1 3539 51 IMMUNE SENESCENCE, EPIGENETICS AND AUTOIMMUNITY. AGING OF THE IMMUNE SYSTEM IN HUMANS AND ANIMALS IS CHARACTERIZED BY A DECLINE IN BOTH ADAPTIVE AND INNATE IMMUNE RESPONSES. PARADOXICALLY, AGING IS ALSO ASSOCIATED WITH A STATE OF CHRONIC INFLAMMATION ("INFLAMMAGING") AND AN INCREASED LIKELIHOOD OF DEVELOPING AUTOIMMUNE DISEASES. EPIGENETIC CHANGES IN NON-DIVIDING AND DIVIDING CELLS, INCLUDING IMMUNE CELLS, DUE TO ENVIRONMENTAL FACTORS CONTRIBUTE TO THE INFLAMMATION AND AUTOIMMUNITY THAT CHARACTERIZE BOTH THE STATE AND DISEASES OF AGING. HERE, WE REVIEW THE EPIGENETIC MECHANISMS INVOLVED IN THE DEVELOPMENT OF IMMUNE SENESCENCE AND AUTOIMMUNITY IN OLD AGE. 2018 2 6344 31 THE ROLE OF EPIGENETICS IN AGING AND AUTOIMMUNITY. THE DECLINE IN IMMUNOCOMPETENCE WITH AGE IS ACCOMPANIED BY THE INCREASE IN THE INCIDENCE OF AUTOIMMUNE DISEASES. AGING OF THE IMMUNE SYSTEM, OR IMMUNOSENESCENCE, IS CHARACTERIZED BY A DECLINE OF BOTH T AND B CELL FUNCTION, AND PARADOXICALLY THE PRESENCE OF LOW-GRADE CHRONIC INFLAMMATION. THERE IS GROWING EVIDENCE THAT EPIGENETICS, THE STUDY OF INHERITED CHANGES IN GENE EXPRESSION THAT ARE NOT ENCODED BY THE DNA SEQUENCE ITSELF, CHANGES WITH AGING. INTERESTINGLY, EMERGING EVIDENCE SUGGESTS A KEY ROLE FOR EPIGENETICS IN HUMAN PATHOLOGIES, INCLUDING INFLAMMATORY AND NEOPLASTIC DISORDERS. HERE, WE WILL REVIEW THE POTENTIAL MECHANISMS THAT CONTRIBUTE TO THE INCREASE IN AUTOIMMUNE RESPONSES IN AGING. IN PARTICULAR, WE WILL DISCUSS HOW EPIGENETIC ALTERATIONS, ESPECIALLY DNA METHYLATION AND HISTONE ACETYLATION, ARE ACCUMULATED DURING AGING AND HOW THESE EVENTS CONTRIBUTE TO AUTOIMMUNITY RISK. 2010 3 4037 27 MACROPHAGE IMMUNOMETABOLISM AND INFLAMMAGING: ROLES OF MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, CD38, AND NAD. AGING IS A COMPLEX PROCESS THAT INVOLVES DYSFUNCTION ON MULTIPLE LEVELS, ALL OF WHICH SEEM TO CONVERGE ON INFLAMMATION. MACROPHAGES ARE INTIMATELY INVOLVED IN INITIATING AND RESOLVING INFLAMMATION, AND THEIR DYSREGULATION WITH AGE IS A PRIMARY CONTRIBUTOR TO INFLAMMAGING-A STATE OF CHRONIC, LOW-GRADE INFLAMMATION THAT DEVELOPS DURING AGING. AMONG THE AGE-RELATED CHANGES THAT OCCUR TO MACROPHAGES ARE A HEIGHTENED STATE OF BASAL INFLAMMATION AND DIMINISHED OR HYPERACTIVE INFLAMMATORY RESPONSES, WHICH SEEM TO BE DRIVEN BY METABOLIC-DEPENDENT EPIGENETIC CHANGES. IN THIS REVIEW ARTICLE WE PROVIDE A BRIEF OVERVIEW OF MITOCHONDRIAL FUNCTIONS AND AGE-RELATED CHANGES THAT OCCUR TO MACROPHAGES, WITH AN EMPHASIS ON HOW THE INFLAMMAGING ENVIRONMENT, SENESCENCE, AND NAD DECLINE CAN AFFECT THEIR METABOLISM, PROMOTE DYSREGULATION, AND CONTRIBUTE TO INFLAMMAGING AND AGE-RELATED PATHOLOGIES. 