1 1956 211 EPIGENETIC AGE IN PERIPHERAL BLOOD AMONG CHILDREN, ADOLESCENT, AND ADULT SURVIVORS OF CHILDHOOD CANCER. IMPORTANCE: CERTAIN CANCER THERAPIES ARE RISK FACTORS FOR EPIGENETIC AGE ACCELERATION (EAA) AMONG SURVIVORS OF CHILDHOOD CANCER, AND EAA IS ASSOCIATED WITH CHRONIC HEALTH CONDITIONS (CHCS). HOWEVER, SMALL NUMBERS OF YOUNGER SURVIVORS (AGED <20 YEARS) PREVIOUSLY EVALUATED HAVE LIMITED THE ABILITY TO CALCULATE EAA AMONG THIS AGE GROUP. OBJECTIVE: TO EVALUATE THE CHANGE RATE OF EPIGENETIC AGE (EA) AND EAA IN YOUNGER COMPARED WITH OLDER SURVIVORS AND THE POSSIBLE ASSOCIATION OF EAA WITH EARLY-ONSET OBESITY (AGED <20 YEARS), SEVERITY/BURDEN OF CHCS, AND LATE MORTALITY (>5 YEARS FROM CANCER DIAGNOSIS). DESIGN, SETTING, AND PARTICIPANTS: STUDY PARTICIPANTS WERE FROM THE ST JUDE LIFETIME COHORT, INITIATED IN 2007 WITH ONGOING FOLLOW-UP. THE PRESENT STUDY WAS CONDUCTED FROM APRIL 17, 2022, TO MARCH 23, 2023. SURVIVORS IN THIS COHORT OF EUROPEAN ANCESTRY WITH DNA METHYLATION DATA WERE INCLUDED. CROSS-SECTIONAL ANNUAL CHANGES IN EA AND EAA WERE COMPARED ACROSS 5 DIFFERENT CHRONOLOGIC AGE GROUPS: AGE 0 TO 9 (CHILDREN), 10 TO 19 (ADOLESCENTS), 20 TO 34 (YOUNGER ADULTS), 35 TO 49 (MIDDLE-AGED ADULTS), AND GREATER THAN OR EQUAL TO 50 (OLDER ADULTS) YEARS. LOGISTIC REGRESSION EVALUATED THE ASSOCIATION BETWEEN EAA AND EARLY-ONSET OBESITY OR SEVERITY/BURDEN OF CHCS. COX PROPORTIONAL HAZARDS REGRESSION ASSESSED THE ASSOCIATION BETWEEN EAA AND LATE MORTALITY. MAIN OUTCOMES AND MEASURES: EARLY-ONSET OBESITY, SEVERITY/BURDEN OF CHCS (GRADED USING THE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (GRADE 1, MILD; 2, MODERATE; 3, SEVERE/DISABLING; 4, LIFE-THREATENING) AND WERE COMBINED INTO HIGH VS LOW SEVERITY/BURDEN BASED ON FREQUENCY AND GRADE), AND LATE MORTALITY WERE THE OUTCOMES BASED ON FOLLOW-UP UNTIL APRIL 2020. EXPANDED DNA METHYLATION PROFILING INCREASED THE NUMBER OF SURVIVORS YOUNGER THAN 20 YEARS (N = 690). EPIGENETIC AGE WAS CALCULATED PRIMARILY USING THE LEVINE CLOCK, AND EAA WAS DERIVED FROM LEAST SQUARES REGRESSION OF EA AGAINST CHRONOLOGIC AGE AND WAS STANDARDIZED TO A Z SCORE (LEVINE EEA). RESULTS: AMONG 2846 PARTICIPANTS (MEDIAN AGE, 30.3 [IQR, 9.3-41.5] YEARS; 53% MALES), THE CROSS-SECTIONAL ANNUAL CHANGE IN EA_LEVINE WAS HIGHER IN CHILDREN (1.63 YEARS) AND ADOLESCENTS (1.14 YEARS), AND THE ADJUSTED LEAST-SQUARES MEAN OF LEVINE EEA WAS LOWER IN CHILDREN (-0.22 YEARS) AND OLDER ADULTS (-1.70 YEARS). EACH 1-SD INCREASE IN LEVINE EEA WAS ASSOCIATED WITH INCREASED RISK OF DEVELOPING EARLY-ONSET OBESITY (ODDS RATIO [OR], 1.46; 95% CI, 1.19-1.78), HIGH SEVERITY/BURDEN OF CHCS (OR, 1.13; 95% CI, 1.03-1.24), AND LATE MORTALITY (HAZARD RATIO, 1.75; 95% CI, 1.35-2.26). CONCLUSIONS AND RELEVANCE: THE FINDINGS OF THIS STUDY SUGGEST THAT EAA MEASURED IN CHILDREN AND ADOLESCENT SURVIVORS OF CHILDHOOD CANCER IS ASSOCIATED WITH EARLY-ONSET OBESITY, SEVERITY/BURDEN OF ALL CHCS, AND LATE MORTALITY. EVALUATING EAA MAY HELP IDENTIFY SURVIVORS OF CHILDHOOD CANCER AT INCREASED RISK FOR EARLY-ONSET OBESITY, MORBIDITY IN GENERAL, AND MORTALITY. 2023 2 180 43 ACCELERATED EPIGENETIC AGING IN OLDER ADULTS WITH HIV DISEASE: ASSOCIATIONS WITH SEROSTATUS, HIV CLINICAL FACTORS, AND HEALTH LITERACY. THE PREVALENCE OF OLDER PERSONS WITH HIV (PWH) DISEASE HAS INCREASED CONSIDERABLY IN THE LAST 20 YEARS, BUT OUR UNDERSTANDING OF BIOLOGICAL FACTORS OF AGING AND THEIR CLINICAL CORRELATES AMONG PWH REMAINS LIMITED. STUDY PARTICIPANTS WERE 149 PERSONS AGED 50 AND OLDER, INCLUDING 107 PWH AND 42 SERONEGATIVES. ALL PARTICIPANTS COMPLETED A BLOOD DRAW, RESEARCH MEDICAL EVALUATION, STRUCTURED PSYCHIATRIC INTERVIEW, NEUROCOGNITIVE ASSESSMENT, QUESTIONNAIRES, AND MEASURES OF HEALTH LITERACY. FOUR EPIGENETIC CLOCKS WERE GENERATED FROM STORED BLOOD SAMPLES USING STANDARDIZED LABORATORY METHODS. IN REGRESSION MODELS ADJUSTING FOR SEX AND SMOKING STATUS, PWH HAD SIGNIFICANTLY HIGHER EPIGENETIC AGING ACCELERATION VALUES THAN SERONEGATIVES ON ALL FOUR INDICATORS. WITHIN THE PWH SAMPLE, HIGHER LEVELS OF EPIGENETIC AGING ACCELERATION WERE MODERATELY ASSOCIATED WITH LOWER CURRENT CD4 COUNT, AIDS DIAGNOSES, HIGHER SCORES ON THE VETERANS AGING COHORT STUDY INDEX, AND LOWER TELOMERE VALUES. HIGHER EPIGENETIC AGING ACCELERATION INDICES WERE ALSO ASSOCIATED WITH LOWER HEALTH LITERACY AMONG PWH. PWH EXPERIENCE ACCELERATED AGING AS MEASURED BY A SERIES OF EPIGENETIC CLOCKS, WHICH MAY BE LINKED TO IMMUNE COMPROMISE AND RISK OF ALL-CAUSE MORTALITY. HEALTH LITERACY MAY BE A MODIFIABLE TARGET FOR MITIGATING THE RISK OF ACCELERATED AGING AMONG OLDER PWH. 2023 3 3850 30 IS GENDER A FACTOR AFFECTING LONG-TERM HETEROTOPIC OSSIFICATION INCIDENCE AFTER SINGLE-LEVEL CERVICAL DISC ARTHROPLASTY? BACKGROUND: CERVICAL DISC DISEASES HAVE BEEN TREATED BY CERVICAL DISC ARTHROPLASTY (CDA). NEVERTHELESS, SOME PATIENTS WILL EXPERIENCE A MOBILITY FAILURE IN THEIR CERVICAL PROSTHESES OVER TIME BECAUSE OF HETEROTOPIC OSSIFICATION. