1 4106 144 MECHANISM OF INFLAMMATION IN AGE-RELATED MACULAR DEGENERATION. AGE-RELATED MACULAR DEGENERATION (AMD) IS A MULTIFACTORIAL DISEASE THAT REPRESENTS THE MOST COMMON CAUSE OF IRREVERSIBLE VISUAL IMPAIRMENT AMONG PEOPLE OVER THE AGE OF 50 IN EUROPE, THE UNITED STATES, AND AUSTRALIA, ACCOUNTING FOR UP TO 50% OF ALL CASES OF CENTRAL BLINDNESS. RISK FACTORS OF AMD ARE HETEROGENEOUS, MAINLY INCLUDING INCREASING AGE AND DIFFERENT GENETIC PREDISPOSITIONS, TOGETHER WITH SEVERAL ENVIRONMENTAL/EPIGENETIC FACTORS, THAT IS, CIGARETTE SMOKING, DIETARY HABITS, AND PHOTOTOXIC EXPOSURE. IN THE AGING RETINA, FREE RADICALS AND OXIDIZED LIPOPROTEINS ARE CONSIDERED TO BE MAJOR CAUSES OF TISSUE STRESS RESULTING IN LOCAL TRIGGERS FOR PARAINFLAMMATION, A CHRONIC STATUS WHICH CONTRIBUTES TO INITIATION AND/OR PROGRESSION OF MANY HUMAN NEURODEGENERATIVE DISEASES SUCH AS AMD. EXPERIMENTAL AND CLINICAL EVIDENCES STRONGLY INDICATE THE PATHOGENETIC ROLE OF IMMUNOLOGIC PROCESSES IN AMD OCCURRENCE, CONSISTING OF PRODUCTION OF INFLAMMATORY RELATED MOLECULES, RECRUITMENT OF MACROPHAGES, COMPLEMENT ACTIVATION, MICROGLIAL ACTIVATION AND ACCUMULATION WITHIN THOSE STRUCTURES THAT COMPOSE AN ESSENTIAL AREA OF THE RETINA KNOWN AS MACULA LUTEA. THIS PAPER REVIEWS SOME ATTRACTIVE ASPECTS OF THE LITERATURE ABOUT THE MECHANISMS OF INFLAMMATION IN AMD, ESPECIALLY FOCUSING ON THOSE FINDINGS OR ARGUMENTS MORE DIRECTLY TRANSLATABLE TO IMPROVE THE CLINICAL MANAGEMENT OF PATIENTS WITH AMD AND TO PREVENT THE SEVERE VISION LOSS CAUSED BY THIS DISEASE. 2012 2 279 37 AGE-RELATED MACULAR DEGENERATION: FROM EPIGENETICS TO THERAPEUTIC IMPLICATIONS. ABERRANT REGULATION OF EPIGENETIC MECHANISMS, INCLUDING THE TWO MOST COMMON TYPES; DNA METHYLATION AND HISTONE MODIFICATION HAVE BEEN IMPLICATED IN COMMON CHRONIC PROGRESSIVE CONDITIONS, INCLUDING ALZHEIMER DISEASE, CARDIOVASCULAR DISEASE, AND AGE-RELATED MACULAR DEGENERATION (AMD). ALL THESE CONDITIONS ARE COMPLEX, MEANING THAT ENVIRONMENTAL FACTORS, GENETIC FACTORS, AND THEIR INTERACTIONS PLAY A ROLE IN DISEASE PATHOPHYSIOLOGY. ALTHOUGH GENOME WIDE ASSOCIATION STUDIES (GWAS), AND STUDIES ON TWINS DEMONSTRATE THE GENETIC/HEREDITARY COMPONENT TO THESE COMPLEX DISEASES, INCLUDING AMD, THIS CONTRIBUTION IS MUCH LESS THAN 100%. MOREOVER, THE CONTRIBUTION OF THE HEREDITARY COMPONENT DECREASES IN THE ADVANCED, LATER ONSET FORMS OF THESE CHRONIC DISEASES INCLUDING AMD. THIS UNDERSCORES THE NEED TO ELUCIDATE HOW THE GENETIC AND ENVIRONMENTAL FACTORS FUNCTION TO EXERT THEIR INFLUENCE ON DISEASE PATHOPHYSIOLOGY. BY TEASING OUT EPIGENETIC MECHANISMS AND HOW THEY EXERT THEIR INFLUENCE ON AMD, THERAPEUTIC TARGETS CAN BE TAILORED TO PREVENT AND/OR SLOW DOWN DISEASE PROGRESSION. EPIGENETIC STUDIES THAT INCORPORATE WELL-CHARACTERIZED PATIENT TISSUE SAMPLES (INCLUDING AFFECTED TISSUES AND PERIPHERAL BLOOD), SIMILAR TO THOSE RELEVANT TO GENE EXPRESSION STUDIES, ALONG WITH GENETIC AND EPIDEMIOLOGICAL INFORMATION, CAN BE THE FIRST STEP IN DEVELOPING APPROPRIATE FUNCTIONAL ASSAYS TO VALIDATE FINDINGS AND IDENTIFY POTENTIAL THERAPIES. 