1 2662 158 EPSTEIN-BARR VIRUS AND MULTIPLE SCLEROSIS: A CONVOLUTED INTERACTION AND THE OPPORTUNITY TO UNRAVEL PREDICTIVE BIOMARKERS. SINCE THE EARLY 1980S, EPSTEIN-BARR VIRUS (EBV) INFECTION HAS BEEN DESCRIBED AS ONE OF THE MAIN RISK FACTORS FOR DEVELOPING MULTIPLE SCLEROSIS (MS), AND RECENTLY, NEW EPIDEMIOLOGICAL EVIDENCE HAS REINFORCED THIS PREMISE. EBV SEROCONVERSION PRECEDES ALMOST 99% OF THE NEW CASES OF MS AND LIKELY PREDATES THE FIRST CLINICAL SYMPTOMS. THE MOLECULAR MECHANISMS OF THIS ASSOCIATION ARE COMPLEX AND MAY INVOLVE DIFFERENT IMMUNOLOGICAL ROUTES, PERHAPS ALL RUNNING IN PARALLEL (I.E., MOLECULAR MIMICRY, THE BYSTANDER DAMAGE THEORY, ABNORMAL CYTOKINE NETWORKS, AND COINFECTION OF EBV WITH RETROVIRUSES, AMONG OTHERS). HOWEVER, DESPITE THE LARGE AMOUNT OF EVIDENCE AVAILABLE ON THESE TOPICS, THE ULTIMATE ROLE OF EBV IN THE PATHOGENESIS OF MS IS NOT FULLY UNDERSTOOD. FOR INSTANCE, IT IS UNCLEAR WHY AFTER EBV INFECTION SOME INDIVIDUALS DEVELOP MS WHILE OTHERS EVOLVE TO LYMPHOPROLIFERATIVE DISORDERS OR SYSTEMIC AUTOIMMUNE DISEASES. IN THIS REGARD, RECENT STUDIES SUGGEST THAT THE VIRUS MAY EXERT EPIGENETIC CONTROL OVER MS SUSCEPTIBILITY GENES BY MEANS OF SPECIFIC VIRULENCE FACTORS. SUCH GENETIC MANIPULATION HAS BEEN DESCRIBED IN VIRALLY-INFECTED MEMORY B CELLS FROM PATIENTS WITH MS AND ARE THOUGHT TO BE THE MAIN SOURCE OF AUTOREACTIVE IMMUNE RESPONSES. YET, THE ROLE OF EBV INFECTION IN THE NATURAL HISTORY OF MS AND IN THE INITIATION OF NEURODEGENERATION IS EVEN LESS CLEAR. IN THIS NARRATIVE REVIEW, WE WILL DISCUSS THE AVAILABLE EVIDENCE ON THESE TOPICS AND THE POSSIBILITY OF HARNESSING SUCH IMMUNOLOGICAL ALTERATIONS TO UNCOVER PREDICTIVE BIOMARKERS FOR THE ONSET OF MS AND PERHAPS FACILITATE PROGNOSTICATION OF THE CLINICAL COURSE. 2023 2 6604 38 TYPE 1 DIABETES AND VIRAL INFECTIONS: WHAT IS THE RELATIONSHIP? TYPE 1 DIABETES (T1D) IS THE MOST COMMON CHRONIC METABOLIC DISORDER IN CHILDREN. EPIGENETIC AND ENVIRONMENTAL FACTORS CAPABLE OF ALTERING THE PENETRANCE OF MAJOR SUSCEPTIBILITY GENES OR CAPABLE OF INCREASING THE PENETRANCE OF LOW-RISK GENES ARE CURRENTLY THOUGHT TO PLAY A ROLE IN TRIGGERING AUTOIMMUNITY AND T1D DEVELOPMENT. THIS PAPER DISCUSSES THE CURRENT KNOWLEDGE OF THE ROLE OF VIRUSES IN T1D. MOST STUDIES THAT HAVE EVALUATED THE POTENTIAL ASSOCIATION BETWEEN VIRAL INFECTIONS AND T1D HAVE INDICATED THAT IT IS HIGHLY LIKELY THAT SOME OF THESE INFECTIOUS AGENTS PLAY A ROLE IN T1D DEVELOPMENT. HOWEVER, MOST T1D CASES ARE IMMUNE-MEDIATED, AND IT IS SUPPOSED THAT THE INITIAL VIRAL INFECTION IS CAPABLE OF CREATING, IN GENETICALLY PREDISPOSED SUBJECTS, A