1 1516 156 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 2 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 3 560 41 BACK TO THE FUTURE: EPIGENETIC CLOCK PLASTICITY TOWARDS HEALTHY AGING. AGING IS THE MOST IMPORTANT RISK FACTOR FOR MAJOR HUMAN LIFESTYLE DISEASES, INCLUDING CANCER, NEUROLOGICAL AND CARDIOMETABOLIC DISORDERS. DUE TO THE COMPLEX INTERPLAY BETWEEN GENETICS, LIFESTYLE AND ENVIRONMENTAL FACTORS, SOME INDIVIDUALS SEEM TO AGE FASTER THAN OTHERS, WHEREAS CENTENARIANS SEEM TO HAVE A SLOWER AGING PROCESS. THEREFORE, A BIOCHEMICAL BIOMARKER REFLECTING THE RELATIVE BIOLOGICAL AGE WOULD BE HELPFUL TO PREDICT AN INDIVIDUAL'S HEALTH STATUS AND AGING DISEASE RISK. ALTHOUGH IT IS ALREADY KNOWN FOR YEARS THAT CUMULATIVE EPIGENETIC CHANGES OCCUR UPON AGING, DNA METHYLATION PATTERNS WERE ONLY RECENTLY USED TO CONSTRUCT AN EPIGENETIC CLOCK PREDICTOR FOR BIOLOGICAL AGE, WHICH IS A MEASURE OF HOW WELL YOUR BODY FUNCTIONS COMPARED TO YOUR CHRONOLOGICAL AGE. MOREOVER, THE EPIGENETIC DNA METHYLATION CLOCK SIGNATURE IS INCREASINGLY APPLIED AS A BIOMARKER TO ESTIMATE AGING DISEASE SUSCEPTIBILITY AND MORTALITY RISK. FINALLY, THE EPIGENETIC CLOCK SIGNATURE COULD BE USED AS A LIFESTYLE MANAGEMENT TOOL TO MONITOR HEALTHY AGING, TO EVALUATE PREVENTIVE INTERVENTIONS AGAINST CHRONIC AGING DISORDERS AND TO EXTEND HEALTHY LIFESPAN. DISSECTING THE MECHANISM OF THE EPIGENETIC AGING CLOCK WILL YIELD VALUABLE INSIGHTS INTO THE AGING PROCESS AND HOW IT CAN BE MANIPULATED TO IMPROVE HEALTH SPAN. 2018 4 1958 44 EPIGENETIC AGING AND COLORECTAL CANCER: STATE OF THE ART AND PERSPECTIVES FOR FUTURE RESEARCH. ALTHOUGH TRANSLATIONAL RESEARCH HAS IDENTIFIED A LARGE NUMBER OF POTENTIAL BIOMARKERS INVOLVED IN COLORECTAL CANCER (CRC) CARCINOGENESIS, A BETTER UNDERSTANDING OF THE MOLECULAR PATHWAYS ASSOCIATED WITH BIOLOGICAL AGING IN COLORECTAL CELLS AND TISSUES IS NEEDED. HERE, WE AIM TO SUMMARIZE THE STATE OF THE ART ABOUT THE ROLE OF AGE ACCELERATION, DEFINED AS THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE, IN THE DEVELOPMENT AND PROGRESSION OF CRC. SOME STUDIES HAVE SHOWN THAT ACCELERATED BIOLOGICAL AGING IS POSITIVELY ASSOCIATED WITH THE RISK OF CANCER AND DEATH IN GENERAL. IN LINE WITH THESE FINDINGS, OTHER STUDIES HAVE SHOWN HOW THE ASSESSMENT OF EPIGENETIC AGE IN PEOPLE AT RISK FOR CRC COULD BE HELPFUL FOR MONITORING THE MOLECULAR RESPONSE TO PREVENTIVE INTERVENTIONS. MOREOVER, IT WOULD BE INTERESTING TO INVESTIGATE WHETHER ABERRANT EPIGENETIC AGING COULD HELP IDENTIFY CRC PATIENTS WITH A HIGH RISK OF RECURRENCE AND A WORST PROGNOSIS, AS WELL AS THOSE WHO RESPOND POORLY TO TREATMENT. YET, THE APPLICATION OF THIS NOVEL CONCEPT IS STILL IN ITS INFANCY, AND FURTHER RESEARCH SHOULD BE ENCOURAGED IN ANTICIPATION OF FUTURE APPLICATIONS IN CLINICAL PRACTICE. 