2021 3 6443 30 THERAPEUTIC APPROACHES TO HISTONE REPROGRAMMING IN RETINAL DEGENERATION. RECENT DATA HAVE REVEALED EPIGENETIC DERANGEMENTS AND SUBSEQUENT CHROMATIN REMODELING AS A POTENT BIOLOGIC SWITCH FOR CHRONIC INFLAMMATION AND CELL SURVIVAL WHICH ARE IMPORTANT THERAPEUTIC TARGETS IN THE PATHOGENESIS OF SEVERAL RETINAL DEGENERATIONS. HISTONE DEACETYLASES (HDACS) ARE A MAJOR COMPONENT OF THIS SYSTEM AND SERVE AS A UNIQUE CONTROL OF THE CHROMATIN REMODELING PROCESS. WITH A MULTITUDE OF TARGETED HDAC INHIBITORS NOW AVAILABLE, THEIR USE IN BOTH BASIC SCIENCE AND CLINICAL STUDIES HAS WIDENED SUBSTANTIALLY. IN THE FIELD OF OCULAR BIOLOGY, THERE ARE DATA TO SUGGEST THAT HDAC INHIBITION MAY SUPPRESS NEOVASCULARIZATION AND MAY BE A POSSIBLE TREATMENT FOR RETINITIS PIGMENTOSA AND DRY AGE-RELATED MACULAR DEGENERATION (AMD). HOWEVER, THE EFFECTS OF THESE INHIBITORS ON CELL SURVIVAL AND CHEMOKINE EXPRESSION IN THE CHORIORETINAL TISSUES REMAIN VERY UNCLEAR. HERE, WE REVIEW THE MULTIFACETED BIOLOGY OF HDAC ACTIVITY AND PHARMACOLOGIC INHIBITION WHILE OFFERING FURTHER INSIGHT INTO THE IMPORTANCE OF THIS EPIGENETIC PATHWAY IN RETINAL DEGENERATIONS. OUR LABORATORY INVESTIGATIONS AIM TO OPEN TRANSLATIONAL AVENUES TO ADVANCE DRY AMD THERAPEUTICS WHILE EXPLORING THE ROLE OF ACETYLATION ON INFLAMMATORY GENE EXPRESSION IN THE AGING AND DEGENERATING RETINA. 2016 4 6034 44 THE CHALLENGE BY MULTIPLE ENVIRONMENTAL AND BIOLOGICAL FACTORS INDUCE INFLAMMATION IN AGING: THEIR ROLE IN THE PROMOTION OF CHRONIC DISEASE. THE AGING PROCESS IS DRIVEN BY MULTIPLE MECHANISMS THAT LEAD TO CHANGES IN ENERGY PRODUCTION, OXIDATIVE STRESS, HOMEOSTATIC DYSREGULATION AND EVENTUALLY TO LOSS OF FUNCTIONALITY AND INCREASED DISEASE SUSCEPTIBILITY. MOST AGED INDIVIDUALS DEVELOP CHRONIC LOW-GRADE INFLAMMATION, WHICH IS AN IMPORTANT RISK FACTOR FOR MORBIDITY, PHYSICAL AND COGNITIVE IMPAIRMENT, FRAILTY, AND DEATH. AT ANY AGE, CHRONIC INFLAMMATORY DISEASES ARE MAJOR CAUSES OF MORBIMORTALITY, AFFECTING UP TO 5-8% OF THE POPULATION OF INDUSTRIALIZED COUNTRIES. SEVERAL ENVIRONMENTAL FACTORS CAN PLAY AN IMPORTANT ROLE FOR MODIFYING THE INFLAMMATORY STATE. GENETICS ACCOUNTS FOR ONLY A SMALL FRACTION OF CHRONIC-INFLAMMATORY DISEASES, WHEREAS ENVIRONMENTAL FACTORS APPEAR TO PARTICIPATE, EITHER WITH A CAUSATIVE OR A PROMOTIONAL ROLE IN 50% TO 75% OF PATIENTS. SEVERAL OF THOSE CHANGES DEPEND ON EPIGENETIC CHANGES THAT WILL FURTHER MODIFY THE INDIVIDUAL RESPONSE TO ADDITIONAL STIMULI. THE INTERACTION BETWEEN INFLAMMATION AND THE ENVIRONMENT OFFERS IMPORTANT INSIGHTS ON AGING AND HEALTH. THESE CONDITIONS, OFTEN DEPENDING ON THE INDIVIDUAL'S SEX, APPEAR TO LEAD TO DECREASED LONGEVITY AND PHYSICAL AND COGNITIVE DECLINE. IN ADDITION TO BIOLOGICAL FACTORS, THE ENVIRONMENT IS ALSO INVOLVED IN THE GENERATION OF PSYCHOLOGICAL AND SOCIAL CONTEXT LEADING TO STRESS. POOR PSYCHOLOGICAL ENVIRONMENTS AND OTHER SOURCES OF STRESS ALSO RESULT IN INCREASED INFLAMMATION. HOWEVER, THE MECHANISMS UNDERLYING THE ROLE OF ENVIRONMENTAL AND PSYCHOSOCIAL FACTORS AND NUTRITION ON THE REGULATION OF INFLAMMATION, AND HOW THE RESPONSE ELICITED FOR THOSE FACTORS INTERACT AMONG THEM, ARE POORLY UNDERSTOOD. WHEREAS CERTAIN DELETERIOUS ENVIRONMENTAL FACTORS RESULT IN THE GENERATION OF OXIDATIVE STRESS DRIVEN BY AN INCREASED PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES, ENDOPLASMIC RETICULUM STRESS, AND INFLAMMATION, OTHER FACTORS, INCLUDING NUTRITION (POLYUNSATURATED FATTY ACIDS) AND BEHAVIORAL FACTORS (EXERCISE) CONFER PROTECTION AGAINST INFLAMMATION, OXIDATIVE AND ENDOPLASMIC RETICULUM STRESS, AND THUS AMELIORATE THEIR DELETERIOUS EFFECT. HERE, WE DISCUSS PROCESSES AND MECHANISMS OF INFLAMMATION ASSOCIATED WITH ENVIRONMENTAL FACTORS AND BEHAVIOR, THEIR LINKS TO SEX AND GENDER, AND THEIR OVERALL IMPACT ON AGING. 