2020 4 2644 30 EPIGENOMIC DRIVERS OF IMMUNE DYSFUNCTION IN AGING. AGING INEVITABLY LEADS TO REDUCED IMMUNE FUNCTION, LEAVING THE ELDERLY MORE SUSCEPTIBLE TO INFECTIONS, LESS ABLE TO RESPOND TO PATHOGEN CHALLENGES, AND LESS RESPONSIVE TO PREVENTATIVE VACCINATIONS. NO CELL TYPE IS EXEMPT FROM THE RAVAGES OF AGE, AND EXTENSIVE STUDIES HAVE FOUND AGE-RELATED ALTERATIONS IN THE FREQUENCIES AND FUNCTIONS OF BOTH STEM AND PROGENITOR CELLS, AS WELL AS EFFECTOR CELLS OF BOTH THE INNATE AND ADAPTIVE IMMUNE SYSTEMS. THE INTRINSIC FUNCTIONAL REDUCTION IN IMMUNE COMPETENCE IS ALSO ASSOCIATED WITH LOW-GRADE CHRONIC INFLAMMATION, TERMED "INFLAMM-AGING," WHICH FURTHER PERPETUATES IMMUNE DYSFUNCTION. WHILE MANY OF THESE AGE-RELATED CELLULAR CHANGES ARE WELL CHARACTERIZED, UNDERSTANDING THE MOLECULAR CHANGES THAT UNDERPIN THE FUNCTIONAL DECLINE HAS PROVEN MORE DIFFICULT. CHANGES IN CHROMATIN ARE INCREASINGLY APPRECIATED AS A CAUSATIVE MECHANISM OF CELLULAR AND ORGANISMAL AGING ACROSS SPECIES. THESE CHANGES INCLUDE INCREASED GENOMIC INSTABILITY THROUGH LOSS OF HETEROCHROMATIN AND INCREASED DNA DAMAGE, TELOMERE ATTRITION, AND EPIGENETIC ALTERATIONS. IN THIS REVIEW, WE DISCUSS THE CONNECTIONS BETWEEN CHROMATIN, IMMUNOCOMPETENCE, AND THE LOSS OF FUNCTION ASSOCIATED WITH MAMMALIAN IMMUNE AGING. THROUGH UNDERSTANDING THE MOLECULAR EVENTS WHICH UNDERPIN THE PHENOTYPIC CHANGES OBSERVED IN THE AGED IMMUNE SYSTEM, IT IS HOPED THAT THE AGED IMMUNE SYSTEM CAN BE RESTORED TO PROVIDE YOUTHFUL IMMUNITY ONCE MORE. 2019 5 1523 23 DNA METHYLATION CHANGES AND INFLAMMAGING IN AGING-ASSOCIATED DISEASES. AGING AS AN INEVITABLE PHENOMENON IS ASSOCIATED WITH PERVASIVE CHANGES IN PHYSIOLOGICAL FUNCTIONS. THERE IS A RELATIONSHIP BETWEEN AGING AND THE INCREASE OF SEVERAL CHRONIC DISEASES. MOST AGE-RELATED DISORDERS ARE ACCOMPANIED BY AN UNDERLYING CHRONIC INFLAMMATORY STATE, AS DEMONSTRATED BY LOCAL INFILTRATION OF INFLAMMATORY CELLS AND GREATER LEVELS OF PROINFLAMMATORY CYTOKINES IN THE BLOODSTREAM. WITHIN INFLAMMAGING, MANY EPIGENETIC EVENTS, ESPECIALLY DNA METHYLATION, CHANGE. DURING THE AGING PROCESS, DUE TO ABERRATIONS OF DNA