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ROLE OF GENDER IN LONG-TERM OUTCOMES AFTER CDA. METHODS: A RETROSPECTIVE, SINGLE-CENTER STUDY OF PATIENTS WHO UNDERWENT SINGLE-LEVEL CDA WITH A BRYAN CERVICAL DISC PROSTHESIS WAS PERFORMED, INCLUDING A NARRATIVE REVIEW ABOUT GENDER DIFFERENCES IN BOTH STRUCTURAL AND BIOMECHANICAL FEATURES OF THE CERVICAL SPINE. RESULTS: STUDY PATIENTS (14 MEN, 30 WOMEN) HAD AN AVERAGE FOLLOW-UP OF 9.8 +/- 3.2 YEARS. SIGNIFICANT DIFFERENCES EMERGED BETWEEN GENDERS FOR SPECIFIC ITEMS IN NECK DISABILITY INDEX PREOPERATIVE EVALUATION, WITH WOMEN REPORTING WORSE PAIN SCORES (P = 0.05). AFTER STRATIFICATION BY AGE, WE FOUND A HIGHER PREOPERATIVE OVERALL NECK DISABILITY INDEX SCORE FOR FEMALE PATIENTS <36 YEARS OF AGE (P = 0.03). IN AN INTERGENDER, BODY MASS INDEX-SPECIFIC COMPARISON, WE ALSO FOUND A SIGNIFICANT DIFFERENCE IN NECK DISABILITY INDEX PREOPERATIVE SCORE WITH NORMAL-WEIGHT MALE PATIENTS FARING WORSE THAN OVERWEIGHT MALE PATIENTS (P = 0.05). AT A RADIOLOGICAL LEVEL, WE FOUND A TENDENCY TOWARD A HIGHER HETEROTOPIC OSSIFICATION INCIDENCE IN MALE PATIENTS (62% IN MEN, 17% IN WOMEN, P = 0.06). THE FEMALE CERVICAL SPINE HAS DISTINCTIVE FEATURES, INCLUDING BONE STRUCTURE, MUSCULAR ACTION, SOFT TISSUE RESPONSE, AND GENETIC AND EPIGENETIC RESPONSE TO OSTEOARTHRITIS. CONCLUSIONS: THE INCIDENCE OF MOBILITY FAILURE IN OUR SERIES OF SINGLE-LEVEL CDA WAS LOWER IN FEMALE PATIENTS. SEVERAL GENDER-SPECIFIC FACTORS BOTH IN STATIC AND IN DYNAMIC FEATURES MAY PLAY A SIGNIFICANT ROLE IN SPINAL PATHOLOGY AND CDA LONG-TERM RADIOLOGICAL OUTCOME. 2022 4 5957 47 TELOMERE LENGTH AND EPIGENETIC AGE ACCELERATION IN ADOLESCENTS WITH ANXIETY DISORDERS. EVIDENCE ON THE RELATIONSHIP BETWEEN GENETICS AND MENTAL HEALTH ARE FLOURISHING. HOWEVER, FEW STUDIES ARE EVALUATING EARLY BIOMARKERS THAT MIGHT LINK GENES, ENVIRONMENT, AND PSYCHOPATHOLOGY. WE AIMED TO STUDY TELOMERE LENGTH (TL) AND EPIGENETIC AGE ACCELERATION (AA) IN A COHORT OF ADOLESCENTS WITH AND WITHOUT ANXIETY DISORDERS (N = 234). WE EVALUATED A REPRESENTATIVE SUBSAMPLE OF PARTICIPANTS AT BASELINE AND AFTER 5 YEARS (N = 76) AND CATEGORIZED THEM ACCORDING TO THEIR ANXIETY DISORDER DIAGNOSIS AT BOTH TIME POINTS: (1) CONTROL GROUP (NO ANXIETY DISORDER, N = 18), (2) VARIABLE GROUP (ANXIETY DISORDER IN ONE EVALUATION, N = 38), AND (3) PERSISTENT GROUP (ANXIETY DISORDER AT BOTH TIME POINTS, N = 20). WE ASSESSED RELATIVE MEAN TL BY REAL-TIME QUANTITATIVE PCR AND DNA METHYLATION BY INFINIUM HUMANMETHYLATION450 BEADCHIP. WE CALCULATED AA USING THE HORVATH AGE ESTIMATION ALGORITHM AND ANALYZED DIFFERENCES AMONG GROUPS USING GENERALIZED LINEAR MIXED MODELS. THE PERSISTENT GROUP OF ANXIETY DISORDER DID NOT CHANGE TL OVER TIME (P = 0.495). THE VARIABLE GROUP HAD HIGHER BASELINE TL (P = 0.003) BUT NO ACCELERATED TL EROSION IN COMPARISON TO THE NON-ANXIETY CONTROL GROUP (P = 0.053). FURTHERMORE, THERE WERE NO DIFFERENCES IN AA AMONG GROUPS OVER TIME. OUR FINDINGS SUGGEST THAT ADOLESCENTS WITH CHRONIC ANXIETY DID NOT CHANGE TELOMERE LENGTH OVER TIME, WHICH COULD BE RELATED TO A DELAY IN NEURONAL DEVELOPMENT IN THIS PERIOD OF LIFE. 2021 5 403 75 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 6 1785 42 EFFECT OF APABETALONE ON CARDIOVASCULAR EVENTS IN DIABETES, CKD, AND RECENT ACUTE CORONARY SYNDROME: RESULTS FROM THE BETONMACE RANDOMIZED CONTROLLED TRIAL. BACKGROUND AND OBJECTIVES: CKD AND TYPE 2 DIABETES MELLITUS INTERACT TO INCREASE THE RISK OF MAJOR ADVERSE CARDIOVASCULAR EVENTS (I.E., CARDIOVASCULAR DEATH, NONFATAL MYOCARDIAL INFARCTION, OR STROKE) AND CONGESTIVE HEART FAILURE. A MALADAPTIVE EPIGENETIC RESPONSE MAY BE A CARDIOVASCULAR RISK DRIVER AND AMENABLE TO MODIFICATION WITH APABETALONE, A SELECTIVE MODULATOR OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN TRANSCRIPTION SYSTEM. WE EXAMINED THIS QUESTION IN A PRESPECIFIED ANALYSIS OF BETONMACE, A PHASE 3 TRIAL. