1 6774 139 [AGE-RELATED VASCULAR CHANGES EXEMPLIFIED BY THE CAROTID ARTERY]. ONE OF THE MAIN RISK FACTORS FOR THE PRESENCE OF CAROTID STENOSIS AND CAROTID-RELATED STROKE IS AGE. THE AIM OF THIS REVIEW ARTICLE IS TO PRESENT THE CURRENT STATE OF KNOWLEDGE ON AGE-RELATED VASCULAR CHANGES USING CAROTID STENOSIS AS AN EXAMPLE.VASCULAR AGING (VASCULAR SENESCENCE) IS A DECREASE OF STRUCTURAL AND FUNCTIONAL PROPERTIES OF THE VESSEL WALL THAT TAKES PLACE ON DIFFERENT LEVELS. AT THE MULTICELLULAR LEVEL AN INCREASE IN VESSEL VOLUME AND DIAMETER AS WELL AS INTIMA MEDIA THICKNESS OCCURS WITH AGE MAINLY DUE TO ATHEROSCLEROTIC CHANGES IN THE VESSEL WALL. AT THE CELLULAR AND EXTRACELLULAR LEVELS THERE IS A DECREASE IN ELASTIN FIBERS, SMOOTH MUSCLE CELLS, AND TOTAL CELLULARITY, AN INCREASE IN LIPID, CHOLESTEROL, AND CALCIUM PHOSPHATE DEPOSITION AS WELL AS NEOVASCULARIZATION. THE CAUSES OF VASCULAR AGING AT THE MOLECULAR LEVEL INCLUDE, IN PARTICULAR OXIDATIVE STRESS, CHRONIC INFLAMMATORY RESPONSE, MITOCHONDRIAL DYSFUNCTION, EPIGENETIC CHANGES, DYSREGULATION OF THE EXPRESSION OF NON-CODING RNAS (NCRNAS), AND THE INCREASE IN SENESCENCE. AGE-RELATED LOSS OF TISSUE HEALING AND REPAIR CAPACITY MAKE PLAQUES MORE VULNERABLE AND, IN THE CASE OF THE CAROTID ARTERY, MORE SUSCEPTIBLE TO ISCHEMIC STROKE.INCREASING KNOWLEDGE OF THE INFLUENCE OF AGING ON THE EPIGENETICS AND NCRNAS IN ATHEROSCLEROTIC PLAQUES CAN IN THE FUTURE MORE ACCURATELY QUANTIFY INDIVIDUAL PATIENT RISK AND CONTRIBUTE TO THE DEVELOPMENT OF TARGETED THERAPEUTIC STRATEGIES; HOWEVER, FURTHER STUDIES ARE NEEDED IN THIS FIELD TO UNDERSTAND THE FULL EXTENT OF VASCULAR AGING AND ITS ASSOCIATED DISEASES SO THAT THESE CAN THEN BE SPECIFICALLY TARGETED. 2022 2 506 34 ASSOCIATION OF ENDOMETRIOSIS WITH CARDIOVASCULAR DISEASE: GENETIC ASPECTS (REVIEW). CARDIOVASCULAR DISEASE (CVD) COMPRISES A BROAD SPECTRUM OF PATHOLOGICAL CONDITIONS THAT AFFECT THE HEART OR BLOOD VESSELS, INCLUDING SEQUELAE THAT ARISE FROM DAMAGED VASCULATURE IN OTHER ORGANS OF THE BODY, SUCH AS THE BRAIN, KIDNEYS OR EYES. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE OF THE ARTERIAL INTIMA AND IS THE PRIMARY CAUSE OF CORONARY ARTERY DISEASE, PERIPHERAL VASCULAR DISEASE, HEART ATTACK, STROKE AND RENAL PATHOLOGY. IT REPRESENTS A LEADING CAUSE OF MORTALITY WORLDWIDE AND THE LOSS OF HUMAN PRODUCTIVITY THAT IS MARKED BY AN ALTERED IMMUNE RESPONSE. ENDOMETRIOSIS IS A HERITABLE, HETEROGENEOUS, COMMON GYNECOLOGICAL CONDITION INFLUENCED BY MULTIPLE GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS, AFFECTING UP TO 10% OF THE FEMALE POPULATION OF CHILDBEARING AGE, CAUSING PAIN AND INFERTILITY; IT IS CHARACTERIZED BY THE ECTOPIC GROWTH OF ENDOMETRIAL TISSUE OUTSIDE THE UTERINE CAVITY. OF NOTE, EPIDEMIOLOGICAL DATA OBTAINED THUS FAR HAVE SUGGESTED A LINK BETWEEN ENDOMETRIOSIS AND THE RISK OF DEVELOPING CVD. THE SIMILARITIES OBSERVED IN SPECIFIC MOLECULAR AND CELLULAR PATHWAYS OF ENDOMETRIOSIS AND CVD MAY BE PARTIALLY EXPLAINED BY A SHARED GENETIC BACKGROUND. THE PRESENT REVIEW PRESENTS AND DISCUSSES THE SHARED GENETIC FACTORS WHICH HAVE BEEN REPORTED TO BE ASSOCIATED WITH THE DEVELOPMENT OF BOTH DISORDERS. 