AND DEACETYLASES (HDACS), GROWTH AND ATROPHY SIGNALLING MARKERS, TOTAL PROTEIN AND HISTONE ACETYLATION, TRANSCRIPTION FACTORS, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE CLINICALLY EVALUATED. COMPARED WITH CONTROLS, IN VL OF ALL COPD TOGETHER AND IN MUSCLE-WEAKNESS PATIENTS, EXPRESSION OF MIR-1, MIR-206 AND MIR-27A, LEVELS OF LYSINE-ACETYLATED PROTEINS AND HISTONES AND ACETYLATED HISTONE 3 WERE INCREASED, WHEREAS EXPRESSION OF HDAC3, HDAC4, SIRTUIN-1 (SIRT-1), IGF-1 (INSULIN-LIKE GROWTH FACTOR-1) WERE DECREASED, AKT (V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOGUE 1) EXPRESSION DID NOT DIFFER, FOLLISTATIN EXPRESSION WAS GREATER, WHEREAS MYOSTATIN EXPRESSION WAS LOWER, SERUM REPONSE FACTOR (SRF) EXPRESSION WAS INCREASED AND FIBRE SIZE OF FAST-TWITCH FIBRES WAS SIGNIFICANTLY REDUCED. IN VL OF SEVERE COPD PATIENTS WITH MUSCLE WEAKNESS AND ATROPHY, EPIGENETIC EVENTS REGULATE MUSCLE DIFFERENTIATION RATHER THAN PROLIFERATION AND MUSCLE GROWTH AND ATROPHY SIGNALLING, PROBABLY AS FEEDBACK MECHANISMS TO PREVENT THOSE MUSCLES FROM UNDERGOING FURTHER ATROPHY. LYSINE-HYPERACETYLATION OF HISTONES MAY DRIVE ENHANCED PROTEIN CATABOLISM IN THOSE MUSCLES. THESE FINDINGS MAY HELP DESIGN NOVEL THERAPEUTIC STRATEGIES (ENHANCERS OF MIRNAS PROMOTING MYOGENESIS AND ACETYLATION INHIBITORS) TO SELECTIVELY TARGET MUSCLE WEAKNESS AND ATROPHY IN SEVERE COPD.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11  6018  20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12  2485  23 EPIGENETIC-BASED AGE ACCELERATION IN A REPRESENTATIVE SAMPLE OF OLDER AMERICANS: ASSOCIATIONS WITH AGING-RELATED MORBIDITY AND MORTALITY. BIOMARKERS DEVELOPED FROM DNA METHYLATION (DNAM) DATA ARE OF GROWING INTEREST AS PREDICTORS OF HEALTH OUTCOMES AND MORTALITY IN OLDER POPULATIONS. HOWEVER, IT IS UNKNOWN HOW EPIGENETIC AGING FITS WITHIN THE CONTEXT OF KNOWN SOCIOECONOMIC AND BEHAVIORAL ASSOCIATIONS WITH AGING-RELATED HEALTH OUTCOMES IN A LARGE, POPULATION-BASED, AND DIVERSE SAMPLE. THIS STUDY USES DATA FROM A REPRESENTATIVE, PANEL STUDY OF US OLDER ADULTS TO EXAMINE THE RELATIONSHIP BETWEEN DNAM-BASED AGE ACCELERATION MEASURES IN THE PREDICTION OF CROSS-SECTIONAL AND LONGITUDINAL HEALTH OUTCOMES AND MORTALITY. WE EXAMINE WHETHER RECENT IMPROVEMENTS TO THESE SCORES, USING PRINCIPAL COMPONENT (PC)-BASED MEASURES DESIGNED TO REMOVE SOME OF THE TECHNICAL NOISE AND UNRELIABILITY IN MEASUREMENT, IMPROVE THE PREDICTIVE CAPABILITY OF THESE MEASURES. WE ALSO EXAMINE HOW WELL DNAM-BASED MEASURES PERFORM AGAINST WELL-KNOWN PREDICTORS OF HEALTH OUTCOMES SUCH AS DEMOGRAPHICS, SES, AND HEALTH BEHAVIORS. IN OUR SAMPLE, AGE ACCELERATION CALCULATED USING "SECOND AND THIRD GENERATION CLOCKS," PHENOAGE, GRIMAGE, AND DUNEDINPACE, IS CONSISTENTLY A SIGNIFICANT PREDICTOR OF HEALTH OUTCOMES INCLUDING CROSS-SECTIONAL COGNITIVE DYSFUNCTION, FUNCTIONAL LIMITATIONS AND CHRONIC CONDITIONS ASSESSED 2 Y AFTER DNAM MEASUREMENT, AND 4-Y MORTALITY. PC-BASED EPIGENETIC AGE ACCELERATION MEASURES DO NOT SIGNIFICANTLY CHANGE THE RELATIONSHIP OF DNAM-BASED AGE ACCELERATION MEASURES TO HEALTH OUTCOMES OR MORTALITY COMPARED TO EARLIER VERSIONS OF THESE MEASURES. WHILE THE USEFULNESS OF DNAM-BASED AGE ACCELERATION AS A PREDICTOR OF LATER LIFE HEALTH OUTCOMES IS QUITE CLEAR, OTHER FACTORS SUCH AS DEMOGRAPHICS, SES, MENTAL HEALTH, AND HEALTH BEHAVIORS REMAIN EQUALLY, IF NOT MORE ROBUST, PREDICTORS OF LATER LIFE OUTCOMES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13  1957  18 EPIGENETIC AGE PREDICTORS IN COMMUNITY-DWELLING ADULTS WITH HIGH IMPACT KNEE PAIN. GERONTOLOGICAL RESEARCH REVEALS CONSIDERABLE INTERINDIVIDUAL VARIABILITY IN AGING PHENOTYPES, AND EMERGING EVIDENCE SUGGESTS THAT HIGH IMPACT CHRONIC PAIN MAY BE ASSOCIATED WITH VARIOUS ACCELERATED BIOLOGICAL AGING PROCESSES. IN PARTICULAR, EPIGENETIC AGING IS A ROBUST PREDICTOR OF HEALTH-SPAN AND DISABILITY COMPARED TO CHRONOLOGICAL AGE ALONE. THE CURRENT STUDY AIMED TO DETERMINE WHETHER SEVERAL EPIGENETIC AGING BIOMARKERS WERE ASSOCIATED WITH HIGH IMPACT CHRONIC PAIN IN MIDDLE TO OLDER AGE ADULTS (44-78 YEARS OLD). PARTICIPANTS (N = 213) UNDERWENT A BLOOD DRAW, DEMOGRAPHIC, PSYCHOSOCIAL, PAIN AND FUNCTIONAL ASSESSMENTS. WE ESTIMATED FIVE EPIGENETIC CLOCKS AND CALCULATED THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE, WHICH HAS BEEN PREVIOUSLY REPORTED TO PREDICT OVERALL MORTALITY RISK, AS WELL AS INCLUDED ADDITIONAL DERIVED VARIABLES OF EPIGENETIC AGE PREVIOUSLY ASSOCIATED WITH PAIN. THERE WERE SIGNIFICANT DIFFERENCES ACROSS PAIN IMPACT GROUPS IN THREE OUT OF THE FIVE EPIGENETIC CLOCKS EXAMINED (DNAMAGE, DNAMPHENOAGE AND DNAMGRIMAGE), INDICATING THAT PAIN-RELATED DISABILITY DURING THE PAST 6 MONTHS WAS ASSOCIATED WITH MARKERS OF EPIGENETIC AGING. ONLY DNAMPHENOAGE AND DNAMGRIMAGE WERE ASSOCIATED WITH HIGHER KNEE PAIN INTENSITY DURING THE PAST 48 H. FINALLY, PAIN CATASTROPHIZING, DEPRESSIVE SYMPTOMATOLOGY AND MORE NEUROPATHIC PAIN SYMPTOMS WERE SIGNIFICANTLY ASSOCIATED WITH AN OLDER EPIGENOME IN ONLY ONE OF THE FIVE EPIGENETIC CLOCKS (I.E. DNAMGRIMAGE) AFTER CORRECTING FOR MULTIPLE COMPARISONS (CORRECTED P'S < 0.05). GIVEN THE SCANT LITERATURE IN RELATION TO EPIGENETIC AGING AND THE COMPLEX EXPERIENCE OF PAIN, ADDITIONAL RESEARCH IS NEEDED TO UNDERSTAND WHETHER EPIGENETIC AGING MAY HELP IDENTIFY PEOPLE WITH CHRONIC PAIN AT