2020 5 739 39 CANCER TREATMENT-INDUCED ACCELERATED AGING IN CANCER SURVIVORS: BIOLOGY AND ASSESSMENT. RAPID IMPROVEMENTS IN CANCER SURVIVAL LED TO THE REALIZATION THAT MANY MODALITIES USED TO TREAT OR CONTROL CANCER MAY CAUSE ACCELERATED AGING IN CANCER SURVIVORS. CLINICALLY, "ACCELERATED AGING" PHENOTYPES IN CANCER SURVIVORS INCLUDE SECONDARY CANCERS, FRAILTY, CHRONIC ORGAN DYSFUNCTION, AND COGNITIVE IMPAIRMENT, ALL OF WHICH CAN IMPACT LONG-TERM HEALTH AND QUALITY OF LIFE IN CANCER SURVIVORS. THE TREATMENT-INDUCED ACCELERATED AGING IN CANCER SURVIVORS COULD BE EXPLAINED BY TELOMERE ATTRITION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, DNA DAMAGE, AND EPIGENETIC ALTERATIONS. SEVERAL AGING CLOCKS AND BIOMARKERS OF AGING HAVE BEEN PROPOSED TO BE POTENTIALLY USEFUL IN ESTIMATING BIOLOGICAL AGE, WHICH CAN PROVIDE SPECIFIC INFORMATION ABOUT HOW OLD AN INDIVIDUAL IS BIOLOGICALLY INDEPENDENT OF CHRONOLOGICAL AGE. MEASURING BIOLOGICAL AGE IN CANCER SURVIVORS MAY BE IMPORTANT FOR TWO REASONS. FIRST, IT CAN BETTER PREDICT THE RISK OF CANCER TREATMENT-RELATED COMORBIDITIES THAN CHRONOLOGICAL AGE. SECOND, BIOLOGICAL AGE MAY PROVIDE ADDITIONAL VALUE IN EVALUATING THE EFFECTS OF TREATMENTS AND PERSONALIZING CANCER THERAPIES TO MAXIMIZE EFFICACY OF TREATMENT. A DEEPER UNDERSTANDING OF TREATMENT-INDUCED ACCELERATED AGING IN INDIVIDUALS WITH CANCER MAY LEAD TO NOVEL STRATEGIES THAT REDUCE THE ACCELERATED AGING AND IMPROVE THE QUALITY OF LIFE IN CANCER SURVIVORS. 2021 6 625 40 BIOLOGICAL AGE AND ENVIRONMENTAL RISK FACTORS FOR DEMENTIA AND STROKE: MOLECULAR MECHANISMS. SINCE THE DEVELOPMENT OF ANTIBIOTICS AND VACCINATION, AS WELL AS MAJOR IMPROVEMENTS IN PUBLIC HYGIENE, THE MAIN RISK FACTORS FOR MORBIDITY AND MORTALITY ARE AGE AND CHRONIC EXPOSURE TO ENVIRONMENTAL FACTORS, BOTH OF WHICH CAN INTERACT WITH GENETIC PREDISPOSITIONS. AS THE AVERAGE AGE OF THE POPULATION INCREASES, THE PREVALENCE AND COSTS OF CHRONIC DISEASES, ESPECIALLY NEUROLOGICAL CONDITIONS, ARE RAPIDLY INCREASING. THE DELETERIOUS EFFECTS OF AGE AND ENVIRONMENTAL RISK FACTORS, DEVELOP CHRONICALLY OVER RELATIVELY LONG PERIODS OF TIME, IN CONTRAST TO THE RELATIVELY RAPID DELETERIOUS EFFECTS OF INFECTIOUS DISEASES OR ACCIDENTS. OF PARTICULAR INTEREST IS THE HYPOTHESIS THAT THE DELETERIOUS EFFECTS OF ENVIRONMENTAL FACTORS MAY BE MEDIATED BY ACCELERATION OF BIOLOGICAL AGE. THIS HYPOTHESIS IS SUPPORTED BY EVIDENCE THAT DIETARY RESTRICTION, WHICH UNIVERSALLY DELAYS AGE-RELATED DISEASES, ALSO AMELIORATES DELETERIOUS EFFECTS OF ENVIRONMENTAL FACTORS. CONVERSELY, BOTH AGE AND ENVIRONMENTAL RISK FACTORS ARE ASSOCIATED WITH THE ACCUMULATION OF SOMATIC MUTATIONS IN MITOTIC CELLS AND EPIGENETIC MODIFICATIONS THAT ARE A MEASURE OF "BIOLOGICAL AGE", A BETTER PREDICTOR OF AGE-RELATED MORBIDITY AND MORTALITY THAN CHRONOLOGICAL AGE. HERE WE REVIEW EVIDENCE THAT ENVIRONMENTAL RISK FACTORS SUCH AS SMOKING AND AIR POLLUTION MAY ALSO DRIVE NEUROLOGICAL CONDITIONS, INCLUDING ALZHEIMER'S DISEASE, BY THE ACCELERATION OF BIOLOGICAL AGE, MEDIATED BY CUMULATIVE AND PERSISTENT EPIGENETIC EFFECTS AS WELL AS SOMATIC MUTATIONS. ELUCIDATION OF SUCH MECHANISMS COULD PLAUSIBLY ALLOW THE DEVELOPMENT OF INTERVENTIONS WHICH DELAY DELETERIOUS EFFECTS OF BOTH AGING AND ENVIRONMENTAL RISK FACTORS. 