2023 3 3846 35 IS ATHEROSCLEROSIS A NEUROGENIC PHENOMENON? IDENTIFIED RISK FACTORS FOR ATHEROSCLEROSIS INCLUDE DIET, AGE, GENDER, FAMILY HISTORY, STRESS, LIFESTYLE, SMOKING, DIABETES, DYSLIPIDEMIAS, HYPERTENSION, AND HIV. THE MECHANISTIC RATIONALE TO EXPLAIN THESE ASSOCIATIONS REMAINS POORLY UNDERSTOOD. WE BELIEVE THAT THESE SEEMINGLY UNRELATED ENTITIES MAY PROMOTE ATHEROSCLEROSIS THROUGH A COMMON PATHWAY BY INDUCING ADVENTITIAL AUTONOMIC DYSFUNCTION, SPECIFICALLY AS AN ADVENTITIAL STRESS DYSFUNCTION OF NEUROGENIC ORIGIN. ATHEROSCLEROSIS MAY REPRESENT A LOCAL VASCULAR MANIFESTATION OF THE GLOBAL AUTONOMIC DYSFUNCTION INDUCED BY AGE, SMOKING, HYPERTENSION, HIV, AND DIABETES. ATHEROSCLEROSIS MAY ALSO PARTICIPATE IN A FEED-FORWARD CYCLE AS AGING, DIABETES, DYSLIPIDEMIA, AND HYPERTENSION MAY ALSO REPRESENT INDEPENDENT DOWNSTREAM CONSEQUENCES OF GLOBAL SYMPATHETIC BIAS. CHRONIC PHYSIOLOGIC STRESS AND BEHAVIORAL STRESS CAN SHIFT THE AUTONOMIC BALANCE TOWARDS A STATE OF SYMPATHETIC PREDOMINANCE. THE HIGHLY COMMUNICABLE NATURE OF BEHAVIORAL STRESS MAY PARTIALLY IMPLICATE THE FAMILIAL ASSOCIATION OF ATHEROSCLEROSIS AS AN EPIGENETIC PHENOMENON, INDEPENDENT OF PUTATIVE GENETIC MECHANISMS. HOST STRESS, GLOBAL AUTONOMIC DYSFUNCTION, AND SYMPATHETIC BIAS MAY ALSO ARISE FROM CHRONIC MALADAPTIVE CONSUMPTION OF STRESSED FOODS, AS ORGANISMS DETECT AND ASSIMILATE THE STRESS PHENOTYPES OF THEIR DIETARY CONSTITUENTS THROUGH A PROCESS CALLED XENOHORMESIS. THE BENEFITS OF EXERCISE MAY OPERATE THROUGH REDUCTION OF CHRONIC PHYSIOLOGIC STRESS ASSOCIATED WITH GLOBAL SYMPATHETIC BIAS. THE NEUROGENIC ADVENTITIAL STRESS RESPONSE MAY EXPLAIN THE LOCAL TISSUE REMODELING SEEN IN ATHEROSCLEROSIS, INCLUDING ADVENTITIAL ADIPOSE DYSFUNCTION, INFLAMMATION, ADVENTITIAL ANGIOGENESIS, THROMBOSIS, AND ENDOTHELIAL DYSFUNCTION. WE BELIEVE THAT THE LOCATIONS OF ATHEROSCLEROTIC LESIONS CORRESPOND TO REGIONS OF NEUROGENIC ADVENTITIAL AUTONOMIC DYSFUNCTION, IN SIMILAR FASHION TO THE SEGMENTAL PATTERNS OF INVOLVEMENT FOUND IN INFLAMMATORY BOWEL DISEASE. THE DIFFUSE ATHEROSCLEROSIS EXHIBITED IN TRANSPLANTED HEARTS MAY REFLECT A DIFFUSE SYMPATHETIC BIAS OF THE DONOR HEART, SINCE TISSUES AND ORGANS EXHIBIT AN INTRINSIC SYMPATHETIC BIAS IN THE ABSENCE OF AN EXTRINSIC SOURCE OF AUTONOMIC HEGEMONY. ONCE WE REGARD ATHEROSCLEROSIS AS A NEUROGENIC PHENOMENON MANIFESTED IN ADVENTITIAL AUTONOMIC DYSFUNCTION, NOVEL DIAGNOSTIC AND THERAPEUTIC PARADIGMS BECOME EVIDENT. 2007 4 2687 37 EVIDENCE OF EPIGENETIC ALTERATIONS IN THROMBOSIS AND COAGULATION: A SYSTEMATIC REVIEW. THROMBOSIS IN THE CONTEXT OF CARDIOVASCULAR DISEASE (CVD) AFFECTS MAINLY THE BLOOD VESSELS SUPPLYING THE HEART, BRAIN AND PERIPHERIES AND IT IS THE LEADING CAUSE OF DEATH WORLDWIDE. THE PATHOPHYSIOLOGICAL THROMBOTIC MECHANISMS ARE LARGELY UNKNOWN. HERITABILITY CONTRIBUTES TO A 30% OF THE INCIDENCE OF CVD. THE REMAINING VARIATION CAN BE EXPLAINED BY LIFE STYLE FACTORS SUCH AS SMOKING, DIETARY AND EXERCISE HABITS, ENVIRONMENTAL EXPOSURE TO TOXINS, AND DRUG USAGE AND OTHER COMORBIDITIES. EPIGENETIC VARIATION CAN BE ACQUIRED OR INHERITED AND CONSTITUTES AN INTERACTION BETWEEN GENES AND THE ENVIRONMENT. EPIGENETICS HAVE BEEN IMPLICATED IN ATHEROSCLEROSIS, ISCHEMIA/REPERFUSION DAMAGE AND THE CARDIOVASCULAR RESPONSE TO HYPOXIA. EPIGENETIC REGULATORS OF GENE EXPRESSION ARE MAINLY THE METHYLATION OF CPG ISLANDS, HISTONE POST TRANSLATIONAL MODIFICATIONS (PTMS) AND MICRORNAS (MIRNAS). THESE EPIGENETIC REGULATORS CONTROL GENE EXPRESSION EITHER THROUGH ACTIVATION OR SILENCING. EPIGENETIC CONTROL IS MOSTLY DYNAMIC AND CAN POTENTIALLY BE MANIPULATED TO PREVENT OR REVERSE THE UNCONTROLLED EXPRESSION OF GENES, A TRAIT THAT RENDERS THEM PUTATIVE THERAPEUTIC TARGETS. IN THE CURRENT REVIEW, WE SYSTEMATICALLY