METHYLATION, BIOLOGICAL PROCESSES ARE DISRUPTED, LEADING TO THE EMERGENCE OR PROGRESSION OF A VARIETY OF HUMAN DISEASES, INCLUDING CANCER, NEURODEGENERATIVE DISORDERS, CARDIOVASCULAR DISEASE AND DIABETES. THE FOCUS OF THIS REVIEW IS ON DNA METHYLATION, WHICH IS INVOLVED IN INFLAMMAGING-RELATED ACTIVITIES, AND HOW ITS DYSREGULATION LEADS TO HUMAN DISORDERS. 2022 6 1876 21 EMERGING ROLES FOR EPIGENETIC PROGRAMMING IN THE CONTROL OF INFLAMMATORY SIGNALING INTEGRATION IN HEATH AND DISEASE. MACROPHAGES AND DENDRITIC CELLS INITIATE THE INNATE IMMUNE RESPONSE TO INFECTION AND INJURY AND CONTRIBUTE TO INFLAMMATORY SIGNALING TO MAINTAIN THE HOMEOSTASIS OF VARIOUS TISSUES, WHICH INCLUDES RESIDENT MACROPHAGES FOR THE ELIMINATION OF INVADING MICROORGANISMS AND TISSUE DAMAGE. INAPPROPRIATE INFLAMMATORY SIGNALING CAN LEAD TO PERSISTENT INFLAMMATION AND FURTHER DEVELOP INTO AUTOIMMUNE AND INFLAMMATION-ASSOCIATED DISEASES. INFLAMMATORY SIGNALING PATHWAYS HAVE BEEN WELL CHARACTERIZED, BUT HOW THESE SIGNALING PATHWAYS ARE CONVERTED INTO SUSTAINED AND DIVERSE PATTERNS OF EXPRESSION OF CYTOKINES, CHEMOKINES, AND OTHER GENES IN RESPONSE TO ENVIRONMENTAL CHALLENGES IS UNCLEAR. EMERGING EVIDENCE SUGGESTS THE IMPORTANT ROLE OF EPIGENETIC MECHANISMS IN FINELY TUNING THE OUTCOME OF THE HOST INNATE IMMUNE RESPONSE. AN UNDERSTANDING OF EPIGENETIC REGULATION OF INNATE IMMUNE CELL IDENTITY AND FUNCTION WILL ENABLE THE IDENTIFICATION OF THE MECHANISM BETWEEN GENE-SPECIFIC HOST DEFENSES AND INFLAMMATORY DISEASE AND WILL ALSO ALLOW FOR EXPLORATION OF THE PROGRAM OF INNATE IMMUNE MEMORY IN HEALTH AND DISEASE. THIS INFORMATION COULD BE USED TO DEVELOP THERAPEUTIC AGENTS TO ENHANCE THE HOST RESPONSE, PREVENTING CHRONIC INFLAMMATION THROUGH PRESERVING TISSUES AND SIGNALING INTEGRITY. 2017 7 278 20 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 8 6135 26 THE EPIGENETICS OF INFLAMMAGING: THE CONTRIBUTION OF AGE-RELATED HETEROCHROMATIN LOSS AND LOCUS-SPECIFIC REMODELLING AND THE MODULATION BY ENVIRONMENTAL STIMULI. A GROWING AMOUNT OF EVIDENCES INDICATES THAT INFLAMMAGING - THE CHRONIC, LOW GRADE INFLAMMATION STATE CHARACTERISTIC OF THE ELDERLY - IS THE RESULT OF GENETIC AS WELL AS ENVIRONMENTAL OR STOCHASTIC FACTORS. SOME OF THESE, SUCH AS THE ACCUMULATION OF SENESCENT CELLS THAT ARE PERSISTENT DURING AGING OR ACCOMPANY ITS PROGRESSION, SEEM TO BE SUFFICIENT TO INITIATE THE AGING