1 5336 105 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  177  22 ACCELERATED EPIGENETIC AGING AND INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) IN PATIENTS WITH CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY A REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). THIS FAILURE CAN BE RELATED TO A PHENOTYPE OF ACCELERATED AGING. IN THIS WORK, WE CONSIDERED 76 PATIENTS WITH END-STAGE RENAL DISEASE (ESRD) AND 83 HEALTHY CONTROLS. WE CONCOMITANTLY EVALUATED FOR THE FIRST TIME TWO MEASURES THAT CAN BE INFORMATIVE OF THE RATE OF AGING, I.E., WHOLE BLOOD DNA METHYLATION USING THE ILLUMINA INFINIUM EPIC ARRAY AND PLASMA LEVELS OF A SELECTION OF INFLAMMATORY/IMMUNOLOGICAL PROTEINS USING MULTIPLEX IMMUNOASSAYS. FIRST OF ALL, WE DEMONSTRATED ACCELERATED AGING IN TERMS OF THE MOST COMMON EPIGENETIC AGE ESTIMATORS IN CKD PATIENTS. MOREOVER, WE DEVELOPED A NEW CLOCK/PREDICTOR OF AGE BASED ON THE INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) AND IDENTIFIED THE INFLAMMATORY/IMMUNOLOGICAL BIOMARKERS DIFFERENTIALLY EXPRESSED BETWEEN CASES AND CONTROLS. IPAGE APPEARED TO BE MORE SENSITIVE THAN EPIGENETIC CLOCKS IN QUANTIFYING THE ACCELERATED AGING PHENOTYPE OF ESRD PATIENTS. INTERESTINGLY, WE DID NOT FIND ANY CORRELATION BETWEEN THE AGE ACCELERATION EVALUATED ACCORDING TO THE EPIGENETIC CLOCKS AND IPAGE IN EITHER THE ESRD GROUP OR THE CONTROL GROUP. ON THE WHOLE, OUR DATA SHOW A CONSISTENT ACCELERATED AGING PHENOTYPE IN ESRD PATIENTS, WHICH IS BETTER APPRECIATED BY QUANTIFYING THE UNDERLYING INFLAMMATORY PROCESSES (INFLAMMAGING) BY IPAGE THAN BY USING EPIGENETIC CLOCKS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
3 1782  29 EFFECT OF A 3-WEEK MULTIDISCIPLINARY BODY WEIGHT REDUCTION PROGRAM ON THE EPIGENETIC AGE ACCELERATION IN OBESE ADULTS. OBESITY AND AGING SHARE COMMON MOLECULAR AND CELLULAR MECHANISMS UNDERLYING THE PATHOPHYSIOLOGY OF CARDIOVASCULAR DISEASES (CVD), WHICH OCCUR FREQUENTLY IN BOTH CONDITIONS. DNA METHYLATION (DNAM) AGE, A BIOMARKER OF THE EPIGENETIC CLOCK, HAS BEEN PROPOSED AS A MORE ACCURATE PREDICTOR OF BIOLOGICAL AGING THAN CHRONOLOGICAL AGE. A POSITIVE DIFFERENCE BETWEEN AN INDIVIDUAL'S CHRONOLOGICAL AGE AND DNAM AGE IS REFERRED TO AS EPIGENETIC AGE ACCELERATION. THE OBJECTIVE OF THE PRESENT STUDY WAS TO EVALUATE THE EFFECTS OF A 3-WEEK IN-HOSPITAL BODY WEIGHT REDUCTION PROGRAM (BWRP) ON THE EPIGENETIC AGE ACCELERATION, AS WELL AS ON OTHER CARDIOMETABOLIC OUTCOMES, IN A COHORT OF 72 OBESE ADULTS (F/M: 43/29; (CHRONOLOGICAL) AGE: 51.5 +/- 14.5 YRS; BMI: 46.5 +/- 6.3 KG/M2). AT THE END OF THE BWRP, WHEN CONSIDERING THE ENTIRE POPULATION, BMI DECREASED, AND CHANGES IN BODY COMPOSITION WERE OBSERVED. THE BWRP ALSO PRODUCED BENEFICIAL METABOLIC EFFECTS AS DEMONSTRATED BY DECREASES IN GLUCOSE, INSULIN, HOMA-IR, TOTAL CHOLESTEROL, AND LDL CHOLESTEROL. A POST-BWRP IMPROVEMENT IN CARDIOVASCULAR FUNCTION WAS ALSO EVIDENT (I.E., DECREASES IN SYSTOLIC AND DIASTOLIC BLOOD PRESSURES AND HEART RATE). THE BWRP REDUCED SOME MARKERS OF SYSTEMIC INFLAMMATION, PARTICULARLY C-REACTIVE PROTEIN (CRP). FINALLY, VASCULAR AGE (VA) AND FRAMINGHAM RISK SCORE (FRS) WERE REDUCED AFTER THE BWRP. WHEN CONSIDERING THE ENTIRE POPULATION, DNAM AGE AND EPIGENETIC AGE ACCELERATION