1 1341 125 DETANGLING THE INTERRELATIONS BETWEEN MAFLD, INSULIN RESISTANCE, AND KEY HORMONES. METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASE (MAFLD) HAS INCREASINGLY BECOME A SIGNIFICANT AND HIGHLY PREVALENT CAUSE OF CHRONIC LIVER DISEASE, DISPLAYING A WIDE ARRAY OF RISK FACTORS AND PATHOPHYSIOLOGIC MECHANISMS OF WHICH ONLY A FEW HAVE SO FAR BEEN CLEARLY ELUCIDATED. A BIDIRECTIONAL INTERACTION BETWEEN HORMONAL DISCREPANCIES AND METABOLIC-RELATED DISORDERS, INCLUDING OBESITY, TYPE 2 DIABETES MELLITUS (T2DM), AND POLYCYSTIC OVARIAN SYNDROME (PCOS) HAS BEEN DESCRIBED. SINCE THE CHANGE IN NOMENCLATURE FROM NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) TO MAFLD IS BASED ON THE CLEAR IMPACT OF METABOLIC ELEMENTS ON THE DISEASE, THE RECIPROCAL INTERACTIONS OF HORMONES SUCH AS INSULIN, ADIPOKINES (LEPTIN AND ADIPONECTIN), AND ESTROGENS HAVE STRONGLY POINTED TO THE INTRINSIC LINKS THAT LEAD TO THE HETEROGENEOUS EPIDEMIOLOGY, CLINICAL PRESENTATIONS, AND RISK FACTORS INVOLVED IN MAFLD IN DIFFERENT POPULATIONS. THE OBJECTIVE OF THIS WORK IS TWOFOLD. FIRSTLY, THERE IS A BRIEF DISCUSSION REGARDING THE CHANGE IN NOMENCLATURE AS WELL AS EPIDEMIOLOGY, RISK FACTORS, AND PATHOPHYSIOLOGIC MECHANISMS OTHER THAN HORMONAL EFFECTS, WHICH INCLUDE NUTRITION AND THE GUT MICROBIOME, AS WELL AS GENETIC AND EPIGENETIC INFLUENCES. SECONDLY, WE REVIEW THE BASIS OF THE MOST IMPORTANT HORMONAL FACTORS INVOLVED IN THE DEVELOPMENT AND PROGRESSION OF MAFLD THAT ACT BOTH INDEPENDENTLY AND IN AN INTERRELATED MANNER. 2022 2 4520 36 MULTI-OMICS NUTRITIONAL APPROACHES TARGETING METABOLIC-ASSOCIATED FATTY LIVER DISEASE. CURRENTLY, METABOLIC-ASSOCIATED FATTY LIVER DISEASE (MAFLD) IS A LEADING GLOBAL CAUSE OF CHRONIC LIVER DISEASE, AND IS EXPECTED TO BECOME ONE OF THE MOST COMMON INDICATIONS OF LIVER TRANSPLANTATION. MAFLD IS ASSOCIATED WITH OBESITY, INVOLVING MULTIPLE MECHANISMS SUCH AS ALTERATIONS IN LIPID METABOLISM, INSULIN RESISTANCE, HYPERINFLAMMATION, MITOCHONDRIAL DYSFUNCTION, CELL APOPTOSIS, OXIDATIVE STRESS, AND EXTRACELLULAR MATRIX FORMATION. HOWEVER, THE ONSET AND PROGRESSION OF MAFLD IS VARIABLE AMONG INDIVIDUALS, BEING INFLUENCED BY INTRINSIC (PERSONAL) AND EXTERNAL ENVIRONMENTAL FACTORS. IN THIS CONTEXT, SEQUENCE STRUCTURAL VARIANTS ACROSS THE HUMAN GENOME, EPIGENETIC PHENOMENA (I.E., DNA METHYLATION, HISTONE MODIFICATIONS, AND LONG NON-CODING RNAS) AFFECTING GENE EXPRESSION, GUT MICROBIOTA DYSBIOSIS, AND METABOLOMICS/LIPIDOMIC FINGERPRINTS MAY ACCOUNT FOR DIFFERENCES IN MAFLD OUTCOMES THROUGH INTERACTIONS WITH NUTRITIONAL FEATURES. THIS KNOWLEDGE MAY CONTRIBUTE TO GAINING A DEEPER UNDERSTANDING OF THE MOLECULAR AND PHYSIOLOGICAL PROCESSES UNDERLYING MAFLD PATHOGENESIS AND PHENOTYPE HETEROGENEITY, AS WELL AS FACILITATING THE IDENTIFICATION OF BIOMARKERS OF DISEASE PROGRESSION AND THERAPEUTIC TARGETS FOR THE IMPLEMENTATION OF TAILORED NUTRITIONAL STRATEGIES. THIS COMPREHENSIVE LITERATURE REVIEW HIGHLIGHTS THE POTENTIAL OF NUTRIGENETIC, NUTRIEPIGENETIC, NUTRIMETAGENOMIC, NUTRITRANSCRIPTOMICS, AND NUTRIMETABOLOMIC APPROACHES FOR THE PREVENTION AND MANAGEMENT OF MAFLD IN HUMANS THROUGH THE LENS OF PRECISION NUTRITION. 2022 3 4710 35 NON-ALCOHOLIC FATTY LIVER DISEASE AND THE IMPACT OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS IN THE OFFSPRING. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CHRONIC LIVER DISEASE WORLDWIDE AND IS STRONGLY ASSOCIATED WITH METABOLIC DEREGULATION. MORE RECENTLY, A SIGNIFICANT IMPACT OF PARENTAL NAFLD IN THE OFFSPRING WAS DEMONSTRATED AND HAS BEEN WIDELY DISCUSSED. HOWEVER, PATHOGENETIC PATHWAYS IMPLICATED IN THE INHERITANCE BY THE OFFSPRING AND RELATIVES ARE STILL UNDER DEBATE. PROBABLY, MULTIPLE MECHANISMS ARE INVOLVED AS WELL AS IN NAFLD PATHOGENESIS ITSELF. AMONG THE MULTIFACTORIAL INVOLVED MECHANISMS, GENETIC, EPIGENETIC AND ENVIRONMENTAL BACKGROUNDS ARE STRONGLY RELATED TO NAFLD DEVELOPMENT IN THE OFFSPRING. THUS, BASED ON RECENT EVIDENCE FROM THE AVAILABLE LITERATURE CONCERNING GENETIC, EPIGENETIC AND ENVIRONMENTAL DISEASE MODIFIERS, THIS REVIEW AIMED TO DISCUSS THE RELATIONSHIP BETWEEN PARENTAL NAFLD AND ITS IMPACT ON THE OFFSPRING. 