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: BETONMACE WAS AN EVENT-DRIVEN, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL COMPARING EFFECTS OF APABETALONE VERSUS PLACEBO ON MAJOR ADVERSE CARDIOVASCULAR EVENTS AND HEART FAILURE HOSPITALIZATIONS IN 2425 PARTICIPANTS WITH TYPE 2 DIABETES AND A RECENT ACUTE CORONARY SYNDROME, INCLUDING 288 PARTICIPANTS WITH CKD WITH EGFR <60 ML/MIN PER 1.73 M(2) AT BASELINE. THE PRIMARY END POINT IN BETONMACE WAS THE TIME TO THE FIRST MAJOR ADVERSE CARDIOVASCULAR EVENT, WITH A SECONDARY END POINT OF TIME TO HOSPITALIZATION FOR HEART FAILURE. RESULTS: MEDIAN FOLLOW-UP WAS 27 MONTHS (INTERQUARTILE RANGE, 20-32 MONTHS). IN PARTICIPANTS WITH CKD, APABETALONE COMPARED WITH PLACEBO WAS ASSOCIATED WITH FEWER MAJOR ADVERSE CARDIOVASCULAR EVENTS (13 EVENTS IN 124 PATIENTS [11%] VERSUS 35 EVENTS IN 164 PATIENTS [21%]; HAZARD RATIO, 0.50; 95% CONFIDENCE INTERVAL, 0.26 TO 0.96) AND FEWER HEART FAILURE-RELATED HOSPITALIZATIONS (THREE HOSPITALIZATIONS IN 124 PATIENTS [3%] VERSUS 14 HOSPITALIZATIONS IN 164 PATIENTS [9%]; HAZARD RATIO, 0.48; 95% CONFIDENCE INTERVAL, 0.26 TO 0.86). IN THE NON-CKD GROUP, THE CORRESPONDING HAZARD RATIO VALUES WERE 0.96 (95% CONFIDENCE INTERVAL, 0.74 TO 1.24) FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND 0.76 (95% CONFIDENCE INTERVAL, 0.46 TO 1.27) FOR HEART FAILURE-RELATED HOSPITALIZATION. INTERACTION OF CKD ON TREATMENT EFFECT WAS P=0.03 FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND P=0.12 FOR HEART FAILURE-RELATED HOSPITALIZATION. PARTICIPANTS WITH CKD SHOWED SIMILAR NUMBERS OF ADVERSE EVENTS, REGARDLESS OF RANDOMIZATION TO APABETALONE OR PLACEBO (119 [73%] VERSUS 88 [71%] PATIENTS), AND THERE WERE FEWER SERIOUS ADVERSE EVENTS (29% VERSUS 43%; P=0.02) IN THE APABETALONE GROUP. CONCLUSIONS: APABETALONE MAY REDUCE THE INCIDENCE OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH CKD AND TYPE 2 DIABETES WHO HAVE A HIGH BURDEN OF CARDIOVASCULAR DISEASE. 2021 7 2734 46 EXPLORING THE RELATIONSHIP BETWEEN DNA METHYLATION AGE MEASURES AND PSYCHONEUROLOGICAL SYMPTOMS IN WOMEN WITH EARLY-STAGE BREAST CANCER. PURPOSE: THE EPIGENETIC CLOCK HAS BEEN ACKNOWLEDGED AS AN INDICATOR FOR MOLECULAR AGING, BUT FEW STUDIES HAVE EXAMINED POSSIBLE ASSOCIATIONS OF DNA METHYLATION (DNAM) AGE OR AGE ACCELERATION (AA) WITH SYMPTOM BURDEN IN INDIVIDUALS WHO ARE TREATED FOR CANCER. THIS STUDY EXPLORED THE ASSOCIATION OF DNAM AGE OR AA WITH PSYCHONEUROLOGICAL (PN) SYMPTOMS, INCLUDING COGNITIVE IMPAIRMENT, FATIGUE, SLEEP DISTURBANCES, PAIN, AND DEPRESSIVE SYMPTOMS, IN BREAST CANCER SURVIVORS OVER A 2-YEAR PERIOD. METHODS: WE MEASURED PN SYMPTOMS USING RELIABLE INSTRUMENTS AND DNAM LEVELS BY INFINIUM HUMANMETHYLATION450K BEADCHIP (N = 72). DNAM AGE WAS CALCULATED BY THE HORVATH, GRIM, AND HANNUM-BASED INTRINSIC AND EXTRINSIC AGE ESTIMATIONS. AA WAS DEFINED BY THE RESIDUAL REGRESSING ESTIMATED EPIGENETIC AGE ON CHRONOLOGICAL AGE. MIXED REGRESSION MODELS WERE FITTED FOR AA AND CHANGES IN AA TO STUDY THE ASSOCIATION OVER TIME. SEPARATE LINEAR REGRESSION MODELS AND A MIXED-EFFECTS MODEL WERE FITTED FOR AA AT EACH TIME POINT. RESULTS: HORVATH-AA, GRIM-AA, AND EXTRINSIC EPIGENETIC AA WERE SIGNIFICANTLY CHANGED OVER TIME, WHILE INTRINSIC EPIGENETIC AA DID NOT EXHIBIT ANY TEMPORAL CHANGES. INCREASED AA WAS ASSOCIATED WITH GREATER ANXIETY AND FATIGUE, AS WELL AS WORSE COGNITIVE MEMORY, ADJUSTING FOR RACE, BMI, INCOME, CHEMOTHERAPY, RADIATION THERAPY, AND CHRONOLOGICAL AGE. INCREASED DNAM AGE WAS ASSOCIATED WITH GREATER ANXIETY OVER 2 YEARS. CONCLUSION: OUR FINDINGS SUGGEST DNAM AGE AND AA MAY BE ASSOCIATED WITH PN SYMPTOMS OVER THE COURSE OF CANCER TREATMENT AND SURVIVORSHIP. SOME PN SYMPTOMS MAY BE AMENABLE TO PREVENTIVE INTERVENTIONS TARGETED TO EPIGENETIC CLOCKS THAT INFLUENCE AGING-ASSOCIATED PROCESSES. 2022 8 3179 43 HAIR CORTISOL AS A HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BIOMARKER IN PREGNANT WOMEN WITH ASTHMA: A RETROSPECTIVE OBSERVATIONAL STUDY. BACKGROUND: CORTISOL IS A HORMONE INVOLVED IN MANY PHYSIOLOGICAL FUNCTIONS INCLUDING FETAL MATURATION AND EPIGENETIC PROGRAMMING DURING PREGNANCY. THIS STUDY AIMED TO USE HAIR CORTISOL AS A BIOMARKER OF CHRONIC INHALED CORTICOSTEROID (ICS) EXPOSURE AND ASSESS THE POTENTIAL EFFECTS OF ASTHMA ON THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN PREGNANT WOMEN. WE HYPOTHESIZED THAT PREGNANT WOMEN WITH ASTHMA TREATED WITH ICS WOULD EXHIBIT LOWER HAIR CORTISOL CONCENTRATIONS, INDICATIVE OF ADRENAL SUPPRESSION, COMPARED TO WOMEN WITH ASTHMA NOT USING ICS AND WOMEN WHO DO NOT HAVE ASTHMA. METHODS: WE PERFORMED AN OBSERVATIONAL RETROSPECTIVE COHORT STUDY. HAIR SAMPLES WERE ANALYZED FROM PREGNANT WOMEN WITH ASTHMA, WITH (N = 56) AND WITHOUT (N = 31) ICS TREATMENT, AND PREGNANT WOMEN WITHOUT ASTHMA (N = 31). HAIR SAMPLES WERE SEGMENTED BASED ON THE GROWTH RATE OF 1 CM/MONTH AND ANALYZED BY ENZYME IMMUNOASSAY TO PROVIDE CORTISOL CONCENTRATIONS CORRESPONDING TO PRECONCEPTION, TRIMESTERS 1-3, AND POSTPARTUM. HAIR CORTISOL CONCENTRATIONS WERE COMPARED WITHIN AND AMONG THE GROUPS USING NON-PARAMETRIC STATISTICAL TESTS. RESULTS: HAIR CORTISOL CONCENTRATIONS INCREASED ACROSS TRIMESTERS FOR ALL THREE GROUPS, BUT