2020 5 6629 25 UNDERSTANDING THE HUMAN AGING PROTEOME USING EPIDEMIOLOGICAL MODELS. HUMAN AGING IS A COMPLEX MULTIFACTORIAL PROCESS ASSOCIATED WITH A DECLINE OF PHYSICAL AND COGNITIVE FUNCTION AND HIGH SUSCEPTIBILITY TO CHRONIC DISEASES, INFLUENCED BY GENETIC, EPIGENETIC, ENVIRONMENTAL, AND DEMOGRAPHIC FACTORS. THIS CHAPTER WILL PROVIDE AN OVERVIEW ON THE USE OF EPIDEMIOLOGICAL MODELS WITH PROTEOMICS DATA AS A METHOD THAT CAN BE USED TO IDENTIFY FACTORS THAT MODULATE THE AGING PROCESS IN HUMANS. THIS IS DEMONSTRATED WITH PROTEOMICS DATA FROM HUMAN PLASMA AND SKELETAL MUSCLE, WHERE THE COMBINATION WITH EPIDEMIOLOGICAL MODELS IDENTIFIED A SET OF MITOCHONDRIAL, SPLICEOSOME, AND SENESCENCE PROTEINS AS WELL AS THE ROLE OF ENERGETIC PATHWAYS SUCH AS GLYCOLYSIS, AND ELECTRON TRANSPORT PATHWAYS THAT REGULATE THE AGING PROCESS. 2022 6 1027 31 CIRCULATING MIRNAS IN SUCCESSFUL AND UNSUCCESSFUL AGING. A MINI-REVIEW. AGING IS A MULTIFACTORIAL PROCESS THAT AFFECTS THE ORGANISMS AT GENETIC, MOLECULAR AND CELLULAR LEVELS. THIS PROCESS MODIFIES SEVERAL TISSUES WITH A NEGATIVE IMPACT ON CELLS PHYSIOLOGY, TISSUES AND ORGANS FUNCTIONALITY, ALTERING THEIR REGENERATION CAPACITY. THE CHRONIC LOW-GRADE INFLAMMATION TYPICAL OF AGING, DEFINED AS INFLAMMAGING, IS A COMMON BIOLOGICAL FACTOR RESPONSIBLE FOR THE DECLINE AND BEGINNING OF THE DISEASE IN AGE. A MURINE PARABIOSIS MODEL THAT COMBINES THE VASCULAR SYSTEM OF OLD AND YOUNG ANIMALS, SUGGESTS THAT SOLUBLE FACTORS RELEASED BY YOUNG INDIVIDUALS MAY IMPROVE THE REGENERATIVE POTENTIAL OF OLD TISSUE. THEREFORE, CIRCULATING FACTORS HAVE A KEY ROLE IN THE INDUCTION OF AGING PHENOTYPE. MOREOVER, LIFESTYLE CAN INFLUENCE THE PHYSIOLOGICAL STATUS OF MULTIPLE ORGANS, VIA EPIGENETIC MECHANISMS. RECENTLY, MICRORNAS ARE CONSIDERED POTENTIAL SENSORS OF AGING. 2019 7 3676 41 INFLAMMATION AND NEUTROPHIL IMMUNOSENESCENCE IN HEALTH AND DISEASE: TARGETED TREATMENTS TO IMPROVE CLINICAL OUTCOMES IN THE ELDERLY. DESPITE INCREASING LONGEVITY, MANY OLD PEOPLE ARE NOT IN GOOD HEALTH. THERE HAS BEEN AN INCREASE IN THE PREVALENCE OF AGE-ASSOCIATED MULTI-MORBIDITY (TWO OR MORE CHRONIC CONDITIONS IN THE SAME PERSON). ALSO, SEVERE INFECTIONS, SUCH AS PNEUMONIA, REMAIN SIGNIFICANT CAUSES OF MORTALITY AND MORBIDITY IN THIS AGING GROUP. MANY CHRONIC HEALTH CONDITIONS SHARE RISK FACTORS SUCH AS INCREASING AGE, SMOKING, A SEDENTARY LIFE STYLE AND BEING PART OF A LOWER SOCIOECONOMIC GROUP. HOWEVER, DESPITE THIS, MULTI-MORBIDITIES OFTEN CO-OCCUR MORE COMMONLY THAN WOULD BE PREDICTED. THIS HAS LED TO THE HYPOTHESIS THAT THEY SHARE COMMON UNDERLYING MECHANISMS. THIS IS AN IMPORTANT CONCEPT, FOR IF IT WERE TRUE, TREATMENTS COULD BE DEVISED WHICH TARGET THESE COMMON PATHWAYS AND IMPROVE A NUMBER OF AGE-ASSOCIATED HEALTH CONDITIONS. MANY CHRONIC ILLNESSES ASSOCIATED WITH MULTI-MORBIDITY AND SEVERE INFECTIONS ARE CHARACTERIZED BY AN ABNORMAL AND SUSTAINED INFLAMMATORY RESPONSE, WITH NEUTROPHILS BEING KEY EFFECTOR CELLS IN THE PATHOLOGICAL PROCESS. STUDIES HAVE DESCRIBED ABERRANT NEUTROPHIL FUNCTIONS ACROSS THESE CONDITIONS, AND SOME HAVE HIGHLIGHTED POTENTIAL MECHANISMS FOR ALTERED CELL BEHAVIOURS WHICH APPEAR SHARED ACROSS DISEASE STATES. IT HAS BEEN SUGGESTED THAT ALTERED FUNCTIONS MAY REPRESENT NEUTROPHIL "SENESCENCE". THIS REVIEW CONSIDERS HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE CELL AGES, AND HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE HOST AGES IN HEALTH AND DISEASE AND DISCUSSES WHETHER NEUTROPHIL FUNCTIONS COULD BE TARGETED TO IMPROVE HEALTH OUTCOMES IN OLDER ADULTS. 