2022 4 4188 45 METABOLIC ASSOCIATED FATTY LIVER DISEASE IN CHILDREN AND ADOLESCENTS: MECHANISMS OF A SILENT EPIDEMIC AND THERAPEUTIC OPTIONS. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS NOW IDENTIFIED AS A HEPATIC SIGN OF METABOLIC SYNDROME AND IS THE MOST FREQUENT CAUSE OF CHRONIC LIVER DISEASE IN ALL AGES. IT IS ASSUMED THAT A GENETIC PREDISPOSITION ASSOCIATED WITH EPIGENETIC FACTORS PARTICIPATES IN THE EVOLUTION OF THIS CONDITION. VISCERAL OBESITY AND INSULIN RESISTANCE (IR) HAVE ALWAYS BEEN CONSIDERED THE MOST IMPORTANT CAUSATIVE FACTORS OF METABOLIC SYNDROME (METS) AND NAFLD, BUT CURRENTLY, THE INTERACTION BETWEEN GENETIC HERITAGE AND ENVIRONMENTAL FACTORS IS INCREASINGLY CONSIDERED FUNDAMENTAL IN THE GENESIS OF METABOLIC DISORDERS ASSOCIATED WITH NAFLD. IN FACT, IN PATIENTS WITH NAFLD, INSULIN RESISTANCE, ARTERIAL HYPERTENSION, ABDOMINAL OBESITY, DYSLIPIDEMIA AND REDUCED INTESTINAL PERMEABILITY HAVE OFTEN BEEN FOUND, AS WELL AS A HIGHER PREVALENCE OF CORONARY ARTERY DISEASE, OBSTRUCTIVE SLEEP APNEA, POLYCYSTIC OVARY SYNDROME AND OSTEOPENIA, WHICH DEFINE A METS FRAMEWORK. EARLY DIAGNOSIS IS NEEDED TO PREVENT DISEASE PROGRESSION THROUGH PRIMARILY LIFESTYLE INTERVENTIONS. UNFORTUNATELY, AT PRESENT, THERE ARE NO MOLECULES RECOMMENDED FOR PEDIATRIC PATIENTS. HOWEVER, SEVERAL NEW DRUGS ARE IN CLINICAL TRIALS. FOR THIS REASON, TARGETED STUDIES ON THE INTERACTION BETWEEN GENETICS AND ENVIRONMENTAL FACTORS INVOLVED IN THE DEVELOPMENT OF NAFLD AND METS AND ON THE PATHOGENETIC MECHANISMS THAT DETERMINE THE EVOLUTION IN NON-ALCOHOLIC STEATOHEPATITIS (NASH), SHOULD BE IMPLEMENTED. THEREFORE, IT IS DESIRABLE THAT FUTURE STUDIES MAY BE USEFUL IN IDENTIFYING PATIENTS AT RISK OF DEVELOPING NAFLD AND METS EARLY. 2023 5 5558 33 ROLE OF GUT MICROBIOTA IN THE AETIOLOGY OF OBESITY: PROPOSED MECHANISMS AND REVIEW OF THE LITERATURE. THE AETIOLOGY OF OBESITY HAS BEEN ATTRIBUTED TO SEVERAL FACTORS (ENVIRONMENTAL, DIETARY, LIFESTYLE, HOST, AND GENETIC FACTORS); HOWEVER NONE OF THESE FULLY EXPLAIN THE INCREASE IN THE PREVALENCE OF OBESITY WORLDWIDE. GUT MICROBIOTA LOCATED AT THE INTERFACE OF HOST AND ENVIRONMENT IN THE GUT ARE A NEW AREA OF RESEARCH BEING EXPLORED TO EXPLAIN THE EXCESS ACCUMULATION OF ENERGY IN OBESE INDIVIDUALS AND MAY BE A POTENTIAL TARGET FOR THERAPEUTIC MANIPULATION TO REDUCE HOST ENERGY STORAGE. SEVERAL MECHANISMS HAVE BEEN SUGGESTED TO EXPLAIN THE ROLE OF GUT MICROBIOTA IN THE AETIOLOGY OF OBESITY SUCH AS SHORT CHAIN FATTY ACID PRODUCTION, STIMULATION OF HORMONES, CHRONIC LOW-GRADE INFLAMMATION, LIPOPROTEIN AND BILE ACID METABOLISM, AND INCREASED ENDOCANNABINOID RECEPTOR SYSTEM TONE. HOWEVER, EVIDENCE FROM ANIMAL AND HUMAN STUDIES CLEARLY INDICATES CONTROVERSIES IN DETERMINING THE CAUSE OR EFFECT RELATIONSHIP BETWEEN THE GUT MICROBIOTA AND OBESITY. METAGENOMICS BASED STUDIES INDICATE THAT FUNCTIONALITY RATHER THAN THE COMPOSITION OF GUT MICROBIOTA MAY BE IMPORTANT. FURTHER MECHANISTIC STUDIES CONTROLLING FOR ENVIRONMENTAL AND EPIGENETIC FACTORS ARE THEREFORE REQUIRED TO HELP UNRAVEL OBESITY PATHOGENESIS. 