STUDIED AND PRESENT AVAILABLE DATA ON EPIGENETIC ALTERATIONS IMPLICATED IN THROMBOSIS DERIVED FROM HUMAN STUDIES. EVIDENCE OF EPIGENETIC ALTERATIONS IS OBSERVED IN SEVERAL THROMBOTIC DISEASES SUCH AS CORONARY ARTERY DISEASE AND CEREBROVASCULAR DISEASE, PREECLAMPSIA AND ANTIPHOSPHOLIPID SYNDROME. DIFFERENTIAL CPG METHYLATION AND SPECIFIC HISTONE PTMS THAT CONTROL TRANSCRIPTION OF PROTHROMBOTIC AND PROINFLAMMATORY GENES HAVE ALSO BEEN ASSOCIATED WITH PREDISPOSING FACTORS OF THROMBOSIS AND CVD, SUCH US SMOKING, AIR POLLUTION, HYPERTRIGLYCERIDEMIA, OCCUPATIONAL EXPOSURE TO PARTICULATE MATTER AND COMORBIDITIES INCLUDING CANCER, CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND CHRONIC KIDNEY DISEASE. THESE CLINICAL OBSERVATIONS ARE FURTHER SUPPORTED BY IN VITRO EXPERIMENTS AND INDICATE THAT EPIGENETIC REGULATION AFFECTS THE PATHOPHYSIOLOGY OF THROMBOTIC DISORDERS WITH POTENTIAL DIAGNOSTIC OR THERAPEUTIC UTILITY. 2019 5 1712 44 DYSFUNCTIONAL VASCULAR ENDOTHELIUM AS A DRIVER OF ATHEROSCLEROSIS: EMERGING INSIGHTS INTO PATHOGENESIS AND TREATMENT. ATHEROSCLEROSIS, THE CHRONIC ACCUMULATION OF CHOLESTEROL-RICH PLAQUE WITHIN ARTERIES, IS ASSOCIATED WITH A BROAD SPECTRUM OF CARDIOVASCULAR DISEASES INCLUDING MYOCARDIAL INFARCTION, AORTIC ANEURYSM, PERIPHERAL VASCULAR DISEASE, AND STROKE. ATHEROSCLEROTIC CARDIOVASCULAR DISEASE REMAINS A LEADING CAUSE OF MORTALITY IN HIGH-INCOME COUNTRIES AND RECENT YEARS HAVE WITNESSED A NOTABLE INCREASE IN PREVALENCE WITHIN LOW- AND MIDDLE-INCOME REGIONS OF THE WORLD. CONSIDERING THIS PROMINENT AND EVOLVING GLOBAL BURDEN, THERE IS A NEED TO IDENTIFY THE CELLULAR MECHANISMS THAT UNDERLIE THE PATHOGENESIS OF ATHEROSCLEROSIS TO DISCOVER NOVEL THERAPEUTIC TARGETS FOR PREVENTING OR MITIGATING ITS CLINICAL SEQUELAE. DESPITE DECADES OF RESEARCH, WE STILL DO NOT FULLY UNDERSTAND THE COMPLEX CELL-CELL INTERACTIONS THAT DRIVE ATHEROSCLEROSIS, BUT NEW INVESTIGATIVE APPROACHES ARE RAPIDLY SHEDDING LIGHT ON THESE ESSENTIAL MECHANISMS. THE VASCULAR ENDOTHELIUM RESIDES AT THE INTERFACE OF SYSTEMIC CIRCULATION AND THE UNDERLYING VESSEL WALL AND PLAYS AN ESSENTIAL ROLE IN GOVERNING PATHOPHYSIOLOGICAL PROCESSES DURING ATHEROGENESIS. IN THIS REVIEW, WE PRESENT EMERGING EVIDENCE THAT IMPLICATES THE ACTIVATED ENDOTHELIUM AS A DRIVER OF ATHEROSCLEROSIS BY DIRECTING SITE-SPECIFICITY OF PLAQUE FORMATION AND BY PROMOTING PLAQUE DEVELOPMENT THROUGH INTRACELLULAR PROCESSES, WHICH REGULATE ENDOTHELIAL CELL PROLIFERATION AND TURNOVER, METABOLISM, PERMEABILITY, AND PLASTICITY. MOREOVER, WE HIGHLIGHT NOVEL MECHANISMS OF INTERCELLULAR COMMUNICATION BY WHICH ENDOTHELIAL CELLS MODULATE THE ACTIVITY OF KEY VASCULAR CELL POPULATIONS INVOLVED IN ATHEROGENESIS, AND DISCUSS HOW ENDOTHELIAL CELLS CONTRIBUTE TO RESOLUTION BIOLOGY - A PROCESS THAT IS DYSREGULATED IN ADVANCED PLAQUES. FINALLY, WE DESCRIBE IMPORTANT FUTURE DIRECTIONS FOR PRECLINICAL ATHEROSCLEROSIS RESEARCH, INCLUDING EPIGENETIC AND TARGETED THERAPIES, TO LIMIT THE PROGRESSION OF ATHEROSCLEROSIS IN AT-RISK OR AFFECTED PATIENTS. 