2022 7 5959 38 TELOMERE LENGTH AS A MARKER OF BIOLOGICAL AGE: STATE-OF-THE-ART, OPEN ISSUES, AND FUTURE PERSPECTIVES. TELOMERE SHORTENING IS A WELL-KNOWN HALLMARK OF BOTH CELLULAR SENESCENCE AND ORGANISMAL AGING. AN ACCELERATED RATE OF TELOMERE ATTRITION IS ALSO A COMMON FEATURE OF AGE-RELATED DISEASES. THEREFORE, TELOMERE LENGTH (TL) HAS BEEN RECOGNIZED FOR A LONG TIME AS ONE OF THE BEST BIOMARKERS OF AGING. RECENT RESEARCH FINDINGS, HOWEVER, INDICATE THAT TL PER SE CAN ONLY ALLOW A ROUGH ESTIMATE OF AGING RATE AND CAN HARDLY BE REGARDED AS A CLINICALLY IMPORTANT RISK MARKER FOR AGE-RELATED PATHOLOGIES AND MORTALITY. EVIDENCE IS OBTAINED THAT OTHER INDICATORS SUCH AS CERTAIN IMMUNE PARAMETERS, INDICES OF EPIGENETIC AGE, ETC., COULD BE STRONGER PREDICTORS OF THE HEALTH STATUS AND THE RISK OF CHRONIC DISEASE. HOWEVER, DESPITE THESE ISSUES AND LIMITATIONS, TL REMAINS TO BE VERY INFORMATIVE MARKER IN ACCESSING THE BIOLOGICAL AGE WHEN USED ALONG WITH OTHER MARKERS SUCH AS INDICES OF HOMEOSTATIC DYSREGULATION, FRAILTY INDEX, EPIGENETIC CLOCK, ETC. THIS REVIEW ARTICLE IS AIMED AT DESCRIBING THE CURRENT STATE OF THE ART IN THE FIELD AND AT DISCUSSING RECENT RESEARCH FINDINGS AND DIVERGENT VIEWPOINTS REGARDING THE USEFULNESS OF LEUKOCYTE TL FOR ESTIMATING THE HUMAN BIOLOGICAL AGE. 2020 8 287 31 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 9 5685 42 SHOULD WE INVEST IN BIOLOGICAL AGE PREDICTORS TO TREAT COLORECTAL CANCER IN OLDER ADULTS? COLORECTAL CANCER (CRC) IS A CHRONIC DISEASE OF THE OLD POPULATION WITH SLOW DEVELOPMENT PROGRESSING INTO CLINICAL SIGNS AND SYMPTOMS. BIOLOGICAL AGING IS CHARACTERIZED BY E.G. MITOCHONDRIAL DYSFUNCTION AND EPIGENETIC ALTERATIONS (E.G. METHYLATION) - MECHANISMS THAT ARE ALSO IMPORTANT IN CANCER DEVELOPMENT. FOR CRC, SPECIFIC TYPES OF TUMORS ARE DISTINGUISHABLE BY THEIR METHYLATION PATTERNS AND SEVERAL DETECTION METHODS USING DIFFERENT EPIGENETIC MARKS HAVE BEEN DEVELOPED AS SIGNATURES FOR THE DISEASE. BIOLOGICAL AGE ASSESSED BY DNA METHYLATION PATTERNS FROM BLOOD, I.E. THE EPIGENETIC CLOCK, IS HIGHER IN CRC PATIENTS COMPARED TO CONTROLS, AND MAY BE A TOOL FOR IDENTIFYING INDIVIDUALS AT INCREASED RISK FOR CRC. OTHER TYPES OF BIOMARKERS OF AGING ARE USEFUL TO CALCULATE BIOLOGICAL AGE, SUCH AS METABOLITES, PROTEIN LEVELS, INFLAMMATORY MARKERS AND CLINICAL BIOMARKERS, WHERE COMPOSITE SCORES OF BIOMARKERS HAVE BEEN USED TO ASSESS THE RISK OF CRC AND COLORECTAL ADENOMAS. CLINICAL ASSESSMENTS OF BIOLOGICAL AGING INCLUDES FRAILTY, WHICH IS A GERIATRIC SYNDROME CHARACTERIZED BY INCREASED VULNERABILITY TO ADVERSE OUTCOMES. MORE THAN HALF OF THE CRC PATIENTS ARE ESTIMATED TO BE FRAIL OR PRE-FRAIL, AND THESE INDIVIDUALS ARE AT INCREASED RISK OF POSTOPERATIVE COMPLICATIONS, POORER PROGNOSIS, TREATMENT INTOLERANCE AND DEATH. HENCE, CONSIDERING FRAILTY AS PART OF BIOLOGICAL AGE IN CRC PATIENTS MAY HELP IDENTIFYING THOSE AT NEED OF CLOSE MONITORING. IN SUMMARY, FUTURE SCREENING PROGRAMS FOR CRC MAY MAKE USE OF BIOLOGICAL AGE ASSESSMENTS, E.G. BY EPIGENETIC CLOCK OR COMPOSITE SCORES. MONITORING DISEASE RELAPSE AND TREATMENT RESPONSE SHOULD BE ENHANCED IN FRAIL INDIVIDUALS FOR BETTER PROGNOSIS. 