1  1780 110 EDUCATION AND LIFESTYLE FACTORS ARE ASSOCIATED WITH DNA METHYLATION CLOCKS IN OLDER AFRICAN AMERICANS. DNA METHYLATION (DNAM) CLOCKS ARE IMPORTANT BIOMARKERS OF CELLULAR AGING AND ARE ASSOCIATED WITH A VARIETY OF AGE-RELATED CHRONIC DISEASES AND ALL-CAUSE MORTALITY. EXAMINING THE RELATIONSHIP BETWEEN EDUCATION AND LIFESTYLE RISK FACTORS FOR AGE-RELATED DISEASES AND MULTIPLE DNAM CLOCKS CAN INCREASE THE UNDERSTANDING OF HOW RISK FACTORS CONTRIBUTE TO AGING AT THE CELLULAR LEVEL. THIS STUDY EXPLORED THE ASSOCIATION BETWEEN EDUCATION OR LIFESTYLE RISK FACTORS FOR AGE-RELATED DISEASES AND THE ACCELERATION OF FOUR DNAM CLOCKS, INCLUDING INTRINSIC (IEAA) AND EXTRINSIC EPIGENETIC AGE ACCELERATION (EEAA), PHENOAGE ACCELERATION (PHENOAA), AND GRIMAGE ACCELERATION (GRIMAA) IN THE AFRICAN AMERICAN PARTICIPANTS OF THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY. WE PERFORMED BOTH CROSS-SECTIONAL AND LONGITUDINAL ANALYSES. IN CROSS-SECTIONAL ANALYSES, GENDER, EDUCATION, BMI, SMOKING, AND ALCOHOL CONSUMPTION WERE ALL INDEPENDENTLY ASSOCIATED WITH GRIMAA, WHEREAS ONLY SOME OF THEM WERE ASSOCIATED WITH OTHER CLOCKS. THE EFFECT OF SMOKING AND EDUCATION ON GRIMAA VARIED BY GENDER. LONGITUDINAL ANALYSES SUGGEST THAT AGE AND BMI CONTINUED TO INCREASE GRIMAA, AND THAT AGE AND CURRENT SMOKING CONTINUED TO INCREASE PHENOAA AFTER CONTROLLING DNAM CLOCKS AT BASELINE. IN CONCLUSION, EDUCATION AND COMMON LIFESTYLE RISK FACTORS WERE ASSOCIATED WITH MULTIPLE DNAM CLOCKS. HOWEVER, THE ASSOCIATION WITH EACH RISK FACTOR VARIED BY CLOCK, WHICH SUGGESTS THAT DIFFERENT CLOCKS MAY CAPTURE ADVERSE EFFECTS FROM DIFFERENT ENVIRONMENTAL STIMULI.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2   327  26 ALLERGIC INFLAMMATORY MEMORY IN HUMAN RESPIRATORY EPITHELIAL PROGENITOR CELLS. BARRIER TISSUE DYSFUNCTION IS A FUNDAMENTAL FEATURE OF CHRONIC HUMAN INFLAMMATORY DISEASES(1). SPECIALIZED SUBSETS OF EPITHELIAL CELLS-INCLUDING SECRETORY AND CILIATED CELLS-DIFFERENTIATE FROM BASAL STEM CELLS TO COLLECTIVELY PROTECT THE UPPER AIRWAY(2-4). ALLERGIC INFLAMMATION CAN DEVELOP FROM PERSISTENT ACTIVATION(5) OF TYPE 2 IMMUNITY(6) IN THE UPPER AIRWAY, RESULTING IN CHRONIC RHINOSINUSITIS, WHICH RANGES IN SEVERITY FROM RHINITIS TO SEVERE NASAL POLYPS(7). BASAL CELL HYPERPLASIA IS A HALLMARK OF SEVERE DISEASE(7-9), BUT IT IS NOT KNOWN HOW THESE PROGENITOR CELLS(2,10,11) CONTRIBUTE TO CLINICAL PRESENTATION AND BARRIER TISSUE DYSFUNCTION IN HUMANS. HERE WE PROFILE PRIMARY HUMAN SURGICAL CHRONIC RHINOSINUSITIS SAMPLES (18,036 CELLS, N = 12) THAT SPAN THE DISEASE SPECTRUM USING SEQ-WELL FOR MASSIVELY PARALLEL SINGLE-CELL RNA SEQUENCING(12), REPORT TRANSCRIPTOMES FOR HUMAN RESPIRATORY EPITHELIAL, IMMUNE AND STROMAL CELL TYPES AND SUBSETS FROM A TYPE 2 INFLAMMATORY DISEASE, AND MAP KEY MEDIATORS. BY COMPARISON WITH NASAL SCRAPINGS (18,704 CELLS, N = 9), WE DEFINE SIGNATURES OF CORE, HEALTHY, INFLAMED AND POLYP SECRETORY CELLS. WE REVEAL MARKED DIFFERENCES BETWEEN THE EPITHELIAL COMPARTMENTS OF THE NON-POLYP AND POLYP CELLULAR ECOSYSTEMS, IDENTIFYING AND VALIDATING A GLOBAL REDUCTION IN CELLULAR DIVERSITY OF POLYPS CHARACTERIZED BY BASAL CELL HYPERPLASIA, CONCOMITANT DECREASES IN GLANDULAR CELLS, AND PHENOTYPIC SHIFTS IN SECRETORY CELL ANTIMICROBIAL EXPRESSION. WE DETECT AN ABERRANT BASAL PROGENITOR DIFFERENTIATION TRAJECTORY IN POLYPS, AND PROPOSE CELL-INTRINSIC(13), EPIGENETIC(14,15) AND EXTRINSIC FACTORS(11,16,17) THAT LOCK POLYP BASAL CELLS INTO THIS UNCOMMITTED STATE. FINALLY, WE FUNCTIONALLY DEMONSTRATE THAT EX VIVO CULTURED BASAL CELLS RETAIN INTRINSIC MEMORY OF IL-4/IL-13 EXPOSURE, AND TEST THE POTENTIAL FOR CLINICAL BLOCKADE OF THE IL-4 RECEPTOR ALPHA-SUBUNIT TO MODIFY BASAL AND SECRETORY CELL STATES IN VIVO. OVERALL, WE FIND THAT REDUCED EPITHELIAL DIVERSITY STEMMING FROM FUNCTIONAL SHIFTS IN BASAL CELLS IS A KEY CHARACTERISTIC OF TYPE 2 IMMUNE-MEDIATED BARRIER TISSUE DYSFUNCTION. OUR RESULTS DEMONSTRATE THAT EPITHELIAL STEM CELLS MAY CONTRIBUTE TO THE PERSISTENCE OF HUMAN DISEASE BY SERVING AS REPOSITORIES FOR ALLERGIC MEMORIES.	2018	
                                                                                                                                                                                                                                                                                                                                 