PARTICULAR CONDITION IN WHICH CHRONIC LOCAL INFLAMMATION OCCURS THROUGH THE PERSISTENCE OF THE INFECTING VIRUS IN PANCREATIC TISSUE AND THE ACTIVATION OF AUTOIMMUNITY BY MEANS OF MOLECULAR MIMICRY, BYSTANDER ACTIVATION, OR BOTH. THEORETICALLY, THIS KNOWLEDGE COULD LEAD TO POSSIBLE PROPHYLAXIS AND THERAPY FOR T1D. FURTHER STUDIES DEVOTED TO EVALUATING WHICH INFECTIOUS AGENTS ARE LINKED TO T1D AND WHICH IMMUNE MECHANISMS INDUCE OR PROTECT AGAINST THE DISEASE ARE NEEDED BEFORE ADEQUATE PROPHYLACTIC AND THERAPEUTIC MEASURES CAN BE DEVELOPED. 2017 3 3223 48 HELICOBACTER PYLORI INFECTION AND AUTOIMMUNE DISEASES; IS THERE AN ASSOCIATION WITH SYSTEMIC LUPUS ERYTHEMATOSUS, RHEUMATOID ARTHRITIS, AUTOIMMUNE ATROPHY GASTRITIS AND AUTOIMMUNE PANCREATITIS? A SYSTEMATIC REVIEW AND META-ANALYSIS STUDY. AUTOIMMUNE DISEASES ARE CONSIDERED AS ONE OF THE MOST IMPORTANT DISORDERS OF THE IMMUNE SYSTEM, IN WHICH THE PROLONGED AND CHRONIC PROCESSES ELIMINATE SELF-TOLERANCE TO THE AUTO-ANTIGENS. THE PREVALENCE OF AUTOIMMUNE DISEASES HAS BEEN INCREASING WORLDWIDE IN THE RECENT YEARS. ACCORDING TO THE LITERATURE, BIOLOGICAL PROCESSES SUCH AS THE HOST GENOME, EPIGENETIC EVENTS, ENVIRONMENTAL CONDITION, DRUG CONSUMPTION, AND INFECTIOUS AGENTS ARE THE MOST IMPORTANT RISK FACTORS THAT MAKE THE HOST SUSCEPTIBLE TO THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN THE RECENT YEARS, THE ROLE OF HELICOBACTER PYLORI IN THE INDUCTION OF AUTOIMMUNE DISEASES HAS ATTRACTED EXTENSIVE ATTENTION. VIA MOLECULAR MIMICRY, EPITOPE SPREADING, BYSTANDER ACTIVATION, POLYCLONAL ACTIVATION, DYSREGULATION IN IMMUNE RESPONSE, AND HIGHLY IMMUNE-DOMINANT VIRULENCE, SUCH AS CAGA, H. PYLORI CAUSES TISSUE DAMAGE, POLARITY, AND PROLIFERATION OF THE HOST CELLS LEADING TO THE MODULATION OF HOST IMMUNE RESPONSES. MOREOVER, GIVEN THE LARGE POPULATION WORLDWIDE INFECTED WITH H. PYLORI, IT SEEMS LIKELY THAT THE BACTERIUM MAY DEVELOP INTO AUTOIMMUNE DISEASES THROUGH DYSREGULATION OF THE IMMUNE RESPONSE. THE FREQUENCY AND RELATIONSHIP BETWEEN H. PYLORI INFECTION AND SYSTEMIC LUPUS ERYTHEMATOSUS, RHEUMATOID ARTHRITIS, AUTOIMMUNE ATROPHY GASTRITIS, AND AUTOIMMUNE PANCREATITIS WERE EVALUATED USING THE DATA FROM 43 STUDIES INVOLVING 5052 PATIENTS. ACCORDING TO STATISTICAL ANALYSIS IT IS PROBABLE THAT INFECTION WITH MORE VIRULENT STRAINS OF H. PYLORI (SUCH AS H. PYLORI CAGA POSITIVE) CAN INCREASE THE RISK OF AUTOIMMUNE DISEASES. IN ADDITION, IT WAS SHOWN THAT INFECTION WITH H. PYLORI CAN PREVENT THE DEVELOPMENT OF ATROPHIC GASTRITIS BY STIMULATING INFLAMMATION IN THE GASTRIC ANTRUM. HOWEVER, FUTURE STUDIES SHOULD CONFIRM THE VALIDITY OF THIS STUDY. 