2021 6 6607 45 TYPE 2 DIABETES MELLITUS AND CARDIOVASCULAR DISEASE: GENETIC AND EPIGENETIC LINKS. TYPE 2 DIABETES MELLITUS (DM) IS A COMMON METABOLIC DISORDER PREDISPOSING TO DIABETIC CARDIOMYOPATHY AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (CVD), WHICH COULD LEAD TO HEART FAILURE THROUGH A VARIETY OF MECHANISMS, INCLUDING MYOCARDIAL INFARCTION AND CHRONIC PRESSURE OVERLOAD. PATHOGENETIC MECHANISMS, MAINLY LINKED TO HYPERGLYCEMIA AND CHRONIC SUSTAINED HYPERINSULINEMIA, INCLUDE CHANGES IN METABOLIC PROFILES, INTRACELLULAR SIGNALING PATHWAYS, ENERGY PRODUCTION, REDOX STATUS, INCREASED SUSCEPTIBILITY TO ISCHEMIA, AND EXTRACELLULAR MATRIX REMODELING. THE CLOSE RELATIONSHIP BETWEEN TYPE 2 DM AND CVD HAS LED TO THE COMMON SOIL HYPOTHESIS, POSTULATING THAT BOTH CONDITIONS SHARE COMMON GENETIC AND ENVIRONMENTAL FACTORS INFLUENCING THIS ASSOCIATION. HOWEVER, ALTHOUGH THE COMMON RISK FACTORS OF BOTH CVD AND TYPE 2 DM, SUCH AS OBESITY, INSULIN RESISTANCE, DYSLIPIDEMIA, INFLAMMATION, AND THROMBOPHILIA, CAN BE IDENTIFIED IN THE MAJORITY OF AFFECTED PATIENTS, LESS IS KNOWN ABOUT HOW THESE FACTORS INFLUENCE BOTH CONDITIONS, SO THAT EFFORTS ARE STILL NEEDED FOR A MORE COMPREHENSIVE UNDERSTANDING OF THIS RELATIONSHIP. THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL BACKGROUNDS OF BOTH TYPE 2 DM AND CVD HAVE BEEN MORE RECENTLY STUDIED AND UPDATED. HOWEVER, THE UNDERLYING PATHOGENETIC MECHANISMS HAVE SELDOM BEEN INVESTIGATED WITHIN THE BROADER SHARED BACKGROUND, BUT RATHER STUDIED IN THE SPECIFIC CONTEXT OF TYPE 2 DM OR CVD, SEPARATELY. AS THE PRECISE PATHOPHYSIOLOGICAL LINKS BETWEEN TYPE 2 DM AND CVD ARE NOT ENTIRELY UNDERSTOOD AND MANY ASPECTS STILL REQUIRE ELUCIDATION, AN INTEGRATED DESCRIPTION OF THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL INFLUENCES INVOLVED IN THE CONCOMITANT DEVELOPMENT OF BOTH DISEASES IS OF PARAMOUNT IMPORTANCE TO SHED NEW LIGHT ON THE INTERLINKS BETWEEN TYPE 2 DM AND CVD. THIS REVIEW ADDRESSES THE CURRENT KNOWLEDGE OF OVERLAPPING GENETIC AND EPIGENETIC ASPECTS IN TYPE 2 DM AND CVD, INCLUDING MICRORNAS AND LONG NON-CODING RNAS, WHOSE ABNORMAL REGULATION HAS BEEN IMPLICATED IN BOTH DISEASE CONDITIONS, EITHER ETIOLOGICALLY OR AS CAUSE FOR THEIR PROGRESSION. UNDERSTANDING THE LINKS BETWEEN THESE DISORDERS MAY HELP TO DRIVE FUTURE RESEARCH TOWARD AN INTEGRATED PATHOPHYSIOLOGICAL APPROACH AND TO PROVIDE FUTURE DIRECTIONS IN THE FIELD. 2018 7 4893 29 OXIDATIVE STRESS BIOMARKERS IN THE RELATIONSHIP BETWEEN TYPE 2 DIABETES AND AIR POLLUTION. THE INCIDENCE AND PREVALENCE OF TYPE 2 DIABETES HAVE INCREASED IN THE LAST DECADES AND ARE EXPECTED TO FURTHER GROW IN THE COMING YEARS. CHRONIC HYPERGLYCEMIA TRIGGERS FREE RADICAL GENERATION AND CAUSES INCREASED OXIDATIVE STRESS, AFFECTING A NUMBER OF MOLECULAR MECHANISMS AND CELLULAR PATHWAYS, INCLUDING THE GENERATION OF ADVANCED GLYCATION END PRODUCTS, PROINFLAMMATORY AND PROCOAGULANT EFFECTS, INDUCTION OF APOPTOSIS, VASCULAR SMOOTH-MUSCLE CELL PROLIFERATION, ENDOTHELIAL AND MITOCHONDRIAL DYSFUNCTION, REDUCTION OF NITRIC OXIDE RELEASE, AND ACTIVATION OF PROTEIN KINASE C. AMONG TYPE 2 DIABETES DETERMINANTS, MANY DATA HAVE DOCUMENTED THE ADVERSE EFFECTS OF ENVIRONMENTAL FACTORS (E.G., AIR POLLUTANTS) THROUGH MULTIPLE EXPOSURE-INDUCED MECHANISMS (E.G., SYSTEMIC INFLAMMATION AND OXIDATIVE STRESS, HYPERCOAGULABILITY, AND ENDOTHELIAL AND IMMUNE RESPONSES). THEREFORE, HERE WE DISCUSS THE ROLE OF AIR POLLUTION IN OXIDATIVE STRESS-RELATED DAMAGE TO GLYCEMIC METABOLISM HOMEOSTASIS, WITH A PARTICULAR FOCUS ON ITS IMPACT ON HEALTH. IN THIS CONTEXT, THE IMPROVEMENT OF NEW ADVANCED TOOLS (E.G., OMIC TECHNIQUES AND THE STUDY OF EPIGENETIC CHANGES) MAY PROVIDE A SUBSTANTIAL CONTRIBUTION, HELPING IN THE EVALUATION OF THE INDIVIDUAL IN HIS BIOLOGICAL TOTALITY, AND OFFER A COMPREHENSIVE ASSESSMENT OF THE MOLECULAR, CLINICAL, ENVIRONMENTAL, AND EPIDEMIOLOGICAL ASPECTS. 