1 4187 201 METABOLIC AND VASCULAR EFFECT OF THE MEDITERRANEAN DIET. SEVERAL STUDIES INDICATED HOW DIETARY PATTERNS THAT WERE OBTAINED FROM NUTRITIONAL CLUSTER ANALYSIS CAN PREDICT DISEASE RISK OR MORTALITY. LOW-GRADE CHRONIC INFLAMMATION REPRESENTS A BACKGROUND PATHOGENETIC MECHANISM LINKING METABOLIC RISK FACTORS TO INCREASED RISK OF CHRONIC DEGENERATIVE DISEASES. A MEDITERRANEAN DIET (MEDI) STYLE HAS BEEN REPORTED AS ASSOCIATED WITH A LOWER DEGREE OF INFLAMMATION BIOMARKERS AND WITH A PROTECTIVE ROLE ON CARDIOVASCULAR AND CEREBROVASCULAR EVENTS. THERE IS HETEROGENEITY IN DEFINING THE MEDDIET, AND IT CAN, OWING TO ITS COMPLEXITY, BE CONSIDERED AS AN EXPOSOME WITH THOUSANDS OF NUTRIENTS AND PHYTOCHEMICALS. RECENTLY, IT HAS BEEN REPORTED A NOVEL POSITIVE ASSOCIATION BETWEEN BASELINE PLASMA CERAMIDE CONCENTRATIONS AND CARDIOVASCULAR EVENTS AND HOW ADHERENCE TO A MEDITERRANEAN DIET-STYLE MAY INFLUENCE THE POTENTIAL NEGATIVE RELATIONSHIP BETWEEN ELEVATED PLASMA CERAMIDE CONCENTRATIONS AND CARDIOVASCULAR DISEASES (CVD). SEVERAL RANDOMIZED CONTROLLED TRIALS (RCTS) SHOWED THE POSITIVE EFFECTS OF THE MEDI DIET STYLE ON SEVERAL CARDIOVASCULAR RISK FACTORS, SUCH AS BODY MASS INDEX, WAIST CIRCUMFERENCE, BLOOD LIPIDS, BLOOD PRESSURE, INFLAMMATORY MARKERS AND ADHESION MOLECULES, AND DIABETES AND HOW THESE ADVANTAGES OF THE MEDI ARE MAINTAINED IN COMPARISON OF A LOW-FAT DIET. SOME STUDIES REPORTED A POSITIVE EFFECT OF ADHERENCE TO A MEDITERRANEAN DIET AND HEART FAILURE INCIDENCE, WHEREAS SOME RECENT STUDIES, SUCH AS THE PREDIMED STUDY, SHOWED THAT THE INCIDENCE OF MAJOR CARDIOVASCULAR EVENTS WAS LOWER AMONG THOSE ASSIGNED TO MEDI SUPPLEMENTED WITH EXTRA-VIRGIN OLIVE OIL OR NUTS THAN AMONG THOSE ASSIGNED TO A REDUCED-FAT DIET. NEW STUDIES ARE NEEDED TO BETTER UNDERSTAND THE MOLECULAR MECHANISMS, WHEREBY THE MEDDIET MAY EXERCISE ITS EFFECTS. HERE, WE PRESENT RECENT ADVANCES IN UNDERSTANDING THE MOLECULAR BASIS OF MEDDIET EFFECTS, MAINLY FOCUSING ON CARDIOVASCULAR DISEASES, BUT ALSO DISCUSSING OTHER RELATED DISEASES. WE REVIEW MEDDIET COMPOSITION AND ASSESSMENT AS WELL AS THE LATEST ADVANCES IN THE GENOMIC, EPIGENOMIC (DNA METHYLATION, HISTONE MODIFICATIONS, MICRORNAS, AND OTHER EMERGING REGULATORS), TRANSCRIPTOMIC (SELECTED GENES AND WHOLE TRANSCRIPTOME), AND METABOLOMIC AND METAGENOMIC ASPECTS OF THE MEDDIET EFFECTS (AS A WHOLE AND FOR ITS MOST TYPICAL FOOD COMPONENTS). WE ALSO PRESENT A REVIEW OF THE CLINICAL EFFECTS OF THIS DIETARY STYLE UNDERLYING THE BIOCHEMICAL AND MOLECULAR EFFECTS OF THE MEDITERRANEAN DIET. OUR PURPOSE IS TO REVIEW THE MAIN FEATURES OF THE MEDITERRANEAN DIET IN PARTICULAR ITS BENEFITS ON HUMAN HEALTH, UNDERLING THE ANTI-INFLAMMATORY, ANTI-OXIDANT AND ANTI-ATHEROSCLEROTIC EFFECTS TO WHICH NEW KNOWLEDGE ABOUT EPIGENETIC AND GUT-MICROBIOTA RELATIONSHIP IS RECENTLY ADDED. 2019 2 3801 48 INTERPLAY OF VITAMIN D AND SIRT1 IN TISSUE-SPECIFIC METABOLISM-POTENTIAL ROLES IN PREVENTION AND TREATMENT OF NON-COMMUNICABLE DISEASES INCLUDING CANCER. THE IMPORTANCE OF THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES, INCLUDING OBESITY, METABOLIC SYNDROME, TYPE 2 DIABETES, CARDIOVASCULAR DISEASES, AND CANCER, IS INCREASING AS A REQUIREMENT OF THE AGING POPULATION IN DEVELOPED COUNTRIES AND THE SUSTAINABILITY OF HEALTHCARE. SIMILARLY, THE 2013-2030 ACTION PLAN OF THE WHO FOR THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES SEEKS THESE ACHIEVEMENTS. ADEQUATE LIFESTYLE CHANGES, ALONE OR WITH THE NECESSARY TREATMENTS, COULD REDUCE THE RISK OF MORTALITY OR THE DETERIORATION OF QUALITY OF LIFE. IN OUR RECENT WORK, WE SUMMARIZED THE ROLE OF TWO CENTRAL FACTORS, I.E., APPROPRIATE LEVELS OF VITAMIN D AND SIRT1, WHICH ARE CONNECTED TO ADEQUATE LIFESTYLES WITH BENEFICIAL EFFECTS ON THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES. BOTH OF THESE FACTORS HAVE RECEIVED INCREASED ATTENTION IN RELATION TO THE