2021 4 748 34 CAPITAL EM, CYRILLICSMALL O, CYRILLICLECULAR MECHANISMS OF INITIATION OF CARCINOGENESIS IN THE TESTIS. IN THIS REVIEW, LITERATURE DATA ON THE STUDY OF PRECANCEROUS CHANGES IN TESTICULAR TISSUE AND MOLECULAR CHANGES, AS WELL AS THE INFLUENCE OF ENVIRONMENTAL FACTORS THAT CAN INITIATE CARCINOGENESIS, WERE ANALYZED AND SUMMARIZED FOR THE FUTURE DETERMINATION OF EARLY DIAGNOSIS OF GERM CELL TUMORS OF THE TESTIS AND THE DEVELOPMENT OF PREVENTIVE MEASURES. THE REVIEW ALSO DISCUSSES THE SIGNIFICANT NEW CHANGES PRESENTED IN THE FOURTH EDITION OF THE WORLD HEALTH ORGANIZATION CLASSIFICATION OF UROGENITAL TUMORS, PUBLISHED IN 2016, AND MODERN CONCEPTS OF THE ETIOLOGY AND PATHOGENESIS OF THESE DISEASES. AMONG THE ENVIRONMENTAL FACTORS THAT CAN INITIATE CARCINOGENESIS, THE MOST NOTEWORTHY ARE THE BIOLOGICAL EFFECTS OF LOW DOSES OF IONIZING RADIATION, SUCH AS THE EFFECT OF RADIATION-INDUCED GENOME INSTABILITY, WHICH INCREASES THE RISK OF CARCINOGENESIS, THE "BYSTANDER EFFECT", AND CHRONIC OXIDATIVE STRESS. DISRUPTION OF UBIQUITIN-PROTEASOMAL PROTEOLYSIS, IMPAIRED MOLECULAR-LEVEL COMPONENTS OF THE BLOOD-TESTIS BARRIER, AND IMPAIRED REGULATORY ACTION OF TGF-BETA ON THE CELL CYCLE CAN PLAY A CRUCIAL ROLE IN THE PATHOGENESIS OF MALE INFERTILITY AND THE INITIATION OF CARCINOGENESIS IN THE TESTIS. THE EFFECT OF LOW DOSES OF IONIZING RADIATION AS AN ADDITIONAL ETIOLOGICAL FACTOR LEADS TO CHANGES IN THE STRUCTURAL, AS WELL AS MOLECULAR, COMPONENTS OF THE TESTIS, INCLUDING EPIGENETIC CHANGES, WHICH CAN BE CHARACTERIZED AS ENVIRONMENTAL PATHOMORPHOSIS, WHICH LEADS TO IMPAIRED SPERMATOGENESIS AND INCREASED RISK OF MALIGNANCY. SUMMARIZING THE LITERATURE REVIEW DATA, WE CAN STATE THAT PATIENTS WITH BLOCKED SPERMATOGENESIS, IN WHICH ATYPICAL GERM CELL NEOPLASIA IN SITU CELLS ARE DETECTED IN TESTICULAR TISSUE, CONSTITUTE A GROUP AT INCREASED RISK OF TESTICULAR CARCINOGENESIS. THE PRESENCE OF ADDITIONAL ETIOLOGICAL FACTORS, SUCH AS CHRONIC LOW DOSES OF IONIZING RADIATION, CAN INITIATE THE PROGRESSION OF CARCINOGENESIS IN THE TESTICLE. 2019 5 3287 34 HIERARCHICAL AND CYBERNETIC NATURE OF BIOLOGIC SYSTEMS AND THEIR RELEVANCE TO HOMEOSTATIC ADAPTATION TO LOW-LEVEL EXPOSURES TO OXIDATIVE STRESS-INDUCING AGENTS. DURING EVOLUTION IN AN AEROBIC ENVIRONMENT, MULTICELLULAR ORGANISMS SURVIVED BY ADAPTIVE RESPONSES TO BOTH THE ENDOGENOUS OXIDATIVE METABOLISM IN THE CELLS OF THE ORGANISM AND THE CHEMICALS AND LOW-LEVEL RADIATION TO WHICH THEY HAD BEEN EXPOSED. THE DEFENSE REPERTOIRE EXISTS AT ALL LEVELS OF THE BIOLOGICAL HIERARCHY--FROM THE MOLECULAR AND BIOCHEMICAL