GREATER RISK OF FUNCTIONAL DECLINE AND POORER HEALTH OUTCOMES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14  1780  21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15  2150  21 EPIGENETIC MEASURES OF AGEING PREDICT THE PREVALENCE AND INCIDENCE OF LEADING CAUSES OF DEATH AND DISEASE BURDEN. BACKGROUND: INDIVIDUALS OF THE SAME CHRONOLOGICAL AGE DISPLAY DIFFERENT RATES OF BIOLOGICAL AGEING. A NUMBER OF MEASURES OF BIOLOGICAL AGE HAVE BEEN PROPOSED WHICH HARNESS AGE-RELATED CHANGES IN DNA METHYLATION PROFILES. THESE MEASURES INCLUDE FIVE 'EPIGENETIC CLOCKS' WHICH PROVIDE AN INDEX OF HOW MUCH AN INDIVIDUAL'S BIOLOGICAL AGE DIFFERS FROM THEIR CHRONOLOGICAL AGE AT THE TIME OF MEASUREMENT. THE FIVE CLOCKS ENCOMPASS METHYLATION-BASED PREDICTORS OF CHRONOLOGICAL AGE (HORVATHAGE, HANNUMAGE), ALL-CAUSE MORTALITY (DNAM PHENOAGE, DNAM GRIMAGE) AND TELOMERE LENGTH (DNAM TELOMERE LENGTH). A SIXTH EPIGENETIC MEASURE OF AGEING DIFFERS FROM THESE CLOCKS IN THAT IT ACTS AS A SPEEDOMETER PROVIDING A SINGLE TIME-POINT MEASUREMENT OF THE PACE OF AN INDIVIDUAL'S BIOLOGICAL AGEING. THIS MEASURE OF AGEING IS TERMED DUNEDINPOAM. IN THIS STUDY, WE TEST THE ASSOCIATION BETWEEN THESE SIX EPIGENETIC MEASURES OF AGEING AND THE PREVALENCE AND INCIDENCE OF THE LEADING CAUSES OF DISEASE BURDEN AND MORTALITY IN HIGH-INCOME COUNTRIES (N </= 9537, GENERATION SCOTLAND: SCOTTISH FAMILY HEALTH STUDY). RESULTS: DNAM GRIMAGE PREDICTED INCIDENCE OF CLINICALLY DIAGNOSED CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), TYPE 2 DIABETES AND ISCHEMIC HEART DISEASE AFTER 13 YEARS OF FOLLOW-UP (HAZARD RATIOS = 2.22, 1.52 AND 1.41, RESPECTIVELY). DUNEDINPOAM PREDICTED THE INCIDENCE OF COPD AND LUNG CANCER (HAZARD RATIOS = 2.02 AND 1.45, RESPECTIVELY). DNAM PHENOAGE PREDICTED INCIDENCE OF TYPE 2 DIABETES (HAZARD RATIO = 1.54). DNAM TELOMERE LENGTH ASSOCIATED WITH THE INCIDENCE OF ISCHEMIC HEART DISEASE (HAZARD RATIO = 0.80). DNAM GRIMAGE ASSOCIATED WITH ALL-CAUSE MORTALITY, THE PREVALENCE OF COPD AND SPIROMETRY MEASURES AT THE STUDY BASELINE. THESE ASSOCIATIONS WERE PRESENT AFTER ADJUSTING FOR POSSIBLE CONFOUNDING RISK FACTORS INCLUDING ALCOHOL CONSUMPTION, BODY MASS INDEX, DEPRIVATION, EDUCATION AND TOBACCO SMOKING AND SURPASSED STRINGENT BONFERRONI-CORRECTED SIGNIFICANCE THRESHOLDS. CONCLUSIONS: OUR DATA SUGGEST THAT EPIGENETIC MEASURES OF AGEING MAY HAVE UTILITY IN CLINICAL SETTINGS TO COMPLEMENT GOLD-STANDARD METHODS FOR DISEASE ASSESSMENT AND MANAGEMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