2016 6 5821 34 STRESS IN OBESITY AND ASSOCIATED METABOLIC AND CARDIOVASCULAR DISORDERS. OBESITY HAS SIGNIFICANT IMPLICATIONS FOR HEALTHCARE, SINCE IT IS A MAJOR RISK FACTOR FOR BOTH TYPE 2 DIABETES AND THE METABOLIC SYNDROME. THIS SYNDROME IS A COMMON AND COMPLEX DISORDER COMBINING OBESITY, DYSLIPIDEMIA, HYPERTENSION, AND INSULIN RESISTANCE. IT IS ASSOCIATED WITH HIGH ATHEROSCLEROTIC CARDIOVASCULAR RISK, WHICH CAN ONLY PARTIALLY BE EXPLAINED BY ITS COMPONENTS. THEREFORE, TO EXPLAIN HOW OBESITY CONTRIBUTES TO THE DEVELOPMENT OF METABOLIC AND CARDIOVASCULAR DISORDERS, MORE AND BETTER INSIGHT IS REQUIRED INTO THE EFFECTS OF PERSONAL AND ENVIRONMENTAL STRESS ON DISEASE PROCESSES. IN THIS PAPER, WE SHOW THAT OBESITY IS A CHRONIC INFLAMMATORY DISEASE, WHICH HAS MANY MOLECULAR MECHANISMS IN COMMON WITH ATHEROSCLEROSIS. FURTHERMORE, WE FOCUS ON THE ROLE OF OXIDATIVE STRESS ASSOCIATED WITH OBESITY IN THE DEVELOPMENT OF THE METABOLIC SYNDROME. WE DISCUSS HOW SEVERAL STRESS CONDITIONS ARE RELATED TO INFLAMMATION AND OXIDATIVE STRESS IN ASSOCIATION WITH OBESITY AND ITS COMPLICATIONS. WE ALSO EMPHASIZE THE RELATION BETWEEN STRESS CONDITIONS AND THE DEREGULATION OF EPIGENETIC CONTROL MECHANISMS BY MEANS OF MICRORNAS AND SHOW HOW THIS IMPAIRMENT FURTHER CONTRIBUTES TO THE DEVELOPMENT OF OBESITY, CLOSING THE VICIOUS CIRCLE. FINALLY, WE DISCUSS THE LIMITATIONS OF CURRENT ANTI-INFLAMMATION AND ANTIOXIDANT THERAPY TO TREAT OBESITY. 2012 7 394 31 AN UPDATE IN EPIGENETICS IN METABOLIC-ASSOCIATED FATTY LIVER DISEASE. METABOLIC-ASSOCIATED FATTY LIVER DISEASE (MAFLD) IS CHARACTERIZED BY HEPATIC STEATOSIS ACCOMPANIED BY ONE OF THREE FEATURES: OVERWEIGHT OR OBESITY, T2DM, OR LEAN OR NORMAL WEIGHT WITH EVIDENCE OF METABOLIC DYSREGULATION. IT IS DISTINGUISHED BY EXCESSIVE FAT ACCUMULATION IN HEPATOCYTES, AND A DECREASE IN THE LIVER'S ABILITY TO OXIDIZE FATS, THE ACCUMULATION OF ECTOPIC FAT, AND THE ACTIVATION OF PROINFLAMMATORY PATHWAYS. CHRONIC DAMAGE WILL KEEP THIS PATHOPHYSIOLOGIC CYCLE ACTIVE CAUSING PROGRESSION FROM HEPATIC STEATOSIS TO CIRRHOSIS AND EVENTUALLY, HEPATOCARCINOMA. EPIGENETICS AFFECTING GENE EXPRESSION WITHOUT ALTERING DNA SEQUENCE ALLOWS US TO STUDY MAFLD PATHOPHYSIOLOGY FROM A DIFFERENT PERSPECTIVE, IN WHICH DNA METHYLATION PROCESSES, HISTONE MODIFICATIONS, AND MIRNAS EXPRESSION HAVE BEEN CLOSELY ASSOCIATED WITH MAFLD PROGRESSION. HOWEVER, THESE CONSIDERATIONS ALSO FACED US WITH THE CIRCUMSTANCE THAT MODIFYING THOSE EPIGENETICS PATTERNS MIGHT LEAD TO MAFLD REGRESSION. CURRENTLY, EPIGENETICS IS AN AREA OF GREAT INTEREST BECAUSE IT COULD PROVIDE NEW INSIGHTS IN THERAPEUTIC TARGETS AND NON-INVASIVE BIOMARKERS. THIS REVIEW COMPRISES AN UPDATE ON THE ROLE OF EPIGENETIC PATTERNS, AS WELL AS INNOVATIVE THERAPEUTIC TARGETS AND BIOMARKERS IN MAFLD. 2021 8 5079 48 PHYSIOPATHOLOGY OF NONALCOHOLIC FATTY LIVER DISEASE: FROM DIET TO NUTRIGENOMICS. PURPOSE OF REVIEW: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE WORLDWIDE AND IS STRONGLY ASSOCIATED WITH METABOLIC DISORDERS, SUCH AS OBESITY, TYPE 2 DIABETES MELLITUS, AND METABOLIC SYNDROME, TO THE EXTENT THAT A NEW DEFINITION OF METABOLIC ASSOCIATED FATTY LIVER DISEASE HAS BEEN PROPOSED. RECENT FINDINGS: INSULIN RESISTANCE, WORSENED BY A HIGH-FAT AND HIGH-CARBOHYDRATE DIET, IS THE KEY TO THE PHYSIOPATHOLOGY OF HEPATIC STEATOSIS. THIS IS DRIVEN BY SEVERAL MECHANISMS THAT ARE MOSTLY ACTIVATED AT A GENETIC LEVEL, SUCH AS DE-NOVO LIPOGENESIS AND TRIGLYCERIDE SYNTHESIS. THEREFORE, MANY DIET REGIMENS HAVE BEEN STUDIED, ALTHOUGH SIGNIFICANT CONTROVERSIES REMAIN REGARDING THEIR METABOLIC EFFECTS AND LONG-TERM SUSTAINABILITY. SUMMARY: IN THIS REVIEW, WE SUMMARIZED THE ROLE AND EFFECTS OF THE MAIN MACRONUTRIENTS ON THE DEVELOPMENT OF NAFLD AND DISCUSSED THE MOLECULAR MECHANISMS INVOLVED. WE ALSO DISCUSSED THE IMPORTANCE OF GENETIC POLYMORPHISMS, EPIGENETIC ALTERATIONS, AND DYSBIOSIS TO DETERMINE IF LIFESTYLE MODIFICATION AND A SPECIFIC DIETARY REGIMEN COULD BE AN ESSENTIAL PART OF NAFLD TREATMENT. 