1 5847 113 SUBCLINICAL ATHEROSCLEROSIS AND ACCELERATED EPIGENETIC AGE MEDIATED BY INFLAMMATION: A MULTI-OMICS STUDY. AIMS: EPIGENETIC AGE IS EMERGING AS A PERSONALIZED AND ACCURATE PREDICTOR OF BIOLOGICAL AGE. THE AIM OF THIS ARTICLE IS TO ASSESS THE ASSOCIATION OF SUBCLINICAL ATHEROSCLEROSIS WITH ACCELERATED EPIGENETIC AGE AND TO INVESTIGATE THE UNDERLYING MECHANISMS MEDIATING THIS ASSOCIATION. METHODS AND RESULTS: WHOLE BLOOD METHYLOMICS, TRANSCRIPTOMICS, AND PLASMA PROTEOMICS WERE OBTAINED FOR 391 PARTICIPANTS OF THE PROGRESSION OF EARLY SUBCLINICAL ATHEROSCLEROSIS STUDY. EPIGENETIC AGE WAS CALCULATED FROM METHYLOMICS DATA FOR EACH PARTICIPANT. ITS DIVERGENCE FROM CHRONOLOGICAL AGE IS TERMED EPIGENETIC AGE ACCELERATION. SUBCLINICAL ATHEROSCLEROSIS BURDEN WAS ESTIMATED BY MULTI-TERRITORY 2D/3D VASCULAR ULTRASOUND AND BY CORONARY ARTERY CALCIFICATION. IN HEALTHY INDIVIDUALS, THE PRESENCE, EXTENSION, AND PROGRESSION OF SUBCLINICAL ATHEROSCLEROSIS WERE ASSOCIATED WITH A SIGNIFICANT ACCELERATION OF THE GRIM EPIGENETIC AGE, A PREDICTOR OF HEALTH AND LIFESPAN, REGARDLESS OF TRADITIONAL CARDIOVASCULAR RISK FACTORS. INDIVIDUALS WITH AN ACCELERATED GRIM EPIGENETIC AGE WERE CHARACTERIZED BY AN INCREASED SYSTEMIC INFLAMMATION AND ASSOCIATED WITH A SCORE OF LOW-GRADE, CHRONIC INFLAMMATION. MEDIATION ANALYSIS USING TRANSCRIPTOMICS AND PROTEOMICS DATA REVEALED KEY PRO-INFLAMMATORY PATHWAYS (IL6, INFLAMMASOME, AND IL10) AND GENES (IL1B, OSM, TLR5, AND CD14) MEDIATING THE ASSOCIATION BETWEEN SUBCLINICAL ATHEROSCLEROSIS AND EPIGENETIC AGE ACCELERATION. CONCLUSION: THE PRESENCE, EXTENSION, AND PROGRESSION OF SUBCLINICAL ATHEROSCLEROSIS IN MIDDLE-AGED ASYMPTOMATIC INDIVIDUALS ARE ASSOCIATED WITH AN ACCELERATION IN THE GRIM EPIGENETIC AGE. MEDIATION ANALYSIS USING TRANSCRIPTOMICS AND PROTEOMICS DATA SUGGESTS A KEY ROLE OF SYSTEMIC INFLAMMATION IN THIS ASSOCIATION, REINFORCING THE RELEVANCE OF INTERVENTIONS ON INFLAMMATION TO PREVENT CARDIOVASCULAR DISEASE. 2023 2 3936 32 LIVING IN ENDEMIC AREA FOR INFECTIOUS DISEASES ACCELERATES EPIGENETIC AGE. INFLAMMAGING IS A LOW-GRADE INFLAMMATORY STATE GENERATED BY THE AGING PROCESS THAT CAN CONTRIBUTE TO FRAILTY AND AGE-RELATED DISEASES IN THE ELDERLY. HOWEVER, IT CAN HAVE DISTINCT EFFECTS IN THE ELDERLY LIVING IN ENDEMIC AREAS FOR INFECTIOUS DISEASES. AN INCREASED INFLAMMATORY RESPONSE MAY CONFER PROTECTION AGAINST INFECTIOUS AGENTS IN THESE AREAS, ALTHOUGH THIS ADVANTAGE CAN CAUSE ACCELERATING EPIGENETIC AGING. IN THIS STUDY, WE EVALUATED THE INFLAMMATORY PROFILE AND THE EPIGENETIC AGE OF INFECTED AND NONINFECTED INDIVIDUALS FROM AN ENDEMIC AREA IN BRAZIL. THE PROFILE OF CYTOKINES, CHEMOKINES AND GROWTH FACTORS ANALYZED IN THE SERA OF THE TWO GROUPS OF INDIVIDUALS SHOWED SIMILARITIES, ALTHOUGH INFECTED INDIVIDUALS HAD A HIGHER CONCENTRATION OF THESE MEDIATORS. A SIGNIFICANT INCREASE IN IL-1RA, CXCL8, CCL2, CCL3 AND CCL4 PRODUCTION WAS ASSOCIATED WITH LEPROSY INFECTION. NOTABLY, ELDERLY INDIVIDUALS DISPLAYED DISTINCT IMMUNE RESPONSES ASSOCIATED WITH THEIR INFECTION STATUS WHEN COMPARED TO ADULTS SUGGESTING AN ADAPTIVE REMODELLING OF THEIR IMMUNE RESPONSES. EPIGENETIC ANALYSIS ALSO SHOWED THAT THERE WAS NO DIFFERENCE IN EPIGENETIC AGE BETWEEN THE TWO GROUPS OF INDIVIDUALS. HOWEVER, INDIVIDUALS FROM THE ENDEMIC AREA HAD A SIGNIFICANT ACCELERATED AGING WHEN COMPARED TO INDIVIDUALS FROM SAO PAULO, A NON-ENDEMIC AREA IN BRAZIL. MOREOVER, THE LATTER COHORT WAS ALSO EPIGENETICALLY AGED IN RELATION TO AN ITALIAN COHORT. OUR DATA SHOWS THAT LIVING IN ENDEMIC AREAS FOR CHRONIC INFECTIOUS DISEASES RESULTS IN REMODELLING OF INFLAMMAGING AND ACCELERATION OF EPIGENETIC AGING IN INDIVIDUALS REGARDLESS OF THEIR INFECTIOUS STATUS. IT ALSO HIGHLIGHTS THAT GEOGRAPHICAL, GENETIC AND ENVIRONMENTAL FACTORS INFLUENCE AGING AND IMMUNOSENESCENCE IN THEIR PACE AND PROFILE. 