THIS INCREASE WAS DAMPENED IN WOMEN WITH ASTHMA (P = 0.03 FOR CONTROLS VS. ICS TREATED AND CONTROLS VS. NO ICS). ICS TREATED WOMEN TAKING MORE THAN FIVE DOSES PER WEEK HAD HAIR CORTISOL CONCENTRATIONS 47 % LOWER IN THIRD TRIMESTER THAN CONTROLS. LINEAR REGRESSION OF THE THIRD TRIMESTER HAIR CORTISOL RESULTS IDENTIFIED ASTHMA AS A SIGNIFICANT FACTOR WHEN COMPARING CONSISTENT ICS USE OR ASTHMA AS THE PREDICTOR (F(1, 25) = 9.7, P = 0.005, R(2) ADJ = 0.257). CONCLUSIONS: HAIR CORTISOL SUCCESSFULLY SHOWED THE EXPECTED CHANGE IN CORTISOL OVER THE COURSE OF PREGNANCY AND MAY BE A USEFUL BIOMARKER OF HPA AXIS FUNCTION IN PREGNANT WOMEN WITH ASTHMA. THE POTENTIAL IMPACT OF DECREASED MATERNAL CORTISOL IN WOMEN WITH ASTHMA ON PERINATAL OUTCOMES REMAINS TO BE DETERMINED. 2016 9 4249 51 METHYLATION-BASED BIOLOGICAL AGE AND BREAST CANCER RISK. BACKGROUND: AGE IS ONE OF THE STRONGEST PREDICTORS OF CANCER, CHRONIC DISEASE, AND MORTALITY, BUT BIOLOGICAL RESPONSES TO AGING DIFFER AMONG PEOPLE. EPIGENETIC DNA MODIFICATIONS HAVE BEEN USED TO ESTIMATE "BIOLOGICAL AGE," WHICH MAY BE A USEFUL PREDICTOR OF DISEASE RISK. WE TESTED THIS HYPOTHESIS FOR BREAST CANCER. METHODS: USING A CASE-COHORT APPROACH, WE MEASURED BASELINE BLOOD DNA METHYLATION OF 2764 WOMEN ENROLLED IN THE SISTER STUDY, 1566 OF WHOM SUBSEQUENTLY DEVELOPED BREAST CANCER AFTER AN AVERAGE OF 6 YEARS. USING THREE PREVIOUSLY ESTABLISHED METHYLATION-BASED "CLOCKS" (HANNUM, HORVATH, AND LEVINE), WE DEFINED BIOLOGICAL AGE ACCELERATION FOR EACH WOMAN BY COMPARING HER ESTIMATED BIOLOGICAL AGE WITH HER CHRONOLOGICAL AGE. HAZARD RATIOS AND 95% CONFIDENCE INTERVALS FOR BREAST CANCER RISK WERE ESTIMATED USING COX REGRESSION MODELS. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: EACH OF THE THREE CLOCKS SHOWED THAT BIOLOGICAL AGE ACCELERATION WAS STATISTICALLY SIGNIFICANTLY ASSOCIATED WITH INCREASED RISK OF DEVELOPING BREAST CANCER (5-YEAR AGE ACCELERATION, HANNUM'S CLOCK: HAZARD RATIO [HR] = 1.10, 95% CONFIDENCE INTERVAL [CI] = 1.00 TO 1.21, P = .04; HORVATH'S CLOCK: HR = 1.08, 95% CI = 1.00 TO 1.17, P = .04; LEVINE'S CLOCK: HR = 1.15, 95% CI = 1.07 TO 1.23, P < .001). FOR LEVINE'S CLOCK, EACH 5-YEAR ACCELERATION IN BIOLOGICAL AGE CORRESPONDED WITH A 15% INCREASE IN BREAST CANCER RISK. ALTHOUGH BIOLOGICAL AGE MAY ACCELERATE WITH MENOPAUSAL TRANSITION, AGE ACCELERATION IN PREMENOPAUSAL WOMEN INDEPENDENTLY PREDICTED BREAST CANCER. CASE-ONLY ANALYSIS SUGGESTED THAT, AMONG WOMEN WHO DEVELOP BREAST CANCER, INCREASED AGE ACCELERATION IS ASSOCIATED WITH INVASIVE CANCER (ODDS RATIO FOR INVASIVE = 1.09, 95% CI = 0.98 TO 1.22, P = .10). CONCLUSIONS: DNA METHYLATION-BASED MEASURES OF BIOLOGICAL AGE MAY BE IMPORTANT PREDICTORS OF BREAST CANCER RISK. 2019 10 5395 48 REDUCED EPIGENETIC AGE IN OLDER ADULTS WITH HIGH SENSE OF PURPOSE IN LIFE. PSYCHOSOCIAL RISK FACTORS HAVE BEEN LINKED WITH ACCELERATED EPIGENETIC AGING, BUT LITTLE IS KNOWN ABOUT WHETHER PSYCHOSOCIAL RESILIENCE FACTORS (EG, SENSE OF PURPOSE IN LIFE) MIGHT REDUCE EPIGENETIC AGE ACCELERATION. IN THIS STUDY, WE TESTED IF OLDER ADULTS WHO EXPERIENCE HIGH LEVELS OF PURPOSE MIGHT SHOW REDUCED EPIGENETIC AGE ACCELERATION. WE EVALUATED THE RELATIONSHIP BETWEEN PURPOSE AND EPIGENETIC AGE ACCELERATION AS MEASURED BY 13 DNA METHYLATION (DNAM) "EPIGENETIC CLOCKS" ASSESSED IN 1 572 OLDER ADULTS FROM THE HEALTH AND RETIREMENT STUDY (MEAN AGE 70 YEARS). WE QUANTIFIED THE TOTAL ASSOCIATION BETWEEN PURPOSE AND DNAM AGE ACCELERATION AS WELL AS THE EXTENT TO WHICH THAT TOTAL ASSOCIATION MIGHT BE ATTRIBUTABLE TO DEMOGRAPHIC FACTORS, CHRONIC DISEASE, OTHER PSYCHOSOCIAL VARIABLES (EG, POSITIVE AFFECT), AND HEALTH-RELATED BEHAVIORS (HEAVY DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BODY MASS INDEX [BMI]). PURPOSE IN LIFE WAS ASSOCIATED WITH REDUCED EPIGENETIC AGE ACCELERATION ACROSS 4 "SECOND-GENERATION" DNAM CLOCKS OPTIMIZED FOR PREDICTING HEALTH AND LONGEVITY (FALSE DISCOVERY RATE [FDR] Q < 0.0001: PHENOAGE, GRIMAGE, ZHANG EPIGENETIC MORTALITY INDEX; FDR Q < 0.05: DUNEDINPOAM). THESE ASSOCIATIONS WERE INDEPENDENT OF DEMOGRAPHIC AND PSYCHOSOCIAL FACTORS, BUT SUBSTANTIALLY ATTENUATED AFTER ADJUSTING FOR HEALTH-RELATED BEHAVIORS (DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BMI). PURPOSE SHOWED NO SIGNIFICANT ASSOCIATION WITH 9 "FIRST-GENERATION" DNAM EPIGENETIC CLOCKS TRAINED ON CHRONOLOGICAL AGE. OLDER ADULTS WITH GREATER PURPOSE IN LIFE SHOW "YOUNGER" DNAM EPIGENETIC AGE ACCELERATION. THESE RESULTS MAY BE DUE IN PART TO ASSOCIATED DIFFERENCES IN HEALTH-RELATED BEHAVIORS. RESULTS SUGGEST NEW OPPORTUNITIES TO REDUCE BIOLOGICAL AGE ACCELERATION BY ENHANCING PURPOSE AND ITS BEHAVIORAL SEQUELAE IN LATE ADULTHOOD. 