2018 8 5633 23 SENESCENT REMODELING OF THE INNATE AND ADAPTIVE IMMUNE SYSTEM IN THE ELDERLY MEN WITH PROSTATE CANCER. DESPITE YEARS OF INTENSIVE INVESTIGATION THAT HAS BEEN MADE IN UNDERSTANDING PROSTATE CANCER, IT REMAINS A MAJOR CAUSE OF DEATH IN MEN WORLDWIDE. PROSTATE CANCER EMERGES FROM MULTIPLE ALTERATIONS THAT INDUCE CHANGES IN EXPRESSION PATTERNS OF GENES AND PROTEINS THAT FUNCTION IN NETWORKS CONTROLLING CRITICAL CELLULAR EVENTS. BASED ON THE EXPONENTIAL AGING OF THE POPULATION AND THE INCREASING LIFE EXPECTANCY IN INDUSTRIALIZED WESTERN COUNTRIES, PROSTATE CANCER IN THE ELDERLY MEN IS BECOMING A DISEASE OF INCREASING SIGNIFICANCE. AGING IS A PROGRESSIVE DEGENERATIVE PROCESS STRICTLY INTEGRATED WITH INFLAMMATION. SEVERAL THEORIES HAVE BEEN PROPOSED THAT ATTEMPT TO DEFINE THE ROLE OF CHRONIC INFLAMMATION IN AGING INCLUDING REDOX STRESS, MITOCHONDRIAL DAMAGE, IMMUNOSENESCENCE, AND EPIGENETIC MODIFICATIONS. HERE, WE REVIEW THE INNATE AND ADAPTIVE IMMUNE SYSTEMS AND THEIR SENESCENT REMODELING IN ELDERLY MEN WITH PROSTATE CANCER. 2014 9 1112 34 COMMON PATHOGENETIC MECHANISMS UNDERLYING AGING AND TUMOR AND MEANS OF INTERVENTIONS. RECENTLY, THERE HAS BEEN AN INCREASE IN THE INCIDENCE OF MALIGNANT TUMORS AMONG THE OLDER POPULATION. MOREOVER, THERE IS AN ASSOCIATION BETWEEN AGING AND CANCER. DURING THE PROCESS OF SENESCENCE, THE HUMAN BODY SUFFERS FROM A SERIES OF IMBALANCES, WHICH HAVE BEEN SHOWN TO FURTHER ACCELERATE AGING, TRIGGER TUMORIGENESIS, AND FACILITATE CANCER PROGRESSION. THEREFORE, EXPLORING THE JUNCTIONS OF AGING AND CANCER AND SEARCHING FOR NOVEL METHODS TO RESTORE THE JUNCTIONS IS OF GREAT IMPORTANCE TO INTERVENE AGAINST AGING-RELATED CANCERS. IN THIS REVIEW, WE HAVE IDENTIFIED THE UNDERLYING PATHOGENETIC MECHANISMS OF AGING-RELATED CANCERS BY COMPARING ALTERATIONS IN THE HUMAN BODY CAUSED BY AGING AND THE FACTORS THAT TRIGGER CANCERS. WE FOUND THAT THE COMMON MECHANISMS OF AGING AND CANCER INCLUDE CELLULAR SENESCENCE, ALTERATIONS IN PROTEOSTASIS, MICROBIOTA DISORDERS (DECREASED PROBIOTICS AND INCREASED PERNICIOUS BACTERIA), PERSISTENT CHRONIC INFLAMMATION, EXTENSIVE IMMUNOSENESCENCE, INORDINATE ENERGY METABOLISM, ALTERED MATERIAL METABOLISM, ENDOCRINE DISORDERS, ALTERED GENETIC EXPRESSION, AND EPIGENETIC MODIFICATION. FURTHERMORE, WE HAVE PROPOSED THAT AGING AND CANCER HAVE COMMON MEANS OF INTERVENTION, INCLUDING NOVEL USES OF COMMON MEDICINE (METFORMIN, RESVERATROL, AND RAPAMYCIN), DIETARY RESTRICTION, AND ARTIFICIAL MICROBIOTA INTERVENTION OR SELECTIVELY REPLENISHING SCARCE METABOLITES. IN ADDITION, WE HAVE SUMMARIZED THE RESEARCH PROGRESS OF EACH INTERVENTION AND REVEALED THEIR BIDIRECTIONAL EFFECTS ON CANCER PROGRESSION TO COMPARE THEIR RELIABILITY AND FEASIBILITY. THEREFORE, THE STUDY FINDINGS PROVIDE VITAL INFORMATION FOR ADVANCED RESEARCH STUDIES ON AGE-RELATED CANCERS. HOWEVER, THERE IS A NEED FOR FURTHER OPTIMIZATION OF THE DESCRIBED METHODS AND MORE SUITABLE METHODS FOR COMPLICATED CLINICAL PRACTICES. IN CONCLUSION, TARGETING AGING MAY HAVE POTENTIAL THERAPEUTIC EFFECTS ON AGING-RELATED CANCERS. 2022 10 269 42 AGE AND PERIODONTAL HEALTH - IMMUNOLOGICAL VIEW. PURPOSE OF THE REVIEW: AGING CLEARLY IMPACTS A WIDE ARRAY OF SYSTEMS, IN PARTICULAR THE BREADTH OF THE IMMUNE SYSTEM LEADING TO IMMUNOSENESCENCE, ALTERED IMMUNOACTIVATION, AND COINCIDENT INFLAMMAGING PROCESSES. THE NET RESULT OF THESE CHANGES LEADS TO INCREASED SUSCEPTIBILITY TO INFECTIONS, INCREASED NEOPLASTIC OCCURRENCES, AND ELEVATED FREQUENCY OF AUTOIMMUNE DISEASES WITH AGING. HOWEVER, AS THE BACTERIA IN THE ORAL MICROBIOME THAT CONTRIBUTE TO THE CHRONIC INFECTION OF PERIODONTITIS IS ACQUIRED EARLIER IN LIFE, THE CHARACTERISTICS OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMS TO REGULATE THESE MEMBERS OF THE AUTOCHTHONOUS