2022 3 5894 32 T CELL EPIGENETIC REMODELING AND ACCELERATED EPIGENETIC AGING ARE LINKED TO LONG-TERM IMMUNE ALTERATIONS IN CHILDHOOD CANCER SURVIVORS. BACKGROUND: CANCER TREATMENTS HAVE SUBSTANTIALLY IMPROVED CHILDHOOD CANCER SURVIVAL BUT ARE ACCOMPANIED BY LONG-TERM COMPLICATIONS, NOTABLY CHRONIC INFLAMMATORY DISEASES. WE HYPOTHESIZE THAT CANCER TREATMENTS COULD LEAD TO LONG-TERM EPIGENETIC CHANGES IN IMMUNE CELLS, RESULTING IN INCREASED PREVALENCE OF INFLAMMATORY DISEASES IN CANCER SURVIVORS. RESULTS: TO TEST THIS HYPOTHESIS, WE ESTABLISHED THE EPIGENETIC AND TRANSCRIPTOMIC PROFILES OF IMMUNE CELLS FROM 44 CHILDHOOD CANCER SURVIVORS (CCS, > 16 YEARS OLD) ON FULL REMISSION (> 5 YEARS) WHO HAD RECEIVED CHEMOTHERAPY ALONE OR IN COMBINATION WITH TOTAL BODY IRRADIATION (TBI) AND HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). WE FOUND THAT MORE THAN 10 YEARS POST-TREATMENT, CCS TREATED WITH TBI/HSCT SHOWED AN ALTERED DNA METHYLATION SIGNATURE IN T CELL, PARTICULARLY AT GENES CONTROLLING IMMUNE AND INFLAMMATORY PROCESSES AND OXIDATIVE STRESS. DNA METHYLATION REMODELING IN T CELL WAS PARTIALLY ASSOCIATED WITH CHRONIC EXPRESSION CHANGES OF NEARBY GENES, INCREASED FREQUENCY OF TYPE 1 CYTOKINE-PRODUCING T CELL, ELEVATED SYSTEMIC LEVELS OF THESE CYTOKINES, AND OVER-ACTIVATION OF RELATED SIGNALING PATHWAYS. SURVIVORS EXPOSED TO TBI/HSCT WERE FURTHER CHARACTERIZED BY AN EPIGENETIC-AGING-SIGNATURE OF T CELL CONSISTENT WITH ACCELERATED EPIGENETIC AGING. TO INVESTIGATE THE POTENTIAL CONTRIBUTION OF IRRADIATION TO THESE CHANGES, WE ESTABLISHED TWO CELL CULTURE MODELS. WE IDENTIFIED THAT RADIATION PARTIALLY RECAPITULATED THE IMMUNE CHANGES OBSERVED IN SURVIVORS THROUGH A BYSTANDER EFFECT THAT COULD BE MEDIATED BY CIRCULATING FACTORS. CONCLUSION: CANCER TREATMENTS, IN PARTICULAR TBI/HSCT, ARE ASSOCIATED WITH LONG-TERM IMMUNE DISTURBANCES. WE PROPOSE THAT EPIGENETIC REMODELING OF IMMUNE CELLS FOLLOWING CANCER THERAPY AUGMENTS INFLAMMATORY- AND AGE-RELATED DISEASES, INCLUDING METABOLIC COMPLICATIONS, IN CHILDHOOD CANCER SURVIVORS. 2018 4 822 30 CHARACTERIZATION OF BLOOD SURROGATE IMMUNE-METHYLATION BIOMARKERS FOR IMMUNE CELL INFILTRATION IN CHRONIC INFLAMMAGING DISORDERS. ALZHEIMER'S DISEASE (AD) AND ATHEROSCLEROSIS ARE BOTH CHRONIC AGE- AND INFLAMMATION-DEPENDENT DISEASES. IN ADDITION, ATHEROSCLEROSIS IS FREQUENTLY OBSERVED IN AD PATIENTS INDICATING COMMON INVOLVEMENT OF VASCULAR COMPONENTS IN BOTH DISEASE ETIOLOGIES. RECENTLY, EPIGENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED EPIGENETIC ALTERATIONS, AND IN PARTICULARLY DNA METHYLATION CHANGES FOR BOTH DISORDERS. WE HYPOTHESIZED THE EXISTENCE OF A COMMON DNA METHYLATION PROFILE IN ATHEROSCLEROSIS AND AD WHICH MAY BE VALUABLE AS A BLOOD-BASED DNA METHYLATION INFLAMMAGING BIOMARKER. USING PUBLICLY AVAILABLE 450K ILLUMINA METHYLATION DATASETS, WE IDENTIFIED A CO-METHYLATION NETWORK ASSOCIATED WITH BOTH ATHEROSCLEROSIS AND AD IN WHOLE BLOOD SAMPLES. THIS METHYLATION PROFILE APPEARED TO INDICATE SHIFTS IN BLOOD IMMUNE CELL TYPE DISTRIBUTION. REMARKABLY, SIMILAR METHYLATION CHANGES WERE ALSO DETECTED IN DISEASE TISSUES, INCLUDING AD BRAIN TISSUES, ATHEROSCLEROTIC PLAQUES, AND TUMORS AND WERE FOUND TO CORRELATE WITH IMMUNE CELL INFILTRATION. IN ADDITION, THIS IMMUNE-RELATED METHYLATION PROFILE COULD ALSO BE DETECTED IN OTHER INFLAMMAGING DISEASES, INCLUDING PARKINSON'S DISEASE AND OBESITY, BUT NOT IN MULTIPLE SCLEROSIS, SCHIZOPHRENIA, AND OSTEOPOROSIS. IN CONCLUSION, WE IDENTIFIED A BLOOD-BASED IMMUNE-RELATED DNA METHYLATION SIGNATURE IN MULTIPLE INFLAMMAGING DISEASES ASSOCIATED WITH CHANGES IN BLOOD IMMUNE CELL COUNTS AND PREDICTIVE FOR IMMUNE CELL INFILTRATION IN DISEASED TISSUES. IN ADDITION TO EPIGENETIC CLOCK MEASUREMENTS, THIS IMMUNE-METHYLATION SIGNATURE MAY BECOME A VALUABLE BLOOD-BASED BIOMARKER TO PREVENT CHRONIC INFLAMMATORY DISEASE DEVELOPMENT OR MONITOR LIFESTYLE INTERVENTION STRATEGIES WHICH PROMOTE HEALTHY AGING. 