2023 11 518 41 ASSOCIATIONS BETWEEN ANTIBIOTIC EXPOSURE DURING PREGNANCY, BIRTH WEIGHT AND ABERRANT METHYLATION AT IMPRINTED GENES AMONG OFFSPRING. OBJECTIVES: LOW BIRTH WEIGHT (LBW) HAS BEEN ASSOCIATED WITH COMMON ADULT-ONSET CHRONIC DISEASES, INCLUDING OBESITY, CARDIOVASCULAR DISEASE, TYPE II DIABETES AND SOME CANCERS. THE ETIOLOGY OF LBW IS MULTI-FACTORIAL. HOWEVER, RECENT EVIDENCE SUGGESTS EXPOSURE TO ANTIBIOTICS MAY ALSO INCREASE THE RISK OF LBW. THE MECHANISMS UNDERLYING THIS ASSOCIATION ARE UNKNOWN, ALTHOUGH EPIGENETIC MECHANISMS ARE HYPOTHESIZED. IN THIS STUDY, WE EVALUATED THE ASSOCIATION BETWEEN MATERNAL ANTIBIOTIC USE AND LBW AND EXAMINED THE POTENTIAL ROLE OF ALTERED DNA METHYLATION THAT CONTROLS GROWTH REGULATORY IMPRINTED GENES IN THESE ASSOCIATIONS. METHODS: BETWEEN 2009-2011, 397 PREGNANT WOMEN WERE ENROLLED AND FOLLOWED UNTIL DELIVERY. PRENATAL ANTIBIOTIC USE WAS ASCERTAINED THROUGH MATERNAL SELF-REPORT. IMPRINTED GENES METHYLATION LEVELS WERE MEASURED AT DIFFERENTIALLY METHYLATED REGIONS (DMRS) USING BISULFITE PYROSEQUENCING. GENERALIZED LINEAR MODELS WERE USED TO EXAMINE ASSOCIATIONS AMONG ANTIBIOTIC USE, BIRTH WEIGHT AND DMR METHYLATION FRACTIONS. RESULTS: AFTER ADJUSTING FOR INFANT GENDER, RACE/ETHNICITY, MATERNAL BODY MASS INDEX, DELIVERY ROUTE, GESTATIONAL WEIGHT GAIN, GESTATIONAL AGE AT DELIVERY, FOLIC ACID INTAKE, PHYSICAL ACTIVITY, MATERNAL SMOKING AND PARITY, ANTIBIOTIC USE DURING PREGNANCY WAS ASSOCIATED WITH 138 G LOWER BIRTH WEIGHT COMPARED WITH NON-ANTIBIOTIC USE (BETA-COEFFICIENT=-132.99, S.E.=50.70, P=0.008). THESE ASSOCIATIONS WERE STRONGEST IN NEWBORNS OF WOMEN WHO REPORTED ANTIBIOTIC USE OTHER THAN PENICILLINS (BETA-COEFFICIENT=-135.57, S.E.=57.38, P=0.02). METHYLATION AT FIVE DMRS, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) AND PEG3 (P=0.08), WAS ASSOCIATED WITH MATERNAL ANTIBIOTIC USE; AMONG THESE, ONLY METHYLATION AT THE PLAGL1 DMR WAS ALSO ASSOCIATED WITH BIRTH WEIGHT. CONCLUSION: WE REPORT AN INVERSE ASSOCIATION BETWEEN IN UTERO EXPOSURE TO ANTIBIOTICS AND LOWER INFANT BIRTH WEIGHT AND PROVIDE THE FIRST EMPIRICAL EVIDENCE SUPPORTING IMPRINTED GENE PLASTICITY IN THESE ASSOCIATIONS. 2013 12 404 44 ANALYSIS OF EPIGENETIC AGE PREDICTORS IN PAIN-RELATED CONDITIONS. CHRONIC PAIN PREVALENCE IS HIGH WORLDWIDE AND INCREASES AT OLDER AGES. SIGNS OF PREMATURE AGING HAVE BEEN ASSOCIATED WITH CHRONIC PAIN, BUT FEW STUDIES HAVE INVESTIGATED AGING BIOMARKERS IN PAIN-RELATED CONDITIONS. A SET OF DNA METHYLATION (DNAM)-BASED ESTIMATES OF AGE, CALLED "EPIGENETIC CLOCKS," HAS BEEN PROPOSED AS BIOLOGICAL MEASURES OF AGE-RELATED ADVERSE PROCESSES, MORBIDITY, AND MORTALITY. THE AIM OF THIS STUDY IS TO ASSESS IF DIFFERENT PAIN-RELATED PHENOTYPES SHOW ALTERATIONS IN DNAM AGE. IN OUR ANALYSIS, WE CONSIDERED THREE COHORTS FOR WHICH WHOLE-BLOOD DNAM DATA WERE AVAILABLE: HEAT PAIN SENSITIVITY (HPS), INCLUDING 20 MONOZYGOTIC TWIN PAIRS DISCORDANT FOR HEAT PAIN TEMPERATURE THRESHOLD; FIBROMYALGIA (FM), INCLUDING 24 CASES AND 20 CONTROLS; AND HEADACHE, INCLUDING 22 CHRONIC MIGRAINE AND MEDICATION OVERUSE HEADACHE PATIENTS (MOH), 18 EPISODIC MIGRAINEURS (EM), AND 13 HEALTHY SUBJECTS. WE USED THE HORVATH'S EPIGENETIC AGE CALCULATOR TO OBTAIN DNAM-BASED ESTIMATES OF EPIGENETIC AGE, TELOMERE LENGTH, LEVELS OF 7 PROTEINS IN PLASMA, NUMBER OF SMOKED PACKS OF CIGARETTES PER YEAR, AND BLOOD CELL COUNTS. WE DID NOT FIND DIFFERENCES IN EPIGENETIC AGE ACCELERATION, CALCULATED USING FIVE DIFFERENT EPIGENETIC CLOCKS, BETWEEN SUBJECTS DISCORDANT FOR PAIN-RELATED PHENOTYPES. TWINS WITH HIGH HPS HAD INCREASED CD8+ T CELL COUNTS (NOMINAL P = 0.028). HPS THRESHOLDS WERE NEGATIVELY ASSOCIATED WITH ESTIMATED LEVELS OF GDF15 (NOMINAL P = 0.008). FM PATIENTS SHOWED DECREASED NAIVE CD4+ T CELL COUNTS COMPARED WITH CONTROLS (NOMINAL P = 0.015). THE SEVERITY OF FM MANIFESTATIONS EXPRESSED THROUGH VARIOUS EVALUATION TESTS WAS ASSOCIATED WITH DECREASED LEVELS OF LEPTIN, SHORTER LENGTH OF TELOMERES, AND REDUCED CD8+ T AND NATURAL KILLER CELL COUNTS (NOMINAL P < 0.05), WHILE THE DURATION OF PAINFUL SYMPTOMS WAS POSITIVELY ASSOCIATED WITH TELOMERE LENGTH (NOMINAL P = 0.034). NO DIFFERENCES IN DNAM-BASED ESTIMATES WERE DETECTED FOR MOH OR EM COMPARED WITH CONTROLS. IN SUMMARY, OUR STUDY SUGGESTS THAT HPS, FM, AND MOH/EM DO NOT SHOW SIGNS OF EPIGENETIC AGE ACCELERATION IN WHOLE BLOOD, WHILE HPS AND FM ARE ASSOCIATED WITH DNAM-BASED ESTIMATES OF IMMUNOLOGICAL PARAMETERS, PLASMA PROTEINS, AND TELOMERE LENGTH. FUTURE STUDIES SHOULD EXTEND THESE OBSERVATIONS IN LARGER COHORTS. 