2021 8 6909 32 [TOXIC COMPONENTS OF PM(2.5) AND THEIR TOXICITY MECHANISMS-ON THE TOXICITY OF SULFATE AND CARBON COMPONENTS]. RECENTLY, THE MAIN AIR POLLUTANT HAS BEEN FINE PARTICULATE MATTER (PM(2.5)), WHICH IS TAKEN UP BY THE WHOLE BODY WITH SEVERE ADVERSE HEALTH EFFECTS. THE MAIN CHEMICAL COMPONENTS OF PM(2.5) ARE SALTS OF SULFATE (AND NITRATE) AND CARBONS. HOWEVER, IT REMAINS UNKNOWN WHICH COMPONENTS ARE TOXIC. HERE, THE AUTHOR REVIEWED THE LITERATURES TO DETERMINE WHICH COMPONENTS ARE TOXIC AND THE MAIN MECHANISMS UNDERLYING THEIR TOXICITY. MANY EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT SULFATE CONCENTRATION IS STRONGLY RELATED TO MORTALITY. HOWEVER, THERE IS NO EXPERIMENTAL EVIDENCE SHOWING THAT SULFATE AT ENVIRONMENTAL CONCENTRATIONS OF PM(2.5) CAUSES CARDIOVASCULAR DISEASE OR OTHER DISEASE. ON THE OTHER HAND, CARBON COMPONENTS SUCH AS ELEMENTARY CARBON (EC) PRODUCES HIGH CONCENTRATIONS OF REACTIVE OXYGEN SPECIES (ROS) VIA ITS PHAGOCYTOSIS BY MACROPHAGES, AND ORGANIC CARBON (OC) ALSO PRODUCES HIGH CONCENTRATIONS OF ROS DURING ITS METABOLIC PROCESSES, AND THE ROS CAUSE ACUTE AND CHRONIC INFLAMMATION. THEY CAUSE MANY DISEASES INCLUDING CARDIOVASCULAR DISEASE, ASTHMA AND CANCER. FURTHERMORE, THERE ARE MANY LINES OF EVIDENCE SHOWING THAT EPIGENETIC CHANGES SUCH AS DNA METHYLATION OR MICRORNA EXPRESSION INDUCED BY PARTICULATE MATTERS ALSO INDUCE THE DEVELOPMENT OF MANY DISEASES SUCH AS THOSE MENTIONED ABOVE. IT HAS BEEN REPORTED THAT CARBON COMPONENTS ARE INCORPORATED INTO THE BRAIN AND PRODUCE ROS, AND THAT THE ROS CAUSE DAMAGE TO BRAIN CELLS AND ALZHEIMER'S DISEASE AND COGNITIVE DISORDERS IN THE ELDERLY.FROM THESE LINES OF EVIDENCE, THE AUTHOR WOULD LIKE TO EMPHASIZE THAT THE MAIN TOXICITY OF PM(2.5) IS DUE TO CARBON COMPONENTS, AND IT IS IMPORTANT TO TAKE COUNTERMEASURES TO DECREASE THE CONCENTRATION OF CARBON COMPONENTS IN AMBIENT AIR. 2019 9 1673 32 DRIVER GENE MUTATIONS AND EPIGENETICS IN COLORECTAL CANCER. OBJECTIVE: THE MAJORITY OF PATIENTS WITH COLORECTAL CANCER ARE DIAGNOSED WITH LOCALLY ADVANCED AND/OR DISSEMINATED DISEASE, AND TREATMENT OPTIONS INCLUDE SURGERY IN COMBINATION WITH CYTOTOXIC CHEMOTHERAPY REGIMENS, BIOLOGICS, AND/OR RADIOTHERAPY. THUS, COLORECTAL CANCER REMAINS A HEAVY BURDEN ON SOCIETY AND HEALTH CARE SYSTEMS.MOUNTING EVIDENCE SHOW THAT DRIVER GENE MUTATIONS PLAY ONLY PART OF THE ROLE IN CARCINOGENESIS. EPIGENETICS ARE STRONGLY IMPLICATED IN INITIATION AND PROGRESSION OF COLORECTAL CANCER ALONG WITH MAJOR PLAYERS SUCH AS INTESTINAL MICROBIOTIC DYSBIOSIS AND CHRONIC MUCOSAL INFLAMMATION.TO ASSESS PHENOTYPIC CHANGES IN PROTEINS AND GENE EXPRESSION, MULTIGENE EXPRESSION SIGNATURES BASED ON SEQUENCING TECHNIQUES HAVE BEEN DEVELOPED TO HOPEFULLY IMPROVE PREDICTORS OF THE TUMOR PROFILE, IMMUNE RESPONSE, AND THERAPEUTIC OUTCOMES. OUR OBJECTIVE WAS TO REVIEW CURRENT ADVANCES IN THE FIELD AND TO UPDATE SURGEONS AND ACADEMICS ON DRIVER GENE MUTATIONS AND EPIGENETICS IN COLORECTAL CANCER. BACKGROUND AND METHODS: THIS IS A NARRATIVE REVIEW STUDYING RELEVANT RESEARCH PUBLISHED IN THE PUBMED DATABASE FROM 2012-2018. RESULTS AND CONCLUSION: INCREASED UNDERSTANDING OF THE MOLECULAR BIOLOGY WILL IMPROVE OPTIONS TO CHARACTERIZE COLORECTAL CANCER WITH REGARD TO MUTATIONS AND MOLECULAR PATHWAYS, INCLUDING MICROSATELLITE INSTABILITY, EPIGENETICS, MICROBIOTA, AND MICROENVIRONMENT. RESEARCH WILL INEVITABLY IMPROVE RISK GROUP STRATIFICATION AND TARGETED TREATMENT APPROACHES.EPIGENETIC PROFILING AND EPIGENETIC MODULATING DRUGS WILL INCREASE RISK STRATIFICATION, INCREASE ACCESSIBILITY FOR DNA TARGETING CHEMOTHERAPEUTICS AND REDUCE CYTOTOXIC DRUG RESISTANCE.NEW GENERATION ANTIBIOTICS SUCH AS BIOFILM INHIBITORS AND QUORUM SENSING INHIBITORS ARE BEING DEVELOPED TO TARGET THE CARCINOGENETIC IMPACT OF COLONIC DYSBIOSIS AND INFLAMMATION. 