3  4730  39 NOVEL AGE-ASSOCIATED DNA METHYLATION CHANGES AND EPIGENETIC AGE ACCELERATION IN MIDDLE-AGED AFRICAN AMERICANS AND WHITES. BACKGROUND: AFRICAN AMERICANS (AAS) EXPERIENCE PREMATURE CHRONIC HEALTH OUTCOMES AND LONGEVITY DISPARITIES CONSISTENT WITH AN ACCELERATED AGING PHENOTYPE. DNA METHYLATION (DNAM) LEVELS AT SPECIFIC CPG POSITIONS ARE HALLMARKS OF AGING EVIDENCED BY THE PRESENCE OF AGE-ASSOCIATED DIFFERENTIALLY METHYLATED CPG POSITIONS (ADMPS) THAT ARE THE BASIS FOR THE EPIGENETIC CLOCK FOR MEASURING BIOLOGICAL AGE ACCELERATION. SINCE DNAM HAS NOT BEEN WIDELY STUDIED AMONG NON-EUROPEAN POPULATIONS, WE EXAMINED THE ASSOCIATION BETWEEN DNAM AND CHRONOLOGICAL AGE IN AAS AND WHITES, AND THE ASSOCIATION BETWEEN RACE, POVERTY, SEX, AND EPIGENETIC AGE ACCELERATION. RESULTS: WE MEASURED GENOME-WIDE DNA METHYLATION (866,836 CPGS) USING THE ILLUMINA METHYLATIONEPIC BEADCHIP IN BLOOD DNA EXTRACTED FROM 487 MIDDLE-AGED AA (N = 244) AND WHITE (N = 243), MEN (N = 248), AND WOMEN (N = 239). THE MEAN (SD) AGE WAS 48.4 (8.8) IN AA AND 49.0 (8.7) IN WHITES (P = 0.48). WE IDENTIFIED 4930 SIGNIFICANTLY ASSOCIATED ADMPS IN AAS AND 469 IN WHITES. OF THESE, 75.6% AND 53.1% WERE NOVEL, LARGELY DRIVEN BY THE INCREASED NUMBER OF MEASURED CPGS IN THE EPIC ARRAY, IN AA AND WHITES, RESPECTIVELY. AAS HAD MORE AGE-ASSOCIATED DNAM CHANGES THAN WHITES IN GENES IMPLICATED IN AGE-RELATED DISEASES AND CELLULAR PATHWAYS INVOLVED IN GROWTH AND DEVELOPMENT. WE ASSESSED THREE EPIGENETIC AGE ACCELERATION MEASURES (UNIVERSAL, INTRINSIC, AND EXTRINSIC). AAS HAD A SIGNIFICANTLY SLOWER EXTRINSIC AGING COMPARED TO WHITES. FURTHERMORE, COMPARED TO AA WOMEN, BOTH AA AND WHITE MEN HAD FASTER AGING IN THE UNIVERSAL AGE ACCELERATION MEASURE (+ 2.04 AND + 1.24 YEARS, RESPECTIVELY, P < 0.05). CONCLUSIONS: AAS HAVE MORE WIDE-SPREAD METHYLATION CHANGES THAN WHITES. RACE AND SEX INTERACT TO UNDERLIE BIOLOGICAL AGE ACCELERATION SUGGESTING ALTERED DNA METHYLATION PATTERNS MAY BE IMPORTANT IN AGE-ASSOCIATED HEALTH DISPARITIES.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4  4503  27 MOSAIC AGING. ALTHOUGH ALL MULTICELLULAR ORGANISMS UNDERGO STRUCTURAL AND FUNCTIONAL DETERIORATION WITH AGE, SENESCENCE IS NOT A UNIFORM PROCESS. RATHER, EACH ORGANISM EXPERIENCES A CONSTELLATION OF CHANGES THAT REFLECT THE HETEROGENEOUS EFFECTS OF AGE ON MOLECULES, CELLS, ORGANS AND SYSTEMS, AN IDIOSYNCRATIC PATTERN THAT WE REFER TO AS MOSAIC AGING. VARYING GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS (LOCAL AND EXTRINSIC) CONTRIBUTE TO THE AGING PHENOTYPE IN A GIVEN INDIVIDUAL, AND THESE AGENTS INFLUENCE THE TYPE AND RATE OF FUNCTIONAL DECLINE, AS WELL AS THE LIKELIHOOD OF DEVELOPING AGE-ASSOCIATED AFFLICTIONS SUCH AS CARDIOVASCULAR DISEASE, ARTHRITIS, CANCER, AND NEURODEGENERATIVE DISORDERS. IDENTIFYING KEY FACTORS THAT DRIVE AGING, CLARIFYING THEIR ACTIVITIES IN DIFFERENT SYSTEMS, AND IN PARTICULAR UNDERSTANDING HOW THEY INTERACT WILL ENHANCE OUR COMPREHENSION OF THE AGING PROCESS, AND COULD YIELD INSIGHTS INTO THE PERMISSIVE ROLE THAT SENESCENCE PLAYS IN THE EMERGENCE OF ACUTE AND CHRONIC DISEASES OF THE ELDERLY.