2019 5 276 24 AGE-RELATED DIFFERENCES IN MONOCYTE DNA METHYLATION AND IMMUNE FUNCTION IN HEALTHY KENYAN ADULTS AND CHILDREN. BACKGROUND: AGE-RELATED CHANGES IN ADAPTIVE AND INNATE IMMUNE CELLS HAVE BEEN ASSOCIATED WITH A DECLINE IN EFFECTIVE IMMUNITY AND CHRONIC, LOW-GRADE INFLAMMATION. EPIGENETIC, TRANSCRIPTIONAL, AND FUNCTIONAL CHANGES IN MONOCYTES OCCUR WITH AGING, THOUGH MOST STUDIES TO DATE HAVE FOCUSED ON DIFFERENCES BETWEEN YOUNG ADULTS AND THE ELDERLY IN POPULATIONS WITH EUROPEAN ANCESTRY; FEW DATA EXIST REGARDING CHANGES THAT OCCUR IN CIRCULATING MONOCYTES DURING THE FIRST FEW DECADES OF LIFE OR IN AFRICAN POPULATIONS. WE ANALYZED DNA METHYLATION PROFILES, CYTOKINE PRODUCTION, AND INFLAMMATORY GENE EXPRESSION PROFILES IN MONOCYTES FROM YOUNG ADULTS AND CHILDREN FROM WESTERN KENYA. RESULTS: WE IDENTIFIED SEVERAL HYPO- AND HYPER-METHYLATED CPG SITES IN MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN THAT REPLICATED FINDINGS IN THE CURRENT LITERATURE OF DIFFERENTIAL DNA METHYLATION IN MONOCYTES FROM ELDERLY PERSONS VS. YOUNG ADULTS ACROSS DIVERSE POPULATIONS. DIFFERENTIALLY METHYLATED CPG SITES WERE ALSO NOTED IN GENE REGIONS IMPORTANT TO INFLAMMATION AND INNATE IMMUNE RESPONSES. MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN DISPLAYED INCREASED PRODUCTION OF IL-8, IL-10, AND IL-12P70 IN RESPONSE TO TLR4 AND TLR2/1 STIMULATION AS WELL AS DISTINCT INFLAMMATORY GENE EXPRESSION PROFILES. CONCLUSIONS: THESE FINDINGS COMPLEMENT PREVIOUS REPORTS OF AGE-RELATED METHYLATION CHANGES IN ISOLATED MONOCYTES AND PROVIDE NOVEL INSIGHTS INTO THE ROLE OF AGE-ASSOCIATED CHANGES IN INNATE IMMUNE FUNCTIONS. 2021 6 1516 32 DNA METHYLATION AS A BIOMARKER OF AGING IN EPIDEMIOLOGIC STUDIES. CANCER IS LARGELY AN AGING DISEASE. ACCELERATED BIOLOGICAL AGING MAY BE THE STRONGEST PREDICTOR OF CANCER AND OTHER CHRONIC DISEASE RISKS. IN THE ABSENCE OF RELIABLE AND QUANTIFIABLE BIOMARKERS OF AGING TO DATE, IT HAS LONG BEEN OBSERVED THAT TUMORIGENESIS SHARES DISTINCT EPIGENETIC ALTERATIONS WITH THE AGING PROCESS. RECENTLY, EPIGENETIC AGE ESTIMATES HAVE BEEN DEVELOPED BASED ON THE AVAILABILITY OF GENOME-WIDE DNA METHYLATION PROFILES, BY APPLYING IN THE PREDICTION FORMULA THE METHYLATION LEVEL AT A SUBSET OF HIGHLY PREDICTIVE METHYLATION SITES, CALLED EPIGENETIC CLOCK. THESE DNA METHYLATION AGE ESTIMATES HAVE PRODUCED REMARKABLY STRONG CORRELATIONS WITH CHRONOLOGICAL AGE, WITH A SMALL DEVIATION AND HIGH REPRODUCIBILITY ACROSS DIFFERENT AGE GROUPS AND STUDY POPULATIONS. MOREOVER, AN INCREASING NUMBER OF EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED AN INDEPENDENT ASSOCIATION OF DNA METHYLATION AGE OR THE EXTENT OF ACCELERATION WITH MORTALITY AND VARIOUS AGING-RELATED CONDITIONS, EVEN AFTER ACCOUNTING FOR DIFFERENCES IN CHRONOLOGICAL AGE AND OTHER RISK FACTORS. ALTHOUGH EPIGENETIC PROFILES ARE KNOWN TO BE TISSUE-SPECIFIC, BOTH TARGET TISSUE- AND MULTIPLE TISSUE-DERIVED ESTIMATES APPEAR TO PERFORM WELL TO CAPTURE WHAT IS THOUGHT TO BE THE CUMULATIVE EPIGENETIC DRIFT THAT REPRESENTS A MULTIFACTORIAL DEGENERATIVE PROCESS ACROSS TISSUES AND ORGANISMS. FURTHER REFINEMENT OF THE EPIGENETIC AGE ESTIMATES IS ANTICIPATED OVER TIME TO ACCOMMODATE A BETTER TECHNOLOGICAL COVERAGE OF THE METHYLOME AND A BETTER UNDERSTANDING OF THE BIOLOGY UNDERLYING PREDICTIVE REGIONS. EPIDEMIOLOGIC PRINCIPLES WILL REMAIN CRITICAL FOR THE EVALUATION OF RESEARCH FINDINGS INVOLVING, FOR EXAMPLE, DIFFERENT STUDY POPULATIONS, DESIGN, FOLLOW-UP TIME, AND QUALITY OF COVARIATE DATA. OVERALL, THE EPIGENETIC AGE ESTIMATES ARE AN EXCITING DEVELOPMENT WITH USEFUL IMPLICATIONS FOR BIOMEDICAL RESEARCH OF HEALTHY AGING AND DISEASE PREVENTION AND CONTROL. 