2020 10 822 29 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 11 3915 24 LINE-1 IN OBESITY AND CARDIOMETABOLIC DISEASES: A SYSTEMATIC REVIEW. EPIGENETIC MECHANISMS MAY PLAY AN IMPORTANT ROLE IN THE ETIOLOGY OF OBESITY AND CARDIOMETABOLIC DISEASES, BY ACTIVATING OR SILENCING THE RELATED-GENES. SCIENTIFIC EVIDENCE HAS SUGGESTED THAT LINE-1 METHYLATION IS ASSOCIATED WITH BODY COMPOSITION AND OBESITY-RELATED DISEASES, INCLUDING INSULIN RESISTANCE, TYPE 2 DIABETES MELLITUS, AND CARDIOVASCULAR DISEASE (CVD). IT ALSO HAS BEEN EVALUATED AS PREDICTOR OF WEIGHT LOSS. THE STUDIES' RESULTS ARE STILL CONFLICTING, AND POSITIVE AND NEGATIVE ASSOCIATIONS HAVE BEEN FOUND TO LINE-1 METHYLATION REGARDING ADIPOSITY AND CARDIOMETABOLIC MARKERS. OVERALL, THIS REVIEW PRESENTS OBSERVATIONAL (CROSS-SECTIONAL AND LONGITUDINAL) STUDIES AND INTERVENTIONS (DIET, EXERCISES, AND BARIATRIC SURGERY) THAT EVALUATED THE RELATIONSHIP OF THE LINE-1 METHYLATION WITH OBESITY, WEIGHT LOSS, DYSLIPIDEMIAS, HYPERTENSION, INSULIN RESISTANCE, CVD, AND METABOLIC SYNDROME. TEACHING POINTS EPIGENETIC MECHANISMS MAY PLAY AN IMPORTANT ROLE IN THE ETIOLOGY OF OBESITY AND CARDIOMETABOLIC DISEASES. MANY STUDIES HAVE RELATED METHYLATION OF LINE-1 WITH CARDIOMETABOLIC DISEASES; HOWEVER, THE RESULTS ARE STILL CONTROVERSIAL. THE RELATIONSHIP BETWEEN THE ETIOLOGY OF CHRONIC DISEASES AND THE METHYLATION OF LINE-1 IS NOT FULLY ELUCIDATED. WITH ADVANCES IN EPIGENETIC STUDIES, RELATED MECHANISMS MAY BE EARLY BIOMARKERS IN WEIGHT CHANGE AND CARDIOMETABOLIC RISK. 2019 12 6462 39 TISSUE AND CIRCULATING MICRORNAS AS BIOMARKERS OF RESPONSE TO OBESITY TREATMENT STRATEGIES. BACKGROUND: OBESITY, CHARACTERIZED BY AN INCREASED AMOUNT OF ADIPOSE TISSUE, IS A METABOLIC CHRONIC ALTERATION WHICH HAS REACHED PANDEMIC PROPORTION. LIFESTYLE CHANGES ARE THE FIRST LINE THERAPY FOR OBESITY AND A LARGE VARIETY OF DIETARY APPROACHES HAVE DEMONSTRATED EFFICACY IN PROMOTING WEIGHT LOSS AND IMPROVING OBESITY-RELATED METABOLIC ALTERATIONS. BESIDES DIET AND PHYSICAL ACTIVITY, BARIATRIC SURGERY MIGHT BE AN EFFECTIVE THERAPEUTIC STRATEGY FOR MORBID OBESE PATIENTS. RESPONSE TO WEIGHT-LOSS INTERVENTIONS IS CHARACTERISED BY HIGH INTER-INDIVIDUAL VARIABILITY, WHICH MIGHT INVOLVE EPIGENETIC FACTORS. MICRORNAS HAVE CRITICAL ROLES IN METABOLIC PROCESSES AND THEIR DYSREGULATED EXPRESSION HAS BEEN REPORTED IN OBESITY. AIM: THE AIM OF THIS REVIEW IS TO PROVIDE A COMPREHENSIVE OVERVIEW OF CURRENT STUDIES EVALUATING CHANGES IN MICRORNA EXPRESSION IN OBESE PATIENTS UNDERGOING LIFESTYLE INTERVENTIONS OR BARIATRIC SURGERY. RESULTS: A CONSIDERABLE NUMBER OF STUDIES HAVE REPORTED A DIFFERENTIAL EXPRESSION OF CIRCULATING MICRORNAS BEFORE AND AFTER VARIOUS DIETARY AND BARIATRIC SURGERY APPROACHES, IDENTIFYING SEVERAL CANDIDATE BIOMARKERS OF RESPONSE TO WEIGHT LOSS. SIGNIFICANT CHANGES IN MICRORNA EXPRESSION HAVE BEEN OBSERVED AT A TISSUE LEVEL AS WELL, WITH ENTIRELY DIFFERENT PATTERNS BETWEEN VISCERAL AND SUBCUTANEOUS ADIPOSE TISSUE. INTERESTINGLY, RELEVANT DIFFERENCES IN MICRORNA EXPRESSION HAVE EMERGED BETWEEN RESPONDERS AND NON-RESPONDERS TO DIETARY OR SURGICAL INTERVENTIONS. A WIDE VARIETY OF DYSREGULATED MICRORNA TARGET PATHWAYS HAVE ALSO BEEN IDENTIFIED, HELPING TO UNDERSTAND THE PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING OBESITY AND OBESITY-RELATED METABOLIC DISEASES. CONCLUSIONS: ALTHOUGH FURTHER RESEARCH IS NEEDED TO DRAW FIRM CONCLUSIONS, THERE IS INCREASING EVIDENCE ABOUT MICRORNAS AS POTENTIAL BIOMARKERS FOR WEIGHT LOSS AND RESPONSE TO INTERVENTION STRATEGIES IN OBESITY. 