DID NOT DIFFER AFTER THE BWRP. HOWEVER, WHEN SUBDIVIDING THE POPULATION INTO TWO GROUPS BASED ON EACH SUBJECT'S EPIGENETIC AGE ACCELERATION (I.E., </=0 YRS OR >0 YRS), THE BWRP REDUCED THE EPIGENETIC AGE ACCELERATION ONLY IN OBESE SUBJECTS WITH A VALUE > 0 YRS (THUS BIOLOGICALLY OLDER THAN EXPECTED). AMONG ALL THE SINGLE DEMOGRAPHIC, LIFESTYLE, BIOCHEMICAL, AND CLINICAL CHARACTERISTICS INVESTIGATED, ONLY SOME MARKERS OF SYSTEMIC INFLAMMATION, SUCH AS CRP, WERE ASSOCIATED WITH THE EPIGENETIC AGE ACCELERATION. MOREOVER, CHRONOLOGICAL AGE WAS CORRELATED WITH DNAM AGE AND VA; FINALLY, THERE WAS A CORRELATION BETWEEN DNAM AGE AND VA. IN CONCLUSION, A 3-WEEK BWRP IS CAPABLE OF REDUCING THE EPIGENETIC AGE ACCELERATION IN OBESE ADULTS, BEING THE BWRP-INDUCED REJUVENATION EVIDENT IN SUBJECTS WITH AN EPIGENETIC AGE ACCELERATION > 0 YRS. BASED ON THE BWRP-INDUCED DECREASE IN CRP LEVELS, CHRONIC SYSTEMIC INFLAMMATION SEEMS TO PLAY A ROLE IN MEDIATING OBESITY-RELATED EPIGENETIC REMODELING AND BIOLOGICAL AGING. THUS, DUE TO THE STRONG ASSOCIATION OF CVD RISK WITH THE EPIGENETIC CLOCK AND MORBIDITY/MORTALITY, ANY EFFORT SHOULD BE MADE TO REDUCE THE LOW-GRADE CHRONIC INFLAMMATORY STATE IN OBESITY.	2022	

4 5095  20 PLASMA PROTEOMIC BIOMARKER SIGNATURE OF AGE PREDICTS HEALTH AND LIFE SPAN. OLDER AGE IS A STRONG SHARED RISK FACTOR FOR MANY CHRONIC DISEASES, AND THERE IS INCREASING INTEREST IN IDENTIFYING AGING BIOMARKERS. HERE, A PROTEOMIC ANALYSIS OF 1301 PLASMA PROTEINS WAS CONDUCTED IN 997 INDIVIDUALS BETWEEN 21 AND 102 YEARS OF AGE. WE IDENTIFIED 651 PROTEINS ASSOCIATED WITH AGE (506 OVER-REPRESENTED, 145 UNDERREPRESENTED WITH AGE). MEDIATION ANALYSIS SUGGESTED A ROLE FOR PARTIAL CIS-EPIGENETIC CONTROL OF PROTEIN EXPRESSION WITH AGE. OF THE AGE-ASSOCIATED PROTEINS, 33.5% AND 45.3%, WERE ASSOCIATED WITH MORTALITY AND MULTIMORBIDITY, RESPECTIVELY. THERE WAS ENRICHMENT OF PROTEINS ASSOCIATED WITH INFLAMMATION AND EXTRACELLULAR MATRIX AS WELL AS SENESCENCE-ASSOCIATED SECRETORY PROTEINS. A 76-PROTEIN PROTEOMIC AGE SIGNATURE PREDICTED ACCUMULATION OF CHRONIC DISEASES AND ALL-CAUSE MORTALITY. THESE DATA SUPPORT THE USE OF PROTEOMIC BIOMARKERS TO MONITOR AGING TRAJECTORIES AND TO IDENTIFY INDIVIDUALS AT HIGHER RISK OF DISEASE TO BE TARGETED FOR IN DEPTH DIAGNOSTIC PROCEDURES AND EARLY INTERVENTIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5 4502  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6 6751  19 WHY ARE PEOPLE WITH HIV CONSIDERED "OLDER ADULTS" IN THEIR FIFTIES? ONE IN SIX NEW HIV DIAGNOSES IN EUROPE OCCUR AMONG PEOPLE OVER 50 YEARS OF AGE. AS IN THE GENERAL POPULATION, THE AGING PROCESS IS NOT HOMOGENEOUS AMONG OLDER ADULTS WITH HIV, AND SOME OF THEM EXHIBIT IMPAIRED PHYSICAL FUNCTION, HIGHER FRAILTY AND MORE FREQUENT GERIATRIC SYNDROMES. THESE ILLNESS REFLECT A HIGHER BIOLOGICAL AGE INDEPENDENTLY OF THEIR CHRONOLOGICAL AGE. AFTER STARTING ANTIRRETROVIRAL TREATMENT, PEOPLE LIVING WITH HIV (PLWH) OLDER THAN 50 EXHIBIT A POORER IMMUNOLOGICAL RECOVERY THAN YOUNGER PLWH. MOREOVER, OLDER ADULTS WITH HIV PRESENT EARLY ONSET OF COMORBIDITIES AND FUNCTIONAL IMPAIRMENT CAUSED BY PERSISTENT AND CHRONIC ACTIVATION OF THE IMMUNE SYSTEM, WHICH LEADS TO IMMUNE EXHAUSTION AND ACCELERATED IMMUNOSENESCENCE DESPITE OPTIMAL SUPPRESSION OF HIV REPLICATION. THE EVIDENCE OF POORER IMMUNOLOGICAL RESPONSE TO ARV, LINKED WITH EARLY IMMUNOSENESCENCE IN PLWH AND ITS PREMATURELY DELETERIOUS EFFECT IN PHYSIOLOGICAL FUNCTIONS AND ITS CLINICAL CONSEQUENCES, ARE THE BASIS TO ACCEPT THE CUT-OFF OF 50 YEARS OF AGE TO DEFINE AN "OLDER ADULT WITH HIV".	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