PROCESS AND TO FUEL IT. OTHERS, LIKE EXPOSURE TO ENVIRONMENTAL COMPOUNDS OR INFECTIONS, ARE TEMPORARY AND RESOLVE WITHIN A (RELATIVELY) SHORT TIME. IN BOTH CASES, HOWEVER, A CELLULAR MEMORY OF THE EVENT CAN BE ESTABLISHED BY MEANS OF EPIGENETIC MODULATION OF THE GENOME. IN THIS REVIEW WE WILL SPECIFICALLY DISCUSS THE RELATIONSHIP BETWEEN EPIGENETICS AND INFLAMMAGING. IN PARTICULAR, WE WILL SHOW HOW AGE-ASSOCIATED EPIGENETIC MODIFICATIONS CONCERNED WITH HETEROCHROMATIN LOSS AND GENE-SPECIFIC REMODELLING, CAN PROMOTE INFLAMMAGING. FURTHERMORE, WE WILL RECALL HOW THE EXPOSURE TO SPECIFIC NUTRITIONAL, ENVIRONMENTAL AND MICROBIAL STIMULI CAN AFFECT THE RATE OF INFLAMMAGING THROUGH EPIGENETIC MECHANISMS, TOUCHING ALSO ON THE RECENT INSIGHT GIVEN BY THE CONCEPT OF TRAINED IMMUNITY. 2018 9 1027 22 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 10 5765 22 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 11 6255 26 THE MICROBIOTA AND EPIGENETIC REGULATION OF T HELPER 17/REGULATORY T CELLS: IN SEARCH OF A BALANCED IMMUNE SYSTEM. IMMUNE CELLS NOT ONLY AFFECT TISSUE HOMEOSTASIS AT THE SITE OF INFLAMMATION BUT ALSO EXERT SYSTEMIC EFFECTS CONTRIBUTING TO MULTIPLE CHRONIC CONDITIONS. RECENT EVIDENCE CLEARLY SUPPORTS AN ALTERED T HELPER 17/REGULATORY T CELL (TH17/TREG) BALANCE LEADING TO THE DEVELOPMENT AND PROGRESSION OF INFLAMMATORY DISEASES THAT NOT ONLY AFFECT THE GASTROINTESTINAL TRACT BUT ALSO HAVE WHOLE-BODY MANIFESTATIONS, INCLUDING INSULIN RESISTANCE. EPIGENETIC MECHANISMS ARE AMENABLE TO BOTH ENVIRONMENTAL AND CIRCULATING FACTORS AND CONTRIBUTE TO DETERMINING THE T CELL LANDSCAPE. THE RECENTLY IDENTIFIED PARTICIPATION OF THE GUT MICROBIOTA IN THE REMODELING OF THE EPIGENOME OF IMMUNE CELLS HAS TRIGGERED A PARADIGM SHIFT IN OUR UNDERSTANDING OF THE ETIOLOGY OF VARIOUS INFLAMMATORY DISEASES AND OPENED NEW PATHS TOWARD THERAPEUTIC STRATEGIES. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE CONTRIBUTION OF THE TH17/TREG BALANCE IN THE DEVELOPMENT AND PROGRESSION OF INFLAMMATORY BOWEL DISEASES AND METABOLIC DISEASES. WE DISCUSS THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN THE REGULATION OF T CELL FUNCTION IN THE PARTICULAR CONTEXT OF DYSBIOSIS. FINALLY, WE EXAMINE THE POTENTIAL FOR NUTRITIONAL INTERVENTIONS AFFECTING THE GUT MICROBIOTA TO RESHAPE THE T CELL EPIGENOME AND ADDRESS THE INFLAMMATORY COMPONENT OF VARIOUS DISEASES. 