COVID-19 PANDEMIC AS THEY BOTH TAKE PART IN REGULATION OF THE MAIN METABOLIC PROCESSES, I.E., LIPID/GLUCOSE/ENERGY HOMEOSTASIS, OXIDATIVE STRESS, REDOX BALANCE, AND CELL FATE, AS WELL AS IN THE HEALTHY REGULATION OF THE IMMUNE SYSTEM. VITAMIN D AND SIRT1 HAVE DIRECT AND INDIRECT INFLUENCE OF THE REGULATION OF TRANSCRIPTION AND EPIGENETIC CHANGES AND ARE RELATED TO CYTOPLASMIC SIGNALING PATHWAYS SUCH AS PLC/DAG/IP3/PKC/MAPK, MEK/ERK, INSULIN/MTOR/CELL GROWTH, PROLIFERATION; LEPTIN/PI3K-AKT-MTORC1, AKT/NFKB/COX-2, NFKB/TNFALPHA, IL-6, IL-8, IL-1BETA, AND AMPK/PGC-1ALPHA/GLUT4, AMONG OTHERS. THROUGH THEIR PROPER REGULATION, THEY MAINTAIN NORMAL BODY WEIGHT, LIPID PROFILE, INSULIN SECRETION AND SENSITIVITY, BALANCE BETWEEN THE PRO- AND ANTI-INFLAMMATORY PROCESSES UNDER NORMAL CONDITIONS AND INFECTIONS, MAINTAIN ENDOTHELIAL HEALTH; BALANCE CELL DIFFERENTIATION, PROLIFERATION, AND FATE; AND BALANCE THE CIRCADIAN RHYTHM OF THE CELLULAR METABOLISM. THE ROLE OF THESE TWO MOLECULES IS INTERCONNECTED IN THE MOLECULAR NETWORK, AND THEY REGULATE EACH OTHER IN SEVERAL LAYERS OF THE HOMEOSTASIS OF ENERGY AND THE CELLULAR METABOLISM. BOTH HAVE A CENTRAL ROLE IN THE MAINTENANCE OF HEALTHY AND BALANCED IMMUNE REGULATION AND REDOX REACTIONS; THEREFORE, THEY COULD CONSTITUTE PROMISING TARGETS EITHER FOR PREVENTION OR AS COMPLEMENTARY THERAPIES TO ACHIEVE A BETTER QUALITY OF LIFE, AT ANY AGE, FOR HEALTHY PEOPLE AND PATIENTS UNDER CHRONIC CONDITIONS. 2023 3 4399 43 MODULATION OF GENOMIC AND POSTGENOMIC ALTERATIONS IN NONCANCER DISEASES AND CRITICAL PERIODS OF LIFE. GENOMIC AND POSTGENOMIC CHANGES ARE EXTENSIVELY INVESTIGATED IN CANCER RESEARCH. SIMILAR ALTERATIONS, AFFECTING GENOME, TRANSCRIPTOME, MIRNOME AND/OR PROTEOME END-POINTS, HAVE BEEN DETECTED IN A VARIETY OF OTHER CHRONIC DEGENERATIVE DISEASES, SUCH AS ATHEROSCLEROSIS, DEGENERATIVE HEART DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEUROLOGICAL DISORDERS, EYE DISEASES, DIABETES, METABOLIC SYNDROME, SKIN AGEING AND ALOPECIA. NO GENERALIZATION CAN BE MADE DUE TO THE MYRIAD OF DIVERSE CLINICAL ENTITIES CLASSIFIED AS CHRONIC DEGENERATIVE DISEASES. MOREOVER, THE DETECTION OF MOLECULAR CHANGES DOES NOT AUTOMATICALLY IMPLY THEIR CAUSAL ROLE. NEVERTHELESS, COMMON MECHANISMS, SUCH AS DNA DAMAGE, EPIGENETIC ALTERATIONS, OXIDATIVE STRESS, AND CHRONIC INFLAMMATION, IN ADDITION TO GENETIC PREDISPOSITION, ARE OFTEN INVOLVED IN NONCANCER DISEASES. WE DEBATE HERE IN MORE DETAIL THE SUBJECTS OF CARDIOVASCULAR DISEASES AND OF SKIN DISEASES. MOREOVER, WE DISCUSS OUR EXPERIMENTAL STUDIES SUGGESTING THAT GENOMIC AND POSTGENOMIC CHANGES DO ALSO OCCUR DURING CRITICAL PERIODS OF LIFE, INCLUDING THE PRENATAL LIFE, THE PERINATAL PERIOD, AND AGEING. IN ADDITION, WE COMMENT ON THE FINDING THAT STEM-DERIVED CELLS ARE MORE SUSCEPTIBLE TO MOLECULAR DAMAGE THAN MORE DIFFERENTIATED CELLS. ALL THESE DATA ARE VIEWED IN THE PERSPECTIVE OF PREVENTIVE MEDICINE. IN FACT, THERE IS EVIDENCE THAT THE GENOMIC AND POSTGENOMIC ALTERATIONS OCCURRING NOT ONLY IN SEVERAL PATHOLOGICAL CONDITIONS BUT ALSO IN PARAPHYSIOLOGICAL SITUATIONS THAT AFFECT CRITICAL PERIODS OF LIFE CAN BE MODULATED BY MEANS OF DIETARY AND PHARMACOLOGICAL AGENTS. THE DISCOVERY THAT CHEMOPREVENTIVE AGENTS ARE ALSO ABLE TO ATTENUATE NUCLEOTIDE DAMAGE IN STEM-DERIVED CELLS WARRANTS FURTHER STUDIES IN VIEW OF POSSIBLE CLINICAL APPLICATIONS. 