2020 13 1746 31 EARLY LIFE ADVERSITY, PUBERTAL TIMING, AND EPIGENETIC AGE ACCELERATION IN ADULTHOOD. BACKGROUND: GIVEN ASSOCIATIONS LINKING EARLY LIFE ADVERSITY, PUBERTAL TIMING, AND BIOLOGICAL AGING, WE EXAMINED THE DIRECT AND INDIRECT EFFECTS OF EARLY LIFE TRAUMA ON ADULT BIOLOGICAL AGING (VIA AGE OF MENARCHE). METHODS: PARTICIPANTS WERE PREMENOPAUSAL WOMEN (N = 183). PATH MODELS EVALUATED WHETHER EARLY LIFE TRAUMA PREDICTED EARLY PUBERTAL TIMING AND THEREBY, ADULT EPIGENETIC AGE ACCELERATION (INDEXED VIA FOUR EPIGENETIC CLOCKS: HORVATH DNAM AGE, HANNUM DNAM AGE, DNAM PHENOAGE, AND DNAM GRIMAGE). SECONDARY ANALYSES EXPLORED THE EFFECTS OF TYPE OF TRAUMA (ABUSE AND NEGLECT) AND ADULT CHRONIC STRESS STATUS (CAREGIVER OF CHILD WITH AUTISM AND NON-CAREGIVER). RESULTS: EARLY LIFE TRAUMA AND EARLIER AGE AT MENARCHE INDEPENDENTLY PREDICTED ACCELERATED AGING BASED ON ONE OF THE FOUR EPIGENETIC CLOCKS, DNAM GRIMAGE, THOUGH EARLY LIFE TRAUMA WAS NOT ASSOCIATED WITH AGE OF MENARCHE. CHILDHOOD ABUSE, BUT NOT NEGLECT, PREDICTED FASTER EPIGENETIC AGING; RESULTS DID NOT DIFFER BY CHRONIC STRESS STATUS. CONCLUSIONS: EARLY TRAUMA AND EARLY MENARCHE APPEAR TO EXERT INDEPENDENT EFFECTS ON DNAM GRIMAGE, WHICH HAS BEEN SHOWN TO BE THE STRONGEST EPIGENETIC PREDICTOR OF MORTALITY RISK. THIS STUDY IDENTIFIES A POTENTIAL CORRELATE OR DETERMINANT OF ACCELERATED EPIGENETIC AGING-MENARCHEAL AGE. FUTURE RESEARCH SHOULD ADDRESS THE LIMITATIONS OF THIS STUDY BY USING RACIALLY DIVERSE SAMPLES. 2021 14 1955 49 EPIGENETIC AGE ACCELERATION PREDICTS CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY IN A GERMAN CASE COHORT. BACKGROUND: PREVIOUS STUDIES HAVE DEVELOPED MODELS PREDICTING METHYLATION AGE FROM DNA METHYLATION IN BLOOD AND OTHER TISSUES (EPIGENETIC CLOCK) AND SUGGESTED THE DIFFERENCE BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGES AS A MARKER OF HEALTHY AGING. THE GOAL OF THIS STUDY WAS TO CONFIRM AND EXPAND SUCH OBSERVATIONS BY INVESTIGATING WHETHER DIFFERENT CONCEPTS OF THE EPIGENETIC CLOCKS IN A POPULATION-BASED COHORT ARE ASSOCIATED WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. RESULTS: DNA METHYLATION AGE WAS ESTIMATED IN A COHORT OF 1863 OLDER PEOPLE, AND THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE (DELTAAGE) WAS CALCULATED. A CASE-COHORT DESIGN AND WEIGHTED PROPORTIONAL COX HAZARD MODELS WERE USED TO ESTIMATE ASSOCIATIONS OF DELTAAGE WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. HAZARD RATIOS FOR DELTAAGE (PER 5 YEARS) CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HORVATH WERE 1.23 (95 % CI 1.10-1.38) FOR ALL-CAUSE MORTALITY, 1.22 (95 % CI 1.03-1.45) FOR CANCER MORTALITY, AND 1.19 (95 % CI 0.98-1.43) FOR CARDIOVASCULAR MORTALITY AFTER ADJUSTMENT FOR BATCH EFFECTS, AGE, SEX, EDUCATIONAL LEVEL, HISTORY OF CHRONIC DISEASES, HYPERTENSION, SMOKING STATUS, BODY MASS INDEX, AND LEUCOCYTE DISTRIBUTION. ASSOCIATIONS WERE SIMILAR BUT WEAKER FOR DELTAAGE CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HANNUM. CONCLUSIONS: THESE RESULTS SHOW THAT AGE ACCELERATION IN TERMS OF THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE IS AN INDEPENDENT PREDICTOR OF ALL-CAUSE AND CAUSE-SPECIFIC MORTALITY AND MAY BE USEFUL AS A GENERAL MARKER OF HEALTHY AGING. 2016 15 5085 41 PILOT STUDY OF ABSOLUTE TELOMERE LENGTHS IN PRETERM INFANTS. BACKGROUND: ANNUALLY, APPROXIMATELY 15 MILLION BABIES ARE BORN PRETERM (<37 WEEKS GESTATIONAL AGE) GLOBALLY. IN THE NEONATAL INTENSIVE CARE UNIT (NICU) ENVIRONMENT, INFANTS ARE EXPOSED TO REPEATED STRESSFUL OR PAINFUL PROCEDURES AS PART OF ROUTINE LIFESAVING CARE. THESE PROCEDURES HAVE BEEN ASSOCIATED WITH EPIGENETIC ALTERATIONS THAT MAY LEAD TO AN INCREASED RISK OF NEURODEVELOPMENTAL DISORDERS. TELOMERE LENGTH HAS BEEN NEGATIVELY ASSOCIATED WITH ADVERSE LIFE EXPERIENCES IN STUDIES OF ADULTS. OBJECTIVES: THIS PILOT STUDY AIMED TO DESCRIBE TELOMERE LENGTH IN A SAMPLE OF PRETERM INFANTS AT NICU DISCHARGE AND EXAMINE ANY ASSOCIATIONS WITH PAIN, FEEDING METHOD, AND NEURODEVELOPMENT. METHODS: THIS DESCRIPTIVE PILOT STUDY SAMPLE INCLUDES BASELINE ABSOLUTE TELOMERE LENGTH (ATL) OF 36 PRETERM INFANTS IMMEDIATELY PRIOR TO DISCHARGE. QUANTITATIVE POLYMERASE CHAIN REACTION WAS USED TO DETERMINE ATL. INFANT DEMOGRAPHICS, PAIN/STRESS, TYPE OF FEEDING, ANTIBIOTIC USE, NEURODEVELOPMENT, AND BUCCAL SWAB DATA WERE COLLECTED. DESCRIPTIVE DATA ANALYSIS WAS USED TO DESCRIBE THE TELOMERE LENGTH USING GRAPHS. RESULTS: AMONG OUR PRETERM INFANT SAMPLES, THE MEAN ATL WAS FAR GREATER THAN THE AVERAGE ADULT TELOMERE LENGTH. ALTHOUGH NO SIGNIFICANT ASSOCIATIONS WERE FOUND BETWEEN ATL AND PAIN, FEEDING METHOD, AND NEURODEVELOPMENT, A TREND BETWEEN SEX WAS NOTED WHERE MALE TELOMERE LENGTHS WERE SHORTER THAN FEMALES AS THEY AGED. DISCUSSION: THIS IS ONE OF FEW STUDIES TO EVALUATE PRETERM INFANT TELOMERE LENGTH. ALTHOUGH OTHER