2017 12 5932 25 TARGETING EPIGENETIC REGULATORS FOR INFLAMMATION: MECHANISMS AND INTERVENTION THERAPY. EMERGING EVIDENCE INDICATES THAT RESOLUTION OF INFLAMMATION IS A CRITICAL AND DYNAMIC ENDOGENOUS PROCESS FOR HOST TISSUES DEFENDING AGAINST EXTERNAL INVASIVE PATHOGENS OR INTERNAL TISSUE INJURY. IT HAS LONG BEEN KNOWN THAT AUTOIMMUNE DISEASES AND CHRONIC INFLAMMATORY DISORDERS ARE CHARACTERIZED BY DYSREGULATED IMMUNE RESPONSES, LEADING TO EXCESSIVE AND UNCONTROL TISSUE INFLAMMATION. THE DYSREGULATION OF EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, POSTTRANSLATIONAL MODIFICATIONS TO HISTONE PROTEINS, AND NONCODING RNA EXPRESSION HAS BEEN IMPLICATED IN A HOST OF INFLAMMATORY DISORDERS AND THE IMMUNE SYSTEM. THE INFLAMMATORY RESPONSE IS CONSIDERED AS A CRITICAL TRIGGER OF EPIGENETIC ALTERATIONS THAT IN TURN INTERCEDE INFLAMMATORY ACTIONS. THUS, UNDERSTANDING THE MOLECULAR MECHANISM THAT DICTATES THE OUTCOME OF TARGETING EPIGENETIC REGULATORS FOR INFLAMMATORY DISEASE IS REQUIRED FOR INFLAMMATION RESOLUTION. IN THIS ARTICLE, WE ELUCIDATE THE CRITICAL ROLE OF THE NUCLEAR FACTOR-KAPPAB SIGNALING PATHWAY, JAK/STAT SIGNALING PATHWAY, AND THE NLRP3 INFLAMMASOME IN CHRONIC INFLAMMATORY DISEASES. AND WE FORMULATE THE RELATIONSHIP BETWEEN INFLAMMATION, CORONAVIRUS DISEASE 2019, AND HUMAN CANCERS. ADDITIONALLY, WE REVIEW THE MECHANISM OF EPIGENETIC MODIFICATIONS INVOLVED IN INFLAMMATION AND INNATE IMMUNE CELLS. ALL THAT MATTERS IS THAT WE PROPOSE AND DISCUSS THE REJUVENATION POTENTIAL OF INTERVENTIONS THAT TARGET EPIGENETIC REGULATORS AND REGULATORY MECHANISMS FOR CHRONIC INFLAMMATION-ASSOCIATED DISEASES TO IMPROVE THERAPEUTIC OUTCOMES. 2022 13 3549 31 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 14 4392 20 MODIFIABLE RISK FACTORS IN PERIODONTAL DISEASE: EPIGENETIC REGULATION OF GENE EXPRESSION IN THE INFLAMMATORY RESPONSE. EPIGENETICS AS A MODIFIABLE RISK FACTOR IN PERIODONTAL DISEASES HAS BEEN INVESTIGATED IN LIGHT OF THE CURRENT KNOWLEDGE OF HOW CHRONIC INFECTION AND INFLAMMATION CAN AFFECT GENE-SPECIFIC EPIGENETIC REPROGRAMMING IN PERIODONTAL TISSUES. EPIGENOMIC PROGRAMMING MIGHT BE PARTICULARLY SENSITIVE TO ENVIRONMENTAL INFLUENCES, AND A COMBINATION OF PHYSIOLOGICAL STRESSORS AND ENVIRONMENTAL EXPOSURES APPEARS TO AFFECT THE EPIGENOMIC PROGRAM ACQUIRED BY A CELL DURING DIFFERENTIATION AND THROUGHOUT THE CELLULAR LINEAGE LIFESPAN. VIRAL AND BACTERIAL