2009 4 49 41 A CURRENT GENETIC AND EPIGENETIC VIEW ON HUMAN AGING MECHANISMS. THE PROCESS OF AGING IS ONE OF THE MOST COMPLEX AND INTRIGUING BIOLOGICAL PHENOMENONS. AGING IS A GENETICALLY REGULATED PROCESS IN WHICH THE ORGANISM'S MAXIMUM LIFESPAN POTENTIAL IS PRE-DETERMINED, WHILE THE RATE OF AGING IS INFLUENCED BY ENVIRONMENTAL FACTORS AND LIFESTYLE. CONSIDERING THE COMPLEXITY OF MECHANISMS INVOLVED IN THE REGULATION OF AGING PROCESS, UP TO THIS DATE THERE ISN'T A MAJOR, UNIFYING THEORY WHICH COULD EXPLAIN THEM. AS GENETIC/EPIGENETIC AND ENVIRONMENTAL FACTORS BOTH INEVITABLY INFLUENCE THE AGING PROCESS, HERE WE PRESENT A REVIEW ON THE GENETIC AND EPIGENETIC REGULATION OF THE MOST IMPORTANT MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE PROCESS OF AGING. BASED ON THE STUDIES ON OXIDATIVE STRESS, METABOLISM, GENOME STABILITY, EPIGENETIC MODIFICATIONS AND CELLULAR SENESCENCE IN ANIMAL MODELS AND HUMANS, WE GIVE AN OVERVIEW OF KEY GENETIC AND MOLECULAR PATHWAYS RELATED TO AGING. AS MOST OF GENETIC MANIPULATIONS WHICH INFLUENCE THE AGING PROCESS ALSO AFFECT REPRODUCTION, WE DISCUSS AGING IN HUMANS AS A POST-REPRODUCTIVE GENETICALLY DETERMINED PROCESS. AFTER THE AGE OF REPRODUCTIVE SUCCESS, AGING CONTINOUSLY PROGRESSES WHICH CLINICALLY COINCIDES WITH THE ONSET OF MOST CHRONIC DISEASES, CANCERS AND DEMENTIONS. AS EVOLUTION SHAPES THE GENOMES FOR REPRODUCTIVE SUCCESS AND NOT FOR POST-REPRODUCTIVE SURVIVAL, AGING COULD BE DEFINED AS A PROTECTIVE MECHANISM WHICH ENSURES THE PRESERVATION AND PROGRESS OF SPECIES THROUGH THE MODIFICATION, TRASMISSION AND IMPROVEMENT OF GENETIC MATERIAL. 2009 5 4787 53 NUTRITION, AGING AND CANCER: LESSONS FROM DIETARY INTERVENTION STUDIES. THERE IS CONVINCING EPIDEMIOLOGICAL AND CLINICAL EVIDENCE THAT, INDEPENDENT OF AGING, LIFESTYLE AND, NOTABLY, NUTRITION ARE ASSOCIATED WITH DEVELOPMENT OR PROGRESSION OF MAJOR HUMAN CANCERS, INCLUDING BREAST, PROSTATE, COLORECTAL TUMORS, AND AN INCREASINGLY LARGE COLLECTION OF DIET-RELATED CANCERS. MECHANISMS UNDERLYING THIS ASSOCIATION ARE MOSTLY RELATED TO THE DISTINCT EPIGENETIC EFFECTS OF DIFFERENT DIETARY PATTERNS. IN THIS CONTEXT, MEDITERRANEAN DIET HAS BEEN REPORTED TO SIGNIFICANTLY REDUCE MORTALITY RATES FOR VARIOUS CHRONIC ILLNESSES, INCLUDING CARDIOVASCULAR DISEASES, NEURODEGENERATIVE DISEASES AND CANCER. ALTHOUGH MANY OBSERVATIONAL STUDIES HAVE SUPPORTED THIS EVIDENCE, DIETARY INTERVENTION STUDIES USING A MEDITERRANEAN DIETARY PATTERN OR ITS SELECTED FOOD COMPONENTS ARE STILL LIMITED AND AFFECTED BY A RATHER LARGE VARIABILITY IN CHARACTERISTICS OF STUDY SUBJECTS, TYPE AND LENGTH OF INTERVENTION, SELECTED END-POINTS AND STATISTICAL ANALYSIS. HERE WE REVIEW DATA OF TWO OF OUR INTERVENTION STUDIES, THE MEDIET STUDY AND THE DIMESA PROJECT, AIMED AT ASSESSING THE EFFECTS OF TRADITIONAL MEDITERRANEAN DIET AND/OR ITS COMPONENT(S) ON A LARGE PANEL OF BOTH PLASMA AND URINE BIOMARKERS. BOTH PUBLISHED AND UNPUBLISHED RESULTS ARE PRESENTED AND DISCUSSED. 2016 6 705 37 BUILDING RISK-ON-A-CHIP MODELS TO IMPROVE BREAST CANCER RISK ASSESSMENT AND PREVENTION. PREVENTIVE ACTIONS FOR CHRONIC DISEASES HOLD THE PROMISE OF IMPROVING LIVES AND REDUCING HEALTHCARE COSTS. FOR SEVERAL DISEASES, INCLUDING BREAST CANCER, MULTIPLE RISK AND PROTECTIVE FACTORS HAVE BEEN IDENTIFIED BY EPIDEMIOLOGISTS. THE IMPACT OF MOST OF THESE FACTORS HAS YET TO BE FULLY UNDERSTOOD AT THE ORGANISM, TISSUE, CELLULAR AND MOLECULAR LEVELS. IMPORTANTLY, COMBINATIONS OF EXTERNAL AND INTERNAL RISK AND PROTECTIVE FACTORS INVOLVE COOPERATIVITY THUS, SYNERGIZING OR ANTAGONIZING DISEASE ONSET. MODELS ARE NEEDED TO MECHANISTICALLY DECIPHER CANCER RISKS UNDER DEFINED CELLULAR AND MICROENVIRONMENTAL CONDITIONS. HERE, WE BRIEFLY REVIEW BREAST CANCER RISK MODELS BASED ON 3D CELL CULTURE AND PROPOSE TO IMPROVE RISK MODELING WITH LAB-ON-A-CHIP APPROACHES. WE SUGGEST EPITHELIAL TISSUE POLARITY, DNA REPAIR AND EPIGENETIC PROFILES AS ENDPOINTS IN RISK ASSESSMENT MODELS AND DISCUSS THE DEVELOPMENT OF 'RISKS-ON-CHIPS' INTEGRATING BIOSENSORS OF THESE ENDPOINTS AND OF GENERAL TISSUE HOMEOSTASIS. RISKS-ON-CHIPS WILL HELP IDENTIFY BIOMARKERS OF RISK, SERVE AS SCREENING PLATFORMS FOR CANCER PREVENTIVE AGENTS, AND PROVIDE A BETTER UNDERSTANDING OF RISK MECHANISMS, HENCE RESULTING IN NOVEL DEVELOPMENTS IN DISEASE PREVENTION. 