2021 13 1516 35 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 14 4120 37 MECHANISMS OF CARDIOVASCULAR DISORDERS IN PATIENTS WITH CHRONIC KIDNEY DISEASE: A PROCESS RELATED TO ACCELERATED SENESCENCE. CARDIOVASCULAR DISEASES (CVDS), ESPECIALLY THOSE INVOLVING A SYSTEMIC INFLAMMATORY PROCESS SUCH AS ATHEROSCLEROSIS, REMAIN THE LEADING CAUSE OF MORBIDITY AND MORTALITY IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD). CKD IS A SYSTEMIC CONDITION AFFECTING APPROXIMATELY 10% OF THE GENERAL POPULATION. THE PREVALENCE OF CKD HAS INCREASED OVER THE PAST DECADES BECAUSE OF THE AGING OF THE POPULATION WORLDWIDE. INDEED, CVDS IN PATIENTS WITH CKD CONSTITUTE A PREMATURE FORM OF CVD OBSERVED IN THE GENERAL POPULATION. MULTIPLE STUDIES INDICATE THAT PATIENTS WITH RENAL DISEASE UNDERGO ACCELERATED AGING, WHICH PRECIPITATES THE APPEARANCE OF PATHOLOGIES, INCLUDING CVDS, USUALLY ASSOCIATED WITH ADVANCED AGE. IN THIS REVIEW, WE DISCUSS SEVERAL ASPECTS THAT CHARACTERIZE CKD-ASSOCIATED CVDS, SUCH AS ETIOPATHOGENIC ELEMENTS THAT CKD PATIENTS SHARE WITH THE GENERAL POPULATION, CHANGES IN THE CELLULAR BALANCE OF REACTIVE OXYGEN SPECIES (ROS), AND THE ASSOCIATED PROCESS OF CELLULAR SENESCENCE. UREMIA-ASSOCIATED AGING IS LINKED WITH NUMEROUS CHANGES AT THE CELLULAR AND MOLECULAR LEVEL. THESE CHANGES ARE SIMILAR TO THOSE OBSERVED IN THE NORMAL PROCESS OF PHYSIOLOGIC AGING. WE ALSO DISCUSS NEW PERSPECTIVES IN THE STUDY OF CKD-ASSOCIATED CVDS AND EPIGENETIC ALTERATIONS IN INTERCELLULAR SIGNALING, MEDIATED BY MICRORNAS AND/OR EXTRACELLULAR VESICLES (EVS), WHICH PROMOTE VASCULAR DAMAGE AND SUBSEQUENT DEVELOPMENT OF CVD. UNDERSTANDING THE PROCESSES AND FACTORS INVOLVED IN ACCELERATED SENESCENCE AND OTHER ABNORMAL INTERCELLULAR SIGNALING WILL IDENTIFY NEW THERAPEUTIC TARGETS AND LEAD TO IMPROVED METHODS OF DIAGNOSIS AND MONITORING FOR PATIENTS WITH CKD-ASSOCIATED CVDS. 2020 15 4467 36 MOLECULAR MECHANISMS OF VASCULAR HEALTH: INSIGHTS FROM VASCULAR AGING AND CALCIFICATION. CARDIOVASCULAR DISEASE IS THE MOST COMMON CAUSE OF DEATH WORLDWIDE, ESPECIALLY BEYOND THE AGE OF 65 YEARS, WITH THE VAST MAJORITY OF MORBIDITY AND MORTALITY DUE TO MYOCARDIAL INFARCTION AND STROKE. VASCULAR PATHOLOGY STEMS FROM A COMBINATION OF GENETIC RISK, ENVIRONMENTAL FACTORS, AND THE BIOLOGIC CHANGES ASSOCIATED WITH AGING. THE PATHOGENESIS UNDERLYING THE DEVELOPMENT OF VASCULAR AGING, AND VASCULAR CALCIFICATION WITH AGING, IN PARTICULAR, IS STILL NOT FULLY UNDERSTOOD. ACCUMULATING DATA SUGGESTS THAT GENETIC RISK, LIKELY COMPOUNDED BY EPIGENETIC MODIFICATIONS, ENVIRONMENTAL FACTORS, INCLUDING DIABETES AND CHRONIC KIDNEY DISEASE, AND THE PLASTICITY OF VASCULAR SMOOTH MUSCLE CELLS TO ACQUIRE AN OSTEOGENIC PHENOTYPE ARE MAJOR DETERMINANTS OF AGE-ASSOCIATED VASCULAR CALCIFICATION. UNDERSTANDING THE MOLECULAR MECHANISMS UNDERLYING GENETIC AND MODIFIABLE RISK FACTORS IN REGULATING AGE-ASSOCIATED VASCULAR PATHOLOGY MAY INSPIRE STRATEGIES TO PROMOTE HEALTHY VASCULAR AGING. THIS ARTICLE SUMMARIZES CURRENT KNOWLEDGE OF CONCEPTS AND MECHANISMS OF AGE-ASSOCIATED VASCULAR DISEASE, WITH AN EMPHASIS ON VASCULAR CALCIFICATION. 