MICROBIOTA ACROSS THE LIFESPAN REMAINS ILL DEFINED. RECENT FINDINGS: CLEAR DATA DEMONSTRATE THAT BOTH CELLS AND MOLECULES OF THE INNATE AND ADAPTIVE IMMUNE RESPONSE ARE ADVERSELY IMPACTED BY AGING, INCLUDING IN THE ORAL CAVITY, YIELDING A REASONABLE TENET THAT THE INCREASED PERIODONTITIS NOTED IN AGING POPULATIONS IS REFLECTIVE OF THE AGE-ASSOCIATED IMMUNE DYSREGULATION. ADDITIONALLY, THIS FACET OF HOST-MICROBE INTERACTIONS AND DISEASE NEEDS TO ACCOMMODATE THE POPULATION VARIATION IN DISEASE ONSET AND PROGRESSION, WHICH MAY ALSO REFLECT AN ACCUMULATION OF ENVIRONMENTAL STRESSORS AND/OR DECREASED PROTECTIVE NUTRIENTS THAT COULD FUNCTION AT THE GENE LEVEL (IE. EPIGENETIC) OR TRANSLATIONAL LEVEL FOR PRODUCTION AND SECRETION OF IMMUNE SYSTEM MOLECULES. SUMMARY: FINALLY, THE MAJORITY OF STUDIES OF AGING AND PERIODONTITIS HAVE EMPHASIZED THE INCREASED PREVALENCE/SEVERITY OF DISEASE WITH AGING, ALL BASED UPON CHRONOLOGICAL AGE. HOWEVER, EVOLVING AREAS OF STUDY FOCUSING ON "BIOLOGICAL AGING" TO HELP ACCOUNT FOR POPULATION VARIATION IN DISEASE EXPRESSION, MAY SUGGEST THAT CHRONIC PERIODONTITIS REPRESENTS A CO-MORBIDITY THAT CONTRIBUTES TO "GEROVULNERABILITY" WITHIN THE POPULATION. 2018 11 3404 32 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 12 278 33 AGE-RELATED INFLAMMATION: THE CONTRIBUTION OF DIFFERENT ORGANS, TISSUES AND SYSTEMS. HOW TO FACE IT FOR THERAPEUTIC APPROACHES. A TYPICAL FEATURE OF AGEING IS A CHRONIC, LOW-GRADE INFLAMMATION CHARACTERIZED BY A GENERAL INCREASE IN THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES AND INFLAMMATORY MARKERS ("INFLAMM-AGEING"). THIS STATUS MAY SLOWLY DAMAGE ONE OR SEVERAL ORGANS, ESPECIALLY WHEN UNFAVORABLE GENETIC POLYMORPHISMS AND EPIGENETIC ALTERATIONS ARE CONCOMITANT, LEADING TO AN INCREASED RISK OF FRAILTY TOGETHER WITH THE ONSET OF AGE-RELATED CHRONIC DISEASES. THE CONTRIBUTION OF DIFFERENT TISSUES (ADIPOSE TISSUE, MUSCLE), ORGANS (BRAIN, LIVER), IMMUNE SYSTEM AND ECOSYSTEMS (GUT MICROBIOTA) TO AGE-RELATED INFLAMMATION ("INFLAMM-AGEING") WILL BE DISCUSSED IN THIS REVIEW IN THE CONTEXT OF ITS ONSET/PROGRESSION LEADING TO SITE-RESTRICTED AND SYSTEMIC EFFECTS. MOREOVER, SOME OF THE POSSIBLE STRATEGIES AND THERAPIES TO COUNTERACT THE DIFFERENT SOURCES OF MOLECULAR MEDIATORS WHICH LEAD TO THE AGE-RELATED INFLAMMATORY PHENOTYPE WILL BE PRESENTED. 2010 13 1871 46 EMERGING ROLE OF EPIGENETICS IN EXPLAINING RELATIONSHIP OF PERIODONTITIS AND CARDIOVASCULAR DISEASES. CARDIOVASCULAR DISEASES SUCH AS ISCHEMIC HEART DISEASES OR STROKE ARE AMONG THE LEADING CAUSE OF DEATHS GLOBALLY, AND EVIDENCE SUGGESTS THAT THESE DISEASES ARE MODULATED BY A MULTIFACTORIAL AND COMPLEX INTERPLAY OF GENETIC, ENVIRONMENTAL, AND LIFESTYLE FACTORS. GENETIC PREDISPOSITION AND CHRONIC EXPOSURE TO MODIFIABLE RISK FACTORS HAVE BEEN EXPLORED TO BE INVOLVED IN THE PATHOPHYSIOLOGY OF CVD. ENVIRONMENTAL FACTORS CONTRIBUTE TO AN INDIVIDUAL'S PROPENSITY TO DEVELOP MAJOR CARDIOVASCULAR RISK FACTORS THROUGH EPIGENETIC MODIFICATIONS OF DNA AND HISTONES VIA MIRNA REGULATION OF PROTEIN TRANSLATION THAT ARE TYPES OF EPIGENETIC MECHANISMS AND PARTICIPATE IN DISEASE DEVELOPMENT. PERIODONTAL DISEASE (PD) IS ONE OF THE MOST COMMON ORAL DISEASES IN HUMANS THAT IS CHARACTERIZED BY LOW-GRADE INFLAMMATION AND HAS BEEN SHOWN TO INCREASE THE RISK OF CVDS. RISK FACTORS INVOLVED IN PD AND CVD ARE DETERMINED BOTH GENETICALLY AND BEHAVIORALLY. PERIODONTAL DISEASES SUCH AS CHRONIC INFLAMMATION PROMOTE DNA METHYLATION. EPIGENETIC MODIFICATIONS INVOLVED IN THE INITIATION AND PROGRESSION OF