2022 9 4087 39 MATERNAL OBESITY INCREASES THE RISK OF METABOLIC DISEASE AND IMPACTS RENAL HEALTH IN OFFSPRING. OBESITY, TOGETHER WITH INSULIN RESISTANCE, PROMOTES MULTIPLE METABOLIC ABNORMALITIES AND IS STRONGLY ASSOCIATED WITH AN INCREASED RISK OF CHRONIC DISEASE INCLUDING TYPE 2 DIABETES (T2D), HYPERTENSION, CARDIOVASCULAR DISEASE, NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) AND CHRONIC KIDNEY DISEASE (CKD). THE INCIDENCE OF OBESITY CONTINUES TO RISE IN ASTRONOMICAL PROPORTIONS THROUGHOUT THE WORLD AND AFFECTS ALL THE DIFFERENT STAGES OF THE LIFESPAN. IMPORTANTLY, THE PROPORTION OF WOMEN OF REPRODUCTIVE AGE WHO ARE OVERWEIGHT OR OBESE IS INCREASING AT AN ALARMING RATE AND HAS POTENTIAL RAMIFICATIONS FOR OFFSPRING HEALTH AND DISEASE RISK. EVIDENCE SUGGESTS A STRONG LINK BETWEEN THE INTRAUTERINE ENVIRONMENT AND DISEASE PROGRAMMING. THE CURRENT REVIEW WILL DESCRIBE THE IMPORTANCE OF THE INTRAUTERINE ENVIRONMENT IN THE DEVELOPMENT OF METABOLIC DISEASE, INCLUDING KIDNEY DISEASE. IT WILL DETAIL THE KNOWN MECHANISMS OF FETAL PROGRAMMING, INCLUDING THE ROLE OF EPIGENETIC MODULATION. THE EVIDENCE FOR THE ROLE OF MATERNAL OBESITY IN THE DEVELOPMENTAL PROGRAMMING OF CKD IS DERIVED MOSTLY FROM OUR RODENT MODELS WHICH WILL BE DESCRIBED. THE CLINICAL IMPLICATION OF SUCH FINDINGS WILL ALSO BE DISCUSSED. 2018 10 44 36 A COMPREHENSIVE REVIEW ON HIGH -FAT DIET-INDUCED DIABETES MELLITUS: AN EPIGENETIC VIEW. MODERN LIFESTYLE, GENETICS, NUTRITIONAL OVERLOAD THROUGH HIGH-FAT DIET ATTRIBUTED PREVALENCE AND DIABETES OUTCOMES WITH VARIOUS COMPLICATIONS PRIMARILY DUE TO OBESITY IN WHICH ENERGY-DENSE DIETS FREQUENTLY AFFECT METABOLIC HEALTH. ONE POSSIBLE ISSUE USUALLY ASSOCIATED WITH ELEVATED CHRONIC FAT INTAKE IS INSULIN RESISTANCE, AND HYPERGLYCEMIA CONSTITUTES AN IMPORTANT FUNCTION IN ALTERING THE CARBOHYDRATES AND LIPIDS METABOLISM. SIMILARLY, IN ASSESSING HUMAN SUSCEPTIBILITY TO WEIGHT GAIN AND OBESITY, GENETIC VARIATIONS PLAY A CENTRAL ROLE, CONTRIBUTING TO KEEN INTEREST IN IDENTIFYING THE POSSIBLE ROLE OF EPIGENETICS AS A MEDIATOR OF GENE-ENVIRONMENTAL INTERACTIONS INFLUENCING THE PRODUCTION OF TYPE 2 DIABETES MELLITUS AND ITS RELATED CONCERNS. EPIGENETIC MODIFICATIONS ASSOCIATED WITH THE ACCEPTANCE OF A SEDENTARY LIFESTYLE AND ENVIRONMENTAL STRESS FACTORS IN RESPONSE TO ENERGY INTAKE AND EXPENDITURE IMBALANCES COMPLEMENT GENETIC ALTERATIONS AND LEAD TO THE PRODUCTION AND ADVANCEMENT OF METABOLIC DISORDERS SUCH AS DIABETES AND OBESITY. METHYLATION OF DNA, HISTONE MODIFICATIONS, AND INCREASES IN THE EXPRESSION OF NON-CODING RNAS CAN RESULT IN REDUCED TRANSCRIPTIONAL ACTIVITY OF KEY BETA-CELL GENES THUS CREATING INSULIN RESISTANCE. EPIGENETICS CONTRIBUTE TO CHANGES IN THE EXPRESSION OF THE UNDERLYING INSULIN RESISTANCE AND INSUFFICIENCY GENE NETWORKS, ALONG WITH LOW-GRADE OBESITY-RELATED INFLAMMATION, INCREASED ROS GENERATION, AND DNA DAMAGE IN MULTIORGANS. THIS REVIEW FOCUSED ON EPIGENETIC MECHANISMS AND METABOLIC REGULATIONS ASSOCIATED WITH HIGH-FAT DIET (HFD)-INDUCED DIABETES MELLITUS. 2022 11 2584 33 EPIGENETICS OF OBESITY. OBESITY IS A METABOLIC DISEASE, WHICH IS BECOMING AN EPIDEMIC HEALTH PROBLEM: IT HAS BEEN RECENTLY DEFINED IN TERMS OF GLOBAL PANDEMIC. OVER THE YEARS, THE APPROACHES THROUGH FAMILY, TWINS AND ADOPTION STUDIES LED TO THE IDENTIFICATION OF SOME CAUSAL GENES IN MONOGENIC FORMS OF OBESITY BUT THE ORIGINS OF THE PANDEMIC OF OBESITY CANNOT BE CONSIDERED ESSENTIALLY DUE TO GENETIC FACTORS, BECAUSE HUMAN GENOME IS NOT LIKELY TO CHANGE IN JUST A FEW YEARS. EPIGENETIC STUDIES HAVE OFFERED IN RECENT YEARS VALUABLE TOOLS FOR THE UNDERSTANDING OF THE WORLDWIDE SPREAD OF THE PANDEMIC OF OBESITY. THE INVOLVEMENT OF EPIGENETIC MODIFICATIONS-DNA METHYLATION, HISTONE TAILS, AND MIRNAS MODIFICATIONS-IN THE DEVELOPMENT OF OBESITY IS MORE AND MORE EVIDENT. IN THE EPIGENETIC LITERATURE, THERE ARE EVIDENCES THAT THE ENTIRE EMBRYO-FETAL AND PERINATAL