7 1964  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8 6911  16 [TWO GERMAN BIRTH COHORTS: GINIPLUS AND LISAPLUS]. NUMEROUS CHRONIC DISEASES IN CHILDHOOD AND ADULTHOOD HAVE THEIR ORIGINS IN PERINATAL LIFE AND ARE POTENTIALLY INFLUENCED BY TRANS-GENERATIONAL EPIGENETIC PROCESSES. THEREFORE, PROSPECTIVE BIRTH COHORTS CAN SUBSTANTIALLY CONTRIBUTE TO OUR KNOWLEDGE ABOUT THE ETIOLOGY OF DISEASES INCLUDING MODIFIABLE RISK FACTORS. THE TWO POPULATION-BASED GERMAN BIRTH COHORTS GINIPLUS AND LISAPLUS AIM TO DESCRIBE THE NATURAL COURSE OF CHRONIC DISEASES AND INTERMEDIATE PHENOTYPES IN CHILDHOOD AND ITS DETERMINANTS, AND TO IDENTIFY POTENTIAL GENETIC EFFECT MODIFICATIONS. IN THE MID-1990S, 5,991 (GINIPLUS) AND 3,097 (LISAPLUS) HEALTHY, TERM NEWBORNS WERE RECRUITED FOR LONG-TERM FOLLOW-UP IN FOUR REGIONS OF GERMANY. THE FOLLOW-UP RATE FOR THE FIRST 10 YEARS WAS ABOUT 55%. WE ANALYZED THE GROWTH AND DEVELOPMENT OF OVERWEIGHT, INFECTIONS AND ALLERGIC DISEASES, MENTAL AND ORAL HEALTH, METABOLIC AND INFLAMMATORY PARAMETERS AND THE ROLE OF POTENTIAL RISK FACTORS INCLUDING GENETICS. THE RESULTS OF THESE TWO BIRTH COHORTS SUBSTANTIALLY CONTRIBUTE TO THE CURRENT KNOWLEDGE ABOUT THE NATURAL COURSE OF THESE HEALTH PARAMETERS. THESE DATA WERE INCLUDED IN MANY INTERNATIONAL PROJECTS AND CONSORTIA FOR PURPOSES OF INTERNATIONAL COMPARISONS OF PREVALENCE AND CONSISTENCY OF FINDINGS, AND TO INCREASE THE POWER OF THE ANALYSES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9  181  18 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10 1355  23 DEVELOPMENT AND VALIDATION OF A SIMPLE GENERAL POPULATION LUNG CANCER RISK MODEL INCLUDING AHRR-METHYLATION. INTRODUCTION: SCREENING REDUCES LUNG CANCER MORTALITY OF HIGH-RISK POPULATIONS. CURRENTLY PROPOSED SCREENING ELIGIBILITY CRITERIA ONLY IDENTIFY HALF OF THOSE INDIVIDUALS, WHO LATER DEVELOP LUNG CANCER. THIS STUDY AIMED TO DEVELOP AND VALIDATE A SENSITIVE AND SIMPLE MODEL FOR PREDICTING 10-YEAR LUNG CANCER RISK. METHODS: USING THE 1991-94 EXAMINATION OF THE COPENHAGEN CITY HEART STUDY IN DENMARK, 6,820 FORMER OR CURRENT SMOKERS FROM THE GENERAL POPULATION WERE FOLLOWED FOR LUNG CANCER WITHIN 10 YEARS AFTER EXAMINATION. LOGISTIC REGRESSION OF BASELINE VARIABLES (AGE, SEX, EDUCATION, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, FAMILY HISTORY OF LUNG CANCER, SMOKING STATUS AND CUMULATIVE SMOKING, SECONDHAND SMOKING, OCCUPATIONAL EXPOSURES TO DUST AND FUME, BODY MASS INDEX, LUNG FUNCTION, PLASMA C-REACTIVE PROTEIN, AND AHRR(CG05575921) METHYLATION) IDENTIFIED THE BEST PREDICTIVE MODEL. THE MODEL WAS VALIDATED AMONG 3,740 FORMER OR CURRENT SMOKERS FROM THE 2001-03 EXAMINATION, ALSO FOLLOWED FOR 10 YEARS. A SIMPLE RISK CHART WAS DEVELOPED WITH POISSON REGRESSION. RESULTS: AGE, SEX, EDUCATION, SMOKING STATUS, CUMULATIVE SMOKING, AND AHRR(CG05575921) METHYLATION IDENTIFIED 65 OF 