16   181  16 ACCELERATED EPIGENETIC AGING MEDIATES THE ASSOCIATION BETWEEN VITAMIN D LEVELS AND KNEE PAIN IN COMMUNITY-DWELLING INDIVIDUALS. OBJECTIVES: TO EXAMINE THE RELATIONSHIP BETWEEN VITAMIN D STATUS AND PAIN INTENSITY AND DISABILITY IN INDIVIDUALS WITH AND WITHOUT KNEE PAIN, AND TO EXAMINE THE ROLE OF EPIGENETICS IN THIS RELATIONSHIP. DESIGN: CROSS-SECTIONAL ANALYSIS OF DATA FROM THE UPLOAD-2 STUDY (UNDERSTANDING PAIN AND LIMITATIONS IN OSTEOARTHRITIC DISEASE-2). PARTICIPANTS: 189 INDIVIDUALS AGED 45-65 YEARS AND OLDER. MEASUREMENTS: SERUM VITAMIN D LEVELS, PAIN RELATED INTERFERENCE AND CHARACTERISTIC PAIN INTENSITY MEASURES, AND THE EPIGENETIC CLOCK GRIMAGE DERIVED FROM BLOOD ANALYSES. RESULTS: LOWER VITAMIN D WAS ASSOCIATED WITH ADVANCED EPIGENETIC AGING (AGEACCELGRIM), GREATER PAIN AND DISABILITY AND THAT (AGEACCELGRIM) MEDIATED THE RELATIONSHIP BETWEEN VITAMIN D STATUS AND SELF-REPORTED PAIN (AB = -0.0799; CI [-0.1492, -0.0237]) AND DISABILITY (AB = -0.0669; CI [-0.1365, -0.0149]) OUTCOMES. CONCLUSION: THESE DATA SUPPORT THE NOTION THAT LIFESTYLE FACTORS SUCH AS NUTRITION STATUS PLAY A KEY ROLE IN AGING PROCESS, AS WELL AS THE DEVELOPMENT AND MAINTENANCE OF AGE-RELATED DISEASES SUCH AS PAIN. MODIFYING NUTRITION STATUS COULD HELP PROMOTE HEALTHY AGING AND REDUCE PAIN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
17   173  21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18   403  28 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	

19  5336  12 QUANTIFICATION OF THE PACE OF BIOLOGICAL AGING IN HUMANS THROUGH A BLOOD TEST, THE DUNEDINPOAM DNA METHYLATION ALGORITHM. BIOLOGICAL AGING IS THE GRADUAL, PROGRESSIVE DECLINE IN SYSTEM INTEGRITY THAT OCCURS WITH ADVANCING CHRONOLOGICAL AGE, CAUSING MORBIDITY AND DISABILITY. MEASUREMENTS OF THE PACE OF AGING ARE NEEDED AS SURROGATE ENDPOINTS IN TRIALS OF THERAPIES DESIGNED TO PREVENT DISEASE BY SLOWING BIOLOGICAL AGING. WE REPORT A BLOOD-DNA-METHYLATION MEASURE THAT IS SENSITIVE TO VARIATION IN PACE OF BIOLOGICAL AGING AMONG INDIVIDUALS BORN THE SAME YEAR. WE FIRST MODELED CHANGE-OVER-TIME IN 18 BIOMARKERS TRACKING ORGAN-SYSTEM INTEGRITY ACROSS 12 YEARS OF FOLLOW-UP IN N = 954 MEMBERS OF THE DUNEDIN STUDY BORN IN 1972-1973. RATES OF CHANGE IN EACH BIOMARKER OVER AGES 26-38 YEARS WERE COMPOSITED TO FORM A MEASURE OF AGING-RELATED DECLINE, TERMED PACE-OF-AGING. ELASTIC-NET REGRESSION WAS USED TO DEVELOP A DNA-METHYLATION PREDICTOR OF PACE-OF-AGING, CALLED DUNEDINPOAM FOR DUNEDIN(P)ACE(O)F(A)GING(M)ETHYLATION. VALIDATION ANALYSIS IN COHORT STUDIES AND THE CALERIE TRIAL PROVIDE PROOF-OF-PRINCIPLE FOR DUNEDINPOAM AS A SINGLE-TIME-POINT MEASURE OF A PERSON'S PACE OF BIOLOGICAL AGING.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20   624  16 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