2018 7 6013 35 THE APPLICATIONS OF DNA METHYLATION AS A BIOMARKER IN KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW. BACKGROUND: ALTHOUGH KIDNEY TRANSPLANTATION IMPROVES PATIENT SURVIVAL AND QUALITY OF LIFE, LONG-TERM RESULTS ARE HAMPERED BY BOTH IMMUNE- AND NON-IMMUNE-MEDIATED COMPLICATIONS. CURRENT BIOMARKERS OF POST-TRANSPLANT COMPLICATIONS, SUCH AS ALLOGRAFT REJECTION, CHRONIC RENAL ALLOGRAFT DYSFUNCTION, AND CUTANEOUS SQUAMOUS CELL CARCINOMA, HAVE A SUBOPTIMAL PREDICTIVE VALUE. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT DIRECTLY AFFECTS GENE EXPRESSION AND PLAYS AN IMPORTANT ROLE IN PROCESSES SUCH AS ISCHEMIA/REPERFUSION INJURY, FIBROSIS, AND ALLOREACTIVE IMMUNE RESPONSE. NOVEL TECHNIQUES CAN QUICKLY ASSESS THE DNA METHYLATION STATUS OF MULTIPLE LOCI IN DIFFERENT CELL TYPES, ALLOWING A DEEP AND INTERESTING STUDY OF CELLS' ACTIVITY AND FUNCTION. THEREFORE, DNA METHYLATION HAS THE POTENTIAL TO BECOME AN IMPORTANT BIOMARKER FOR PREDICTION AND MONITORING IN KIDNEY TRANSPLANTATION. PURPOSE OF THE STUDY: THE AIM OF THIS STUDY WAS TO EVALUATE THE ROLE OF DNA METHYLATION AS A POTENTIAL BIOMARKER OF GRAFT SURVIVAL AND COMPLICATIONS DEVELOPMENT IN KIDNEY TRANSPLANTATION. MATERIAL AND METHODS: A SYSTEMATIC REVIEW OF SEVERAL DATABASES HAS BEEN CONDUCTED. THE NEWCASTLE-OTTAWA SCALE AND THE JADAD SCALE HAVE BEEN USED TO ASSESS THE RISK OF BIAS FOR OBSERVATIONAL AND RANDOMIZED STUDIES, RESPECTIVELY. RESULTS: TWENTY ARTICLES REPORTING ON DNA METHYLATION AS A BIOMARKER FOR KIDNEY TRANSPLANTATION WERE INCLUDED, ALL USING DNA METHYLATION FOR PREDICTION AND MONITORING. DNA METHYLATION PATTERN ALTERATIONS IN CELLS ISOLATED FROM DIFFERENT TISSUES, SUCH AS KIDNEY BIOPSIES, URINE, AND BLOOD, HAVE BEEN ASSOCIATED WITH ISCHEMIA-REPERFUSION INJURY AND CHRONIC RENAL ALLOGRAFT DYSFUNCTION. THESE ALTERATIONS OCCURRED IN DIFFERENT AND SPECIFIC LOCI. DNA METHYLATION STATUS HAS ALSO PROVED TO BE IMPORTANT FOR IMMUNE RESPONSE MODULATION, HAVING A CRUCIAL ROLE IN REGULATORY T CELL DEFINITION AND ACTIVITY. RESEARCH ALSO FOCUSED ON A BETTER UNDERSTANDING OF THE ROLE OF THIS EPIGENETIC MODIFICATION ASSESSMENT FOR REGULATORY T CELLS ISOLATION AND EXPANSION FOR FUTURE TOLERANCE INDUCTION-ORIENTED THERAPIES. CONCLUSIONS: STUDIES INCLUDED IN THIS REVIEW ARE HETEROGENEOUS IN STUDY DESIGN, BIOLOGICAL SAMPLES, AND OUTCOME. MORE COORDINATED INVESTIGATIONS ARE NEEDED TO AFFIRM DNA METHYLATION AS A CLINICALLY RELEVANT BIOMARKER IMPORTANT FOR PREVENTION, MONITORING, AND INTERVENTION. 2022 8 4787 34 NUTRITION, AGING AND CANCER: LESSONS FROM DIETARY INTERVENTION STUDIES. THERE IS CONVINCING EPIDEMIOLOGICAL AND CLINICAL EVIDENCE THAT, INDEPENDENT OF AGING, LIFESTYLE AND, NOTABLY, NUTRITION ARE ASSOCIATED WITH DEVELOPMENT OR PROGRESSION OF MAJOR HUMAN CANCERS, INCLUDING BREAST, PROSTATE, COLORECTAL TUMORS, AND AN INCREASINGLY LARGE COLLECTION OF DIET-RELATED CANCERS. MECHANISMS UNDERLYING THIS ASSOCIATION ARE MOSTLY RELATED TO THE DISTINCT EPIGENETIC EFFECTS OF DIFFERENT DIETARY PATTERNS. IN THIS CONTEXT, MEDITERRANEAN DIET HAS BEEN REPORTED TO SIGNIFICANTLY REDUCE MORTALITY RATES FOR VARIOUS CHRONIC ILLNESSES, INCLUDING CARDIOVASCULAR DISEASES, NEURODEGENERATIVE DISEASES AND CANCER. ALTHOUGH MANY OBSERVATIONAL STUDIES HAVE SUPPORTED THIS EVIDENCE, DIETARY INTERVENTION STUDIES USING A MEDITERRANEAN DIETARY PATTERN OR ITS SELECTED FOOD COMPONENTS ARE STILL LIMITED AND AFFECTED BY A RATHER LARGE VARIABILITY IN CHARACTERISTICS OF STUDY SUBJECTS, TYPE AND LENGTH OF INTERVENTION, SELECTED END-POINTS AND STATISTICAL ANALYSIS. HERE WE REVIEW DATA OF TWO OF OUR INTERVENTION STUDIES, THE MEDIET STUDY AND THE DIMESA PROJECT, AIMED AT ASSESSING THE EFFECTS OF TRADITIONAL MEDITERRANEAN DIET AND/OR ITS COMPONENT(S) ON A LARGE PANEL OF BOTH PLASMA AND URINE BIOMARKERS. BOTH PUBLISHED AND UNPUBLISHED RESULTS ARE PRESENTED AND DISCUSSED. 