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5  6193  34 THE IMPACT OF PERCEIVED STRESS ON SKIN AGEING. SKIN AGEING CAN BE DIVIDED ACCORDING TO PHENOTYPICAL FEATURES INTO INTRINSIC (BY THE PASSAGE OF TIME) AND EXTRINSIC (WITH THE ADDITION OF THE EFFECTS OF ENVIRONMENTAL FACTORS). PHOTOAGEING IS BY FAR THE MOST RESEARCHED FACTOR OF EXTRINSIC AGEING BUT THE ADDITIONAL IMPACT OF OTHER FACTORS SUCH AS CIGARETTE SMOKING AND EXPOSURE TO AIR POLLUTION OUGHT TO BE TAKEN INTO ACCOUNT. ONE OF THE LEAST RESEARCHED TOPICS IN RELATION TO EXTRINSIC SKIN AGEING IS THE IMPACT OF PSYCHOLOGICAL STRESS. A CONTEMPORARY REVIEW OF RESPONSE OF HUMAN SKIN TO STRESS DESCRIBES THE MOLECULAR MECHANISMS OF EXTRINSIC SKIN AGEING, BUT HAS FALLEN SHORT OF EXPLAINING RESILIENCE TO STRESS EXHIBITED BY PEOPLE. MECHANISMS TO REGULATE GENE EXPRESSION, DEFINE CELLULAR IDENTITY AND PROMOTE FUNCTIONALITY ARE RESPONSIBLE FOR THE ADAPTIVE RESPONSE TO STRESSFUL EVENTS. CONVERSELY, MALADAPTIVE RESPONSE OF HUMAN TISSUES TO CHRONIC STRESS APPEARS TO HAVE AN IMPACT ON GENE REGULATION. EPIGENETICS IS THE STUDY OF HERITABLE CHANGES IN ORGANISMS DUE TO MODIFICATIONS IN GENE ACTIVITY AND EXPRESSION, AS OPPOSED TO THE GENETIC CODE (DNA GENOME). CHRONIC STRESS APPEARS TO BE AN IMPORTANT FACTOR IN DETERMINING AN INDIVIDUAL'S VULNERABILITY TO AGEING AND AGE-RELATED COMORBIDITIES VIA EPIGENETIC MODIFICATIONS. FORERUNNERS IN EPIGENETIC RESEARCH RECOGNIZED THE NECESSITY OF A RELIABLE BIOMARKER IN ORDER TO DEVELOP A BETTER UNDERSTANDING OF THE ROLE OF EPIGENOMICS IN AGEING. GENOMIC DNA METHYLATION PATTERNS (DNAM) APPEAR TO BE VALUABLE IN AGE PREDICTION BUT VARIABILITY IN SPECIFICITY EXISTS ACROSS SPECIES OF MAMMALS, HUMAN RACES AND TISSUES. NEUROSCIENCE RESEARCH APPEARS TO BE LEADING THE WAY IN EPIGENOMICS WHILST THE LACK OF A VALID AND RELIABLE DNAM-ASSOCIATED AGE PREDICTOR COMPATIBLE WITH HUMAN SKIN TISSUE HINDERS RESEARCH ENDEAVOURS FOR THE EPIGENETICS OF SKIN AGEING.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6  4178  19 MEMORY T-CELL HETEROGENEITY AND TERMINOLOGY. IMMUNOLOGICAL MEMORY AND EXHAUSTION ARE FUNDAMENTAL FEATURES OF ADAPTIVE IMMUNITY. RECENT ADVANCES REVEAL INCREASING HETEROGENEITY AND DIVERSITY AMONG CD8 T-CELL SUBSETS, RESULTING IN NEW SUBSETS TO ANNOTATE AND UNDERSTAND. HERE, WE REVIEW OUR CURRENT KNOWLEDGE OF DIFFERENTIATION AND MAINTENANCE OF MEMORY AND EXHAUSTED CD8 T CELLS, INCLUDING PHENOTYPIC CLASSIFICATION, DEVELOPMENTAL PATHS, TRANSCRIPTIONAL AND EPIGENETIC FEATURES, AND CELL INTRINSIC AND EXTRINSIC FACTORS. ADDITIONALLY, WE USE THIS OUTLINE TO DISCUSS THE NOMENCLATURE OF EFFECTOR, MEMORY, AND EXHAUSTED CD8 T CELLS. FINALLY, WE DISCUSS HOW NEW FINDINGS ABOUT THESE CELL TYPES MAY IMPACT THE THERAPEUTIC EFFICACY AND DEVELOPMENT OF IMMUNOTHERAPIES TARGETING EFFECTOR, MEMORY, AND/OR EXHAUSTED CD8 T CELLS IN CHRONIC INFECTIONS AND CANCER.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7   501  42 ASSOCIATION OF ACCELEROMETER-MEASURED PHYSICAL ACTIVITY AND SEDENTARY TIME WITH EPIGENETIC MARKERS OF AGING. INTRODUCTION/PURPOSE: PHYSICAL ACTIVITY MAY INFLUENCE CHRONIC DISEASE RISK, IN PART, THROUGH EPIGENETIC MECHANISMS. PREVIOUS STUDIES HAVE DEMONSTRATED THAT AN ACUTE BOUT OF PHYSICAL ACTIVITY CAN INFLUENCE DNA METHYLATION STATUS. FEW STUDIES HAVE EXPLORED THE RELATIONSHIP BETWEEN HABITUAL, ACCELEROMETER-MEASURED PHYSICAL ACTIVITY OR SEDENTARY TIME WITH EPIGENETIC MARKERS OF AGING. METHODS: WE USED LINEAR REGRESSION TO EXAMINE CROSS-SECTIONAL ASSOCIATIONS OF ACCELEROMETER-MEASURED PHYSICAL ACTIVITY AND SEDENTARY TIME WITH EXTRINSIC AND INTRINSIC EPIGENETIC AGE ACCELERATION (EEAA AND IEAA) MODELS AND GRIMAGE MEASURED FROM BLOOD SAMPLES FROM FRAMINGHAM HEART STUDY PARTICIPANTS WITH ACCELEROMETRY AND DNA METHYLATION DATA ( N = 2435; MEAN AGE, 54.9 +/- 14.3; 46.0% MEN). RESIDUALS OF HANNUM-, HORVATH-, AND GRIMAGE-PREDICTED EPIGENETIC AGE WERE CALCULATED BY REGRESSING EPIGENETIC AGE ON CHRONOLOGICAL AGE. WE TOOK INTO ACCOUNT BLOOD CELL COMPOSITION FOR EEAA, IEAA, AND ADJGRIMAGE. MODERATE