2013 7 2136 50 EPIGENETIC INFLUENCES IN THE OBESITY/COLORECTAL CANCER AXIS: A NOVEL THERAGNOSTIC AVENUE. THE WORLD HEALTH ORGANIZATION (WHO) CONSIDERS THAT OBESITY HAS REACHED PROPORTIONS OF PANDEMIC. EXPERTS ALSO INSIST ON THE IMPORTANCE OF CONSIDERING OBESITY AS A CHRONIC DISEASE AND ONE OF THE MAIN CONTRIBUTORS TO THE WORLDWIDE BURDEN OF OTHER NONTRANSMISSIBLE CHRONIC DISEASES, WHICH HAVE A GREAT IMPACT ON HEALTH, LIFESTYLE, AND ECONOMIC COST. ONE OF THE MOST CURRENT CHALLENGES OF BIOMEDICAL SCIENCE FACES IS TO UNDERSTAND THE ORIGIN OF THE CHRONIC NONTRANSMISSIBLE DISEASES, SUCH AS OBESITY AND CANCER. THERE IS A LARGE EVIDENCE, BOTH IN EPIDEMIOLOGICAL STUDIES IN HUMANS AND IN ANIMAL MODELS, OF THE ASSOCIATION BETWEEN OBESITY AND AN INCREASED RISK OF CANCER INCIDENCE. IN THE LAST YEARS, THE INITIAL DISCOVERY OF EPIGENETIC MECHANISMS REPRESENTS THE MOST RELEVANT FINDING TO EXPLAIN HOW THE GENOME INTERACTS WITH ENVIRONMENTAL FACTORS AND THE RIPPLE EFFECTS ON DISEASE PATHOGENESES. SINCE THEN, ALL EPIGENETIC PROCESS HAS BEEN INVESTIGATED BY THE SCIENTIFIC COMMUNITIES FOR NEARLY TWO DECADES TO DETERMINE WHICH COMPONENTS ARE INVOLVED IN THIS PROCESS. DNA/RNA METHYLATION AND MIRNA ARE CLASSIFIED AS TWO OF THE MOST IMPORTANT REPRESENTATIVE CLASSES OF SUCH EPIGENETIC MECHANISMS AND DYSREGULATED ACTIVITY OF SUCH MECHANISM CAN CERTAINLY CONTRIBUTE TO DISEASE PATHOGENESIS AND/OR PROGRESSION ESPECIALLY IN TUMORS. THIS REVIEW ARTICLE SERVES TO HIGHLIGHT THE IMPACT OF DNA/RNA METHYLATION AND MIRNA-BASED EPIGENETIC MECHANISM ACTIVITIES IN THE INTERPLAY BETWEEN OBESITY AND THE DEVELOPMENT AND CLINICAL SIGNIFICANCE OF COLORECTAL CANCER. 2019 8 4972 47 PATHOPHYSIOLOGICAL BASIS FOR COMPROMISED HEALTH BEYOND GENERATIONS: ROLE OF MATERNAL HIGH-FAT DIET AND LOW-GRADE CHRONIC INFLAMMATION. EARLY EXPOSURE TO A FAT-ENRICHED DIET PROGRAMS THE DEVELOPMENTAL PROFILE AND THUS IS ASSOCIATED WITH DISEASE SUSCEPTIBILITY IN SUBSEQUENT GENERATIONS. CHRONIC LOW-GRADE INFLAMMATION, RESULTING FROM MATERNAL HIGH-FAT DIET, IS ACTIVATED IN THE FETAL ENVIRONMENT AND IN MANY ORGANS OF OFFSPRING, INCLUDING PLACENTA, ADIPOSE, LIVER, VASCULAR SYSTEM AND BRAIN. THE PREVALENCE OF AN INFLAMMATORY RESPONSE IS HIGHLY ASSOCIATED WITH OBESITY INCIDENCE, CARDIOVASCULAR DISEASES, NONALCOHOLIC FATTY LIVER DISEASE AND BRAIN DAMAGE. SUBSTANTIAL STUDIES USING HIGH-FAT MODEL HAVE CONSISTENTLY DEMONSTRATED THE INCIDENCE OF SUCH INFLAMMATORY REACTIONS; HOWEVER, THE POTENTIAL CONTRIBUTION OF ACTIVE INFLAMMATION TOWARD THE PHYSIOLOGICAL OUTCOMES AND DEVELOPMENTAL DISEASES IS NEITHER DISCUSSED IN DEPTH NOR SYSTEMICALLY INTEGRATED. THEREFORE, WE AIM TO SUMMARIZE THE CURRENT FINDINGS IN REGARDS TO HOW A MATERNAL HIGH-FAT DIET INFLUENCES THE INFLAMMATORY STATUS, AND PROBABLE PATHOGENIC EFFECTS ON THE OFFSPRING. MORE IMPORTANTLY, SINCE LIMITED RESEARCH HAS BEEN CONDUCTED TO REVEAL THE EPIGENETIC REGULATION OF THESE INFLAMMATORY MARKERS BY MATERNAL HIGH-FAT DIET, WE SINCERELY HOPE THAT OUR REVIEW WILL NOT ONLY OUTLINE THE PATHOPHYSIOLOGICAL RELEVANCE OF INFLAMMATION BUT ALSO IDENTIFY A FUTURE DIRECTION FOR MECHANISTIC INVESTIGATION AND CLINICAL APPLICATION. 2015 9 1241 40 CURRENT AND FUTURE NUTRITIONAL STRATEGIES TO MODULATE INFLAMMATORY DYNAMICS IN METABOLIC DISORDERS. OBESITY, TYPE 2 DIABETES, AND OTHER METABOLIC DISORDERS HAVE A LARGE IMPACT ON GLOBAL HEALTH, ESPECIALLY IN WESTERN COUNTRIES. AN IMPORTANT HALLMARK OF METABOLIC DISORDERS IS CHRONIC LOW-GRADE INFLAMMATION. A KEY PLAYER IN CHRONIC LOW-GRADE INFLAMMATION IS DYSMETABOLISM, WHICH IS DEFINED AS THE INABILITY TO KEEP HOMEOSTASIS RESULTING IN LOSS OF LIPID CONTROL, OXIDATIVE STRESS, INFLAMMATION, AND INSULIN RESISTANCE. ALTHOUGH OFTEN NOT YET DETECTABLE IN THE CIRCULATION, CHRONIC LOW-GRADE INFLAMMATION CAN BE PRESENT IN ONE OR MULTIPLE ORGANS. THE RESPONSE TO A METABOLIC CHALLENGE CONTAINING LIPIDS MAY MAGNIFY DYSFUNCTIONALITIES AT THE TISSUE LEVEL, CAUSING AN OVERFLOW OF INFLAMMATORY MARKERS INTO THE CIRCULATION