PERIOD OF DEVELOPMENT PLAYS A KEY ROLE IN THE PROGRAMMING OF ALL HUMAN ORGANS AND TISSUES. THEREFORE, THE MOLECULAR MECHANISMS INVOLVED IN THE EPIGENETIC PROGRAMMING REQUIRE A NEW AND GENERAL PATHOGENIC PARADIGM, THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE THEORY, TO EXPLAIN THE CURRENT EPIDEMIOLOGICAL TRANSITION, THAT IS, THE WORLDWIDE INCREASE OF CHRONIC, DEGENERATIVE, AND INFLAMMATORY DISEASES SUCH AS OBESITY, DIABETES, CARDIOVASCULAR DISEASES, NEURODEGENERATIVE DISEASES, AND CANCER. OBESITY AND ITS RELATED COMPLICATIONS ARE MORE AND MORE ASSOCIATED WITH ENVIRONMENTAL POLLUTANTS (OBESOGENS), GUT MICROBIOTA MODIFICATIONS AND UNBALANCED FOOD INTAKE, WHICH CAN INDUCE, THROUGH EPIGENETIC MECHANISMS, WEIGHT GAIN, AND ALTERED METABOLIC CONSEQUENCES. 2016 12 5076 33 PHYSIOLOGICAL AND ENVIRONMENTAL FACTORS AFFECTING CANCER RISK AND PROGNOSIS IN OBESITY. OBESITY RESULTS FROM A CHRONIC EXCESSIVE ACCUMULATION OF ADIPOSE TISSUE DUE TO A LONG-TERM IMBALANCE BETWEEN ENERGY INTAKE AND EXPENDITURE. AVAILABLE EPIDEMIOLOGICAL AND CLINICAL DATA STRONGLY SUPPORT THE LINKS BETWEEN OBESITY AND CERTAIN CANCERS. EMERGING CLINICAL AND EXPERIMENTAL FINDINGS HAVE IMPROVED OUR UNDERSTANDING OF THE ROLES OF KEY PLAYERS IN OBESITY-ASSOCIATED CARCINOGENESIS SUCH AS AGE, SEX (MENOPAUSE), GENETIC AND EPIGENETIC FACTORS, GUT MICROBIOTA AND METABOLIC FACTORS, BODY SHAPE TRAJECTORY OVER LIFE, DIETARY HABITS, AND GENERAL LIFESTYLE. IT IS NOW WIDELY ACCEPTED THAT THE CANCER-OBESITY RELATIONSHIP DEPENDS ON THE SITE OF CANCER, THE SYSTEMIC INFLAMMATORY STATUS, AND MICRO ENVIRONMENTAL PARAMETERS SUCH AS LEVELS OF INFLAMMATION AND OXIDATIVE STRESS IN TRANSFORMING TISSUES. WE HEREBY REVIEW RECENT ADVANCES IN OUR UNDERSTANDING OF CANCER RISK AND PROGNOSIS IN OBESITY WITH RESPECT TO THESE PLAYERS. WE HIGHLIGHT HOW THE LACK OF THEIR CONSIDERATION CONTRIBUTED TO THE CONTROVERSY OVER THE LINK BETWEEN OBESITY AND CANCER IN EARLY EPIDEMIOLOGICAL STUDIES. FINALLY, THE LESSONS AND CHALLENGES OF INTERVENTIONS FOR WEIGHT LOSS AND BETTER CANCER PROGNOSIS, AND THE MECHANISMS OF WEIGHT GAIN IN SURVIVORS ARE ALSO DISCUSSED. 2023 13 6067 40 THE DIABETES MELLITUS-ATHEROSCLEROSIS CONNECTION: THE ROLE OF LIPID AND GLUCOSE METABOLISM AND CHRONIC INFLAMMATION. DIABETES MELLITUS COMPRISES A GROUP OF CARBOHYDRATE METABOLISM DISORDERS THAT SHARE A COMMON MAIN FEATURE OF CHRONIC HYPERGLYCEMIA THAT RESULTS FROM DEFECTS OF INSULIN SECRETION, INSULIN ACTION, OR BOTH. INSULIN IS AN IMPORTANT ANABOLIC HORMONE, AND ITS DEFICIENCY LEADS TO VARIOUS METABOLIC ABNORMALITIES IN PROTEINS, LIPIDS, AND CARBOHYDRATES. ATHEROSCLEROSIS DEVELOPS AS A RESULT OF A MULTISTEP PROCESS ULTIMATELY LEADING TO CARDIOVASCULAR DISEASE ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY. ALTERATION OF LIPID METABOLISM IS A RISK FACTOR AND CHARACTERISTIC FEATURE OF ATHEROSCLEROSIS. POSSIBLE LINKS BETWEEN THE TWO CHRONIC DISORDERS DEPENDING ON ALTERED METABOLIC PATHWAYS HAVE BEEN INVESTIGATED IN NUMEROUS STUDIES. IT WAS SHOWN THAT BOTH TYPES OF DIABETES MELLITUS CAN ACTUALLY INDUCE ATHEROSCLEROSIS DEVELOPMENT OR FURTHER ACCELERATE ITS PROGRESSION. ELEVATED GLUCOSE LEVEL, DYSLIPIDEMIA, AND OTHER METABOLIC ALTERATIONS THAT ACCOMPANY THE DISEASE DEVELOPMENT ARE TIGHTLY INVOLVED IN THE PATHOGENESIS OF ATHEROSCLEROSIS AT ALMOST EVERY STEP OF THE ATHEROGENIC PROCESS. CHRONIC INFLAMMATION IS CURRENTLY CONSIDERED AS ONE OF THE KEY FACTORS IN ATHEROSCLEROSIS DEVELOPMENT AND IS PRESENT STARTING FROM THE EARLIEST STAGES OF THE PATHOLOGY INITIATION. IT MAY ALSO BE REGARDED AS ONE OF THE POSSIBLE LINKS BETWEEN ATHEROSCLEROSIS AND DIABETES MELLITUS. HOWEVER, THE DATA AVAILABLE SO FAR DO NOT ALLOW FOR DEVELOPING EFFECTIVE ANTI-INFLAMMATORY THERAPEUTIC STRATEGIES THAT WOULD STOP ATHEROSCLEROTIC LESION PROGRESSION OR INDUCE LESION REDUCTION. IN THIS REVIEW, WE SUMMARIZE THE MAIN ASPECTS OF DIABETES MELLITUS THAT POSSIBLY AFFECT THE ATHEROGENIC PROCESS AND ITS RELATIONSHIP WITH CHRONIC INFLAMMATION. WE ALSO DISCUSS THE ESTABLISHED PATHOPHYSIOLOGICAL FEATURES THAT LINK ATHEROSCLEROSIS AND DIABETES MELLITUS, SUCH AS OXIDATIVE STRESS, ALTERED PROTEIN KINASE SIGNALING, AND THE ROLE OF CERTAIN MIRNA AND EPIGENETIC MODIFICATIONS. 