2016 9 2483 27 EPIGENETIC VARIATION AND HUMAN DISEASE. CYTOSINE GUANINE DINUCLEOTIDE (CPG) ISLAND METHYLATION IS A KNOWN MECHANISM OF EPIGENETIC INHERITANCE IN POSTMEIOTIC CELLS. THROUGH ASSOCIATED CHROMATIN CHANGES AND SILENCING, SUCH EPIGENETIC STATES CAN INFLUENCE CELLULAR PHYSIOLOGY AND AFFECT DISEASE RISK AND SEVERITY. OUR STUDIES OF CPG ISLAND METHYLATION IN NORMAL COLORECTAL MUCOSA REVEALED PROGRESSIVE AGE-RELATED INCREASES AT MULTIPLE GENE LOCI, SUGGESTING GENOME-WIDE MOLECULAR ALTERATIONS WITH POTENTIAL TO SILENCE GENE EXPRESSION. HOWEVER, THERE WAS CONSIDERABLE VARIATION IN THE DEGREE OF METHYLATION AMONG INDIVIDUALS OF COMPARABLE AGES. SUCH VARIATION COULD BE RELATED TO GENETIC FACTORS, LIFESTYLE, OR ENVIRONMENTAL EXPOSURES. STUDIES IN ULCERATIVE COLITIS AND HEPATOCELLULAR CIRRHOSIS AND NEOPLASIA REVEALED THAT CHRONIC INFLAMMATORY STATES ARE ACCOMPANIED BY MARKED INCREASES IN CPG ISLAND METHYLATION IN NORMAL-APPEARING TISSUES, CONFIRMING THE HYPOTHESIS THAT PROINFLAMMATORY EXPOSURES COULD ACCOUNT FOR PART OF THE EPIGENETIC VARIATION IN HUMAN POPULATIONS. PRELIMINARY DATA ALSO SUGGEST POTENTIAL INFLUENCES OF LIFESTYLE AND EXPOSURE FACTORS ON CPG ISLAND METHYLATION. IT IS SUGGESTED THAT EPIGENETIC VARIATION RELATED TO AGING, LIFESTYLE, EXPOSURES AND POSSIBLY GENETIC FACTORS, IS ONE OF THE MODULATORS OF ACQUIRED, AGE-RELATED HUMAN DISEASES, INCLUDING NEOPLASIA. 2002 10 5737 34 SMOKING AND HEALTH: ASSOCIATION BETWEEN TELOMERE LENGTH AND FACTORS IMPACTING ON HUMAN DISEASE, QUALITY OF LIFE AND LIFE SPAN IN A LARGE POPULATION-BASED COHORT UNDER THE EFFECT OF SMOKING DURATION. REACTIVE OXYGEN SPECIES (ROS) ARE OF PRIMARY IMPORTANCE AS THEY CAUSE DAMAGE TO LIPIDS, PROTEINS, AND DNA EITHER ENDOGENOUSLY BY CELLULAR MECHANISM, OR THROUGH EXOGENOUS EXPOSURE TO ENVIRONMENTAL INJURY FACTORS, INCLUDING OXIDATION INSULT FACTORS, SUCH AS TOBACCO SMOKE. CURRENTLY 46.3 MILLION ADULTS (25.7 PERCENT OF THE POPULATION) ARE SMOKERS. THIS INCLUDES 24 MILLION MEN (28.1 PERCENT OF THE TOTAL) AND MORE THAN 22 MILLION WOMEN (23.5 PERCENT). THE PREVALENCE IS HIGHEST AMONG PERSONS 25-44 YEARS OF AGE. CIGARETTE SMOKERS HAVE A HIGHER RISK OF DEVELOPING SEVERAL CHRONIC DISORDERS. THESE INCLUDE FATTY BUILDUPS IN ARTERIES, SEVERAL TYPES OF CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (LUNG PROBLEMS). AS PERIPHERAL LEUKOCYTES HAVE BEEN THE MAIN TARGET OF HUMAN TELOMERE RESEARCH, MOST OF WHAT IS KNOWN ABOUT HUMAN TELOMERE DYNAMICS IN VIVO IS BASED ON THESE CELLS. LEUKOCYTE TELOMERE LENGTH (TL) IS A COMPLEX TRAIT THAT IS SHAPED BY GENETIC, EPIGENETIC, AND ENVIRONMENTAL DETERMINANTS. IN THIS ARTICLE, WE CONSIDER THAT SMOKING MODIFIES LEUKOCYTE TL IN HUMANS AND CONTRIBUTES TO ITS VARIABILITY AMONG INDIVIDUALS, ALTHOUGH THE SMOKING EFFECT ON TL AND ITS RELATION WITH OTHER METABOLIC INDICES MAY ACCELERATE BIOLOGICAL AGING AND DEVELOPMENT OF SMOKING-INDUCED CHRONIC DISEASES IN A LARGE HUMAN POPULATION-BASED COHORTS WITH SMOKING BEHAVIOR. RECENT STUDIES CONFIRMED THAT INDIVIDUALS WITH SHORTER TELOMERES PRESENT A HIGHER PREVALENCE OF ARTERIAL LESIONS AND HIGHER RISK OF CARDIOVASCULAR DISEASE MORTALITY. THIS STUDY ORIGINALLY SUGGESTS THAT EFFICIENT THERAPEUTIC PROTECTION OF TL AND STRUCTURE IN RESPONSE TO STRESSES THAT ARE KNOWN TO REDUCE TL, SUCH AS OXIDATIVE DAMAGE OR INFLAMMATION ASSOCIATED WITH TOBACCO SMOKING, WOULD LEAD TO BETTER TELOMERE MAINTENANCE. RECENTLY, WE HAVE DISCOVERED THE POTENTIAL USE OF TELOMERE-RESTORATIVE IMIDAZOLE-CONTAINING DIPEPTIDE (NON-HYDROLIZED CARNOSINE, CARCININE) BASED THERAPY FOR BETTER SURVIVAL OF SMOKERS. WE CONCLUDE THAT A BETTER THERAPEUTIC OR NUTRITIONAL MAINTENANCE OF TL MAY CONFER HEALTHY AGING IN SMOKERS AND EXCEPTIONAL LONGEVITY IN REGULARLY ROS-EXPOSED HUMAN SURVIVORS. 