2020 10 2047 38 EPIGENETIC CLOCKS MAY COME OUT OF RHYTHM-IMPLICATIONS FOR THE ESTIMATION OF CHRONOLOGICAL AGE IN FORENSIC CASEWORK. THERE IS A GROWING PERCEPTION THAT DNA METHYLATION MAY BE INFLUENCED BY EXOGENOUS AND ENDOGENOUS PARAMETERS. KNOWLEDGE OF THESE FACTORS IS OF GREAT RELEVANCE FOR THE INTERPRETATION OF DNA-METHYLATION DATA FOR THE ESTIMATION OF CHRONOLOGICAL AGE IN FORENSIC CASEWORK. WE PERFORMED A LITERATURE REVIEW TO IDENTIFY PARAMETERS, WHICH MIGHT BE OF RELEVANCE FOR THE PREDICTION OF CHRONOLOGICAL AGE BASED ON DNA METHYLATION. THE QUALITY OF AGE PREDICTIONS MIGHT PARTICULARLY BE INFLUENCED BY LIFETIME ADVERSITIES (CHRONIC STRESS, TRAUMA/POST-TRAUMATIC STRESS DISORDER (PTSD), VIOLENCE, LOW SOCIOECONOMIC STATUS/EDUCATION), CANCER, OBESITY AND RELATED DISEASES, INFECTIOUS DISEASES (ESPECIALLY HIV AND CYTOMEGALOVIRUS (CMV) INFECTIONS), SEX, ETHNICITY AND EXPOSURE TO TOXINS (ALCOHOL, SMOKING, AIR POLLUTION, PESTICIDES). SUCH FACTORS MAY ALTER THE DNA METHYLATION PATTERN AND MAY EXPLAIN THE PARTLY HIGH DEVIATIONS BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE IN SINGLE CASES (DESPITE OF LOW MEAN ABSOLUTE DEVIATIONS) THAT CAN ALSO BE OBSERVED WITH "EPIGENETIC CLOCKS" COMPRISING A HIGH NUMBER OF CPG SITES. SO FAR, ONLY FEW PUBLICATIONS DEALING WITH FORENSIC AGE ESTIMATION ADDRESS THESE CONFOUNDING FACTORS. FUTURE RESEARCH SHOULD FOCUS ON THE IDENTIFICATION OF FURTHER RELEVANT CONFOUNDING FACTORS AND THE DEVELOPMENT OF MODELS THAT ARE "ROBUST" AGAINST THE INFLUENCE OF SUCH BIOLOGICAL FACTORS BY SYSTEMATIC INVESTIGATIONS UNDER TARGETED INCLUSION OF DIVERSE AND DEFINED COHORTS. 2020 11 5175 35 PREDICTORS OF BIOLOGICAL AGE: THE IMPLICATIONS FOR WELLNESS AND AGING RESEARCH. AS HEALTHSPAN AND LIFESPAN RESEARCH BREAKTHROUGHS HAVE BECOME MORE COMMONPLACE, THE NEED FOR VALID, PRACTICAL MARKERS OF BIOLOGICAL AGE IS BECOMING INCREASINGLY PARAMOUNT. THE ACCESSIBILITY AND AFFORDABILITY OF BIOLOGICAL AGE PREDICTORS THAT CAN REVEAL INFORMATION ABOUT MORTALITY AND MORBIDITY RISK, AS WELL AS REMAINING YEARS OF LIFE, HAS PROFOUND CLINICAL AND RESEARCH IMPLICATIONS. IN THIS REVIEW, WE EXAMINE 5 GROUPS OF AGING BIOMARKERS CAPABLE OF PROVIDING ACCURATE BIOLOGICAL AGE ESTIMATIONS. THE UNIQUE CAPABILITIES OF THESE BIOMARKERS HAVE FAR REACHING IMPLICATIONS FOR THE TESTING OF BOTH PHARMACEUTICAL AND NON-PHARMACEUTICAL INTERVENTIONS DESIGNED TO SLOW OR REVERSE BIOLOGICAL AGING. ADDITIONALLY, THE ENHANCED VALIDITY AND AVAILABILITY OF THESE TOOLS MAY HAVE INCREASINGLY RELEVANT CLINICAL VALUE. THE AUTHORS OF THIS REVIEW EXPLORE THOSE IMPLICATIONS, WITH AN EMPHASIS ON LIFESTYLE MODIFICATION RESEARCH, AND PROVIDE AN OVERVIEW OF THE CURRENT EVIDENCE REGARDING 5 BIOLOGICAL AGE PREDICTOR CATEGORIES: TELOMERE LENGTH, COMPOSITE BIOMARKERS, DNA METHYLATION "EPIGENETIC CLOCKS," TRANSCRIPTIONAL PREDICTORS OF BIOLOGICAL AGE, AND FUNCTIONAL AGE PREDICTORS. 