AND HENCE ALLOW DETECTION OF EARLY LOW-GRADE INFLAMMATION. HERE, WE SUMMARIZE THE EVIDENCE OF SUCCESSFUL APPLICATION OF METABOLIC CHALLENGE TESTS IN TYPE 2 DIABETES, METABOLIC SYNDROME, OBESITY, AND UNHEALTHY AGING. WE ALSO REVIEW HOW METABOLIC CHALLENGE TESTS HAVE BEEN SUCCESSFULLY APPLIED TO EVALUATE NUTRITIONAL INTERVENTION EFFECTS, INCLUDING AN "ANTI-INFLAMMATORY" MIXTURE, DARK CHOCOLATE, WHOLE GRAIN WHEAT AND OVERFEEDING. ADDITIONALLY, WE ELABORATE ON FUTURE STRATEGIES TO (RE)GAIN INFLAMMATORY FLEXIBILITY. THROUGH EPIGENETIC AND METABOLIC REGULATION, THE INFLAMMATORY RESPONSE MAY BE TRAINED BY REGULAR MILD AND METABOLIC TRIGGERS, WHICH CAN BE UNDERSTOOD FROM THE PERSPECTIVE OF TRAINED IMMUNITY, HORMESIS AND PRO-RESOLUTION. NEW STRATEGIES TO OPTIMIZE DYNAMICS OF INFLAMMATION MAY BECOME AVAILABLE. 2019 10 6730 45 WALK MORE, EAT LESS, DON'T STRESS. UNHEALTHY DIET, OBESITY, LACK OF PHYSICAL ACTIVITY, AND PSYCHOLOGIC STRESS ARE ASSOCIATED WITH INCREASED INFLAMMATION, OXIDATIVE STRESS, INSULIN RESISTANCE, AND DNA METHYLATION, WHICH ARE THE MAIN MECHANISMS OF CHRONIC DISEASES SUCH AS CANCER, HYPERTENSION, DIABETES, CARDIOVASCULAR DISEASE, AND ALZHEIMER'S DISEASE. IT HAS RECENTLY BEEN FOUND THAT HEALTHY DIET AND PHYSICAL ACTIVITY CAN REDUCE INFLAMMATORY MARKERS AND IMPROVE INSULIN SENSITIVITY RESULTING IN BETTER SURVIVORSHIP OUTCOMES IN PATIENTS WITH PROSTATE CANCER. AN "ANTI-INFLAMMATORY" LIFESTYLE, INCLUDING PHYSICAL ACTIVITY, HEALTHY BODY WEIGHT, HEALTHY DIET, AND STRESS REDUCTION, HAS BEEN ASSOCIATED WITH DECREASED CANCER RISK AND PROGRESSION. EPIGENETIC CHANGES DUE TO DNA METHYLATION AND ALTERED GENE EXPRESSION ASSOCIATED WITH UNHEALTHY LIFESTYLE CAN BE MODULATED BY HEALTHY BEHAVIORS. NATIONAL CENTER FOR COMPLEMENTARY AND INTEGRATIVE HEALTH (NCCIH) FOCUSES ON HEALTHY LIFESTYLE, AND IT SUPPORTS RESEARCH ON PSYCHOLOGIC AND PHYSICAL APPROACHES INCLUDING DIETARY SUPPLEMENTS AND PLANT-BASED PRODUCTS, AS WELL AS MIND AND BODY APPROACHES, SUCH AS YOGA, MASSAGE, MEDITATION, MINDFULNESS-BASED STRESS REDUCTION, AND ACUPUNCTURE. SEE RELATED ARTICLE BY LANGLAIS ET AL., P. 1760. 2022 11 2616 35 EPIGENOME MODULATION INDUCED BY KETOGENIC DIETS. KETOGENIC DIETS (KD) ARE DIETARY STRATEGIES LOW IN CARBOHYDRATES, NORMAL IN PROTEIN, AND HIGH, NORMAL, OR REDUCED IN FAT WITH OR WITHOUT (VERY LOW-CALORIES KETOGENIC DIET, VLCKD) A REDUCED CALORIC INTAKE. KDS HAVE BEEN SHOWN TO BE USEFUL IN THE TREATMENT OF OBESITY, METABOLIC DISEASES AND RELATED DISORDERS, NEUROLOGICAL DISEASES, AND VARIOUS PATHOLOGICAL CONDITIONS SUCH AS CANCER, NONALCOHOLIC LIVER DISEASE, AND CHRONIC PAIN. SEVERAL STUDIES HAVE INVESTIGATED THE INTRACELLULAR METABOLIC PATHWAYS THAT CONTRIBUTE TO THE BENEFICIAL EFFECTS OF THESE DIETS. ALTHOUGH EPIGENETIC CHANGES ARE AMONG THE MOST IMPORTANT DETERMINANTS OF AN ORGANISM'S ABILITY TO ADAPT TO ENVIRONMENTAL CHANGES, DATA ON THE EPIGENETIC CHANGES ASSOCIATED WITH THESE DIETARY PATHWAYS ARE STILL LIMITED. THIS REVIEW PROVIDES AN OVERVIEW OF THE MAJOR EPIGENETIC CHANGES ASSOCIATED WITH KDS. 2022 12 4198 35 METABOLIC PROFILING DISTINGUISHES THREE SUBTYPES OF ALZHEIMER'S DISEASE. THE CAUSE OF ALZHEIMER'S DISEASE IS INCOMPLETELY DEFINED, AND NO TRULY EFFECTIVE THERAPY EXISTS. HOWEVER, MULTIPLE STUDIES HAVE IMPLICATED METABOLIC ABNORMALITIES SUCH AS INSULIN RESISTANCE, HORMONAL DEFICIENCIES, AND HYPERHOMOCYSTEINEMIA. OPTIMIZING METABOLIC PARAMETERS IN A COMPREHENSIVE WAY HAS YIELDED COGNITIVE IMPROVEMENT, BOTH IN SYMPTOMATIC AND ASYMPTOMATIC INDIVIDUALS. THEREFORE, EXPANDING THE STANDARD LABORATORY EVALUATION IN PATIENTS WITH DEMENTIA MAY BE REVEALING. HERE I REPORT THAT METABOLIC PROFILING REVEALS THREE ALZHEIMER'S DISEASE SUBTYPES. THE FIRST IS INFLAMMATORY, IN WHICH MARKERS SUCH AS HS-CRP AND GLOBULIN:ALBUMIN RATIO ARE INCREASED. THE SECOND TYPE IS NON-INFLAMMATORY, IN WHICH THESE MARKERS ARE NOT INCREASED, BUT OTHER