2011 11 177 27 ACCELERATED EPIGENETIC AGING AND INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) IN PATIENTS WITH CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY A REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). THIS FAILURE CAN BE RELATED TO A PHENOTYPE OF ACCELERATED AGING. IN THIS WORK, WE CONSIDERED 76 PATIENTS WITH END-STAGE RENAL DISEASE (ESRD) AND 83 HEALTHY CONTROLS. WE CONCOMITANTLY EVALUATED FOR THE FIRST TIME TWO MEASURES THAT CAN BE INFORMATIVE OF THE RATE OF AGING, I.E., WHOLE BLOOD DNA METHYLATION USING THE ILLUMINA INFINIUM EPIC ARRAY AND PLASMA LEVELS OF A SELECTION OF INFLAMMATORY/IMMUNOLOGICAL PROTEINS USING MULTIPLEX IMMUNOASSAYS. FIRST OF ALL, WE DEMONSTRATED ACCELERATED AGING IN TERMS OF THE MOST COMMON EPIGENETIC AGE ESTIMATORS IN CKD PATIENTS. MOREOVER, WE DEVELOPED A NEW CLOCK/PREDICTOR OF AGE BASED ON THE INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) AND IDENTIFIED THE INFLAMMATORY/IMMUNOLOGICAL BIOMARKERS DIFFERENTIALLY EXPRESSED BETWEEN CASES AND CONTROLS. IPAGE APPEARED TO BE MORE SENSITIVE THAN EPIGENETIC CLOCKS IN QUANTIFYING THE ACCELERATED AGING PHENOTYPE OF ESRD PATIENTS. INTERESTINGLY, WE DID NOT FIND ANY CORRELATION BETWEEN THE AGE ACCELERATION EVALUATED ACCORDING TO THE EPIGENETIC CLOCKS AND IPAGE IN EITHER THE ESRD GROUP OR THE CONTROL GROUP. ON THE WHOLE, OUR DATA SHOW A CONSISTENT ACCELERATED AGING PHENOTYPE IN ESRD PATIENTS, WHICH IS BETTER APPRECIATED BY QUANTIFYING THE UNDERLYING INFLAMMATORY PROCESSES (INFLAMMAGING) BY IPAGE THAN BY USING EPIGENETIC CLOCKS. 2022 12 2507 30 EPIGENETICS AND OBESITY: THE DEVIL IS IN THE DETAILS. OBESITY IS A COMPLEX DISEASE WITH MULTIPLE WELL-DEFINED RISK FACTORS. NEVERTHELESS, SUSCEPTIBILITY TO OBESITY AND ITS SEQUELAE WITHIN OBESOGENIC ENVIRONMENTS VARIES GREATLY FROM ONE PERSON TO THE NEXT, SUGGESTING A ROLE FOR GENE X ENVIRONMENT INTERACTIONS IN THE ETIOLOGY OF THE DISORDER. EPIGENETIC REGULATION OF THE HUMAN GENOME PROVIDES A PUTATIVE MECHANISM BY WHICH SPECIFIC ENVIRONMENTAL EXPOSURES CONVEY RISK FOR OBESITY AND OTHER HUMAN DISEASES AND IS ONE POSSIBLE MECHANISM THAT UNDERLIES THE GENE X ENVIRONMENT/TREATMENT INTERACTIONS OBSERVED IN EPIDEMIOLOGICAL STUDIES AND CLINICAL TRIALS. A STUDY PUBLISHED IN BMC MEDICINE THIS MONTH BY WANG ET AL. REPORTS ON AN EXAMINATION OF DNA METHYLATION IN PERIPHERAL BLOOD LEUKOCYTES OF LEAN AND OBESE ADOLESCENTS, COMPARING METHYLATION PATTERNS BETWEEN THE TWO GROUPS. THE AUTHORS IDENTIFIED TWO GENES THAT WERE DIFFERENTIALLY METHYLATED, BOTH OF WHICH HAVE ROLES IN IMMUNE FUNCTION. HERE WE OVERVIEW THE FINDINGS FROM THIS STUDY IN THE CONTEXT OF THOSE EMERGING FROM OTHER RECENT GENETIC AND EPIGENETIC STUDIES, DISCUSS THE STRENGTHS AND WEAKNESSES OF THE STUDY AND SPECULATE ON THE FUTURE OF EPIGENETICS IN CHRONIC DISEASE RESEARCH. 2010 13 1567 29 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D. 2018 14 6720 33 VITAMIN D METABOLISM GENES ARE DIFFERENTIALLY METHYLATED IN INDIVIDUALS WITH CHRONIC KNEE PAIN. CONTEXT: RECENT EVIDENCE SUGGESTS THAT VITAMIN D MAY INTERACT WITH THE EPIGENOME AND PLAY A ROLE IN THE PAIN EXPERIENCE. IN ORDER FOR PROPER FUNCTIONING TO OCCUR, THERE MUST BE AN ADEQUATE LEVEL OF VITAMIN D PRESENT, MADE POSSIBLE BY ENZYMATIC REACTIONS THAT ALLOW VITAMIN D TO BE BIOLOGICALLY ACTIVE. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE EPIGENETIC LANDSCAPE OF GENES INVOLVED IN VITAMIN D METABOLISM IN INDIVIDUALS WITH AND WITHOUT CHRONIC KNEE PAIN. PROCEDURES: COMMUNITY-DWELLING INDIVIDUALS RECRUITED AS PART OF A LARGER STUDY FOCUSED ON KNEE PAIN PROVIDED DEMOGRAPHIC, CLINICAL AND PAIN-RELATED INFORMATION, AS WELL AS AN INTRAVENOUS BLOOD SAMPLE TO DETERMINE DNA METHYLATION LEVELS AT CPG SITES. MAIN FINDINGS: THERE WERE DIFFERENCES IN DNA METHYLATION BETWEEN THOSE WITH AND WITHOUT PAIN IN GENES THAT CODE FOR ENZYMES RELATED TO VITAMIN D METABOLISM: CYP24A1 (24-HYDROXYLASE) AND CYP27B1 (1-?