2021 12 1014 32 CIGARETTE SMOKING AND DNA METHYLATION. DNA METHYLATION IS THE MOST STUDIED EPIGENETIC MODIFICATION, CAPABLE OF CONTROLLING GENE EXPRESSION IN THE CONTEXTS OF NORMAL TRAITS OR DISEASES. IT IS HIGHLY DYNAMIC DURING EARLY EMBRYOGENESIS AND REMAINS RELATIVELY STABLE THROUGHOUT LIFE, AND SUCH PATTERNS ARE INTRICATELY RELATED TO HUMAN DEVELOPMENT. DNA METHYLATION IS A QUANTITATIVE TRAIT DETERMINED BY A COMPLEX INTERPLAY OF GENETIC AND ENVIRONMENTAL FACTORS. GENETIC VARIANTS AT A SPECIFIC LOCUS CAN INFLUENCE BOTH REGIONAL AND DISTANT DNA METHYLATION. THE ENVIRONMENT CAN HAVE VARYING EFFECTS ON DNA METHYLATION DEPENDING ON WHEN THE EXPOSURE OCCURS, SUCH AS DURING PRENATAL LIFE OR DURING ADULTHOOD. IN PARTICULAR, CIGARETTE SMOKING IN THE CONTEXT OF BOTH CURRENT SMOKING AND PRENATAL EXPOSURE IS A STRONG MODIFIER OF DNA METHYLATION. EPIGENOME-WIDE ASSOCIATION STUDIES HAVE UNCOVERED CANDIDATE GENES ASSOCIATED WITH CIGARETTE SMOKING THAT HAVE BIOLOGICALLY RELEVANT FUNCTIONS IN THE ETIOLOGY OF SMOKING-RELATED DISEASES. AS SUCH, DNA METHYLATION IS A POTENTIAL MECHANISTIC LINK BETWEEN CURRENT SMOKING AND CANCER, AS WELL AS PRENATAL CIGARETTE-SMOKE EXPOSURE AND THE DEVELOPMENT OF ADULT CHRONIC DISEASES. 2013 13 6790 28 [DNA METHYLATION ANALYSIS IN ENVIRONMENTAL AND OCCUPATIONAL CANCER RESEARCH]. THE PRESENT PAPER REVIEWS RECENT LABORATORY METHODS AND EXPERIMENTAL EVIDENCE CONCERNING EPIGENETIC BIOMARKERS INVOLVED IN CARCINOGENESIS MECHANISMS. WE INTRODUCE DNA METHYLATION AND ITS ROLE IN GENE EXPRESSION CONTROL. DNA METHYLATION ANALYSIS MAY ALLOW TO IDENTIFY EARLY CHANGES LEADING TO CANCER AND OTHER CHRONIC DISEASES. WE DESCRIBE HERE STRATEGIES FOR LABORATORY ANALYSES AND THEIR POSSIBLE APPLICATIONS. WE EXAMINE RESULTS FROM RECENT EXPERIMENTAL STUDIES SUGGESTING THAT THE EFFECTS OF CERTAIN OCCUPATIONAL AGENTS ARE MEDIATED BY ALTERATIONS IN DNA METHYLATION. PLANNING AND CONDUCTING INVESTIGATIONS ON EXPOSED HUMAN SUBJECTS WILL ALLOW TO VERIFY WHETHER DNA METHYLATION CHANGES IDENTIFIED IN ANIMAL AND IN-VITRO STUDIES MAY BE USED AS EARLY-EFFECT AND SUSCEPTIBILITY BIOMARKERS. DNA METHYLATION ANALYSIS HAS THE POTENTIAL FOR FUTURE APPLICATIONS IN RISK ASSESSMENT AND PREVENTION PROGRAMS CONDUCTED ON SUBJECTS EXPOSED TO HUMAN CARCINOGENS. 2005 14 311 40 ALCOHOL AND THE METHYLOME: DESIGN AND ANALYSIS CONSIDERATIONS FOR RESEARCH USING HUMAN SAMPLES. BACKGROUND: A GROWING NUMBER OF STUDIES IN HUMAN SAMPLES HAVE SOUGHT TO DETERMINE WHETHER CHRONIC ALCOHOL USE AND ALCOHOL USE DISORDERS (AUDS) MAY BE ASSOCIATED WITH EPIGENETIC FACTORS, SUCH AS DNA METHYLATION. WE REVIEW THE EXTANT LITERATURE IN LIGHT OF SOME OF THE CHALLENGES THAT CURRENTLY AFFECT THE DESIGN AND INTERPRETATION OF EPIGENETIC RESEARCH IN HUMAN SAMPLES. METHOD: A LITERATURE SEARCH WAS USED TO IDENTIFY STUDIES THAT HAVE EXAMINED DNA METHYLATION IN RELATION TO ALCOHOL USE OR AUDS IN HUMAN SAMPLES (THROUGH JULY 2013). A TOTAL OF 22 STUDIES WERE IDENTIFIED. RESULTS: ASSOCIATIONS WITH QUANTITATIVE OR DIAGNOSTIC PHENOTYPES OF ALCOHOL USE OR AUDS HAVE BEEN REPORTED FOR SEVERAL GENES. HOWEVER, ALL STUDIES TO DATE HAVE RELIED ON RELATIVELY SMALL SAMPLES AND CROSS-SECTIONAL STUDY DESIGNS. ADDITIONALLY, ATTEMPTS TO REPLICATE RESULTS HAVE BEEN RARE. MORE GENERALLY, RESEARCH PROGRESS IS HAMPERED BY SEVERAL ISSUES, INCLUDING LIMITATIONS OF THE TECHNOLOGIES USED TO ASSESS DNA METHYLATION, TISSUE- AND CELL-SPECIFICITY OF METHYLATION PATTERNS, THE DIFFICULTIES OF RELATING OBSERVED METHYLATION DIFFERENCES AT A GIVEN LOCUS TO A FUNCTIONAL EFFECT, AND LIMITED KNOWLEDGE ABOUT THE MOLECULAR MECHANISMS UNDERLYING THE EFFECTS OF ALCOHOL ON DNA METHYLATION. CONCLUSIONS: ALTHOUGH WE SHARE THE OPTIMISM THAT EPIGENETICS MAY LEAD TO NEW INSIGHTS INTO THE ETIOLOGY AND PATHOPHYSIOLOGY OF AUDS, THE METHODOLOGICAL AND SCIENTIFIC CHALLENGES ASSOCIATED WITH CONDUCTING METHYLOMIC RESEARCH IN HUMAN SAMPLES NEED TO BE CAREFULLY CONSIDERED WHEN DESIGNING AND EVALUATING SUCH STUDIES. 