2020 14 5654 35 SEX, NUTRITION, AND NAFLD: RELEVANCE OF ENVIRONMENTAL POLLUTION. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON FORM OF CHRONIC LIVER DISEASE AND REPRESENTS AN INCREASING PUBLIC HEALTH ISSUE GIVEN THE LIMITED TREATMENT OPTIONS AND ITS ASSOCIATION WITH SEVERAL OTHER METABOLIC AND INFLAMMATORY DISORDERS. THE EPIDEMIC, STILL GROWING PREVALENCE OF NAFLD WORLDWIDE CANNOT BE MERELY EXPLAINED BY CHANGES IN DIET AND LIFESTYLE THAT OCCURRED IN THE LAST FEW DECADES, NOR FROM THEIR ASSOCIATION WITH GENETIC AND EPIGENETIC RISK FACTORS. IT IS CONCEIVABLE THAT ENVIRONMENTAL POLLUTANTS, WHICH ACT AS ENDOCRINE AND METABOLIC DISRUPTORS, MAY CONTRIBUTE TO THE SPREADING OF THIS PATHOLOGY DUE TO THEIR ABILITY TO ENTER THE FOOD CHAIN AND BE INGESTED THROUGH CONTAMINATED FOOD AND WATER. GIVEN THE STRICT INTERPLAY BETWEEN NUTRIENTS AND THE REGULATION OF HEPATIC METABOLISM AND REPRODUCTIVE FUNCTIONS IN FEMALES, POLLUTANT-INDUCED METABOLIC DYSFUNCTIONS MAY BE OF PARTICULAR RELEVANCE FOR THE FEMALE LIVER, DAMPENING SEX DIFFERENCES IN NAFLD PREVALENCE. DIETARY INTAKE OF ENVIRONMENTAL POLLUTANTS CAN BE PARTICULARLY DETRIMENTAL DURING GESTATION, WHEN ENDOCRINE-DISRUPTING CHEMICALS MAY INTERFERE WITH THE PROGRAMMING OF LIVER METABOLISM, ACCOUNTING FOR THE DEVELOPMENTAL ORIGIN OF NAFLD IN OFFSPRING. THIS REVIEW SUMMARIZES CAUSE-EFFECT EVIDENCE BETWEEN ENVIRONMENTAL POLLUTANTS AND INCREASED INCIDENCE OF NAFLD AND EMPHASIZES THE NEED FOR FURTHER STUDIES IN THIS FIELD. 2023 15 4795 38 NUTRITIONAL GENOMICS IN NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A COMMON CHRONIC CONDITION ASSOCIATED WITH GENETIC AND ENVIRONMENTAL FACTORS IN WHICH FAT ABNORMALLY ACCUMULATES IN THE LIVER. NAFLD IS EPIDEMIOLOGICALLY ASSOCIATED WITH OBESITY, TYPE 2 DIABETES, AND DYSLIPIDEMIA. ENVIRONMENTAL FACTORS, SUCH AS PHYSICAL INACTIVITY AND AN UNBALANCED DIET, INTERACT WITH GENETIC FACTORS, SUCH AS EPIGENETIC MECHANISMS AND POLYMORPHISMS FOR THE GENESIS AND DEVELOPMENT OF THE CONDITION. DIFFERENT GENETIC POLYMORPHISMS SEEM TO BE INVOLVED IN THIS CONTEXT, INCLUDING VARIANTS IN PNPLA3, TM6SF2, PEMT, AND CHDH GENES, PLAYING A ROLE IN THE DISEASE'S SUSCEPTIBILITY, DEVELOPMENT, AND SEVERITY. FROM CARBOHYDRATE INTAKE AND WEIGHT LOSS TO OMEGA-3 SUPPLEMENTATION AND CALORIC RESTRICTION, DIFFERENT DIETARY AND NUTRITIONAL FACTORS APPEAR TO BE INVOLVED IN CONTROLLING THE ONSET AND PROGRESSION OF NAFLD CONDITIONS INFLUENCING METABOLISM, GENE, AND PROTEIN EXPRESSION. THE POLYGENIC RISK SCORE REPRESENTS A SUM OF TRAIT-ASSOCIATED ALLELES CARRIED BY AN INDIVIDUAL AND SEEMS TO BE ASSOCIATED WITH NAFLD OUTCOMES DEPENDING ON THE DIETARY CONTEXT. UNDERSTANDING THE EXACT EXTENT TO WHICH LIFESTYLE INTERVENTIONS AND GENETIC PREDISPOSITIONS CAN PLAY A ROLE IN THE PREVENTION AND MANAGEMENT OF NAFLD CAN BE CRUCIAL FOR THE ESTABLISHMENT OF A PERSONALIZED AND INTEGRATIVE APPROACH TO PATIENTS. 