METABOLIC ABNORMALITIES ARE PRESENT. THE THIRD TYPE IS A VERY DISTINCTIVE CLINICAL ENTITY THAT AFFECTS RELATIVELY YOUNG INDIVIDUALS, EXTENDS BEYOND THE TYPICAL ALZHEIMER'S DISEASE INITIAL DISTRIBUTION TO AFFECT THE CORTEX WIDELY, IS CHARACTERIZED BY EARLY NON-AMNESTIC FEATURES SUCH AS DYSCALCULIA AND APHASIA, IS OFTEN MISDIAGNOSED OR LABELED ATYPICAL ALZHEIMER'S DISEASE, TYPICALLY AFFECTS APOE4-NEGATIVE INDIVIDUALS, AND IS ASSOCIATED WITH STRIKING ZINC DEFICIENCY. GIVEN THE INVOLVEMENT OF ZINC IN MULTIPLE ALZHEIMER'S-RELATED METABOLIC PROCESSES, SUCH AS INSULIN RESISTANCE, CHRONIC INFLAMMATION, ADAM10 PROTEOLYTIC ACTIVITY, AND HORMONAL SIGNALING, THIS SYNDROME OF ALZHEIMER'S-PLUS WITH LOW ZINC (APLZ) WARRANTS FURTHER METABOLIC, GENETIC, AND EPIGENETIC CHARACTERIZATION. 2015 13 650 28 BISPHENOL A AND HUMAN CHRONIC DISEASES: CURRENT EVIDENCES, POSSIBLE MECHANISMS, AND FUTURE PERSPECTIVES. BISPHENOL-A (BPA) IS ONE OF THE HIGHEST VOLUME CHEMICALS PRODUCED WORLDWIDE, WITH OVER 6BILLION POUNDS PRODUCED AND OVER 100T RELEASED INTO THE ATMOSPHERE EACH YEAR. RECENT EXTENSIVE LITERATURE HAS RAISED CONCERNS ABOUT ITS POSSIBLE IMPLICATION IN THE ETIOLOGY OF SOME HUMAN CHRONIC DISEASES SUCH AS DIABETES, OBESITY, REPRODUCTIVE DISORDERS, CARDIOVASCULAR DISEASES, BIRTH DEFECTS, CHRONIC RESPIRATORY AND KIDNEY DISEASES AND BREAST CANCER. IN THIS REVIEW, WE PRESENT THE HIGHLIGHTED EVIDENCES ON THE RELATIONSHIP BETWEEN BPA EXPOSURE AND HUMAN CHRONIC DISEASES AND WE DISCUSS ITS EVENTUAL MECHANISMS OF ACTION, ESPECIALLY GENETIC, EPIGENETIC AND ENDOCRINE DISRUPTION MECHANISMS WITH THE POSSIBLE INVOLVEMENT OF OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION AND CELL SIGNALING. 2014 14 6334 39 THE ROLE OF DNA METHYLATION AND HYDROXYMETHYLATION IN IMMUNOSENESCENCE. A HEALTHY FUNCTIONING IMMUNE SYSTEM IS CRITICAL TO STAVE OFF INFECTIOUS DISEASES, BUT AS HUMANS AND OTHER ORGANISMS AGE, THEIR IMMUNE SYSTEMS DECLINE. AS A RESULT, DISEASES THAT WERE READILY THWARTED IN EARLY LIFE POSE NONTRIVIAL HARM AND CAN EVEN BE DEADLY IN LATE LIFE. IMMUNOSENESCENCE IS DEFINED AS THE GENERAL DETERIORATION OF THE IMMUNE SYSTEM WITH AGE, AND IT IS CHARACTERIZED BY FUNCTIONAL CHANGES IN HEMATOPOIETIC STEM CELLS (HSCS) AND SPECIFIC BLOOD CELL TYPES AS WELL AS CHANGES IN LEVELS OF NUMEROUS FACTORS, PARTICULARLY THOSE INVOLVED IN INFLAMMATION. POTENTIAL MECHANISMS UNDERLYING IMMUNOSENESCENCE INCLUDE EPIGENETIC CHANGES SUCH AS CHANGES IN DNA METHYLATION (DNAM) AND DNA HYDROXYMETHYLATION (DNAHM) THAT OCCUR WITH AGE. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE WHAT IS CURRENTLY KNOWN ABOUT THE RELATIONSHIP BETWEEN IMMUNOSENESCENCE AND THE AGE-RELATED CHANGES TO DNAM AND DNAHM, AND TO DISCUSS EXPERIMENTAL APPROACHES BEST SUITED TO FILL GAPS IN OUR UNDERSTANDING. 2019 15 3919 65 LINKING DIET TO COLORECTAL CANCER: THE EMERGING ROLE OF MICRORNA IN THE COMMUNICATION BETWEEN PLANT AND ANIMAL KINGDOMS. ENVIRONMENTAL AND LIFESTYLE FACTORS, INCLUDING DIET AND NUTRITIONAL HABITS HAVE BEEN STRONGLY LINKED TO COLORECTAL CANCER (CRC). OF NOTE, UNHEALTHY DIETARY HABITS LEADING TO ADIPOSITY REPRESENT A MAIN RISK FACTOR FOR CRC AND ARE ASSOCIATED WITH A CHRONIC LOW-GRADE INFLAMMATORY STATUS. INFLAMMATION IS A HALLMARK OF ALMOST EVERY TYPE OF CANCER AND CAN BE MODULATED BY SEVERAL FOOD COMPOUNDS EXHIBITING EITHER PROTECTIVE OR PROMOTING EFFECTS. HOWEVER, IN SPITE OF AN EXTENSIVE RESEARCH, THE UNDERLYING MECHANISMS BY WHICH DIETARY PATTERNS OR BIOACTIVE FOOD COMPONENTS MAY INFLUENCE TUMOR ONSET AND OUTCOME HAVE NOT BEEN FULLY CLARIFIED YET. GROWING EVIDENCE INDICATES THAT DIET, COMBINING BENEFICIAL SUBSTANCES AND POTENTIALLY HARMFUL INGREDIENTS, HAS AN IMPACT ON THE EXPRESSION OF KEY REGULATORS OF GENE EXPRESSION SUCH AS THE NON-CODING RNA (NCRNA). SINCE THE EXPRESSION OF THESE MOLECULES IS DERANGED IN CHRONIC INFLAMMATION AND CANCER, MODULATING THEIR EXPRESSION MAY