2023 16 2704 24 EXERCISE AND COLORECTAL CANCER: PREVENTION AND MOLECULAR MECHANISMS. EXERCISE AND PHYSICAL ACTIVITY HAVE BEEN SHOWN TO BE STRONGLY ASSOCIATED WITH A DECREASED INCIDENCE RATE OF VARIOUS CHRONIC DISEASES ESPECIALLY NUMEROUS HUMAN MALIGNANCIES. A HUGE NUMBER OF CLINICAL TRIALS AND META-ANALYSIS HAVE DEMONSTRATED THAT EXERCISE IS SIGNIFICANTLY EFFECTIVE IN LOWERING THE RISK OF COLORECTAL CANCER. IN ADDITION, IT IS SUGGESTED AS AN EFFECTIVE THERAPEUTIC MODALITY AGAINST THIS CANCER TYPE. THEREFORE, IN THIS REVIEW, WE WILL REVIEW COMPREHENSIBLY THE EFFECTS OF EXERCISE IN PREVENTING, TREATING, AND ALLEVIATING THE ADVERSE EFFECTS OF CONVENTIONAL THERAPEUTIC OPTIONS IN COLORECTAL CANCER. MOREOVER, THE POSSIBLE MECHANISMS UNDERLYING THE POSITIVE EFFECTS OF EXERCISE AND PHYSICAL ACTIVITY IN COLORECTAL CANCER, INCLUDING REGULATION OF INFLAMMATION, APOPTOSIS, GROWTH FACTOR AXIS, IMMUNITY, EPIGENETIC, ETC. WILL BE ALSO DISCUSSED. 2022 17 2849 22 FROM AIR POLLUTION TO CARDIOVASCULAR DISEASES: THE EMERGING ROLE OF EPIGENETICS. THE ASSOCIATION BETWEEN AIR POLLUTION AND A WIDE-RANGING SPECTRUM OF ACUTE AND CHRONIC DISORDERS-INCLUDING CARDIOVASCULAR DISEASES-IS WIDELY ACKNOWLEDGED. EXPOSURE TO AIRBORNE POLLUTANTS TRIGGERS HARMFUL MECHANISMS SUCH AS OXIDATIVE STRESS AND SYSTEMIC INFLAMMATION, WHICH LEAD TO INCREASED INCIDENCE OF MYOCARDIAL INFARCTION, ARTERIAL HYPERTENSION, STROKE, AND HEART FAILURE. SUSTAINED EFFORTS HAVE BEEN MADE IN RECENT YEARS TO DISCOVER HOW ENVIRONMENTAL EXPOSURES AFFECT HUMAN HEALTH THROUGH EPIGENETIC PHENOMENA, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNA-MEDIATED GENE REGULATION. THIS REVIEW SUMMARIZES THE CURRENT EVIDENCES ON THE RELATIONSHIP BETWEEN AIR POLLUTION EXPOSURE, EPIGENETIC ALTERATIONS AND CARDIOVASCULAR IMPACT, IN VIEW OF PRESENT IMPLICATIONS AND FUTURE PERSPECTIVES. 2020 18 4425 48 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 19 625 33 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 20 5635 27 SEPTIC SHOCK AND THE AGING PROCESS: A MOLECULAR COMPARISON. AGING IS A CONTINUOUS PROCESS PROMOTED BY BOTH INTRINSIC AND EXTRINSIC FACTORS THAT EACH TRIGGER A MULTITUDE OF MOLECULAR EVENTS. INCREASING EVIDENCE SUPPORTS A CENTRAL ROLE FOR INFLAMMATION IN THIS PROGRESSION. HERE, WE DISCUSS HOW THE LOW-GRADE CHRONIC INFLAMMATION THAT CHARACTERIZES AGING IS TIGHTLY INTERCONNECTED WITH OTHER IMPORTANT ASPECTS OF THIS PROCESS, SUCH AS DNA DAMAGE, MITOCHONDRIAL DYSFUNCTION, AND EPIGENETIC CHANGES. SIMILARLY, INFLAMMATION ALSO PLAYS A CRITICAL ROLE IN MANY MORBID CONDITIONS THAT AFFECT PATIENTS WHO ARE ADMITTED TO INTENSIVE CARE. ALTHOUGH THE INFLAMMATORY RESPONSE IS LOW GRADE AND PERSISTENT IN HEALTHY AGING WHILE IT IS ACUTE AND SEVERE IN CRITICALLY ILL STATES, WE HYPOTHESIZE THAT BOTH SITUATIONS HAVE IMPORTANT INTERCONNECTIONS. HERE, WE PERFORMED AN EXTENSIVE REVIEW OF THE LITERATURE TO INVESTIGATE THIS POTENTIAL LINK. BECAUSE SEPSIS IS THE MOST EXTENSIVELY STUDIED DISEASE AND IS THE LEADING CAUSE OF DEATH IN CRITICAL CARE, WE FOCUS OUR DISCUSSION ON COMPARING THE INFLAMMATORY PROFILE OF HEALTHY OLDER PEOPLE WITH THAT OF PATIENTS IN SEPTIC SHOCK TO EXPLAIN WHY WE BELIEVE THAT BOTH SITUATIONS HAVE SYNERGISTIC EFFECTS, LEADING TO CRITICALLY ILL AGED PATIENTS HAVING A WORSE PROGNOSIS WHEN COMPARED WITH CRITICALLY ILL YOUNG PATIENTS. 2017