2013 15 1546 34 DNA METHYLATION IN NASAL EPITHELIUM: STRENGTHS AND LIMITATIONS OF AN EMERGENT BIOMARKER FOR CHILDHOOD ASTHMA. ASTHMA IS ONE OF THE MOST WIDESPREAD CHRONIC RESPIRATORY CONDITIONS. THIS DISEASE PRIMARILY DEVELOPS IN CHILDHOOD AND IS INFLUENCED BY DIFFERENT FACTORS, MAINLY GENETICS AND ENVIRONMENTAL FACTORS. DNA METHYLATION IS AN EPIGENETIC MECHANISM WHICH MAY REPRESENT A BRIDGE BETWEEN THESE TWO FACTORS, PROVIDING A TOOL TO COMPREHEND THE INTERACTION BETWEEN GENETICS AND ENVIRONMENT. MOST EPIDEMIOLOGICAL STUDIES IN THIS FIELD HAVE BEEN CONDUCTED USING BLOOD SAMPLES, ALTHOUGH DNA METHYLATION MARKS IN BLOOD MAY NOT BE RELIABLE FOR DRAWING EXHAUSTIVE CONCLUSIONS ABOUT DNA METHYLATION IN THE AIRWAYS. BECAUSE OF THE ROLE OF NASAL EPITHELIUM IN ASTHMA AND THE TISSUE SPECIFICITY OF DNA METHYLATION, STUDYING THE RELATIONSHIP BETWEEN DNA METHYLATION AND CHILDHOOD ASTHMA MIGHT REVEAL CRUCIAL INFORMATION ABOUT THIS WIDESPREAD RESPIRATORY DISEASE. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE CURRENT FINDINGS IN THIS FIELD OF RESEARCH. WE WILL PRESENT A VIEWPOINT OF SELECTED STUDIES, CONSIDER STRENGTHS AND LIMITATIONS, AND PROPOSE FUTURE RESEARCH IN THIS AREA. 2020 16 3676 42 INFLAMMATION AND NEUTROPHIL IMMUNOSENESCENCE IN HEALTH AND DISEASE: TARGETED TREATMENTS TO IMPROVE CLINICAL OUTCOMES IN THE ELDERLY. DESPITE INCREASING LONGEVITY, MANY OLD PEOPLE ARE NOT IN GOOD HEALTH. THERE HAS BEEN AN INCREASE IN THE PREVALENCE OF AGE-ASSOCIATED MULTI-MORBIDITY (TWO OR MORE CHRONIC CONDITIONS IN THE SAME PERSON). ALSO, SEVERE INFECTIONS, SUCH AS PNEUMONIA, REMAIN SIGNIFICANT CAUSES OF MORTALITY AND MORBIDITY IN THIS AGING GROUP. MANY CHRONIC HEALTH CONDITIONS SHARE RISK FACTORS SUCH AS INCREASING AGE, SMOKING, A SEDENTARY LIFE STYLE AND BEING PART OF A LOWER SOCIOECONOMIC GROUP. HOWEVER, DESPITE THIS, MULTI-MORBIDITIES OFTEN CO-OCCUR MORE COMMONLY THAN WOULD BE PREDICTED. THIS HAS LED TO THE HYPOTHESIS THAT THEY SHARE COMMON UNDERLYING MECHANISMS. THIS IS AN IMPORTANT CONCEPT, FOR IF IT WERE TRUE, TREATMENTS COULD BE DEVISED WHICH TARGET THESE COMMON PATHWAYS AND IMPROVE A NUMBER OF AGE-ASSOCIATED HEALTH CONDITIONS. MANY CHRONIC ILLNESSES ASSOCIATED WITH MULTI-MORBIDITY AND SEVERE INFECTIONS ARE CHARACTERIZED BY AN ABNORMAL AND SUSTAINED INFLAMMATORY RESPONSE, WITH NEUTROPHILS BEING KEY EFFECTOR CELLS IN THE PATHOLOGICAL PROCESS. STUDIES HAVE DESCRIBED ABERRANT NEUTROPHIL FUNCTIONS ACROSS THESE CONDITIONS, AND SOME HAVE HIGHLIGHTED POTENTIAL MECHANISMS FOR ALTERED CELL BEHAVIOURS WHICH APPEAR SHARED ACROSS DISEASE STATES. IT HAS BEEN SUGGESTED THAT ALTERED FUNCTIONS MAY REPRESENT NEUTROPHIL "SENESCENCE". THIS REVIEW CONSIDERS HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE CELL AGES, AND HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE HOST AGES IN HEALTH AND DISEASE AND DISCUSSES WHETHER NEUTROPHIL FUNCTIONS COULD BE TARGETED TO IMPROVE HEALTH OUTCOMES IN OLDER ADULTS. 