88 INDIVIDUALS WHO DEVELOPED LUNG CANCER IN THE VALIDATION COHORT. THE HIGHEST RISK GROUP, CONSISTING OF LESS EDUCATED MEN AGED >65 WITH CURRENT SMOKING STATUS AND CUMULATIVE SMOKING >20 PACK-YEARS, HAD ABSOLUTE 10-YEAR RISKS VARYING FROM 4% TO 16% BY AHRR(CG05575921) METHYLATION. CONCLUSION: A SIMPLE RISK CHART INCLUDING AGE, SEX, EDUCATION, SMOKING STATUS, CUMULATIVE SMOKING, AND AHRR(CG05575921) METHYLATION, IDENTIFIES INDIVIDUALS WITH 10-YEAR LUNG CANCER RISK FROM BELOW 1% TO 16%. INCLUDING AHRR(CG05575921) METHYLATION IN THE ELIGIBILITY CRITERIA FOR SCREENING IDENTIFIES SMOKERS WHO WOULD BENEFIT THE MOST FROM SCREENING.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11 3162  25 GREATER STRESS AND TRAUMA MEDIATE RACE-RELATED DIFFERENCES IN EPIGENETIC AGE BETWEEN BLACK AND WHITE YOUNG ADULTS IN A COMMUNITY SAMPLE. BLACK AMERICANS SUFFER LOWER LIFE EXPECTANCY AND SHOW SIGNS OF ACCELERATED AGING COMPARED TO OTHER AMERICANS. WHILE PREVIOUS STUDIES OBSERVE THESE DIFFERENCES IN CHILDREN AND POPULATIONS WITH CHRONIC ILLNESS, WHETHER THESE PATHOLOGIC PROCESSES EXIST OR HOW THESE PATHOLOGIC PROCESSES PROGRESS HAS YET TO BE EXPLORED PRIOR TO THE ONSET OF SIGNIFICANT CHRONIC ILLNESS, WITHIN A YOUNG ADULT POPULATION. THEREFORE, WE INVESTIGATED RACE-RELATED DIFFERENCES IN EPIGENETIC AGE IN A CROSS-SECTIONAL SAMPLE OF YOUNG PUTATIVELY HEALTHY ADULTS AND ASSESSED WHETHER LIFETIME STRESS AND/OR TRAUMA MEDIATE THOSE DIFFERENCES. BIOLOGICAL AND PSYCHOLOGICAL DATA WERE COLLECTED FROM SELF-REPORTED HEALTHY ADULT VOLUNTEERS WITHIN THE LOCAL NEW HAVEN AREA (399 VOLUNTEERS, 19.8% BLACK, MEAN AGE: 29.28). STRESS AND TRAUMA DATA WAS COLLECTED USING THE CUMULATIVE ADVERSITY INVENTORY (CAI) INTERVIEW, WHICH ASSESSED SPECIFIC TYPES OF STRESSORS, INCLUDING MAJOR LIFE EVENTS, TRAUMATIC EVENTS, WORK, FINANCIAL, RELATIONSHIP AND CHRONIC STRESSORS CUMULATIVELY OVER TIME. GRIMAGE ACCELERATION (GAA), DETERMINED FROM WHOLE BLOOD COLLECTED FROM PARTICIPANTS, MEASURED EPIGENETIC AGE. IN ORDER TO UNDERSTAND THE IMPACT OF STRESS AND TRAUMA ON GAA, EXPLORATORY MEDIATION ANALYSES WERE THEN USED. WE FOUND CUMULATIVE STRESSORS ACROSS ALL TYPES OF EVENTS (MEAN DIFFERENCE OF 6.9 P = 2.14E-4) AND GAA (BETA = 2.29 YEARS [1.57-3.01, P = 9.70E-10] FOR RACE, PARTIAL ETA(2) = 0.091, MODEL ADJUSTED R(2) = 0.242) WERE SIGNIFICANTLY GREATER IN BLACK COMPARED TO WHITE PARTICIPANTS. CRITICALLY, CAI TOTAL SCORE (PROPORTION MEDIATED: 0.185 [0.073-0.34, P = 6E-4]) SIGNIFICANTLY MEDIATED THE RELATIONSHIP BETWEEN RACE AND GAA. FURTHER ANALYSIS ATTRIBUTED THIS DIFFERENCE TO MORE TRAUMATIC EVENTS, PARTICULARLY ASSAULTIVE TRAUMAS AND DEATH OF LOVED ONES. OUR RESULTS SUGGEST THAT, PRIOR TO DEVELOPMENT OF SIGNIFICANT CHRONIC DISEASE, BLACK INDIVIDUALS HAVE INCREASED EPIGENETIC AGE COMPARED TO WHITE PARTICIPANTS AND THAT INCREASED CUMULATIVE STRESS AND TRAUMATIC EVENTS MAY CONTRIBUTE SIGNIFICANTLY TO THIS EPIGENETIC AGING DIFFERENCE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12  175  23 ACCELERATED AGING WITH HIV BEGINS AT THE TIME OF INITIAL HIV INFECTION. LIVING WITH HIV INFECTION IS ASSOCIATED WITH EARLY ONSET OF AGING-RELATED CHRONIC CONDITIONS, SOMETIMES DESCRIBED AS ACCELERATED AGING. EPIGENETIC DNA METHYLATION PATTERNS CAN EVALUATE