RESEARCHERS HAVE USED RELATIVE TELOMERE LENGTH, WE USED THE MORE ACCURATE ATL. WE FOUND NONSIGNIFICANT SHORTER TELOMERE LENGTHS AMONG MALES. ADDITIONAL LARGE-SCALE, LONGITUDINAL STUDIES ARE NEEDED TO BETTER IDENTIFY THE PREDICTORS OF TELOMERE LENGTH AT THE TIME OF DISCHARGE FROM NICU. 2021 16 2150 47 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 2500 G) CONTROL PARTICIPANTS. METHODS: BUCCAL CELLS WERE COLLECTED FROM 45 ELBW SURVIVORS AND 49 NBW CONTROL PARTICIPANTS AT 30 TO 35 YEARS OF AGE. EPIGENETIC AGE WAS CALCULATED FROM THE WEIGHTED AVERAGE OF DNA METHYLATION AT 353 CYTOSINE-PHOSPHATE-GUANINE SEQUENCE WITHIN DNA SITES, BY USING THE ILLUMINA INFINIUM HUMAN METHYLATION EPIC 850K BEADCHIP ARRAY. RESULTS: BEFORE AND AFTER STATISTICALLY ADJUSTING FOR NEUROSENSORY IMPAIRMENT AND THE PRESENCE OF CHRONIC HEALTH CONDITIONS, A SIGNIFICANT SEX BY BIRTH WEIGHT GROUP INTERACTION WAS OBSERVED IN THE 353-SITE EPIGENETIC-CLOCK ASSAY (P = .03), WHEREBY ELBW MEN HAD A SIGNIFICANTLY OLDER EPIGENETIC AGE THAN NBW MEN (4.6 YEARS; P = .01). WOMEN BORN AT ELBW WERE NOT FOUND TO BE EPIGENETICALLY OLDER THAN THEIR NBW PEERS. CONCLUSIONS: THE RESULTS OF THIS STUDY SUGGEST THAT PRENATAL EXPOSURES MAY PLAY AN IMPORTANT ROLE IN AGING, AND THAT MEN BORN PRETERM MAY EXPERIENCE ACCELERATED AGING RELATIVE TO THEIR PEERS. WE FURTHER HIGHLIGHT THE NEED TO MONITOR AND PROMOTE THE HEALTH OF PRETERM SURVIVORS, WITH A PARTICULAR FOCUS ON HEALTHY AGING ACROSS THE LIFE SPAN. 2021 20 3884 70 KIDNEY DISEASE IN DIABETES. PERSONS WITH DIABETES MAKE UP THE FASTEST GROWING GROUP OF KIDNEY DIALYSIS AND TRANSPLANT RECIPIENTS IN THE UNITED STATES. IN 1985, WHEN THE FIRST EDITION OF DIABETES IN AMERICA WAS PUBLISHED, 20,961 PERSONS WITH DIABETES WERE RECEIVING RENAL REPLACEMENT THERAPY, REPRESENTING 29% OF ALL NEW CASES OF END-STAGE RENAL DISEASE (ESRD). BY 2012, 239,837 PERSONS WITH DIABETES WERE ON RENAL REPLACEMENT THERAPY, ACCOUNTING FOR 44% OF ALL NEW ESRD CASES. THE INCREASED COUNT REFLECTS GROWTH IN DIABETES PREVALENCE AND INCREASED ACCESS TO DIALYSIS AND TRANSPLANTATION. THOSE WITH A PRIMARY DIAGNOSIS OF DIABETES HAVE LOWER SURVIVAL RELATIVE TO OTHER CAUSES OF ESRD, PRIMARILY BECAUSE OF THE COEXISTENT MORBIDITY ASSOCIATED WITH DIABETES, PARTICULARLY CARDIOVASCULAR DISEASES (CVD). WHILE SURVIVAL ON DIALYSIS HAS SLOWLY IMPROVED ACROSS MODALITIES SINCE THE 1990S, IT REMAINS REDUCED IN PERSONS WITH DIABETES, HALF OF WHOM DIE WITHIN 3 YEARS OF BEGINNING DIALYSIS IN THE UNITED STATES. SIMILAR TO PERSONS WITH ESRD IN GENERAL, THE LEADING CAUSES OF DEATH AMONG ADULTS WITH DIABETES WHO STARTED DIALYSIS IN 1995-2009 WERE CVD (58% OF THE DEATHS) AND INFECTIONS (13% OF THE DEATHS). KIDNEY TRANSPLANT RECIPIENTS WITH DIABETES HAVE MUCH BETTER SURVIVAL THAN THOSE ON DIALYSIS, INDICATING A SIGNIFICANT IMPACT OF THE TYPE OF RENAL REPLACEMENT THERAPY (TRANSPLANT VERSUS DIALYSIS) ON LONG-TERM SURVIVAL. KIDNEY FAILURE AFFECTS ABOUT 1% OF PERSONS WITH DIABETES IN THE UNITED STATES. A CONSIDERABLY HIGHER PROPORTION, ABOUT 40%, HAVE LESS SEVERE KIDNEY DISEASE. SINCE THE SECOND EDITION OF DIABETES IN AMERICA WAS PUBLISHED IN 1995, A WEALTH OF NEW INFORMATION HAS CONTRIBUTED SUBSTANTIALLY TO THE UNDERSTANDING OF KIDNEY DISEASE ASSOCIATED WITH DIABETES. IN 2002, THE NATIONAL KIDNEY FOUNDATION'S KIDNEY DISEASE OUTCOME QUALITY INITIATIVE PUBLISHED A UNIFORM DEFINITION OF CHRONIC KIDNEY DISEASE (CKD) AND CLASSIFICATION OF ITS STAGES IRRESPECTIVE OF UNDERLYING CAUSE, THUS PROVIDING A COMMON LANGUAGE FOR DEFINING BOTH THE SEVERITY AND PROGNOSIS OF KIDNEY DISEASE. THE DEFINITION AND CLASSIFICATION OF CKD WERE SUBSEQUENTLY UPDATED AND REFINED BY THE KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES IN 2012. ACCORDINGLY, CKD IS CLASSIFIED BASED ON BOTH ALBUMINURIA AND GLOMERULAR FILTRATION RATE (GFR) CATEGORIES, AND TOGETHER WITH KIDNEY FAILURE, THESE CONDITIONS ARE COLLECTIVELY REFERRED TO AS CKD, REGARDLESS OF ETIOLOGY. IN ADDITION, THE KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES RECOMMENDS USING EQUATIONS TO ESTIMATE GFR (EGFR), WHICH INCLUDE THE ROUTINELY OBTAINED VARIABLES SERUM CREATININE, AGE, SEX, AND RACE/ETHNICITY. THE USE OF SERUM CYSTATIN C, AN ENDOGENOUS FILTRATION MARKER LESS INFLUENCED THAN SERUM CREATININE BY VARIATIONS IN MUSCLE MASS, DIET, AND TUBULAR SECRETION, HAS EMERGED AS AN ALTERNATIVE OR AN ADJUNCT TO SERUM CREATININE-BASED EQUATIONS, PARTICULARLY IN PERSONS WITH DIABETES, IN WHOM EARLY KIDNEY DISEASE IS OFTEN CHARACTERIZED BY ELEVATED GFR. SINCE THE LATE 1990S, NEW MOLECULAR MECHANISMS HAVE BEEN DEFINED THAT ARE HELPING TO EXPLAIN THE DEVELOPMENT AND PROGRESSION OF DIABETIC KIDNEY DISEASE. GLOMERULAR STRUCTURAL LESIONS