ATHEROSCLEROSIS PLAY AN ESSENTIAL ROLE IN PLAQUE DEVELOPMENT AND VULNERABILITY. EPIGENETICS HAS OPENED A NEW WORLD TO UNDERSTAND AND MANAGE HUMAN DISEASES, INCLUDING CVDS AND PERIODONTAL DISEASES. GENETIC MEDICINE HAS STARTED A NEW ERA OF EPIGENETICS TO OVERCOME HUMAN DISEASES WITH VARIOUS NEW METHODOLOGY. EPIGENETIC PROFILING MAY AID IN BETTER DIAGNOSIS AND STRATIFICATION OF PATIENTS SHOWING POTENTIAL PREDISPOSED STATES FOR DISEASE. A BETTER UNDERSTANDING OF THE EXACT REGULATORY MECHANISMS OF EPIGENETIC PATHWAYS DRIVING INFLAMMATION IS SLOWLY EMERGING AND WILL AID IN DEVELOPING NOVEL TOOLS FOR THE TREATMENT OF DISEASE. 2021 14 2570 31 EPIGENETICS OF CHRONIC INFLAMMATORY DISEASES. CHRONIC, NONCOMMUNICABLE, AND INFLAMMATION-ASSOCIATED DISEASES REMAIN THE LARGEST CAUSE OF MORBIDITY AND MORTALITY GLOBALLY AND WITHIN THE UNITED STATES. THIS IS MAINLY DUE TO OUR LIMITED UNDERSTANDING OF THE MOLECULAR MECHANISMS THAT UNDERLIE THESE COMPLEX PATHOLOGIES. THE AVAILABLE EVIDENCE INDICATES THAT STUDIES OF EPIGENETICS (TRADITIONALLY DEFINED AS THE HERITABLE CHANGES TO GENE EXPRESSION THAT ARE INDEPENDENT OF CHANGES TO DNA) ARE SIGNIFICANTLY ADVANCING OUR KNOWLEDGE OF THESE INFLAMMATORY CONDITIONS. THIS REVIEW WILL FOCUS ON EPIGENETIC STUDIES OF THREE DISEASES, THAT ARE AMONG THE MOST BURDENSOME GLOBALLY: CARDIOVASCULAR DISEASE, THE NUMBER ONE CAUSE OF DEATHS WORLDWIDE, TYPE 2 DIABETES AND, ALZHEIMER'S DISEASE. THE CURRENT STATUS OF EPIGENETIC RESEARCH, INCLUDING THE ABILITY TO PREDICT DISEASE RISK, AND KEY PATHOPHYSIOLOGICAL DEFECTS ARE DISCUSSED. THE SIGNIFICANCE OF DEFINING THE CONTRIBUTION OF EPIGENETIC DEFECTS TO NONRESOLVING INFLAMMATION AND AGING, EACH ASSOCIATED WITH THESE DISEASES, IS HIGHLIGHTED, AS THESE ARE LIKELY TO PROVIDE NEW INSIGHTS INTO INFLAMMATORY DISEASE PATHOGENESIS. 2019 15 6880 35 [RESEARCH PROGRESS OF LUNG AGING IN CHRONIC RESPIRATORY DISEASES]. CELL AGING IS AN EXTREMELY COMPLEX PROCESS, WHICH IS CHARACTERIZED BY MITOCHONDRIAL STRUCTURAL DYSFUNCTION, TELOMERE SHORTENING, INFLAMMATORY MICROENVIRONMENT, PROTEIN HOMEOSTASIS IMBALANCE, EPIGENETIC CHANGES, ABNORMAL DNA DAMAGE AND REPAIR, ETC. AGING IS USUALLY ACCOMPANIED BY STRUCTURAL AND FUNCTIONAL DAMAGE OF TISSUES AND ORGANS WHICH FURTHER INDUCES THE OCCURRENCE AND DEVELOPMENT OF AGING-RELATED DISEASES. AGING INCLUDES PHYSIOLOGICAL AGING CAUSED BY INCREASED AGE AND PATHOLOGICAL AGING INDUCED BY A VARIETY OF FACTORS. NOTEWORTHY, AS A TARGET ORGAN DIRECTLY CONTACTING WITH THE OUTSIDE AIR, LUNG IS MORE PRONE TO VARIOUS STIMULI, CAUSING PATHOLOGICAL PREMATURE AGING WHICH IS LUNG AGING. STUDIES HAVE FOUND THAT THERE IS A CERTAIN PROPORTION OF SENESCENT CELLS IN THE LUNGS OF MOST CHRONIC RESPIRATORY DISEASES. HOWEVER, THE UNDERLYING MECHANISM BY WHICH THESE SENESCENT CELLS INDUCE LUNG SENESCENCE AND THEIR ROLE IN CHRONIC RESPIRATORY DISEASES IS STILL OBSCURE. THIS PAPER FOCUSES ON THE CAUSES AND CLASSIFICATION OF LUNG AGING, THE INTERNAL MECHANISM OF LUNG AGING INVOLVED IN CHRONIC RESPIRATORY DISEASES, AND THE APPLICATION OF ANTI-AGING TREATMENTS IN CHRONIC RESPIRATORY DISEASES. WE HOPE TO PROVIDE NEW RESEARCH IDEAS AND THEORETICAL BASIS FOR THE CLINICAL PREVENTION AND TREATMENT IN CHRONIC RESPIRATORY DISEASES. 