ACCELERATION OF BIOLOGICAL AGE RELATIVE TO CHRONOLOGICAL AGE. THE IMPACT OF INITIAL HIV INFECTION ON FIVE EPIGENETIC MEASURES OF AGING WAS EXAMINED BEFORE AND APPROXIMATELY 3 YEARS AFTER HIV INFECTION IN THE SAME INDIVIDUALS (N=102). SIGNIFICANT EPIGENETIC AGE ACCELERATION (MEDIAN 1.9-4.8 YEARS) AND ESTIMATED TELOMERE LENGTH SHORTENING (ALL P</= 0.001) WERE OBSERVED FROM PRE-TO POST-HIV INFECTION, AND REMAINED SIGNIFICANT IN THREE EPIGENETIC MEASURES AFTER CONTROLLING FOR T CELL CHANGES. NO ACCELERATION WAS SEEN IN AGE- AND TIME INTERVAL-MATCHED HIV-UNINFECTED CONTROLS. CHANGES IN GENOME-WIDE CO-METHYLATION CLUSTERS WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INITIAL HIV INFECTION (P</= 2.0 X 10(-4)). THESE LONGITUDINAL OBSERVATIONS CLEARLY DEMONSTRATE AN EARLY AND SUBSTANTIAL IMPACT OF HIV INFECTION ON THE EPIGENETIC AGING PROCESS, AND SUGGEST A ROLE FOR HIV ITSELF IN THE EARLIER ONSET OF CLINICAL AGING.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
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	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14 2645  30 EPIGENOMIC INDICATORS OF AGE IN AFRICAN AMERICANS. AGE IS A WELL-ESTABLISHED RISK FACTOR FOR CHRONIC DISEASES. HOWEVER, THE CELLULAR AND MOLECULAR CHANGES ASSOCIATED WITH AGING PROCESSES THAT ARE RELATED TO CHRONIC DISEASE INITIATION AND PROGRESSION ARE NOT WELL-UNDERSTOOD. THUS, THERE IS AN INCREASED NEED TO IDENTIFY NEW MARKERS OF CELLULAR AND MOLECULAR CHANGES THAT OCCUR DURING AGING PROCESSES. IN THIS STUDY, WE USE GENOME-WIDE DNA METHYLATION FROM 26,428 CPG SITES IN 13,877 GENES TO INVESTIGATE THE RELATIONSHIP BETWEEN AGE AND EPIGENETIC VARIATION IN THE PERIPHERAL BLOOD CELLS OF 972 AFRICAN AMERICAN ADULTS FROM THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY (GENOA) STUDY (MEAN AGE=66.3 YEARS, RANGE=39-95). AGE WAS SIGNIFICANTLY ASSOCIATED WITH 7,601 (28.8%) CPG SITES AFTER BONFERRONI CORRECTION FOR ALPHA=0.05 (P<1.89X10(-6)). DUE TO THE EXTRAORDINARILY STRONG ASSOCIATIONS BETWEEN AGE AND MANY OF THE CPG SITES (>7,000 SITES WITH P-VALUES RANGING FROM 10(-6) TO 10(-43)), WE INVESTIGATED HOW WELL THE DNA METHYLATION MARKERS PREDICT AGE. WE FOUND THAT 2,095 (7.9%) CPG SITES WERE SIGNIFICANT PREDICTORS OF AGE AFTER BONFERRONI CORRECTION. THE TOP FIVE PRINCIPAL COMPONENTS OF THE 2,095 AGE-ASSOCIATED CPG SITES ACCOUNTED FOR 69.3% OF THE VARIABILITY IN THESE CPG SITES, AND THEY EXPLAINED 26.8% OF THE VARIATION IN AGE. THE ASSOCIATIONS BETWEEN METHYLATION MARKERS AND ADULT AGE ARE SO UBIQUITOUS AND STRONG THAT WE HYPOTHESIZE THAT DNA METHYLATION PATTERNS MAY BE AN IMPORTANT MEASURE OF CELLULAR AGING PROCESSES. GIVEN THE HIGHLY CORRELATED NATURE OF THE AGE-ASSOCIATED EPIGENOME (AS EVIDENCED BY THE PRINCIPAL COMPONENTS ANALYSIS), WHOLE PATHWAYS MAY BE REGULATED AS A CONSEQUENCE OF AGING.