TO VIGOROUS PHYSICAL ACTIVITY WAS LOG-TRANSFORMED TO NORMALIZE ITS DISTRIBUTION. ADJUSTMENT MODELS ACCOUNTED FOR FAMILY STRUCTURE, AGE, SEX, SMOKING STATUS, COHORT-LABORATORY INDICATOR, AND ACCELEROMETER WEAR TIME. WE ADDITIONALLY EXPLORED ADJUSTMENT FOR BODY MASS INDEX (BMI). RESULTS: WALKING 1500 MORE STEPS PER DAY OR SPENDING 3 FEWER HOURS SEDENTARY WAS ASSOCIATED WITH >10 MONTHS LOWER GRIMAGE BIOLOGICAL AGE (OR ~1 MONTH LOWER ADJGRIMAGE, AFTER ADJUSTING FOR BLOOD CELLS, P < 0.05). EVERY 5 MIN.D -1 MORE MODERATE TO VIGOROUS PHYSICAL ACTIVITY WAS ASSOCIATED WITH 19-79 D OF LOWER GRIMAGE (4-23 D LOWER USING EEAA OR ADJGRIMAGE, P < 0.01). ADJUSTING FOR BMI ATTENUATED THESE RESULTS, BUT ALL STATISTICALLY SIGNIFICANT ASSOCIATIONS WITH ADJGRIMAGE REMAINED. CONCLUSIONS: GREATER HABITUAL PHYSICAL ACTIVITY AND LOWER SEDENTARY TIME WERE ASSOCIATED WITH LOWER EPIGENETIC AGE, WHICH WAS PARTIALLY EXPLAINED BY BMI. FURTHER RESEARCH SHOULD EXPLORE WHETHER CHANGES IN PHYSICAL ACTIVITY INFLUENCE METHYLATION STATUS AND WHETHER THOSE MODIFICATIONS INFLUENCE CHRONIC DISEASE RISK.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
8  3180  26 HALLMARKS OF AGING IN MACROPHAGES: CONSEQUENCES TO SKIN INFLAMMAGING. THE SKIN IS OUR LARGEST ORGAN AND THE OUTERMOST PROTECTIVE BARRIER. ITS AGING REFLECTS BOTH INTRINSIC AND EXTRINSIC PROCESSES RESULTING FROM THE CONSTANT INSULTS IT IS EXPOSED TO. AGING IN THE SKIN IS ACCOMPANIED BY SPECIFIC EPIGENETIC MODIFICATIONS, ACCUMULATION OF SENESCENT CELLS, REDUCED CELLULAR PROLIFERATION/TISSUE RENEWAL, ALTERED EXTRACELLULAR MATRIX, AND A PROINFLAMMATORY ENVIRONMENT FAVORING UNDESIRABLE CONDITIONS, INCLUDING DISEASE ONSET. MACROPHAGES (MPHI) ARE THE MOST ABUNDANT IMMUNE CELL TYPE IN THE SKIN AND COMPRISE A GROUP OF HETEROGENEOUS AND PLASTIC CELLS THAT ARE KEY FOR SKIN HOMEOSTASIS AND HOST DEFENSE. HOWEVER, THEY HAVE ALSO BEEN IMPLICATED IN ORCHESTRATING CHRONIC INFLAMMATION DURING AGING. SINCE MPHI ARE RELATED TO INNATE AND ADAPTIVE IMMUNITY, IT IS POSSIBLE THAT AGE-MODIFIED SKIN MPHI PROMOTE ADAPTIVE IMMUNITY EXACERBATION AND EXHAUSTION, FAVORING THE EMERGENCE OF PROINFLAMMATORY PATHOLOGIES, SUCH AS SKIN CANCER. IN THIS REVIEW, WE WILL HIGHLIGHT RECENT FINDINGS PERTAINING TO THE EFFECTS OF AGING HALLMARKS OVER MPHI, SUPPORTING THE RECOGNITION OF SUCH CELL TYPES AS A DRIVING FORCE IN SKIN INFLAMMAGING AND AGE-RELATED DISEASES. WE WILL ALSO PRESENT RECENT RESEARCH TARGETING MPHI AS POTENTIAL THERAPEUTIC INTERVENTIONS IN INFLAMMATORY SKIN DISORDERS AND CANCER.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9  2734  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10  1206  35 COUNTERACTING AGED DNA METHYLATION STATES TO COMBAT AGEING AND AGE-RELATED DISEASES. DNA METHYLATION (DNAM) OVERWRITES INFORMATION ABOUT MULTIPLE EXTRINSIC FACTORS ON THE GENOME. AGE IS ONE OF THESE FACTORS. AGE CAUSES CHARACTERISTIC DNAM CHANGES THAT ARE THOUGHT TO BE NOT ONLY MAJOR DRIVERS OF NORMAL AGEING BUT ALSO PRECURSORS TO DISEASES, CANCER BEING ONE OF THESE. ALTHOUGH THERE IS STILL MUCH TO LEARN ABOUT THE RELATIONSHIP BETWEEN AGEING, AGE-RELATED DISEASES AND DNAM, WE NOW KNOW HOW TO INTERPRET SOME OF THE EFFECTS CAUSED BY AGE IN THE FORM OF CHANGES IN METHYLATION MARKS AT SPECIFIC LOCI. IN FACT, THESE CHANGES FORM THE BASIS OF THE SO CALLED "EPIGENETIC CLOCKS", WHICH TRANSLATE THE GENOMIC METHYLATION PROFILE INTO AN "EPIGENETIC AGE". EPIGENETIC AGE DOES NOT ONLY ESTIMATE CHRONOLOGICAL AGE BUT CAN ALSO PREDICT THE RISK OF CHRONIC DISEASES AND MORTALITY. EPIGENETIC AGE IS BELIEVED TO BE ONE OF THE MOST ACCURATE METRICS OF BIOLOGICAL AGE. INITIAL EVIDENCE HAS RECENTLY BEEN GATHERED POINTING TO THE POSSIBILITY THAT THE RATE OF EPIGENETIC AGEING CAN BE SLOWED DOWN OR EVEN REVERSED. IN THIS REVIEW, WE DISCUSS SOME OF THE MOST RELEVANT ADVANCES IN THIS FIELD. EXPECTED OUTCOME IS