2023 16 2699 39 EXCESS BODY WEIGHT: NOVEL INSIGHTS INTO ITS ROLES IN OBESITY COMORBIDITIES. EXCESS BODY WEIGHT IS A GLOBAL HEALTH PROBLEM DUE TO SEDENTARY LIFESTYLE AND UNHEALTHY DIET, AFFECTING 2 BILLION POPULATION WORLDWIDE. OBESITY IS A MAJOR RISK FACTOR FOR METABOLIC DISEASES. NOTABLY, THE METABOLIC RISK OF OBESITY LARGELY DEPENDS ON BODY WEIGHT DISTRIBUTION, OF WHICH VISCERAL ADIPOSE TISSUES BUT NOT SUBCUTANEOUS FATS ARE CLOSELY ASSOCIATED WITH OBESITY COMORBIDITIES, INCLUDING TYPE 2 DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, CARDIOVASCULAR DISEASE AND CERTAIN TYPES OF CANCER. LATEST MULTI-OMICS AND MECHANISTICAL STUDIES REPORTED THE CRUCIAL INVOLVEMENT OF GENETIC AND EPIGENETIC ALTERATIONS, ADIPOKINES DYSREGULATION, IMMUNITY CHANGES, IMBALANCE OF WHITE AND BROWN ADIPOSE TISSUES, AND GUT MICROBIAL DYSBIOSIS IN MEDIATING THE PATHOGENIC ASSOCIATION BETWEEN VISCERAL ADIPOSE TISSUES AND COMORBIDITIES. IN THIS REVIEW, WE EXPLORE THE EPIDEMIOLOGY OF EXCESS BODY WEIGHT AND THE UP-TO-DATE MECHANISM OF HOW EXCESS BODY WEIGHT AND OBESITY LEAD TO CHRONIC COMPLICATIONS. WE ALSO EXAMINE THE UTILIZATION OF VISCERAL FAT MEASUREMENT AS AN ACCURATE CLINICAL PARAMETER FOR RISK ASSESSMENT IN HEALTHY INDIVIDUALS AND CLINICAL OUTCOME PREDICTION IN OBESE SUBJECTS. IN ADDITION, CURRENT APPROACHES FOR THE PREVENTION AND TREATMENT OF EXCESS BODY WEIGHT AND ITS RELATED METABOLIC COMORBIDITIES ARE FURTHER DISCUSSED. 2023 17 3293 41 HIGH FAT DIET-TRIGGERED NON-ALCOHOLIC FATTY LIVER DISEASE: A REVIEW OF PROPOSED MECHANISMS. OBESITY IS CHARACTERIZED BY THE DEPOSITION OF EXCESSIVE BODY FAT, AND IS CAUSED BY ENERGY IMBALANCE, ESPECIALLY WHEN CONSUMING FAT-RICH DIETS. HIGH FAT DIET (HFD)-ASSOCIATED OBESITY IS GREATLY COMMON IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) THAT IS EMERGING AS ONE OF THE MOST UNIVERSAL CAUSES OF LIVER DISEASE WORLDWIDE, ESPECIALLY IN WESTERN COUNTRIES. IN SPITE OF ITS HIGH PREVALENCE, ONLY A SMALL PROPORTION OF AFFECTED INDIVIDUALS WILL BECOME INFLAMED, FOLLOWED BY FIBROSIS AND CHRONIC LIVER DISEASES, AND MOST PATIENTS ONLY SHOW SIMPLE STEATOSIS. IN THIS CASE, THE FULL COMPREHENSION OF THE MECHANISMS UNDERLYING THE PROGRESSION OF NAFLD IS OF EXTREME SIGNIFICANCE; IN SPITE OF PROGRESS IN THIS FIELD, AWARENESS ON THE DEVELOPMENT OF NAFLD IS STILL INCOMPLETE. TRADITIONALLY, LIVER STEATOSIS IS COMMONLY CONNECTED WITH HFD, OBESITY, AND INSULIN RESISTANCE (IR). RECENTLY, VARIOUS POSSIBLE MECHANISMS HAVE BEEN PUT FORWARD FOR LIVER DAMAGE, INCLUDING ENDOPLASMIC RETICULUM STRESS, PERTURBATION OF AUTOPHAGY, MITOCHONDRIAL DYSFUNCTION, HEPATOCELLULAR APOPTOSIS, GUT MICROBIOTA IMBALANCE, DYSREGULATION OF MICRORNAS, AND GENETIC/EPIGENETIC RISK FACTORS, AS WELL AS AN INCREASE IN INFLAMMATORY RESPONSES, AMONG MANY OTHERS. COLLECTIVELY, THESE PROPOSED MECHANISMS ALLOW FOR A VARIETY OF HITS ACTING TOGETHER ON SUBJECTS TO MEDIATED NAFLD AND WILL OFFER A MORE ACCURATE EXPLANATION FOR PROGRESSION OF NAFLD. THEREFORE, THIS REVIEW SUMMARIZES THE PRESENT INFORMATION CONCERNING NAFLD AFTER HFD EXPOSURE, AS WELL AS DISCUSSES POSSIBLE MECHANISMS THROUGH WHICH IT MAY ARISE. 2020 18 6204 39 THE INFLUENCE OF EPIGENETICS AND INFLAMMATION ON CARDIOMETABOLIC RISKS. CARDIOMETABOLIC DISEASES INCLUDE METABOLIC SYNDROME, OBESITY, TYPE 2 DIABETES MELLITUS, AND HYPERTENSION. EPIGENETIC MODIFICATIONS PARTICIPATE IN CARDIOMETABOLIC DISEASES THROUGH SEVERAL PATHWAYS, INCLUDING INFLAMMATION, VASCULAR DYSFUNCTION, AND INSULIN RESISTANCE. EPIGENETIC MODIFICATIONS, WHICH ENCOMPASS ALTERATIONS TO GENE EXPRESSION WITHOUT MUTATING THE DNA SEQUENCE, HAVE GAINED MUCH ATTENTION IN RECENT YEARS, SINCE THEY HAVE BEEN CORRELATED WITH CARDIOMETABOLIC DISEASES AND MAY BE TARGETED FOR THERAPEUTIC INTERVENTIONS. EPIGENETIC MODIFICATIONS ARE GREATLY INFLUENCED BY ENVIRONMENTAL FACTORS, SUCH AS DIET, PHYSICAL ACTIVITY, CIGARETTE SMOKING, AND POLLUTION. SOME MODIFICATIONS ARE HERITABLE, INDICATING THAT THE BIOLOGICAL EXPRESSION OF EPIGENETIC ALTERATIONS MAY BE OBSERVED ACROSS GENERATIONS. MOREOVER, MANY PATIENTS WITH CARDIOMETABOLIC DISEASES PRESENT WITH CHRONIC INFLAMMATION, WHICH CAN BE INFLUENCED BY ENVIRONMENTAL AND GENETIC FACTORS. THE INFLAMMATORY ENVIRONMENT WORSENS THE PROGNOSIS OF CARDIOMETABOLIC DISEASES AND