2022 16 3549 37 IMMUNOSENESCENCE AND MULTIPLE SCLEROSIS. CHANGES IN THE IMMUNE SYSTEM ASSOCIATED WITH AGEING ARE KNOWN AS IMMUNOSENESCENCE. THIS IS CHARACTERISED BY A DECLINE IN IMMUNE RESPONSE, CHRONIC INFLAMMATION AND AN INCREASED RISK OF AUTOIMMUNE DISEASES. A CHRONIC INFLAMMATORY PROCESS WITH PERSISTENT PRODUCTION OF PROINFLAMMATORY MEDIATORS INCREASES THE RISK FOR MORBIDITY AND MORTALITY RELATED TO AGE, AND HAS BEEN DUBBED 'INFLAMM-AGEING'. IMMUNOSENESCENCE IS ASSOCIATED WITH A DECREASE IN THE NUMBER OF NAIVE T AND B CELLS, NK CELLS AND DISRUPTION OF THE PRO- AND ANTI-INFLAMMATORY BALANCE BY CHANGES IN THE PRODUCTION OF CYTOKINES. IN FACT, AGEING OF THE IMMUNE SYSTEM HAS A COMPLEX NETWORK OF UNDERLYING CAUSES WHICH INCLUDE NOT ONLY NATURAL MECHANISMS OF SENESCENCE BUT ALSO CHRONIC DISORDERS, LIFESTYLE, ENVIRONMENTAL AND EPIGENETIC FACTORS, AND INFECTIONS. MOREOVER, IMMUNOSENESCENCE HAS AN INFLUENCE ON THE COURSE OF CHRONIC DISEASES WHICH HAVE AN ONSET IN YOUNG ADULTS, SUCH AS MULTIPLE SCLEROSIS (MS). CURRENT DISEASE MODIFYING THERAPIES (DMTS) IN MS AIM TO REDUCE THE FREQUENCY OF RELAPSES AND TO SLOW DISEASE PROGRESSION, BUT THEY DO NOT NECESSARILY STOP THE ACCUMULATION OF DISABILITY RELATED TO DISEASE PROGRESSION. SOME FEATURES OF IMMUNOSENESCENCE FOUND IN AGED HEALTHY CONTROLS ARE ALREADY OBSERVED IN MS PATIENTS AT A YOUNGER AGE. THE OLDER POPULATION IS CHARACTERISED BY AN INCREASED SUSCEPTIBILITY TO INFECTIONS, A POOR RESPONSE TO VACCINATIONS, AND A HIGHER RISK OF DEVELOPING CANCER, VASCULAR DISEASES AND NEURODEGENERATION. IMMUNOSENESCENCE IS AN IMPORTANT FACTOR INFLUENCING THE COURSE OF MS, AND THE SAFETY AND EFFECTIVENESS OF DMTS. THE RELATIONSHIP BETWEEN THE PATHOGENIC PROCESS UNDERLYING THE DEVELOPMENT OF MS AND IMMUNOSENESCENCE REQUIRES FURTHER INVESTIGATION. 2022 17 2333 27 EPIGENETIC REGULATION OF INFLAMMATION: THE METABOLOMICS CONNECTION. EPIGENETIC FACTORS ARE CONSIDERED THE REGULATOR OF COMPLEX MACHINERY BEHIND INFLAMMATORY DISORDERS AND SIGNIFICANTLY CONTRIBUTED TO THE EXPRESSION OF INFLAMMATION-ASSOCIATED GENES. EPIGENETIC MODIFICATIONS MODULATE VARIATION IN THE EXPRESSION PATTERN OF TARGET GENES WITHOUT AFFECTING THE DNA SEQUENCE. THE CURRENT KNOWLEDGE OF EPIGENETIC RESEARCH FOCUSED ON THEIR ROLE IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES THAT CAUSES MORBIDITY AND MORTALITY WORLDWIDE. INFLAMMATORY DISEASES ARE CATEGORIZED AS ACUTE AND CHRONIC BASED ON THE DISEASE SEVERITY AND ARE REGULATED BY THE EXPRESSION PATTERN OF VARIOUS GENES. HENCE, UNDERSTANDING THE ROLE OF EPIGENETIC MODIFICATIONS DURING INFLAMMATION PROGRESSION WILL CONTRIBUTE TO THE DISEASE OUTCOMES AND THERAPEUTIC APPROACHES. THIS REVIEW ALSO FOCUSES ON THE METABOLOMICS APPROACH ASSOCIATED WITH THE STUDY OF INFLAMMATORY DISORDERS. INFLAMMATORY RESPONSES AND METABOLIC REGULATION ARE HIGHLY INTEGRATED AND VARIOUS ADVANCED TECHNIQUES ARE ADOPTED TO STUDY THE METABOLIC SIGNATURE MOLECULES. HERE WE DISCUSS SEVERAL METABOLOMICS APPROACHES USED TO LINK INFLAMMATORY DISORDERS AND EPIGENETIC CHANGES. WE PROPOSED THAT DECIPHERING THE MECHANISM BEHIND THE INFLAMMATION-METABOLISM LOOP MAY HAVE IMMENSE IMPORTANCE IN BIOMARKERS RESEARCH AND MAY ACT AS A PRINCIPAL COMPONENT IN DRUG DISCOVERY AS WELL AS THERAPEUTIC APPLICATIONS. 2022 18 2984 35 GENETIC DETERMINANTS OF POOR RESPONSE TO TREATMENT IN SEVERE ASTHMA. SEVERE ASTHMA IS A MULTIFACTORIAL DISORDER WITH MARKED PHENOTYPIC HETEROGENEITY AND COMPLEX INTERACTIONS BETWEEN GENETICS AND ENVIRONMENTAL RISK FACTORS, WHICH COULD, AT LEAST IN PART, EXPLAIN WHY DURING STANDARD PHARMACOLOGIC TREATMENT, MANY PATIENTS REMAIN POORLY CONTROLLED AND AT AN INCREASED RISK OF AIRWAY REMODELING AND DISEASE PROGRESSION. THE CONCEPT OF "PRECISION MEDICINE" TO BETTER SUIT INDIVIDUAL UNIQUE NEEDS IS AN EMERGING TREND IN THE MANAGEMENT OF CHRONIC RESPIRATORY DISEASES. OVER THE PAST FEW