LEVEL TO THE CELLULAR AND TISSUE LEVEL TO THE ORGAN AND ORGAN SYSTEM LEVEL. CELLS CONTAIN PREVENTIVE ANTIOXIDANTS TO SUPPRESS OXIDATIVE DAMAGE TO MEMBRANES. CELLS ALSO CONTAIN PROTEINS AND DNA; BUILT-IN REDUNDANCIES FOR DAMAGED MOLECULES AND ORGANELLES; TIGHTLY COUPLED REDOX SYSTEMS; POOLS OF REDUCTANTS; ANTIOXIDANTS; DNA REPAIR MECHANISMS AND SENSITIVE SENSOR MOLECULES SUCH AS NUCLEAR FACTOR KAPPA BETA; AND SIGNAL TRANSDUCTION MECHANISMS AFFECTING BOTH TRANSCRIPTION AND POST-TRANSLATIONAL MODIFICATION OF PROTEINS NEEDED TO COPE WITH OXIDATIVE STRESS. THE BIOLOGIC CONSEQUENCES OF THE LOW-LEVEL RADIATION THAT EXCEEDS THE BACKGROUND LEVEL OF OXIDATIVE DAMAGE COULD BE NECROSIS OR APOPTOSIS, CELL PROLIFERATION, OR CELL DIFFERENTIATION. THESE EFFECTS ARE TRIGGERED BY OXIDATIVE STRESS-INDUCED SIGNAL TRANSDUCTION MECHANISMS--AN EPIGENETIC, NOT GENOTOXIC, PROCESS. IF THE END POINTS OF CELL PROLIFERATION, DIFFERENTIATION, OR CELL DEATH ARE NOT SEEN AT FREQUENCIES ABOVE BACKGROUND LEVELS IN AN ORGANISM, IT IS UNLIKELY THAT LOW-LEVEL RADIATION WOULD PLAY A ROLE IN THE MULTISTEP PROCESSES OF CHRONIC DISEASES SUCH AS CANCER. THE MECHANISM LINKED TO HOMEOSTATIC REGULATION OF PROLIFERATION AND ADAPTIVE FUNCTIONS IN A MULTICELLULAR ORGANISM COULD PROVIDE PROTECTION OF ANY ONE CELL RECEIVING DEPOSITED ENERGY BY THE RADIATION TRACT THROUGH THE SHARING OF REDUCTANTS AND BY TRIGGERING APOPTOSIS OF TARGET STEM CELLS. EXAMPLES OF THE ROLE OF GAP JUNCTIONAL INTERCELLULAR COMMUNICATION IN THE ADAPTIVE RESPONSE OF CELLS AND THE BYSTANDER EFFECT ILLUSTRATE HOW THE INTERACTION OF CELLS CAN MODULATE THE EFFECT OF RADIATION ON THE SINGLE CELL. 1998 6 708 24 BYSTANDER EFFECTS IN RADIATION-INDUCED GENOMIC INSTABILITY. EXPOSURE OF GM10115 HAMSTER-HUMAN HYBRID CELLS TO X-RAYS CAN RESULT IN THE INDUCTION OF CHROMOSOMAL INSTABILITY IN THE PROGENY OF SURVIVING CELLS. THIS INSTABILITY MANIFESTS AS THE DYNAMIC PRODUCTION OF NOVEL SUB-POPULATIONS OF CELLS WITH UNIQUE CYTOGENETIC REARRANGEMENTS INVOLVING THE "MARKER" HUMAN CHROMOSOME. WE HAVE USED THE COMET ASSAY TO INVESTIGATE WHETHER THERE WAS AN ELEVATED LEVEL OF ENDOGENOUS DNA BREAKS IN CHROMOSOMALLY UNSTABLE CLONES THAT COULD PROVIDE A SOURCE FOR THE CHROMOSOMAL REARRANGEMENTS AND THUS ACCOUNT FOR THE PERSISTENT INSTABILITY OBSERVED. OUR RESULTS INDICATE NO SIGNIFICANT DIFFERENCE IN COMET TAIL MEASUREMENT BETWEEN NON-IRRADIATED AND RADIATION-INDUCED CHROMOSOMALLY UNSTABLE CLONES. USING TWO-COLOR FLUORESCENCE IN SITU HYBRIDIZATION WE ALSO INVESTIGATED WHETHER RECOMBINATIONAL EVENTS INVOLVING THE INTERSTITIAL TELOMERE REPEAT-LIKE SEQUENCES