THAT THIS APPROACH CAN PROVIDE INSIGHTS INTO HOW TO PRESERVE HEALTH AND REDUCE THE IMPACT OF AGEING DISEASES IN HUMANS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  5258  29 PROGRESSION OF TUBULOINTERSTITIAL FIBROSIS AND THE CHRONIC KIDNEY DISEASE PHENOTYPE - ROLE OF RISK FACTORS AND EPIGENETICS. ALTHOUGH THE KIDNEY HAS CAPACITY TO REPAIR AFTER MILD INJURY, ONGOING OR SEVERE DAMAGE RESULTS IN SCARRING (FIBROSIS) AND AN ASSOCIATED PROGRESSIVE LOSS OF KIDNEY FUNCTION. HOWEVER, DESPITE ITS UNIVERSAL SIGNIFICANCE, EVIDENCE HIGHLIGHTS A POPULATION BASED HETEROGENEITY IN THE TRAJECTORY OF CHRONIC KIDNEY DISEASE (CKD) IN THESE PATIENTS. TO EXPLAIN THE HETEROGENEITY OF THE CKD PHENOTYPE REQUIRES AN UNDERSTANDING OF THE RELEVANT RISK FACTORS FOR FIBROSIS. THESE FACTORS INCLUDE BOTH THE EXTRINSIC NATURE OF INJURY, AND INTRINSIC FACTORS SUCH AS AGE, GENDER, GENETICS, AND PERPETUAL ACTIVATION OF FIBROBLASTS THROUGH PRIMING. IN MANY CASES AN ADDITIONAL LEVEL OF REGULATION IS PROVIDED BY EPIGENETIC MECHANISMS WHICH INTEGRATE THE VARIOUS PRO-FIBROTIC AND ANTI-FIBROTIC TRIGGERS IN FIBROGENESIS. IN THIS REVIEW WE THEREFORE EXAMINE THE VARIOUS MOLECULAR AND STRUCTURAL CHANGES OF FIBROSIS, AND HOW THEY ARE INFLUENCED BY EXTRINSIC AND INTRINSIC FACTORS. OUR AIM IS TO PROVIDE A UNIFYING HYPOTHESIS TO HELP EXPLAIN THE TRANSITION FROM ACUTE TO CKD.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12  1625  52 DNAM-BASED SIGNATURES OF ACCELERATED AGING AND MORTALITY IN BLOOD ARE ASSOCIATED WITH LOW RENAL FUNCTION. BACKGROUND: THE DIFFERENCE BETWEEN AN INDIVIDUAL'S CHRONOLOGICAL AND DNA METHYLATION PREDICTED AGE (DNAMAGE), TERMED DNAMAGE ACCELERATION (DNAMAA), CAN CAPTURE LIFE-LONG ENVIRONMENTAL EXPOSURES AND AGE-RELATED PHYSIOLOGICAL CHANGES REFLECTED IN METHYLATION STATUS. SEVERAL STUDIES HAVE LINKED DNAMAA TO MORBIDITY AND MORTALITY, YET ITS RELATIONSHIP WITH KIDNEY FUNCTION HAS NOT BEEN ASSESSED. WE EVALUATED THE ASSOCIATIONS BETWEEN SEVEN DNAM AGING AND LIFESPAN PREDICTORS (AS WELL AS GRIMAGE COMPONENTS) AND FIVE KIDNEY TRAITS (ESTIMATED GLOMERULAR FILTRATION RATE [EGFR], URINE ALBUMIN-TO-CREATININE RATIO [UACR], SERUM URATE, MICROALBUMINURIA AND CHRONIC KIDNEY DISEASE [CKD]) IN UP TO 9688 EUROPEAN, AFRICAN AMERICAN AND HISPANIC/LATINO INDIVIDUALS FROM SEVEN POPULATION-BASED STUDIES. RESULTS: WE IDENTIFIED 23 SIGNIFICANT ASSOCIATIONS IN OUR LARGE TRANS-ETHNIC META-ANALYSIS (P < 1.43E-03 AND CONSISTENT DIRECTION OF EFFECT ACROSS STUDIES). AGE ACCELERATION MEASURED BY THE EXTRINSIC AND PHENOAGE ESTIMATORS, AS WELL AS ZHANG'S 10-CPG EPIGENETIC MORTALITY RISK SCORE (MRS), WERE ASSOCIATED WITH ALL PARAMETERS OF POOR KIDNEY HEALTH (LOWER EGFR, PREVALENT CKD, HIGHER UACR, MICROALBUMINURIA AND HIGHER SERUM URATE). SIX OF THESE ASSOCIATIONS WERE INDEPENDENTLY OBSERVED IN EUROPEAN AND AFRICAN AMERICAN POPULATIONS. MRS IN PARTICULAR WAS CONSISTENTLY ASSOCIATED WITH EGFR (BETA = - 0.12, 95% CI = [- 0.16, - 0.08] CHANGE IN LOG-TRANSFORMED EGFR PER UNIT INCREASE IN MRS, P = 4.39E-08), PREVALENT CKD (ODDS RATIO (OR) = 1.78 [1.47, 2.16], P = 2.71E-09) AND HIGHER SERUM URATE LEVELS (BETA = 0.12 [0.07, 0.16], P = 2.08E-06). THE "FIRST-GENERATION" CLOCKS (HANNUM, HORVATH) AND GRIMAGE SHOWED DIFFERENT PATTERNS OF ASSOCIATION WITH THE KIDNEY TRAITS. THREE OF THE DNAM-ESTIMATED COMPONENTS OF GRIMAGE, NAMELY ADRENOMEDULLIN, PLASMINOGEN-ACTIVATION INHIBITION 1 AND PACK YEARS, WERE POSITIVELY ASSOCIATED WITH HIGHER UACR, SERUM URATE AND MICROALBUMINURIA. CONCLUSION: DNAMAGE ACCELERATION AND DNAM MORTALITY PREDICTORS ESTIMATED IN WHOLE BLOOD WERE ASSOCIATED WITH MULTIPLE KIDNEY TRAITS, INCLUDING EGFR AND CKD, IN THIS MULTI-ETHNIC STUDY. EPIGENETIC BIOMARKERS WHICH REFLECT THE SYSTEMIC EFFECTS OF AGE-RELATED MECHANISMS SUCH AS IMMUNOSENESCENCE, INFLAMMAGING AND OXIDATIVE STRESS MAY HAVE IMPORTANT MECHANISTIC OR PROGNOSTIC ROLES IN KIDNEY DISEASE. OUR STUDY HIGHLIGHTS NEW FINDINGS LINKING KIDNEY DISEASE TO BIOLOGICAL AGING, AND OPPORTUNITIES WARRANTING FUTURE INVESTIGATION INTO DNA METHYLATION BIOMARKERS FOR PROGNOSTIC OR RISK STRATIFICATION IN KIDNEY DISEASE.	2021	