-HYDROXYLASE). THERE WAS ALSO HYPERMETHYLATION ON THE GENE THAT CODES FOR THE VITAMIN D RECEPTOR (VDR). PRINCIPAL CONCLUSIONS: THE PRESENCE OF CHRONIC PAIN IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS IN GENES RESPONSIBLE FOR THE EXPRESSION OF ENZYMES INVOLVED IN VITAMIN D METABOLISM AND CELLULAR FUNCTION. THESE RESULTS LAY GROUNDWORK IN UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION BETWEEN VITAMIN D AND CHRONIC PAIN. 2023 15 5638 39 SERUM METABOLOMICS REVEALS PATHWAYS AND BIOMARKERS ASSOCIATED WITH ASTHMA PATHOGENESIS. BACKGROUND: ASTHMA IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY COMPLEX INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. FOR THIS REASON, NEW APPROACHES ARE REQUIRED TO CLARIFY THE PATHOGENESIS OF ASTHMA BY SYSTEMIC REVIEW. OBJECTIVE: WE APPLIED A (1)H-NMR METABOLOMICS APPROACH TO INVESTIGATE THE ALTERED METABOLIC PATTERN IN SERA FROM PATIENTS WITH ASTHMA AND SOUGHT TO IDENTIFY THE MECHANISM UNDERLYING ASTHMA AND POTENTIAL BIOMARKERS. METHOD: A GLOBAL PROFILE OF SERA FROM PATIENTS WITH ASTHMA (N = 39) AND CONTROLS (N = 26) WAS GENERATED USING (1)H-NMR SPECTROSCOPY COUPLED WITH MULTIVARIATE STATISTICAL ANALYSIS. ENDOGENOUS METABOLITES IN SERUM WERE RAPIDLY MEASURED USING THE TARGET-PROFILING PROCEDURE. RESULTS: MULTIVARIATE STATISTICAL ANALYSIS SHOWED A CLEAR DISTINCTION BETWEEN PATIENTS WITH ASTHMA AND HEALTHY SUBJECTS. SERA OF ASTHMA PATIENTS WERE CHARACTERIZED BY INCREASED LEVELS OF METHIONINE, GLUTAMINE, AND HISTIDINE AND BY DECREASED LEVELS OF FORMATE, METHANOL, ACETATE, CHOLINE, O-PHOSPHOCHOLINE, ARGININE, AND GLUCOSE. THE METABOLITES DETECTED IN THE SERA OF PATIENTS WITH ASTHMA ARE INVOLVED IN HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTION. FURTHERMORE, THE LEVELS OF SERUM METABOLITES FROM PATIENTS WITH ASTHMA CORRELATED WITH ASTHMA SEVERITY; IN PARTICULAR, LIPID METABOLISM WAS ALTERED IN PATIENTS WITH LOWER FORCED EXPIRATORY VOLUME IN 1 S PERCENTAGE (FEV(1)%) PREDICTED VALUES. IN ADDITION, POTENTIAL BIOMARKERS SHOWED STRONG PREDICTIVE POWER IN ROC ANALYSIS, AND THE PRESENCE OF ASTHMA IN EXTERNAL VALIDATION MODELS WAS PREDICTED WITH HIGH ACCURACY (90.9% FOR ASTHMA AND 100% FOR CONTROL SUBJECTS). CONCLUSION & CLINICAL RELEVANCE: THESE DATA SHOWED THAT (1)H-NMR-BASED METABOLITE PROFILING OF SERUM MAY BE USEFUL FOR THE EFFECTIVE DIAGNOSIS OF ASTHMA AND A FURTHER UNDERSTANDING OF ITS PATHOGENESIS. 2013 16 1519 21 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS. 2021 17 4255 27 METHYLOME-WIDE ANALYSIS OF CHRONIC HIV INFECTION REVEALS FIVE-YEAR INCREASE IN BIOLOGICAL AGE AND EPIGENETIC TARGETING OF HLA. HIV-INFECTED INDIVIDUALS ARE LIVING LONGER ON ANTIRETROVIRAL THERAPY, BUT MANY PATIENTS DISPLAY SIGNS THAT IN SOME WAYS RESEMBLE PREMATURE AGING. TO INVESTIGATE AND QUANTIFY THE IMPACT OF CHRONIC HIV INFECTION ON AGING, WE REPORT A GLOBAL ANALYSIS OF THE WHOLE-BLOOD DNA METHYLOMES OF 137 HIV+ INDIVIDUALS UNDER SUSTAINED THERAPY ALONG WITH 44 MATCHED HIV- INDIVIDUALS. FIRST, WE DEVELOP AND VALIDATE EPIGENETIC MODELS OF AGING THAT ARE INDEPENDENT OF BLOOD CELL COMPOSITION. USING THESE MODELS, WE FIND THAT BOTH CHRONIC AND RECENT HIV INFECTION LEAD TO AN AVERAGE AGING ADVANCEMENT OF 4.9 YEARS, INCREASING EXPECTED MORTALITY RISK BY 19%. IN ADDITION, SUSTAINED INFECTION RESULTS IN GLOBAL DEREGULATION OF THE METHYLOME ACROSS >80,000 CPGS AND SPECIFIC HYPOMETHYLATION OF THE REGION ENCODING THE HUMAN LEUKOCYTE ANTIGEN LOCUS (HLA). WE FIND THAT DECREASED HLA METHYLATION IS PREDICTIVE OF LOWER CD4 / CD8 T CELL RATIO, LINKING MOLECULAR AGING, EPIGENETIC REGULATION, AND DISEASE PROGRESSION. 