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15 5755  20 SOCIALLY STRATIFIED EPIGENETIC PROFILES ARE ASSOCIATED WITH COGNITIVE FUNCTIONING IN CHILDREN AND ADOLESCENTS. CHILDREN'S COGNITIVE FUNCTIONING AND EDUCATIONAL PERFORMANCE ARE SOCIALLY STRATIFIED. SOCIAL INEQUALITY, INCLUDING CLASSISM AND RACISM, MAY OPERATE PARTLY VIA EPIGENETIC MECHANISMS THAT MODULATE NEUROCOGNITIVE DEVELOPMENT. FOLLOWING PREREGISTERED ANALYSES OF DATA FROM 1,183 PARTICIPANTS, AGES 8 TO 19 YEARS, FROM THE TEXAS TWIN PROJECT, WE FOUND THAT CHILDREN GROWING UP IN MORE SOCIOECONOMICALLY DISADVANTAGED FAMILIES AND NEIGHBORHOODS AND CHILDREN FROM MARGINALIZED RACIAL/ETHNIC GROUPS EXHIBIT DNA METHYLATION PROFILES THAT, IN PREVIOUS STUDIES OF ADULTS, WERE INDICATIVE OF HIGHER CHRONIC INFLAMMATION, LOWER COGNITIVE FUNCTIONING, AND A FASTER PACE OF BIOLOGICAL AGING. FURTHERMORE, CHILDREN'S SALIVARY DNA METHYLATION PROFILES WERE ASSOCIATED WITH THEIR PERFORMANCE ON IN-LABORATORY TESTS OF COGNITIVE AND ACADEMIC SKILLS, INCLUDING PROCESSING SPEED, GENERAL EXECUTIVE FUNCTION, PERCEPTUAL REASONING, VERBAL COMPREHENSION, READING, AND MATH. GIVEN THAT THE DNA METHYLATION MEASURES THAT WE EXAMINED WERE ORIGINALLY DEVELOPED IN ADULTS, OUR RESULTS SUGGEST THAT CHILDREN SHOW MOLECULAR SIGNATURES THAT REFLECT THE EARLY LIFE SOCIAL DETERMINANTS OF LIFELONG DISPARITIES IN HEALTH AND COGNITION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16 4024  28 LUNG ALLOGRAFT EPITHELIUM DNA METHYLATION AGE IS ASSOCIATED WITH GRAFT CHRONOLOGIC AGE AND PRIMARY GRAFT DYSFUNCTION. ADVANCED DONOR AGE IS A RISK FACTOR FOR POOR SURVIVAL FOLLOWING LUNG TRANSPLANTATION. HOWEVER, RECENT WORK IDENTIFYING EPIGENETIC DETERMINANTS OF AGING HAS SHOWN THAT BIOLOGIC AGE MAY NOT ALWAYS REFLECT CHRONOLOGIC AGE AND THAT STRESSORS CAN ACCELERATE BIOLOGIC AGING. WE HYPOTHESIZED THAT LUNG ALLOGRAFTS THAT EXPERIENCED PRIMARY GRAFT DYSFUNCTION (PGD), CHARACTERIZED BY POOR OXYGENATION IN THE FIRST THREE POST-TRANSPLANT DAYS, WOULD HAVE INCREASED BIOLOGIC AGE. WE CULTURED AIRWAY EPITHELIAL CELLS ISOLATED BY TRANSBRONCHIAL BRUSH AT 1-YEAR BRONCHOSCOPIES FROM 13 SUBJECTS WITH SEVERE PGD AND 15 CONTROLS MATCHED ON AGE AND TRANSPLANT INDICATION. WE MEASURED EPIGENETIC AGE USING THE HORVATH EPIGENETIC CLOCK. LINEAR MODELS WERE USED TO DETERMINE THE ASSOCIATION OF AIRWAY EPIGENETIC AGE WITH CHRONOLOGIC AGES AND PGD STATUS, ADJUSTED FOR RECIPIENT PGD RISK FACTORS. SURVIVAL MODELS ASSESSED THE ASSOCIATION WITH CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD) OR DEATH. DISTRIBUTIONS OF PROMOTER METHYLATION WITHIN PATHWAYS WERE COMPARED BETWEEN GROUPS. DNA METHYLTRANSFERASE (DNMT) ACTIVITY WAS QUANTIFIED IN AIRWAY EPITHELIAL CELLS UNDER HYPOXIC OR NORMOXIC CONDITIONS. AIRWAY EPIGENETIC AGE APPEARED YOUNGER BUT WAS STRONGLY ASSOCIATED WITH THE AGE OF THE ALLOGRAFT (SLOPE 0.38 PER YEAR, 95% CI 0.27-0.48). THERE WAS NO CORRELATION BETWEEN EPIGENETIC AGE AND RECIPIENT AGE (P = 0.96). EPIGENETIC AGE WAS 6.5 YEARS GREATER (95% CI 1.7-11.2) IN SUBJECTS WHO HAD EXPERIENCED PGD, AND THIS EFFECT REMAINED SIGNIFICANT AFTER ADJUSTING FOR DONOR AND RECIPIENT CHARACTERISTICS (P = 0.03). EPIGENETIC AGE WAS NOT ASSOCIATED WITH CLAD-FREE SURVIVAL RISK (P = 0.11). ANALYSIS OF DIFFERENTIAL METHYLATION OF PROMOTERS OF KEY BIOLOGIC PATHWAYS REVEALED HYPOMETHYLATION IN REGIONS RELATED TO HYPOXIA, INFLAMMATION, AND METABOLISM-ASSOCIATED PATHWAYS. ACCORDINGLY, AIRWAY EPITHELIAL CELLS CULTURED IN HYPOXIC CONDITIONS SHOWED SUPPRESSED DNMT ACTIVITY. WHILE AIRWAY METHYLATION AGE WAS PRIMARILY DETERMINED BY DONOR CHRONOLOGIC AGE, EARLY INJURY IN THE FORM OF PGD WAS ASSOCIATED WITH INCREASED ALLOGRAFT EPIGENETIC AGE. THESE DATA