WERE FOUND TO EXPLAIN 95% OF THE VARIABILITY IN ALBUMIN EXCRETION AND 78% OF GFR VARIABILITY. THE LATTER PERCENTAGE INCREASED TO 92% BY ADDING INDICES OF GLOMERULAR-TUBULAR JUNCTION ABNORMALITIES AND INTERSTITIAL EXPANSION TO THE REGRESSION MODELS. PODOCYTE INJURY APPEARS TO PLAY AN ESSENTIAL ROLE IN THE PROGRESSION OF DIABETIC NEPHROPATHY. IN PERSONS WITH EITHER TYPE 1 OR TYPE 2 DIABETES, PODOCYTE CHANGES MAY OCCUR EVEN BEFORE THE INCREASE IN ALBUMINURIA, SUGGESTING THAT DIABETES ITSELF MAY INDUCE PODOCYTE ALTERATIONS. MUCH HAS ALSO BEEN WRITTEN ABOUT THE PROGNOSTIC IMPLICATIONS OF CKD. ELEVATED ALBUMINURIA AND LOW GFR ARE ASSOCIATED WITH ESRD, FATAL AND NONFATAL CVD, AND ALL-CAUSE MORTALITY. A META-ANALYSIS OF 1,024,977 PARTICIPANTS (NEARLY 13% WITH DIABETES) FROM 30 GENERAL POPULATION AND HIGH-RISK CARDIOVASCULAR COHORTS AND 13 CKD COHORTS INDICATED THAT WHILE THE ABSOLUTE RISKS FOR ALL-CAUSE AND CVD MORTALITY ARE HIGHER IN THE PRESENCE OF DIABETES, THE RELATIVE RISKS OF ESRD OR DEATH BY EGFR AND ALBUMINURIA ARE SIMILAR WITH OR WITHOUT DIABETES. THESE FINDINGS UNDERSCORE THE IMPORTANCE OF KIDNEY DISEASE PER SE AS A PREDICTOR OF IMPORTANT CLINICAL OUTCOMES, REGARDLESS OF THE UNDERLYING CAUSE OF KIDNEY DISEASE. NEW BIOMARKERS OF DIABETIC KIDNEY DISEASE APPEAR TO HAVE ADDITIONAL PROGNOSTIC INFORMATION BEYOND THAT PROVIDED BY ALBUMINURIA. THESE MARKERS INCLUDE KIDNEY INJURY MOLECULE 1, LIVER FATTY ACID-BINDING PROTEIN, N-ACETYL-BETA-D-GLUCOSAMINIDASE, NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN, BETA-TRACE PROTEIN, BETA(2)-MICROGLOBULIN, AND TUMOR NECROSIS FACTOR RECEPTORS 1 AND 2. MANY CONCEPTS ABOUT RISK FACTORS FOR CKD ILLUSTRATED IN THIS CHAPTER HAVE NOT CHANGED SINCE 1995, AND WHERE THEY HAVE, THOSE CHANGES ARE DISCUSSED. IN PARTICULAR, MAJOR ADVANCES HAVE BEEN MADE IN ELUCIDATING THE GENETIC AND EPIGENETIC COMPLEXITY OF CKD, WHICH CONTRIBUTED TO DEFINING CELLULAR METABOLIC MEMORY AND THE UNDERSTANDING OF THE LONGLASTING EFFECTS OF STRICT GLYCEMIC CONTROL OBSERVED IN PERSONS WITH TYPE 1 DIABETES OR TYPE 2 DIABETES. IMPROVEMENTS IN THE MANAGEMENT OF PERSONS WITH DIABETES AND CKD HAVE EXTENDED THE TIME COURSE FROM ONSET OF SEVERE ALBUMINURIA TO ESRD AND REDUCED THE OCCURRENCE OF CVD. IN TYPE 1 DIABETES, THE COMBINED DIABETES CONTROL AND COMPLICATIONS TRIAL (DCCT) AND ITS LONG-TERM FOLLOW-UP, THE EPIDEMIOLOGY OF DIABETES INTERVENTIONS AND COMPLICATIONS (EDIC) OBSERVATIONAL STUDY, INDICATED THAT INTENSIVE EARLY METABOLIC CONTROL REDUCED THE RISK OF IMPAIRED GFR BY 50% AND OF CVD OUTCOMES BY 42%, WITH A SPECIFIC 57% DECREASE IN MYOCARDIAL INFARCTION, STROKE, OR DEATH FROM CVD, EFFECTS THAT WERE PARTLY MEDIATED BY THE REDUCED INCIDENCE OF DIABETIC KIDNEY DISEASE. AMONG PERSONS WITH TYPE 2 DIABETES, A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS INDICATED THAT MORE INTENSIVE GLYCEMIC CONTROL (GLYCOSYLATED HEMOGLOBIN [A1C] <7%) WAS ASSOCIATED WITH A SIGNIFICANT 10% REDUCTION IN ALBUMINURIA BUT HAD NO EFFECTS ON MORTALITY, KIDNEY FAILURE, OR OTHER VASCULAR OUTCOMES. THE ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES (ACCORD) TRIAL, TARGETING AN A1C LEVEL <6.0% IN THE INTENSIVE INTERVENTION ARM, REPORTED AN INCREASED RISK OF CVD DEATH FOR INTENSIVE VERSUS CONVENTIONAL GLYCEMIC CONTROL, ALTHOUGH IT REMAINS UNCLEAR WHETHER THIS EFFECT WAS RELATED TO MORE HYPOGLYCEMIC EPISODES, THE USE OF ADDITIONAL HYPOGLYCEMIC MEDICINES, OR TO THE TARGET GLYCEMIC LEVEL ITSELF. LIKEWISE, THE MODEST GAINS IN INTERMEDIATE OUTCOMES IN THE INTENSIVE TREATMENT ARMS OF THE ACTION IN DIABETES AND VASCULAR DISEASE: PRETERAX AND DIAMICRON MODIFIED RELEASE CONTROLLED EVALUATION (ADVANCE) AND THE VETERANS AFFAIRS DIABETES (VADT) TRIAL WERE COUNTERBALANCED BY A TWOFOLD TO THREEFOLD HIGHER RISK OF SEVERE HYPOGLYCEMIA. TOGETHER, THESE TRIALS INDICATE THAT GLYCEMIC CONTROL IS EXTREMELY USEFUL UP TO A POINT, BUT MORE AGGRESSIVE GLYCEMIC CONTROL MAY BE HARMFUL. SIMILARLY, FOR BLOOD PRESSURE CONTROL, 2014-2015 RECOMMENDATIONS BY THE GUIDELINE-WRITING GROUPS ENDORSE LESS INTENSIVE AND MORE INDIVIDUALIZED BLOOD PRESSURE TARGETS FOR DIABETES AND CKD THAN IN THE PAST. PERSONS WITH DIABETES AND CKD REQUIRE MULTIDISCIPLINARY MANAGEMENT INVOLVING A COMBINATION OF TREATMENTS AND BEHAVIORAL ADJUSTMENTS TO DELAY PROGRESSION OF CKD AND TO PREVENT THE ASSOCIATED COMPLICATIONS. THE STENO-2 STUDY, A LANDMARK PROSPECTIVE, RANDOMIZED TRIAL IN DENMARK, DEMONSTRATED THAT COMPARED WITH CONVENTIONAL TREATMENT, INTENSIVE MULTIFACTORIAL INTERVENTION LED TO 46% LOWER DEATH RATE, 56% LESS SEVERE ALBUMINURIA, 43% LOWER INCIDENCE OF DIABETIC RETINOPATHY, AND 47% LOWER INCIDENCE OF AUTONOMIC NEUROPATHY DURING THE 13.3-YEAR STUDY PERIOD. 2018