2018 17 822 39 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 18 2075 38 EPIGENETIC DIFFERENCES IN INFLAMMATION GENES OF MONOZYGOTIC TWINS ARE RELATED TO PARENT-CHILD EMOTIONAL AVAILABILITY AND HEALTH. THE INFLAMMATORY RESPONSE IS AN IMMUNE DEFENSE ENGAGED IMMEDIATELY AFTER INJURY OR INFECTION. CHRONIC INFLAMMATION CAN BE DELETERIOUS FOR VARIOUS HEALTH OUTCOMES AND IS CHARACTERIZED BY HIGH LEVELS OF PRO-INFLAMMATORY MARKERS SUCH AS C-REACTIVE PROTEIN (CRP), INTERLEUKIN 6 (IL-6), AND TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA). A LARGE BODY OF RESEARCH DEMONSTRATES THESE INFLAMMATORY MARKERS ARE RESPONSIVE TO STRESS AND QUALITY OF SOCIAL RELATIONSHIPS THROUGHOUT THE LIFESPAN. FOR EXAMPLE, THE QUALITY OF THE EARLY PARENTAL BOND PREDICTS VARIOUS HEALTH OUTCOMES AND MAY BE DRIVEN BY CHANGES IN IMMUNE FUNCTION. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION, MAY BE ONE MECHANISM BY WHICH EARLY SOCIAL EXPERIENCES SHAPE IMMUNE FUNCTIONING. THE PRESENT STUDY USED A MONOZYGOTIC TWIN DIFFERENCE DESIGN TO ASSESS IF MOTHER-REPORTED EMOTIONAL AVAILABILITY AT 1 YEAR AND 2.5 YEARS PREDICTED IMMUNE GENE METHYLATION AT 8 YEARS OF AGE. FURTHER, WE ASSESSED IF INFLAMMATION GENE METHYLATION WAS RELATED TO GENERAL HEALTH PROBLEMS (E.G. INFECTIONS, ALLERGIES, ETC.). WE FOUND THAT MOTHER-REPORTED EMOTIONAL AVAILABILITY AT 1 YEAR, BUT NOT 2.5 YEARS, WAS RELATED TO METHYLATION OF VARIOUS IMMUNE GENES IN MONOZYGOTIC TWINS. FURTHERMORE, TWIN PAIRS DISCORDANT IN HEALTH PROBLEMS HAVE MORE DIFFERENCE IN IMMUNE GENE METHYLATION COMPARED TO TWIN PAIRS CONCORDANT FOR HEALTH PROBLEMS, SUGGESTING THAT METHYLATION OF IMMUNE GENES MAY HAVE FUNCTIONAL CONSEQUENCES FOR GENERAL HEALTH. THESE RESULTS SUGGEST THAT THE EMOTIONAL COMPONENT OF ATTACHMENT QUALITY DURING INFANCY CONTRIBUTES TO IMMUNE EPIGENETIC PROFILES IN CHILDHOOD, WHICH MAY INFLUENCE GENERAL HEALTH. 2020 19 1599 40 DNA METHYLATION SIGNATURE OF CHILDHOOD CHRONIC PHYSICAL AGGRESSION IN T CELLS OF BOTH MEN AND WOMEN. BACKGROUND: HIGH FREQUENCY OF PHYSICAL AGGRESSION IS THE CENTRAL FEATURE OF SEVERE CONDUCT DISORDER AND IS ASSOCIATED WITH A WIDE RANGE OF SOCIAL, MENTAL AND PHYSICAL HEALTH PROBLEMS. WE HAVE PREVIOUSLY TESTED THE HYPOTHESIS THAT DIFFERENTIAL DNA METHYLATION SIGNATURES IN PERIPHERAL T CELLS ARE ASSOCIATED WITH A CHRONIC AGGRESSION TRAJECTORY IN MALES. DESPITE THE FACT THAT SEX DIFFERENCES APPEAR TO PLAY A PIVOTAL ROLE IN DETERMINING THE DEVELOPMENT, MAGNITUDE AND FREQUENCY OF AGGRESSION, MOST OF PREVIOUS STUDIES FOCUSED ON MALES, SO LITTLE IS KNOWN ABOUT FEMALE CHRONIC PHYSICAL AGGRESSION. WE THEREFORE TESTED HERE WHETHER OR NOT THERE IS A SIGNATURE OF PHYSICAL AGGRESSION IN FEMALE DNA METHYLATION AND, IF THERE IS, HOW IT RELATES TO THE SIGNATURE OBSERVED IN MALES. METHODOLOGY/PRINCIPAL FINDINGS: METHYLATION PROFILES WERE CREATED USING THE METHOD OF METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) FOLLOWED BY MICROARRAY HYBRIDIZATION AND STATISTICAL AND