13  6508  30 TRAJECTORIES OF INFLAMMATORY BIOMARKERS OVER THE EIGHTH DECADE AND THEIR ASSOCIATIONS WITH IMMUNE CELL PROFILES AND EPIGENETIC AGEING. BACKGROUND: EPIGENETIC AGE ACCELERATION (AN OLDER METHYLATION AGE COMPARED TO CHRONOLOGICAL AGE) CORRELATES STRONGLY WITH VARIOUS AGE-RELATED MORBIDITIES AND MORTALITY. CHRONIC SYSTEMIC INFLAMMATION IS THOUGHT TO BE A HALLMARK OF AGEING, BUT THE RELATIONSHIP BETWEEN AN INCREASED EPIGENETIC AGE AND THIS LIKELY KEY PHENOTYPE OF AGEING HAS NOT YET BEEN EXTENSIVELY INVESTIGATED. METHODS: WE MODELLED THE TRAJECTORIES OF THE INFLAMMATORY BIOMARKERS C-REACTIVE PROTEIN (CRP; MEASURED USING BOTH A HIGH- AND LOW-SENSITIVITY ASSAY) AND INTERLEUKIN-6 (IL-6) OVER THE EIGHTH DECADE IN THE LOTHIAN BIRTH COHORT 1936. USING LINEAR MIXED MODELS, WE INVESTIGATED THE ASSOCIATION BETWEEN CRP AND IMMUNE CELL PROFILES IMPUTED FROM THE METHYLATION DATA AND EXAMINED THE CROSS-SECTIONAL AND LONGITUDINAL ASSOCIATION BETWEEN THE INFLAMMATORY BIOMARKERS AND TWO MEASURES OF EPIGENETIC AGE ACCELERATION, DERIVED FROM THE HORVATH AND HANNUM EPIGENETIC CLOCKS. RESULTS: WE FOUND THAT LOW-SENSITIVITY CRP DECLINED, HIGH-SENSITIVITY CRP DID NOT CHANGE, AND IL-6 INCREASED OVER TIME WITHIN THE COHORT. CRP LEVELS INVERSELY ASSOCIATED WITH CD8+T CELLS AND CD4+T CELLS AND POSITIVELY ASSOCIATED WITH SENESCENT CD8+T CELLS, PLASMABLASTS AND GRANULOCYTES. CROSS-SECTIONALLY, THE HANNUM, BUT NOT THE HORVATH, MEASURE OF AGE ACCELERATION WAS POSITIVELY ASSOCIATED WITH EACH OF THE INFLAMMATORY BIOMARKERS, INCLUDING A RESTRICTED MEASURE OF CRP (</= 10 MG/L) LIKELY REFLECTING LEVELS RELEVANT TO CHRONIC INFLAMMATION. CONCLUSIONS: WE FOUND A DIVERGENT RELATIONSHIP BETWEEN INFLAMMATION AND IMMUNE SYSTEM PARAMETERS IN OLDER AGE. WE ADDITIONALLY REPORT THE HANNUM MEASURE OF EPIGENETIC AGE ACCELERATION ASSOCIATED WITH AN ELEVATED INFLAMMATORY PROFILE CROSS-SECTIONALLY, BUT NOT LONGITUDINALLY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
14   769  26 CD8 T CELL EXHAUSTION DURING CHRONIC VIRAL INFECTION AND CANCER. EXHAUSTED CD8 T (TEX) CELLS ARE A DISTINCT CELL LINEAGE THAT ARISE DURING CHRONIC INFECTIONS AND CANCERS IN ANIMAL MODELS AND HUMANS. TEX CELLS ARE CHARACTERIZED BY PROGRESSIVE LOSS OF EFFECTOR FUNCTIONS, HIGH AND SUSTAINED INHIBITORY RECEPTOR EXPRESSION, METABOLIC DYSREGULATION, POOR MEMORY RECALL AND HOMEOSTATIC SELF-RENEWAL, AND DISTINCT TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS. THE ABILITY TO REINVIGORATE TEX CELLS THROUGH INHIBITORY RECEPTOR BLOCKADE, SUCH AS ALPHAPD-1, HIGHLIGHTS THE THERAPEUTIC POTENTIAL OF TARGETING THIS POPULATION. EMERGING INSIGHTS INTO THE MECHANISMS OF EXHAUSTION ARE INFORMING IMMUNOTHERAPIES FOR CANCER AND CHRONIC INFECTIONS. HOWEVER, LIKE OTHER IMMUNE CELLS, TEX CELLS ARE HETEROGENEOUS AND INCLUDE PROGENITOR AND TERMINAL SUBSETS WITH UNIQUE CHARACTERISTICS AND RESPONSES TO CHECKPOINT BLOCKADE. HERE, WE REVIEW OUR CURRENT UNDERSTANDING OF TEX CELL BIOLOGY, INCLUDING THE DEVELOPMENTAL PATHS, TRANSCRIPTIONAL AND EPIGENETIC FEATURES, AND CELL INTRINSIC AND EXTRINSIC FACTORS CONTRIBUTING TO EXHAUSTION AND HOW THIS KNOWLEDGE MAY INFORM THERAPEUTIC TARGETING OF TEX CELLS IN CHRONIC INFECTIONS, AUTOIMMUNITY, AND CANCER.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