STRONGLY INFLUENCE THE CANCER PHENOTYPE AND OUTCOMES. IN ADDITION, THE RECENTLY ACQUIRED KNOWLEDGE ON THE EXISTENCE OF INTRICATE INTER-KINGDOM COMMUNICATION NETWORKS, IS OPENING NEW AVENUES FOR A DEEPER UNDERSTANDING OF THE INTIMATE RELATIONSHIPS LINKING DIET TO CRC. IN THIS NOVEL SCENARIO, DIET-MODULATED NCRNA MAY REPRESENT KEY ACTORS IN THE INTERACTION BETWEEN PLANT AND ANIMAL KINGDOMS, CAPABLE OF INFLUENCING DISEASE ONSET AND OUTCOME. IN THIS REVIEW, WE WILL SUMMARIZE THE STUDIES DEMONSTRATING A LINK BETWEEN BIOACTIVE FOOD COMPONENTS, INCLUDING FOOD-DERIVED, MICROBIOTA-PROCESSED, SECONDARY METABOLITES, AND HOST NCRNA. WE WILL FOCUS ON MICRORNA, HIGHLIGHTING HOW THIS PLANT/ANIMAL INTER-KINGDOM CROSS-TALK MAY HAVE AN IMPACT ON CRC ESTABLISHMENT AND PROGRESSION. 2017 16 3593 49 IMPLICATION OF THE MEDITERRANEAN DIET ON THE HUMAN EPIGENOME. EPIGENETICS, DEFINED AS "HEREDITARY CHANGES IN GENE EXPRESSION THAT OCCUR WITHOUT ANY CHANGE IN THE DNA SEQUENCE", CONSISTS OF VARIOUS EPIGENETIC MARKS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING RNAS. THE EPIGENOME, WHICH HAS A DYNAMIC STRUCTURE IN RESPONSE TO INTRACELLULAR AND EXTRACELLULAR STIMULI, HAS A KEY ROLE IN THE CONTROL OF GENE ACTIVITY, SINCE IT IS LOCATED AT THE INTERSECTION OF CELLULAR INFORMATION ENCODED IN THE GENOME AND MOLECULAR/CHEMICAL INFORMATION OF EXTRACELLULAR ORIGIN. THE FOCUS SHIFT OF STUDIES TO EPIGENETIC REPROGRAMMING HAS LED TO THE FORMATION AND PROGRESSIVE IMPORTANCE OF A CONCEPT CALLED "NUTRIEPIGENETICS", WHOSE AIM IS TO PREVENT DISEASES BY INTERVENING ON NUTRITION STYLE. AMONG THE DIET TYPES ADOPTED IN THE WORLD, THE RENOWNED MEDITERRANEAN DIET (MD), BEING RICH IN UNSATURATED FATTY ACIDS AND CONTAINING HIGH LEVELS OF WHOLE GRAIN FOODS AND LARGE QUANTITIES OF FRUITS, VEGETABLES, AND LEGUMES, HAS SHOWN NUMEROUS ADVANTAGES IN EXCLUDING CHRONIC DISEASES. ADDITIONALLY, THE FACT THAT THIS DIET IS RICH IN POLYPHENOLS WITH HIGH ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES HAS AN UNDENIABLE EFFECT IN TURNING SOME CELLULAR PATHWAYS AGAINST THE DISEASE. IT IS ALSO APPARENT THAT THE EFFECTS OF POLYPHENOLS ON THE EPIGENOME CAUSE CHANGES IN MECHANISMS SUCH AS DNA METHYLATION AND HISTONE ACETYLATION/DEACETYLATION, WHICH HAVE A REGULATORY EFFECT ON GENE REGULATION. THIS REVIEW PRESENTS THE EFFECTS OF LONG-TERM CONSUMPTION OF NUTRIENTS FROM THE MD ON THE EPIGENOME AND DISCUSSES THE BENEFITS OF THIS DIET IN THE TREATMENT AND EVEN PREVENTION OF CHRONIC DISEASES. 2022 17 5362 39 RECENT ADVANCES IN CALORIE RESTRICTION RESEARCH ON AGING. THE EXTENSION OF BOTH MEDIAN AND MAXIMUM LIFESPAN AND THE SUPPRESSION OF AGE-RELATED DISEASES IN LABORATORY ANIMALS BY REDUCED FOOD INTAKE, I.E., CALORIE RESTRICTION (CR) ARE REGARDED AS HALLMARKS OF CR'S ANTI-AGING ACTION. THE DIVERSE EFFICACY OF CR TO COUNTERACT AGING EFFECTS AND ITS EXPERIMENTAL REPRODUCIBILITY HAS MADE IT THE GOLD STANDARD OF MANY AGING INTERVENTION STUDIES OF RECENT YEARS. ALTHOUGH CR ORIGINALLY WAS USED AS A TOOL TO PERTURB THE AGING PROCESS OF LABORATORY ANIMALS AS TO UNCOVER CLUES OF UNDERLYING MECHANISMS OF AGING PROCESSES, CURRENT CR RESEARCH INTERESTS HAVE SHIFTED TO THE RETARDATION OF AGING-RELATED FUNCTIONAL DECLINE AND THE PREVENTION OF AGE-RELATED DISEASES. ADVANCES IN CR RESEARCH ON NON-HUMAN PRIMATES AND RECENT ENDEAVORS USING HUMAN SUBJECTS OFFER A PROMISING OUTLOOK FOR CR'S BENEFICIAL EFFECTS IN HEALTHY HUMAN AGING. IN THIS REVIEW, SEVERAL MAJOR ISSUES RELATED TO CR'S ANTI-AGING MECHANISMS ARE DISCUSSED BY HIGHLIGHTING THE IMPORTANCE OF MODULATING DELETERIOUS CHRONIC INFLAMMATION AT MOLECULAR LEVELS AND THE IMPACT OF EPIGENETIC CHROMATIN AND HISTONE MODIFICATIONS BY CR AT THE ULTIMATE CONTROL SITES OF GENE EXPRESSION. THE RECENT RESEARCH ON RAPAMYCIN AS A CR MIMETIC IS SUMMARIZED AND A BRIEF DESCRIPTION OF INTERMITTENT FEEDING PATTERNS IS REVIEWED IN COMPARISON TO THE CR EFFECT. 