BIOINFORMATIC ANALYSES ON T CELL DNA OBTAINED FROM ADULT WOMEN WHO WERE FOUND TO BE ON A CHRONIC PHYSICAL AGGRESSION TRAJECTORY (CPA) BETWEEN 6 AND 12 YEARS OF AGE COMPARED TO WOMEN WHO FOLLOWED A NORMAL PHYSICAL AGGRESSION TRAJECTORY. WE CONFIRMED THE EXISTENCE OF A WELL-DEFINED, GENOME-WIDE SIGNATURE OF DNA METHYLATION ASSOCIATED WITH CHRONIC PHYSICAL AGGRESSION IN THE PERIPHERAL T CELLS OF ADULT FEMALES THAT INCLUDES MANY OF THE GENES SIMILARLY ASSOCIATED WITH PHYSICAL AGGRESSION IN THE SAME CELL TYPES OF ADULT MALES. CONCLUSIONS: THIS STUDY IN A SMALL NUMBER OF WOMEN PRESENTS PRELIMINARY EVIDENCE FOR A GENOME-WIDE VARIATION IN PROMOTER DNA METHYLATION THAT ASSOCIATES WITH CPA IN WOMEN THAT WARRANT LARGER STUDIES FOR FURTHER VERIFICATION. A SIGNIFICANT PROPORTION OF THESE ASSOCIATIONS WERE PREVIOUSLY OBSERVED IN MEN WITH CPA SUPPORTING THE HYPOTHESIS THAT THE EPIGENETIC SIGNATURE OF EARLY LIFE AGGRESSION IN FEMALES IS COMPOSED OF A COMPONENT SPECIFIC TO FEMALES AND ANOTHER COMMON TO BOTH MALES AND FEMALES. 2014 20 1385 45 DIABETES IN CHILDHOOD CANCER SURVIVORS: EMERGING CONCEPTS IN PATHOPHYSIOLOGY AND FUTURE DIRECTIONS. WITH ADVANCEMENTS IN CANCER TREATMENT AND SUPPORTIVE CARE, THERE IS A GROWING POPULATION OF CHILDHOOD CANCER SURVIVORS WHO EXPERIENCE A SUBSTANTIAL BURDEN OF COMORBIDITIES RELATED TO HAVING RECEIVED CANCER TREATMENT AT A YOUNG AGE. DESPITE AN OVERALL REDUCTION IN THE INCIDENCE OF MOST CHRONIC HEALTH CONDITIONS IN CHILDHOOD CANCER SURVIVORS OVER THE PAST SEVERAL DECADES, THE CUMULATIVE INCIDENCE OF CERTAIN LATE EFFECTS, IN PARTICULAR DIABETES MELLITUS (DM), HAS INCREASED. THE IMPLICATIONS ARE SIGNIFICANT, BECAUSE DM IS A KEY RISK FACTOR FOR CARDIOVASCULAR DISEASE, A LEADING CAUSE OF PREMATURE DEATH IN CHILDHOOD CANCER SURVIVORS. THE UNDERLYING PATHOPHYSIOLOGY OF DM IN CANCER SURVIVORS IS MULTIFACTORIAL. DM DEVELOPS AT YOUNGER AGES IN SURVIVORS COMPARED TO CONTROLS, WHICH MAY REFLECT AN "ACCELERATED AGING" PHENOTYPE IN THESE INDIVIDUALS. THE TREATMENT-RELATED EXPOSURES (I.E., CHEMOTHERAPY, RADIATION) THAT INCREASE RISK FOR DM IN CHILDHOOD CANCER SURVIVORS MAY BE MORE THAN ADDITIVE WITH ESTABLISHED DM RISK FACTORS (E.G., OLDER AGE, OBESITY, RACE, AND ETHNICITY). EMERGING RESEARCH ALSO POINTS TO PARALLELS IN CELLULAR PROCESSES IMPLICATED IN AGING- AND CANCER TREATMENT-RELATED DM. STILL, THERE REMAINS MARKED INTER-INDIVIDUAL VARIABILITY REGARDING RISK OF DM THAT IS NOT EXPLAINED BY DEMOGRAPHIC AND THERAPEUTIC RISK FACTORS ALONE. RECENT STUDIES HAVE HIGHLIGHTED THE ROLE OF GERMLINE GENETIC RISK FACTORS AND EPIGENETIC MODIFICATIONS THAT ARE ASSOCIATED WITH RISK OF DM IN BOTH THE GENERAL AND ONCOLOGY POPULATIONS. THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF RECOGNIZED RISK FACTORS FOR DM IN CHILDHOOD CANCER SURVIVORS TO HELP INFORM TARGETED APPROACHES FOR DISEASE SCREENING, PREVENTION, AND TREATMENT. FURTHERMORE, IT HIGHLIGHTS THE EXISTING SCIENTIFIC GAPS IN UNDERSTANDING THE RELATIVE CONTRIBUTIONS OF INDIVIDUAL THERAPEUTIC EXPOSURES AND THE MECHANISMS BY WHICH THEY EXERT THEIR EFFECTS THAT UNIQUELY PREDISPOSE THIS POPULATION TO DM FOLLOWING CANCER TREATMENT. 2023