15  5428  24 REGULATION OF STRESS-INDUCED HEMATOPOIESIS. PURPOSE OF REVIEW: THE HEMATOPOIETIC COMPARTMENT IS TASKED WITH THE ESTABLISHMENT AND MAINTENANCE OF THE ENTIRE BLOOD PROGRAM IN STEADY-STATE AND IN RESPONSE TO STRESS. KEY TO THIS PROCESS ARE HEMATOPOIETIC STEM CELLS (HSCS), WHICH POSSESS THE UNIQUE ABILITY TO SELF-RENEW AND DIFFERENTIATE TO REPLENISH BLOOD CELLS THROUGHOUT AN ORGANISM'S LIFETIME. THOUGH TIGHTLY REGULATED, THE HEMATOPOIETIC SYSTEM IS VULNERABLE TO BOTH INTRINSIC AND EXTRINSIC FACTORS THAT INFLUENCE HEMATOPOIETIC STEM AND PROGENITOR CELL (HSPC) FATE. HERE, WE REVIEW RECENT ADVANCES IN OUR UNDERSTANDING OF HEMATOPOIETIC REGULATION UNDER STRESS CONDITIONS SUCH AS INFLAMMATION, AGING, MITOCHONDRIAL DEFECTS, AND DAMAGE TO DNA OR ENDOPLASMIC RETICULUM. RECENT FINDINGS: RECENT STUDIES HAVE ILLUSTRATED THE VAST MECHANISMS INVOLVED IN REGULATING STRESS-INDUCED HEMATOPOIESIS, INCLUDING CYTOKINE-MEDIATED LINEAGE BIAS, GENE SIGNATURE CHANGES IN AGED HSCS ASSOCIATED WITH CHRONIC INFLAMMATION, THE IMPACT OF CLONAL HEMATOPOIESIS AND STRESS TOLERANCE, CHARACTERIZATION OF THE HSPC RESPONSE TO ENDOPLASMIC RETICULUM STRESS AND OF SEVERAL EPIGENETIC REGULATORS THAT INFLUENCE HSPC RESPONSE TO CELL CYCLE STRESS. SUMMARY: SEVERAL KEY RECENT FINDINGS HAVE DEEPENED OUR UNDERSTANDING OF STRESS HEMATOPOIESIS. THESE STUDIES WILL ADVANCE OUR ABILITIES TO REDUCE THE IMPACT OF STRESS IN DISEASE AND AGING THROUGH CLINICAL INTERVENTIONS TO TREAT STRESS-RELATED OUTCOMES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16  2045  44 EPIGENETIC CLOCK ANALYSIS OF DIET, EXERCISE, EDUCATION, AND LIFESTYLE FACTORS. BEHAVIORAL AND LIFESTYLE FACTORS HAVE BEEN SHOWN TO RELATE TO A NUMBER OF HEALTH-RELATED OUTCOMES, YET THERE IS A NEED FOR STUDIES THAT EXAMINE THEIR RELATIONSHIP TO MOLECULAR AGING RATES. TOWARD THIS END, WE USE RECENT EPIGENETIC BIOMARKERS OF AGE THAT HAVE PREVIOUSLY BEEN SHOWN TO PREDICT ALL-CAUSE MORTALITY, CHRONIC CONDITIONS, AND AGE-RELATED FUNCTIONAL DECLINE. WE ANALYZE CROSS-SECTIONAL DATA FROM 4,173 POSTMENOPAUSAL FEMALE PARTICIPANTS FROM THE WOMEN'S HEALTH INITIATIVE, AS WELL AS 402 MALE AND FEMALE PARTICIPANTS FROM THE ITALIAN COHORT STUDY, INVECCHIARE NEL CHIANTI.EXTRINSIC EPIGENETIC AGE ACCELERATION (EEAA) EXHIBITS SIGNIFICANT ASSOCIATIONS WITH FISH INTAKE (P=0.02), MODERATE ALCOHOL CONSUMPTION (P=0.01), EDUCATION (P=3X10(-5)), BMI (P=0.01), AND BLOOD CAROTENOID LEVELS (P=1X10(-5))-AN INDICATOR OF FRUIT AND VEGETABLE CONSUMPTION, WHEREAS INTRINSIC EPIGENETIC AGE ACCELERATION (IEAA) IS ASSOCIATED WITH POULTRY INTAKE (P=0.03) AND BMI (P=0.05). BOTH EEAA AND IEAA WERE ALSO FOUND TO RELATE TO INDICATORS OF METABOLIC SYNDROME, WHICH APPEAR TO MEDIATE THEIR ASSOCIATIONS WITH BMI. METFORMIN-THE FIRST-LINE MEDICATION FOR THE TREATMENT OF TYPE 2 DIABETES-DOES NOT DELAY EPIGENETIC AGING IN THIS OBSERVATIONAL STUDY. FINALLY, LONGITUDINAL DATA SUGGESTS THAT AN INCREASE IN BMI IS ASSOCIATED WITH INCREASE IN BOTH EEAA AND IEAA.OVERALL, THE EPIGENETIC AGE ANALYSIS OF BLOOD CONFIRMS THE CONVENTIONAL WISDOM REGARDING THE BENEFITS OF EATING A HIGH PLANT DIET WITH LEAN MEATS, MODERATE ALCOHOL CONSUMPTION, PHYSICAL ACTIVITY, AND EDUCATION, AS WELL AS THE HEALTH RISKS OF OBESITY AND METABOLIC SYNDROME.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17  3777  20 INTERACTOME OF OBESITY: OBESIDOME : GENETIC OBESITY, STRESS INDUCED OBESITY, PATHOGENIC OBESITY INTERACTION. OBESITY IS A CHRONIC DISEASE OF INCREASING PREVALENCE REACHING EPIDEMIC PROPORTIONS. GENETIC DEFECTS AS WELL AS EPIGENETIC EFFECTS CONTRIBUTE TO THE OBESITY PHENOTYPE. INVESTIGATING GENE (E.G. MC4R DEFECTS)-ENVIRONMENT (BEHAVIOR, INFECTIOUS AGENTS, STRESS) INTERACTIONS IS A RELATIVE NEW FIELD OF GREAT RESEARCH INTEREST. IN THIS STUDY, WE HAVE MADE AN EFFORT TO CREATE AN INTERACTOME (HENCEFORTH REFERRED TO AS "OBESIDOME"), WHERE EXTRINSIC STRESSORS RESPONSE, INTRINSIC PREDISPOSITION, IMMUNITY RESPONSE TO INFLAMMATION AND AUTONOMOUS NERVOUS SYSTEM IMPLICATIONS ARE INTEGRATED. THESE PATHWAYS ARE PRESENTED IN ONE INTERACTOME NETWORK FOR THE FIRST TIME. IN OUR STUDY, OBESITY-RELATED GENES/GENE PRODUCTS WERE FOUND TO FORM A COMPLEX INTERACTIONS NETWORK.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