SHOW HOW PGD MIGHT SUPPRESS KEY PROMOTER METHYLATION RESULTING IN LONG-TERM IMPACTS ON THE ALLOGRAFT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17 4912  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18 6678  23 USING GENETIC BURDEN SCORES FOR GENE-BY-METHYLATION INTERACTION ANALYSIS ON METABOLIC SYNDROME IN AFRICAN AMERICANS. WITH THE RAPID ADVANCEMENT OF OMICS-BASED RESEARCH, PARTICULARLY BIG DATA SUCH AS GENOME- AND EPIGENOME-WIDE ASSOCIATION STUDIES THAT INCLUDE EXTENSIVE ENVIRONMENTAL AND CLINICAL VARIABLES, DATA ANALYTICS HAVE BECOME INCREASINGLY COMPLEX. RESEARCHERS FACE SIGNIFICANT CHALLENGES REGARDING HOW TO ANALYZE MULTIFACTORIAL DATA AND MAKE USE OF THE FINDINGS FOR CLINICAL TRANSLATION. THE PURPOSE OF THIS ARTICLE IS TO PROVIDE A SCIENTIFIC EXEMPLAR FOR USE OF GENETIC BURDEN SCORES AS A DATA ANALYSIS METHOD FOR STUDIES WITH BOTH GENOTYPE AND DNA METHYLATION DATA IN WHICH THE GOAL IS TO EVALUATE ASSOCIATIONS WITH CHRONIC CONDITIONS SUCH AS METABOLIC SYNDROME (METS). THIS STUDY INCLUDED 739 AFRICAN AMERICAN MEN AND WOMEN FROM THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY STUDY WHO MET DIAGNOSTIC CRITERIA FOR METS AND HAD AVAILABLE GENETIC AND EPIGENETIC DATA. GENETIC BURDEN SCORES FOR EVALUATED GENES WERE NOT SIGNIFICANT AFTER MULTIPLE TESTING CORRECTIONS, BUT DNA METHYLATION AT 2 CPG SITES (DIHYDROOROTATE DEHYDROGENASE CG22381196 PFDR = .014; CTNNA3 CG00132141 PFDR = .043) WAS SIGNIFICANTLY ASSOCIATED WITH METS AFTER CONTROLLING FOR MULTIPLE COMPARISONS. INTERACTIONS BETWEEN THE MARGINALLY SIGNIFICANT CPG SITES AND BURDEN SCORES, HOWEVER, WERE NOT SIGNIFICANT. MORE WORK IS REQUIRED IN THIS AREA TO IDENTIFY INTERMEDIATE BIOLOGICAL PATHWAYS INFLUENCED BY ENVIRONMENTAL, GENETIC, AND EPIGENETIC VARIATION THAT MAY EXPLAIN THE HIGH PREVALENCE OF METS AMONG AFRICAN AMERICANS. THIS STUDY DOES SERVE, HOWEVER, AS AN EXAMPLE OF THE USE OF THE GENETIC BURDEN SCORE AS AN ALTERNATIVE DATA ANALYSIS APPROACH FOR COMPLEX STUDIES INVOLVING THE ANALYSIS OF GENETIC AND EPIGENETIC DATA SIMULTANEOUSLY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19 5737  28 SMOKING AND HEALTH: ASSOCIATION BETWEEN TELOMERE LENGTH AND FACTORS IMPACTING ON HUMAN DISEASE, QUALITY OF LIFE AND LIFE SPAN IN A LARGE POPULATION-BASED COHORT UNDER THE EFFECT OF SMOKING DURATION. REACTIVE OXYGEN SPECIES (ROS) ARE OF PRIMARY IMPORTANCE AS THEY CAUSE DAMAGE TO LIPIDS, PROTEINS, AND DNA EITHER ENDOGENOUSLY BY CELLULAR MECHANISM, OR THROUGH EXOGENOUS EXPOSURE TO ENVIRONMENTAL INJURY FACTORS, INCLUDING OXIDATION INSULT FACTORS, SUCH AS TOBACCO SMOKE. CURRENTLY 46.3 MILLION ADULTS (25.7 PERCENT OF THE POPULATION) ARE SMOKERS. THIS INCLUDES 24 MILLION MEN (28.1 PERCENT OF THE TOTAL) AND MORE THAN 22 MILLION WOMEN (23.5 PERCENT). THE PREVALENCE IS HIGHEST AMONG PERSONS 25-44 YEARS OF AGE. CIGARETTE SMOKERS HAVE A HIGHER RISK OF DEVELOPING SEVERAL CHRONIC DISORDERS. THESE INCLUDE FATTY BUILDUPS IN ARTERIES, SEVERAL TYPES OF CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (LUNG PROBLEMS). AS PERIPHERAL LEUKOCYTES HAVE BEEN THE MAIN TARGET OF HUMAN TELOMERE RESEARCH, MOST OF WHAT IS KNOWN ABOUT HUMAN TELOMERE DYNAMICS IN VIVO IS BASED ON THESE CELLS. LEUKOCYTE TELOMERE LENGTH (TL) IS A COMPLEX TRAIT THAT