FURTHER INDUCES EPIGENETIC MODIFICATIONS, PREDISPOSING PATIENTS TO THE DEVELOPMENT OF OTHER METABOLISM-ASSOCIATED DISEASES AND COMPLICATIONS. A DEEPER UNDERSTANDING OF INFLAMMATORY PROCESSES AND EPIGENETIC MODIFICATIONS IN CARDIOMETABOLIC DISEASES IS NECESSARY TO IMPROVE OUR DIAGNOSTIC CAPABILITIES, PERSONALIZED MEDICINE APPROACHES, AND THE DEVELOPMENT OF TARGETED THERAPEUTIC INTERVENTIONS. FURTHER UNDERSTANDING MAY ALSO ASSIST IN PREDICTING DISEASE OUTCOMES, ESPECIALLY IN CHILDREN AND YOUNG ADULTS. THIS REVIEW DESCRIBES EPIGENETIC MODIFICATIONS AND INFLAMMATORY PROCESSES UNDERLYING CARDIOMETABOLIC DISEASES, AND FURTHER DISCUSSES ADVANCES IN THE RESEARCH FIELD WITH A FOCUS ON SPECIFIC POINTS FOR INTERVENTIONAL THERAPY. 2023 19 4314 43 MICRORNAS AS CONTROLLED SYSTEMS AND CONTROLLERS IN NON-ALCOHOLIC FATTY LIVER DISEASE. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A MULTI-FACETED CONDITION INCLUDING SIMPLE STEATOSIS ALONE OR ASSOCIATED WITH INFLAMMATION AND BALLOONING (NON-ALCOHOLIC STEATOHEPATITIS) AND EVENTUALLY FIBROSIS. THE NAFLD INCIDENCE HAS INCREASED OVER THE LAST TWENTY YEARS BECOMING THE MOST FREQUENT CHRONIC LIVER DISEASE IN INDUSTRIALIZED COUNTRIES. OBESITY, VISCERAL ADIPOSITY, INSULIN RESISTANCE, AND MANY OTHER DISORDERS THAT CHARACTERIZE METABOLIC SYNDROME ARE THE MAJOR PREDISPOSING RISK FACTORS FOR NAFLD. FURTHERMORE, DIFFERENT FACTORS, INCLUDING GENETIC BACKGROUND, EPIGENETIC MECHANISMS AND ENVIRONMENTAL FACTORS, SUCH AS DIET AND PHYSICAL EXERCISE, CONTRIBUTE TO NAFLD DEVELOPMENT AND PROGRESSION. SEVERAL LINES OF EVIDENCE DEMONSTRATE THAT SPECIFIC MICRORNAS EXPRESSION PROFILES ARE STRONGLY ASSOCIATED WITH SEVERAL PATHOLOGICAL CONDITIONS INCLUDING NAFLD. IN NAFLD, MICRORNA DEREGULATION IN RESPONSE TO INTRINSIC GENETIC OR EPIGENETIC FACTORS OR ENVIRONMENTAL FACTORS CONTRIBUTES TO METABOLIC DYSFUNCTION. IN THIS REVIEW WE FOCUSED ON MICRORNAS ROLE BOTH AS CONTROLLED AND CONTROLLERS MOLECULES IN NAFLD DEVELOPMENT AND/OR THEIR EVENTUAL VALUE AS NON-INVASIVE BIOMARKERS OF DISEASE. 2014 20 4425 45 MOLECULAR BASIS OF AGEING IN CHRONIC METABOLIC DISEASES. AIM: OVER THE LAST DECADES, THE SHIFT IN AGE DISTRIBUTION TOWARDS OLDER AGES AND THE PROGRESSIVE AGEING WHICH HAS OCCURRED IN MOST POPULATIONS HAVE BEEN PARALLELED BY A GLOBAL EPIDEMIC OF OBESITY AND ITS RELATED METABOLIC DISORDERS, PRIMARILY, TYPE 2 DIABETES (T2D). DYSFUNCTION OF THE ADIPOSE TISSUE (AT) IS WIDELY RECOGNIZED AS A SIGNIFICANT HALLMARK OF THE AGEING PROCESS THAT, IN TURN, RESULTS IN SYSTEMIC METABOLIC ALTERATIONS. THESE INCLUDE INSULIN RESISTANCE, ACCUMULATION OF ECTOPIC LIPIDS AND CHRONIC INFLAMMATION, WHICH ARE RESPONSIBLE FOR AN ELEVATED RISK OF OBESITY AND T2D ONSET ASSOCIATED TO AGEING. ON THE OTHER HAND, OBESITY AND T2D, THE PARADIGMS OF AT DYSFUNCTION, SHARE MANY PHYSIOLOGICAL CHARACTERISTICS WITH THE AGEING PROCESS, SUCH AS AN INCREASED BURDEN OF SENESCENT CELLS AND EPIGENETIC ALTERATIONS. THUS, THESE CHRONIC METABOLIC DISORDERS MAY REPRESENT A STATE OF ACCELERATED AGEING. MATERIALS AND METHODS: A MORE PRECISE EXPLANATION OF THE FUNDAMENTAL AGEING MECHANISMS THAT OCCUR IN AT AND A DEEPER UNDERSTANDING OF THEIR ROLE IN THE INTERPLAY BETWEEN ACCELERATED AGEING AND AT DYSFUNCTION CAN BE A FUNDAMENTAL LEAP TOWARDS NOVEL THERAPIES THAT ADDRESS THE CAUSES, NOT JUST THE SYMPTOMS, OF OBESITY AND T2D, UTILIZING STRATEGIES THAT TARGET EITHER SENESCENT CELLS OR DNA METHYLATION. RESULTS: IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE PATHWAYS THAT LEAD TO AT DYSFUNCTION IN THE CHRONOLOGICAL AGEING PROCESS AS WELL AS THE PATHOPHYSIOLOGY OF OBESITY AND T2D, EMPHASIZING THE CRITICAL ROLE OF CELLULAR SENESCENCE AND DNA METHYLATION. CONCLUSION: FINALLY, WE HIGHLIGHT THE NEED FOR FURTHER RESEARCH FOCUSED ON TARGETING THESE MECHANISMS. 2020