INFECTIONS CAN ESTABLISH SEVERAL TYPES OF EPIGENETIC MODIFICATIONS, WHICH SOMETIMES ENGAGE IN A COMPLEX EPIGENETIC CROSSTALK ALSO REFLECTING IN THE ESTABLISHMENT AND PROGRESS OF PERIODONTAL DISEASES. THE INFLAMMATORY AND METABOLIC STATES OF THE PERIODONTAL TISSUES ARE DRIVEN BY THE INFECTIOUS STIMULI, AND THE MAGNITUDE OF THE CELLULAR AND MOLECULAR SIGNATURE RESPONSE IS FURTHER DICTATED BY THE HOST GENETIC AND EPIGENETIC TRAITS ASSOCIATED WITH VARIOUS SYSTEMIC EXPOSURES, INCLUDING SMOKING, OBESITY AND DIABETES/HYPERGLYCEMIA. THIS REVIEW DISCUSSES THE ADVANCES IN EPIGENETICS, FOCUSING ON THE ROLE OF DNA METHYLATION IN THE PATHOGENESIS OF PERIODONTAL DISEASE AND THE POTENTIAL OF EPIGENETIC THERAPY. 2014 15 3551 24 IMMUNOSENESCENCE: MOLECULAR MECHANISMS AND DISEASES. INFECTION SUSCEPTIBILITY, POOR VACCINATION EFFICACY, AGE-RELATED DISEASE ONSET, AND NEOPLASMS ARE LINKED TO INNATE AND ADAPTIVE IMMUNE DYSFUNCTION THAT ACCOMPANIES AGING (KNOWN AS IMMUNOSENESCENCE). DURING AGING, ORGANISMS TEND TO DEVELOP A CHARACTERISTIC INFLAMMATORY STATE THAT EXPRESSES HIGH LEVELS OF PRO-INFLAMMATORY MARKERS, TERMED INFLAMMAGING. THIS CHRONIC INFLAMMATION IS A TYPICAL PHENOMENON LINKED TO IMMUNOSENESCENCE AND IT IS CONSIDERED THE MAJOR RISK FACTOR FOR AGE-RELATED DISEASES. THYMIC INVOLUTION, NAIVE/MEMORY CELL RATIO IMBALANCE, DYSREGULATED METABOLISM, AND EPIGENETIC ALTERATIONS ARE STRIKING FEATURES OF IMMUNOSENESCENCE. DISTURBED T-CELL POOLS AND CHRONIC ANTIGEN STIMULATION MEDIATE PREMATURE SENESCENCE OF IMMUNE CELLS, AND SENESCENT IMMUNE CELLS DEVELOP A PROINFLAMMATORY SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE THAT EXACERBATES INFLAMMAGING. ALTHOUGH THE UNDERLYING MOLECULAR MECHANISMS REMAIN TO BE ADDRESSED, IT IS WELL DOCUMENTED THAT SENESCENT T CELLS AND INFLAMMAGING MIGHT BE MAJOR DRIVING FORCES IN IMMUNOSENESCENCE. POTENTIAL COUNTERACTIVE MEASURES WILL BE DISCUSSED, INCLUDING INTERVENTION OF CELLULAR SENESCENCE AND METABOLIC-EPIGENETIC AXES TO MITIGATE IMMUNOSENESCENCE. IN RECENT YEARS, IMMUNOSENESCENCE HAS ATTRACTED INCREASING ATTENTION FOR ITS ROLE IN TUMOR DEVELOPMENT. AS A RESULT OF THE LIMITED PARTICIPATION OF ELDERLY PATIENTS, THE IMPACT OF IMMUNOSENESCENCE ON CANCER IMMUNOTHERAPY IS UNCLEAR. DESPITE SOME SURPRISING RESULTS FROM CLINICAL TRIALS AND DRUGS, IT IS NECESSARY TO INVESTIGATE THE ROLE OF IMMUNOSENESCENCE IN CANCER AND OTHER AGE-RELATED DISEASES. 