18  6408  27 THE SEX-DEPENDENT RESPONSE TO PSYCHOSOCIAL STRESS AND ISCHAEMIC HEART DISEASE. STRESS IS AN IMPORTANT RISK FACTOR FOR MODERN CHRONIC DISEASES, WITH DISTINCT INFLUENCES IN MALES AND FEMALES. THE SEX SPECIFICITY OF THE MAMMALIAN STRESS RESPONSE CONTRIBUTES TO THE SEX-DEPENDENT DEVELOPMENT AND IMPACTS OF CORONARY ARTERY DISEASE (CAD). COMPARED TO MEN, WOMEN APPEAR TO HAVE GREATER SUSCEPTIBILITY TO CHRONIC FORMS OF PSYCHOSOCIAL STRESS, EXTENDING BEYOND AN INCREASED INCIDENCE OF MOOD DISORDERS TO INCLUDE A 2- TO 4-FOLD HIGHER RISK OF STRESS-DEPENDENT MYOCARDIAL INFARCTION IN WOMEN, AND UP TO 10-FOLD HIGHER RISK OF TAKOTSUBO SYNDROME-A STRESS-DEPENDENT CORONARY-MYOCARDIAL DISORDER MOST PREVALENT IN POST-MENOPAUSAL WOMEN. SEX DIFFERENCES ARISE AT ALL LEVELS OF THE STRESS RESPONSE: FROM INITIAL PERCEPTION OF STRESS TO BEHAVIOURAL, COGNITIVE, AND AFFECTIVE RESPONSES AND LONGER-TERM DISEASE OUTCOMES. THESE FUNDAMENTAL DIFFERENCES INVOLVE INTERACTIONS BETWEEN CHROMOSOMAL AND GONADAL DETERMINANTS, (MAL)ADAPTIVE EPIGENETIC MODULATION ACROSS THE LIFESPAN (PARTICULARLY IN EARLY LIFE), AND THE EXTRINSIC INFLUENCES OF SOCIO-CULTURAL, ECONOMIC, AND ENVIRONMENTAL FACTORS. PRE-CLINICAL INVESTIGATIONS OF BIOLOGICAL MECHANISMS SUPPORT DISTINCT EARLY LIFE PROGRAMMING AND A HEIGHTENED CORTICOLIMBIC-NORADRENALINE-NEUROINFLAMMATORY REACTIVITY IN FEMALES VS. MALES, AMONG IMPLICATED DETERMINANTS OF THE CHRONIC STRESS RESPONSE. UNRAVELLING THE INTRINSIC MOLECULAR, CELLULAR AND SYSTEMS BIOLOGICAL BASIS OF THESE DIFFERENCES, AND THEIR INTERACTIONS WITH EXTERNAL LIFESTYLE/SOCIO-CULTURAL DETERMINANTS, CAN GUIDE PREVENTATIVE AND THERAPEUTIC STRATEGIES TO BETTER TARGET CORONARY HEART DISEASE IN A TAILORED SEX-SPECIFIC MANNER.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
19  1772  39 EARLY-LIFE SOCIOECONOMIC DISADVANTAGE, NOT CURRENT, PREDICTS ACCELERATED EPIGENETIC AGING OF MONOCYTES. LOW SOCIOECONOMIC STATUS (SES) IN EARLY-LIFE AND ADULTHOOD INDEPENDENTLY CONTRIBUTE TO INCREASED RISK FOR AGING-RELATED CHRONIC DISEASES. ONE MECHANISTIC HYPOTHESIS FOR THESE ASSOCIATIONS INVOLVES FASTER CELLULAR AGING OF IMMUNE CELLS, WHICH COULD PLAUSIBLY CONTRIBUTE TO CHRONIC DISEASE PATHOGENESIS BY COMPROMISING HOST RESISTANCE AND/OR UP-REGULATING INFLAMMATION. HOWEVER, LITTLE IS KNOWN ABOUT THE ASSOCIATION BETWEEN LIFE-COURSE SES AND CELLULAR AGING. THE PRESENT STUDY EXAMINES THE ASSOCIATION OF EARLY-LIFE AND CURRENT SES WITH A NOVEL BIOMARKER OF CELLULAR AGING TERMED THE "EPIGENETIC CLOCK," IN MONOCYTES. ADDITIONALLY, WE EXAMINE HEALTH BEHAVIORS AND DEPRESSIVE SYMPTOMS AS POTENTIAL EXPLANATORY PATHWAYS. THE STUDY INVOLVED 335 PARTICIPANTS BETWEEN THE AGES OF 15 AND 55 FROM VANCOUVER, CANADA AND SURROUNDING AREAS. ENROLLED PARTICIPANTS HAD TO FIT INTO FOUR LIFE-COURSE SES TRAJECTORIES, CORRESPONDING TO LOW-LOW, LOW-HIGH, HIGH-LOW AND HIGH-HIGH COMBINATIONS OF EARLY-LIFE (AGES 0 TO 5) AND CURRENT SES RESPECTIVELY. CELLULAR AGING OF MONOCYTES WAS MEASURED USING HORVATH'S DNA METHYLATION DERIVED MEASURE OF EPIGENETIC AGE ACCELERATION. RESULTS INDICATED THAT SOCIOECONOMIC DISADVANTAGE DURING EARLY-LIFE, BUT NOT LATER IN LIFE, WAS ASSOCIATED WITH ACCELERATED EPIGENETIC AGING OF MONOCYTES. NO EARLY-LIFE SES BY CURRENT SES INTERACTION WAS DETECTED, SUGGESTING THAT SOCIOECONOMIC MOBILITY IS UNRELATED TO EPIGENETIC AGE ACCELERATION. IN PATH ANALYSES, NEITHER CURRENT HEALTH BEHAVIORS NOR CURRENT DEPRESSIVE SYMPTOMS EMERGED AS MEDIATORS OF THE EARLY-LIFE SES EFFECT. THESE FINDINGS SUGGEST SOCIOECONOMIC DISADVANTAGE IN EARLY-LIFE IS INDEPENDENTLY PREDICTIVE OF CELLULAR AGING OF IMMUNE CELLS, WITH POTENTIAL IMPLICATIONS FOR AGING-RELATED DISEASES LATER IN LIFE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20  3914  42 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