IS SHAPED BY GENETIC, EPIGENETIC, AND ENVIRONMENTAL DETERMINANTS. IN THIS ARTICLE, WE CONSIDER THAT SMOKING MODIFIES LEUKOCYTE TL IN HUMANS AND CONTRIBUTES TO ITS VARIABILITY AMONG INDIVIDUALS, ALTHOUGH THE SMOKING EFFECT ON TL AND ITS RELATION WITH OTHER METABOLIC INDICES MAY ACCELERATE BIOLOGICAL AGING AND DEVELOPMENT OF SMOKING-INDUCED CHRONIC DISEASES IN A LARGE HUMAN POPULATION-BASED COHORTS WITH SMOKING BEHAVIOR. RECENT STUDIES CONFIRMED THAT INDIVIDUALS WITH SHORTER TELOMERES PRESENT A HIGHER PREVALENCE OF ARTERIAL LESIONS AND HIGHER RISK OF CARDIOVASCULAR DISEASE MORTALITY. THIS STUDY ORIGINALLY SUGGESTS THAT EFFICIENT THERAPEUTIC PROTECTION OF TL AND STRUCTURE IN RESPONSE TO STRESSES THAT ARE KNOWN TO REDUCE TL, SUCH AS OXIDATIVE DAMAGE OR INFLAMMATION ASSOCIATED WITH TOBACCO SMOKING, WOULD LEAD TO BETTER TELOMERE MAINTENANCE. RECENTLY, WE HAVE DISCOVERED THE POTENTIAL USE OF TELOMERE-RESTORATIVE IMIDAZOLE-CONTAINING DIPEPTIDE (NON-HYDROLIZED CARNOSINE, CARCININE) BASED THERAPY FOR BETTER SURVIVAL OF SMOKERS. WE CONCLUDE THAT A BETTER THERAPEUTIC OR NUTRITIONAL MAINTENANCE OF TL MAY CONFER HEALTHY AGING IN SMOKERS AND EXCEPTIONAL LONGEVITY IN REGULARLY ROS-EXPOSED HUMAN SURVIVORS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                
20 3914  30 LIFETIME STRESS ACCELERATES EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT: RELEVANCE OF GLUCOCORTICOID SIGNALING. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ACCELERATED AGING AND INCREASED RISK FOR AGING-RELATED DISEASES, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNCLEAR. RESULTS: WE EXAMINED THE EFFECT OF LIFETIME STRESSORS ON A DNA METHYLATION-BASED AGE PREDICTOR, EPIGENETIC CLOCK. AFTER CONTROLLING FOR BLOOD CELL-TYPE COMPOSITION AND LIFESTYLE PARAMETERS, CUMULATIVE LIFETIME STRESS, BUT NOT CHILDHOOD MALTREATMENT OR CURRENT STRESS ALONE, PREDICTED ACCELERATED EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT (N = 392). THIS EFFECT WAS PRIMARILY DRIVEN BY PERSONAL LIFE STRESSORS, WAS MORE PRONOUNCED WITH ADVANCING AGE, AND WAS BLUNTED IN INDIVIDUALS WITH HIGHER CHILDHOOD ABUSE EXPOSURE. HYPOTHESIZING THAT THESE EPIGENETIC EFFECTS COULD BE MEDIATED BY GLUCOCORTICOID SIGNALING, WE FOUND THAT A HIGH NUMBER (N = 85) OF EPIGENETIC CLOCK CPG SITES WERE LOCATED WITHIN GLUCOCORTICOID RESPONSE ELEMENTS. WE FURTHER EXAMINED THE FUNCTIONAL EFFECTS OF GLUCOCORTICOIDS ON EPIGENETIC CLOCK CPGS IN AN INDEPENDENT SAMPLE WITH GENOME-WIDE DNA METHYLATION (N = 124) AND GENE EXPRESSION DATA (N = 297) BEFORE AND AFTER EXPOSURE TO THE GLUCOCORTICOID RECEPTOR AGONIST DEXAMETHASONE. DEXAMETHASONE INDUCED DYNAMIC CHANGES IN METHYLATION IN 31.2 % (110/353) OF THESE CPGS AND TRANSCRIPTION IN 81.7 % (139/170) OF GENES NEIGHBORING EPIGENETIC CLOCK CPGS. DISEASE ENRICHMENT ANALYSIS OF THESE DEXAMETHASONE-REGULATED GENES SHOWED ENRICHED ASSOCIATION FOR AGING-RELATED DISEASES, INCLUDING CORONARY ARTERY DISEASE, ARTERIOSCLEROSIS, AND LEUKEMIAS. CONCLUSIONS: CUMULATIVE LIFETIME STRESS MAY ACCELERATE EPIGENETIC AGING, AN EFFECT THAT COULD BE DRIVEN BY GLUCOCORTICOID-INDUCED EPIGENETIC CHANGES. THESE FINDINGS CONTRIBUTE TO OUR UNDERSTANDING OF MECHANISMS LINKING CHRONIC STRESS WITH ACCELERATED AGING AND HEIGHTENED DISEASE RISK.	2015