2023 16 5633 24 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 17 5543 28 ROLE OF ENDOGENOUS GLUCOCORTICOIDS IN CANCER IN THE ELDERLY. ALTHOUGH NOT A DISEASE ITSELF, AGING REPRESENTS A RISK FACTOR FOR MANY AGING-RELATED ILLNESSES, INCLUDING CANCER. NUMEROUS CAUSES UNDERLIE THE INCREASED INCIDENCE OF MALIGNANCIES IN THE ELDERLY, FOR EXAMPLE, GENOMIC INSTABILITY AND EPIGENETIC ALTERATIONS THAT OCCUR AT CELLULAR LEVEL, WHICH ALSO INVOLVE THE IMMUNE CELLS. THE PROGRESSIVE DECLINE OF THE IMMUNE SYSTEM FUNCTIONS THAT OCCURS IN AGING DEFINES IMMUNOSENESCENCE, AND INCLUDES BOTH INNATE AND ADAPTIVE IMMUNITY; THE LATTER UNDERGOES MAJOR ALTERATIONS. AGING AND CHRONIC STRESS SHARE THE ABNORMAL HYPOTHALAMIC(-)PITUITARY(-)ADRENAL AXIS ACTIVATION, WHERE ALTERED PERIPHERAL GLUCOCORTICOIDS (GC) LEVELS AND CHRONIC STRESS HAVE BEEN ASSOCIATED WITH ACCELERATED CELLULAR AGING, PREMATURE IMMUNOSENESCENCE, AND AGING-RELATED DISEASES. CONSEQUENTLY, CHANGES IN GC LEVELS AND SENSITIVITY CONTRIBUTE TO THE SIGNS OF IMMUNOSENESCENCE, NAMELY FEWER NAIVE T CELLS, POOR IMMUNE RESPONSE TO NEW ANTIGENS, DECREASED CELL-MEDIATED IMMUNITY, AND THYMIC INVOLUTION. GC SIGNALING ALTERATIONS ALSO INVOLVE EPIGENETIC ALTERATIONS IN DNA METHYLATION, WITH TRANSCRIPTION MODIFICATIONS THAT MAY CONTRIBUTE TO IMMUNOSENESCENCE. IMMUNE CELL AGING LEADS TO DECREASED LEVELS OF IMMUNOSURVEILLANCE, THEREBY PROVIDING TUMOR CELLS ONE MORE ROUTE FOR IMMUNE SYSTEM ESCAPE. HERE, THE CONTRIBUTION OF GC SECRETION AND SIGNALING DYSREGULATION TO THE INCREASED INCIDENCE OF TUMORIGENESIS IN THE ELDERLY IS REVIEWED. 2018 18 2070 17 EPIGENETIC CONTROL OF SKIN IMMUNITY. EPIGENETICS HAS BEEN WELL UNDERSTOOD FOR ITS ROLE IN CELL DEVELOPMENT; HOWEVER, IT IS NOW KNOWN TO REGULATE MANY PROCESSES INVOLVED IN IMMUNE CELL ACTIVATION IN A VARIETY OF CELLS. THE SKIN MAINTAINS HOMEOSTASIS VIA CROSSTALK BETWEEN IMMUNE AND NON-IMMUNE CELLS. DISRUPTION OF NORMAL EPIGENETIC REGULATION IN THESE CELLS MAY ALTER THE TRANSCRIPTION OF IMMUNE-REGULATORY FACTORS AND AFFECT THE IMMUNOLOGICAL BALANCE IN THE SKIN. THIS REVIEW SUMMARIZES RECENT EVIDENCE FOR THE EPIGENETIC REGULATION OF SKIN IMMUNITY. MUCH OF WHAT IS KNOWN ABOUT EPIGENETIC INVOLVEMENT IN SKIN IMMUNITY IS ASSOCIATED WITH DNA METHYLATION. THIS REVIEW FOCUSES ON EPIGENETIC REGULATION OF HISTONE MODIFICATION AND CHROMATIN REMODELING AND DESCRIBES THEIR ROLE IN THE TRANSCRIPTIONAL REGULATION OF IMMUNE-REGULATORY FACTORS. WHILE MUCH IS STILL UNKNOWN REGARDING THE REGULATION OF SKIN IMMUNITY VIA HISTONE MODIFICATION OR CHROMATIN REMODELING, THESE PROCESSES MAY UNDERLIE THE PATHOGENESIS OF CHRONIC CUTANEOUS IMMUNE DISORDERS. 