YEARS, GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE REVEALED NOVEL PHARMACOGENETIC VARIANTS RELATED TO RESPONSES TO INHALED CORTICOSTEROIDS AND THE CLINICAL EFFICACY OF BRONCHODILATORS. OPTIMAL CLINICAL RESPONSE TO TREATMENT MAY VARY BETWEEN RACIAL/ETHNIC GROUPS OR INDIVIDUALS DUE TO GENETIC DIFFERENCES. IT IS ALSO PLAUSIBLE TO ASSUME THAT EPIGENETIC FACTORS PLAY A KEY ROLE IN THE MODULATION OF GENE EXPRESSION PATTERNS AND INFLAMMATORY CYTOKINES. REMARKABLY, SPECIFIC GENETIC VARIANTS RELATED TO TREATMENT EFFECTIVENESS MAY INDICATE PROMISING PATHWAYS FOR NOVEL THERAPIES IN SEVERE ASTHMA. IN THIS REVIEW, WE PROVIDE A CONCISE UPDATE OF GENETIC DETERMINANTS OF POOR RESPONSE TO TREATMENT IN SEVERE ASTHMA AND FUTURE DIRECTIONS IN THE FIELD. 2021 19 3669 38 INFLAMMAGING AND CANCER: A CHALLENGE FOR THE MEDITERRANEAN DIET. AGING IS CONSIDERED THE MAJOR RISK FACTOR FOR CANCER, ONE OF THE MOST IMPORTANT MORTALITY CAUSES IN THE WESTERN WORLD. INFLAMMAGING, A STATE OF CHRONIC, LOW-LEVEL SYSTEMIC INFLAMMATION, IS A PERVASIVE FEATURE OF HUMAN AGING. CHRONIC INFLAMMATION INCREASES CANCER RISK AND AFFECTS ALL CANCER STAGES, TRIGGERING THE INITIAL GENETIC MUTATION OR EPIGENETIC MECHANISM, PROMOTING CANCER INITIATION, PROGRESSION AND METASTATIC DIFFUSION. THUS, INFLAMMAGING IS A STRONG CANDIDATE TO CONNECT AGE AND CANCER. A COROLLARY OF THIS HYPOTHESIS IS THAT INTERVENTIONS AIMING TO DECREASE INFLAMMAGING SHOULD PROTECT AGAINST CANCER, AS WELL AS MOST/ALL AGE-RELATED DISEASES. EPIDEMIOLOGICAL DATA ARE CONCORDANT IN SUGGESTING THAT THE MEDITERRANEAN DIET (MD) DECREASES THE RISK OF A VARIETY OF CANCERS BUT THE UNDERPINNING MECHANISM(S) IS (ARE) STILL UNCLEAR. HERE WE REVIEW DATA INDICATING THAT THE MD (AS A WHOLE DIET OR SINGLE BIOACTIVE NUTRIENTS TYPICAL OF THE MD) MODULATES MULTIPLE INTERCONNECTED PROCESSES INVOLVED IN CARCINOGENESIS AND INFLAMMATORY RESPONSE SUCH AS FREE RADICAL PRODUCTION, NF-KAPPAB ACTIVATION AND EXPRESSION OF INFLAMMATORY MEDIATORS, AND THE EICOSANOIDS PATHWAY. PARTICULAR ATTENTION IS DEVOTED TO THE CAPABILITY OF MD TO AFFECT THE BALANCE BETWEEN PRO- AND ANTI-INFLAMMAGING AS WELL AS TO EMERGING TOPICS SUCH AS MAINTENANCE OF GUT MICROBIOTA (GM) HOMEOSTASIS AND EPIGENETIC MODULATION OF ONCOGENESIS THROUGH SPECIFIC MICRORNAS. 2015 20 5765 34 SOURCE OF CHRONIC INFLAMMATION IN AGING. AGING IS A COMPLEX PROCESS THAT RESULTS FROM A COMBINATION OF ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS. A CHRONIC PRO-INFLAMMATORY STATUS IS A PERVASIVE FEATURE OF AGING. THIS CHRONIC LOW-GRADE INFLAMMATION OCCURRING IN THE ABSENCE OF OVERT INFECTION HAS BEEN DEFINED AS "INFLAMMAGING" AND REPRESENTS A SIGNIFICANT RISK FACTOR FOR MORBIDITY AND MORTALITY IN THE ELDERLY. THE LOW-GRADE INFLAMMATION PERSISTS EVEN AFTER REVERSING PRO-INFLAMMATORY STIMULI SUCH AS LDL CHOLESTEROL AND THE RENIN-ANGIOTENSIN SYSTEM (RAS). RECENTLY, SEVERAL POSSIBLE SOURCES OF CHRONIC LOW-GRADE INFLAMMATION OBSERVED DURING AGING AND AGE-RELATED DISEASES HAVE BEEN PROPOSED. CELL SENESCENCE AND DYSREGULATION OF INNATE IMMUNITY IS ONE SUCH MECHANISM BY WHICH PERSISTENT PROLONGED INFLAMMATION OCCURS EVEN AFTER THE INITIAL STIMULUS HAS BEEN REMOVED. ADDITIONALLY, THE COAGULATION FACTOR THAT ACTIVATES INFLAMMATORY SIGNALING BEYOND ITS ROLE IN THE COAGULATION SYSTEM HAS BEEN IDENTIFIED. THIS SIGNAL COULD BE A NEW SOURCE OF CHRONIC INFLAMMATION AND CELL SENESCENCE. HERE, WE SUMMARIZED THE FACTORS AND CELLULAR PATHWAYS/PROCESSES THAT ARE KNOWN TO REGULATE LOW-GRADE PERSISTENT INFLAMMATION IN AGING AND AGE-RELATED DISEASE. 2018