2016 18 287 26 AGING AND CHRONIC SUN EXPOSURE CAUSE DISTINCT EPIGENETIC CHANGES IN HUMAN SKIN. EPIGENETIC CHANGES ARE WIDELY CONSIDERED TO PLAY AN IMPORTANT ROLE IN AGING, BUT EXPERIMENTAL EVIDENCE TO SUPPORT THIS HYPOTHESIS HAS BEEN SCARCE. WE HAVE USED ARRAY-BASED ANALYSIS TO DETERMINE GENOME-SCALE DNA METHYLATION PATTERNS FROM HUMAN SKIN SAMPLES AND TO INVESTIGATE THE EFFECTS OF AGING, CHRONIC SUN EXPOSURE, AND TISSUE VARIATION. OUR RESULTS REVEAL A HIGH DEGREE OF TISSUE SPECIFICITY IN THE METHYLATION PATTERNS AND ALSO SHOWED VERY LITTLE INTERINDIVIDUAL VARIATION WITHIN TISSUES. DATA STRATIFICATION BY AGE REVEALED THAT DNA FROM OLDER INDIVIDUALS WAS CHARACTERIZED BY A SPECIFIC HYPERMETHYLATION PATTERN AFFECTING LESS THAN 1% OF THE MARKERS ANALYZED. INTERESTINGLY, STRATIFICATION BY SUN EXPOSURE PRODUCED A FUNDAMENTALLY DIFFERENT PATTERN WITH A SIGNIFICANT TREND TOWARDS HYPOMETHYLATION. OUR RESULTS THUS IDENTIFY DEFINED AGE-RELATED DNA METHYLATION CHANGES AND SUGGEST THAT THESE ALTERATIONS MIGHT CONTRIBUTE TO THE PHENOTYPIC CHANGES ASSOCIATED WITH SKIN AGING. 2010 19 3555 32 IMPACT OF AGE, ANTIRETROVIRAL THERAPY, AND CANCER ON EPIGENETIC AGING IN PEOPLE LIVING WITH HIV. BACKGROUND: PREMATURE AGING HAS BEEN IDENTIFIED AS A GLOBAL RISK FACTOR FOR CANCER. CAUSES OF PREMATURE AGING ARE MULTIFACTORIAL, INCLUDING INFLAMMATION, INFECTION, CHRONIC STRESS, AND LIFESTYLE FACTORS. METHOD: WE EVALUATED WHETHER PREMATURE AGING IN PEOPLE LIVING WITH HIV (PLWH) WAS ASSOCIATED WITH ANTIRETROVIRAL THERAPY (ART) OR THE DIAGNOSIS OF CANCER. WE USED WELL-ESTABLISHED DNA METHYLATION PATTERNS TO ASSESS PREMATURE AGING, USING HORVATH ET AL., IN INDIVIDUALS WITH HIV LOCATED IN CLEVELAND, OHIO AND COMPARED THESE TO STANDARDIZED DATASETS OF US HISTORICAL BLOOD SAMPLES. SOME OF THE PLWH DEVELOPED CANCER OVER TIME. RESULTS: WE FOUND THAT DNA METHYLATION ANALYSIS IDENTIFIED ACCELERATED AGING IN PLWH WHEREAS ART THERAPY MITIGATED THE ADVANCEMENT OF DNA METHYLATION AGE. A VARIETY OF CANCERS WERE OBSERVED IN THIS POPULATION, BUT A CANCER DIAGNOSIS WAS NOT SIGNIFICANTLY ASSOCIATED WITH MORE ADVANCED DNA METHYLATION AGE. CONCLUSION: WE FIND THAT THE AGE ACCELERATION DETECTED IN PLWH IS MITIGATED BY ART THERAPY AND IS NOT FURTHER ACCELERATED BY A DIAGNOSIS OF CANCER. 2023 20 1025 31 CIRCULATING MIRNAS ARE ASSOCIATED WITH INFLAMMATION BIOMARKERS IN CHILDREN WITH OVERWEIGHT AND OBESITY: RESULTS OF THE I.FAMILY STUDY. INCREASING DATA SUGGEST THAT OVERNUTRITION-INDUCED OBESITY MAY TRIGGER AN INFLAMMATORY PROCESS IN ADIPOSE TISSUE AND UPTURN IN THE INNATE IMMUNE SYSTEM. NUMEROUS PLAYERS HAVE BEEN INVOLVED IN GOVERNING THE INFLAMMATORY RESPONSE, INCLUDING EPIGENETICS. AMONG EPIGENETIC PLAYERS, MIRNAS ARE EMERGING AS CRUCIAL REGULATORS OF IMMUNE CELL DEVELOPMENT, IMMUNE RESPONSES, AUTOIMMUNITY, AND INFLAMMATION. IN THIS STUDY, WE AIMED AT IDENTIFYING THE INVOLVEMENT OF CANDIDATE MIRNAS IN RELATION TO INFLAMMATION-ASSOCIATED BIOMARKERS IN A SUBSAMPLE OF EUROPEAN CHILDREN WITH OVERWEIGHT AND OBESITY PARTICIPATING IN THE I.FAMILY STUDY. THE STUDY SAMPLE INCLUDED INDIVIDUALS WITH INCREASED ADIPOSITY SINCE THIS CONDITION CONTRIBUTES TO THE EARLY OCCURRENCE OF CHRONIC LOW-GRADE INFLAMMATION. WE FOCUSED ON THE ACUTE-PHASE REAGENT C-REACTIVE PROTEIN (CRP) AS THE PRIMARY OUTCOME AND SELECTED CYTOKINES AS PLAUSIBLE BIOMARKERS OF INFLAMMATION. WE FOUND THAT CHRONIC LOW-GRADE CRP ELEVATION SHOWS A HIGHLY SIGNIFICANT ASSOCIATION WITH MIR-26B-3P AND HSA-MIR-576-5P IN BOYS. FURTHERMORE, THE ASSOCIATION OF CRP WITH HSA-MIR-10B-5P AND HSA-MIR-31-5P IS HIGHLY SIGNIFICANT IN GIRLS. WE ALSO OBSERVED MAJOR SEX-RELATED ASSOCIATIONS OF CANDIDATE MIRNAS WITH SELECTED CYTOKINES. EXCEPT FOR IL-6, A SIGNIFICANT ASSOCIATION OF HSA-MIR-26B-3P AND HSA-MIR-576-5P WITH TNF-ALPHA, IL1-RA, IL-8, AND IL-15 LEVELS WAS FOUND EXCLUSIVELY IN BOYS. THE FINDINGS OF THIS EXPLORATORY STUDY SUGGEST SEX DIFFERENCES IN THE ASSOCIATION OF CIRCULATING MIRNAS WITH INFLAMMATORY RESPONSE BIOMARKERS, AND INDICATE A POSSIBLE ROLE OF MIRNAS AMONG THE CANDIDATE EPIGENETIC MECHANISMS RELATED TO THE PROCESS OF LOW-GRADE INFLAMMATION IN CHILDHOOD OBESITY. 2022