2023 19 3679 20 INFLAMMATION IN AGING: CAUSE, EFFECT, OR BOTH? AGING IS A PROGRESSIVE DEGENERATIVE PROCESS TIGHTLY INTEGRATED WITH INFLAMMATION. CAUSE AND EFFECT ARE NOT CLEAR. A NUMBER OF THEORIES HAVE BEEN DEVELOPED THAT ATTEMPT TO DEFINE THE ROLE OF CHRONIC INFLAMMATION IN AGING: REDOX STRESS, MITOCHONDRIAL DAMAGE, IMMUNOSENESCENCE, ENDOCRINOSENESCENCE, EPIGENETIC MODIFICATIONS, AND AGE-RELATED DISEASES. HOWEVER, NO SINGLE THEORY EXPLAINS ALL ASPECTS OF AGING; INSTEAD, IT IS LIKELY THAT MULTIPLE PROCESSES CONTRIBUTE AND THAT ALL ARE INTERTWINED WITH INFLAMMATORY RESPONSES. HUMAN IMMUNODEFICIENCY VIRUS (HIV)-INFECTED PATIENTS UNDERGO A PREMATURE AGING PHENOMENON WHICH MAY PROVIDE CLUES TO BETTER ELUCIDATE THE NATURE OF INFLAMMATION IN AGING. ENVIRONMENTAL AND LIFESTYLE EFFECTORS OF INFLAMMATION MAY ALSO CONTRIBUTE TO MODULATION OF BOTH INFLAMMATION AND AGE-RELATED DYSFUNCTION. 2012 20 282 25 AGEING AND LOW-LEVEL CHRONIC INFLAMMATION: THE ROLE OF THE BIOLOGICAL CLOCK. AGEING IS A MULTIFACTORIAL PHYSIOLOGICAL MANIFESTATION THAT OCCURS INEXORABLY AND GRADUALLY IN ALL FORMS OF LIFE. THIS PROCESS IS LINKED TO THE DECAY OF HOMEOSTASIS DUE TO THE PROGRESSIVE DECREASE IN THE REPARATIVE AND REGENERATIVE CAPACITY OF TISSUES AND ORGANS, WITH REDUCED PHYSIOLOGICAL RESERVE IN RESPONSE TO STRESS. AGEING IS CLOSELY RELATED TO OXIDATIVE DAMAGE AND INVOLVES IMMUNOSENESCENCE AND TISSUE IMPAIRMENT OR METABOLIC IMBALANCES THAT TRIGGER INFLAMMATION AND INFLAMMASOME FORMATION. ONE OF THE MAIN AGEING-RELATED ALTERATIONS IS THE DYSREGULATION OF THE IMMUNE RESPONSE, WHICH RESULTS IN CHRONIC LOW-LEVEL, SYSTEMIC INFLAMMATION, TERMED "INFLAMMAGING". GENETIC AND EPIGENETIC CHANGES, AS WELL AS ENVIRONMENTAL FACTORS, PROMOTE AND/OR MODULATE THE MECHANISMS OF AGEING AT THE MOLECULAR, CELLULAR, ORGAN, AND SYSTEM LEVELS. MOST OF THESE MECHANISMS ARE CHARACTERIZED BY TIME-DEPENDENT PATTERNS OF VARIATION DRIVEN BY THE BIOLOGICAL CLOCK. IN THIS REVIEW, WE DESCRIBE THE INVOLVEMENT OF AGEING-RELATED PROCESSES WITH INFLAMMATION IN RELATION TO THE FUNCTIONING OF THE BIOLOGICAL CLOCK AND THE MECHANISMS OPERATING THIS INTRICATE INTERACTION. 2022