2013 18 3418 30 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000 19 5737 57 SMOKING AND HEALTH: ASSOCIATION BETWEEN TELOMERE LENGTH AND FACTORS IMPACTING ON HUMAN DISEASE, QUALITY OF LIFE AND LIFE SPAN IN A LARGE POPULATION-BASED COHORT UNDER THE EFFECT OF SMOKING DURATION. REACTIVE OXYGEN SPECIES (ROS) ARE OF PRIMARY IMPORTANCE AS THEY CAUSE DAMAGE TO LIPIDS, PROTEINS, AND DNA EITHER ENDOGENOUSLY BY CELLULAR MECHANISM, OR THROUGH EXOGENOUS EXPOSURE TO ENVIRONMENTAL INJURY FACTORS, INCLUDING OXIDATION INSULT FACTORS, SUCH AS TOBACCO SMOKE. CURRENTLY 46.3 MILLION ADULTS (25.7 PERCENT OF THE POPULATION) ARE SMOKERS. THIS INCLUDES 24 MILLION MEN (28.1 PERCENT OF THE TOTAL) AND MORE THAN 22 MILLION WOMEN (23.5 PERCENT). THE PREVALENCE IS HIGHEST AMONG PERSONS 25-44 YEARS OF AGE. CIGARETTE SMOKERS HAVE A HIGHER RISK OF DEVELOPING SEVERAL CHRONIC DISORDERS. THESE INCLUDE FATTY BUILDUPS IN ARTERIES, SEVERAL TYPES OF CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (LUNG PROBLEMS). AS PERIPHERAL LEUKOCYTES HAVE BEEN THE MAIN TARGET OF HUMAN TELOMERE RESEARCH, MOST OF WHAT IS KNOWN ABOUT HUMAN TELOMERE DYNAMICS IN VIVO IS BASED ON THESE CELLS. LEUKOCYTE TELOMERE LENGTH (TL) IS A COMPLEX TRAIT THAT IS SHAPED BY GENETIC, EPIGENETIC, AND ENVIRONMENTAL DETERMINANTS. IN THIS ARTICLE, WE CONSIDER THAT SMOKING MODIFIES LEUKOCYTE TL IN HUMANS AND CONTRIBUTES TO ITS VARIABILITY AMONG INDIVIDUALS, ALTHOUGH THE SMOKING EFFECT ON TL AND ITS RELATION WITH OTHER METABOLIC INDICES MAY ACCELERATE BIOLOGICAL AGING AND DEVELOPMENT OF SMOKING-INDUCED CHRONIC DISEASES IN A LARGE HUMAN POPULATION-BASED COHORTS WITH SMOKING BEHAVIOR. RECENT STUDIES CONFIRMED THAT INDIVIDUALS WITH SHORTER TELOMERES PRESENT A HIGHER PREVALENCE OF ARTERIAL LESIONS AND HIGHER RISK OF CARDIOVASCULAR DISEASE MORTALITY. THIS STUDY ORIGINALLY SUGGESTS THAT EFFICIENT THERAPEUTIC PROTECTION OF TL AND STRUCTURE IN RESPONSE TO STRESSES THAT ARE KNOWN TO REDUCE TL, SUCH AS OXIDATIVE DAMAGE OR INFLAMMATION ASSOCIATED WITH TOBACCO SMOKING, WOULD LEAD TO BETTER TELOMERE MAINTENANCE. RECENTLY, WE HAVE DISCOVERED THE POTENTIAL USE OF TELOMERE-RESTORATIVE IMIDAZOLE-CONTAINING DIPEPTIDE (NON-HYDROLIZED CARNOSINE, CARCININE) BASED THERAPY FOR BETTER SURVIVAL OF SMOKERS. WE CONCLUDE THAT A BETTER THERAPEUTIC OR NUTRITIONAL MAINTENANCE OF TL MAY CONFER HEALTHY AGING IN SMOKERS AND EXCEPTIONAL LONGEVITY IN REGULARLY ROS-EXPOSED HUMAN SURVIVORS. 2011 20 4204 40 METABOLISM, EPIGENETICS, AND CAUSAL INFERENCE IN HEART FAILURE. EUKARYOTES MUST BALANCE THE METABOLIC AND CELL DEATH ACTIONS OF MITOCHONDRIA VIA CONTROL OF GENE EXPRESSION AND CELL FATE BY CHROMATIN, THEREBY FUNCTIONALLY BINDING THE METABOLOME AND EPIGENOME. THIS INTERACTION HAS FAR-REACHING IMPLICATIONS FOR CHRONIC DISEASES IN HUMANS, THE MOST COMMON OF WHICH ARE THOSE OF THE CARDIOVASCULAR SYSTEM. THE MOST DEVASTATING CONSEQUENCE OF CARDIOVASCULAR DISEASE, HEART FAILURE, IS NOT A SINGLE DISEASE, DIAGNOSIS, OR ENDPOINT. HUMAN AND ANIMAL STUDIES HAVE REVEALED THAT, REGARDLESS OF ETIOLOGY AND SYMPTOMS, HEART FAILURE IS UNIVERSALLY ASSOCIATED WITH ABNORMAL METABOLISM AND GENE EXPRESSION - TO FRAME THIS AS CAUSE OR CONSEQUENCE, HOWEVER, MAY BE TO WRONGFOOT THE QUESTION. THIS ESSAY AIMS TO CHALLENGE CURRENT THINKING ON METABOLIC-EPIGENETIC CROSSTALK IN HEART FAILURE, PRESENTING HYPOTHESES FOR HOW CHRONIC DISEASES ARISE, TAKE HOLD, AND PERSIST. WE UNPACK ASSUMPTIONS ABOUT THE ORDER OF OPERATIONS FOR GENE EXPRESSION AND METABOLISM, EXPLORING RECENT FINDINGS IN NONCARDIAC SYSTEMS THAT LINK METABOLIC INTERMEDIATES DIRECTLY TO CHROMATIN REMODELING. LASTLY, WE DISCUSS POTENTIAL MECHANISMS BY WHICH CHROMATIN MAY SERVE AS A SUBSTRATE FOR METABOLIC MEMORY, AND HOW CHANGES IN CELLULAR TRANSCRIPTOMES (AND HENCE IN CELLULAR BEHAVIOR) IN RESPONSE TO STRESS CORRESPOND TO GLOBAL CHANGES IN CHROMATIN ACCESSIBILITY AND STRUCTURE. 2020