IN GM10115 CELLS WERE INVOLVED AT FREQUENCIES HIGHER THAN RANDOM PROCESSES WOULD OTHERWISE PREDICT. NINE OF 11 CLONES DEMONSTRATED A SIGNIFICANTLY HIGHER THAN EXPECTED INVOLVEMENT OF THESE INTERSTITIAL TELOMERE REPEAT-LIKE SEQUENCES AT THE RECOMBINATION JUNCTION BETWEEN THE HUMAN AND HAMSTER CHROMOSOMES. SINCE ELEVATED LEVELS OF ENDOGENOUS BREAKS WERE NOT DETECTED IN UNSTABLE CLONES WE PROPOSE THAT EPIGENETIC OR BYSTANDER EFFECTS (BSES) LEAD TO THE ACTIVATION OF RECOMBINATIONAL PATHWAYS THAT PERPETUATE THE UNSTABLE PHENOTYPE. SPECIFICALLY, WE EXPAND UPON THE HYPOTHESIS THAT RADIATION INDUCES CONDITIONS AND/OR FACTORS THAT STIMULATE THE PRODUCTION OF REACTIVE OXYGEN SPECIES (ROS). THESE REACTIVE INTERMEDIATES THEN CONTRIBUTE TO A CHRONIC PRO-OXIDANT ENVIRONMENT THAT CYCLES OVER MULTIPLE GENERATIONS, PROMOTING CHROMOSOMAL RECOMBINATION AND OTHER PHENOTYPES ASSOCIATED WITH GENOMIC INSTABILITY. 2002 7 4018 34 LOW-DOSE IONIZING RADIATION: INDUCTION OF DIFFERENTIAL INTRACELLULAR SIGNALLING POSSIBLY AFFECTING INTERCELLULAR COMMUNICATION. GIVEN THE COMPLEXITY OF THE CARCINOGENIC PROCESS AND THE LACK OF ANY MECHANISTIC UNDERSTANDING OF HOW IONIZING RADIATION AT LOW-LEVEL EXPOSURES AFFECTS THE MULTISTAGE, MULTIMECHANISM PROCESSES OF CARCINOGENESIS, IT IS IMPERATIVE THAT CONCEPTS AND PARADIGMS BE REEXAMINED WHEN EXTRAPOLATING FROM HIGH DOSE TO LOW DOSE. ANY HEALTH EFFECT DIRECTLY LINKED TO LOW-DOSE RADIATION EXPOSURE MUST HAVE MOLECULAR/BIOCHEMICAL AND BIOLOGICAL BASES. ON THE OTHER HAND, DEMONSTRATING SOME MOLECULAR/BIOCHEMICAL OR CELLULAR EFFECT, USING SURROGATE SYSTEMS FOR THE HUMAN BEING, DOES NOT NECESSARILY IMPLY A CORRESPONDING HEALTH EFFECT. GIVEN THE GENERAL ACCEPTANCE OF AN EXTRAPOLATED LNT MODEL, OUR CURRENT UNDERSTANDING OF CARCINOGENESIS CRIES OUT FOR A RESOLUTION OF A REAL PROBLEM. HOW CAN A LOW-LEVEL ACUTE, OR EVEN A CHRONIC, EXPOSURE OF IONIZING RADIATION BRING ABOUT ALL THE DIFFERENT MECHANISMS (MUTAGENIC, CYTOTOXIC, AND EPIGENETIC) AND GENOTYPIC/PHENOTYPIC CHANGES NEEDED TO CONVERT NORMAL CELLS TO AN INVASIVE, MALIGNANT CELL, GIVEN ALL THE PROTECTIVE, REPAIR, AND SUPPRESSIVE SYSTEMS KNOWN TO EXIST IN THE HUMAN BODY? UNTIL RECENTLY, THE PREVAILING PARADIGM THAT IONIZING RADIATION BRINGS ABOUT CANCER PRIMARILY BY DNA DAMAGE AND ITS CONVERSION TO GENE AND CHROMOSOMAL MUTATIONS, DROVE OUR INTERPRETATION OF RADIATION CARCINOGENESIS. TODAY, OUR KNOWLEDGE INCLUDES THE FACTS BOTH THAT EPIGENETIC EVENTS PLAY A MAJOR ROLE IN CARCINOGENESIS AND THAT LOW-DOSE RADIATION CAN ALSO INDUCE EPIGENETIC EVENTS IN AND BETWEEN CELLS IN TISSUES. THIS CHALLENGES ANY SIMPLE EXTRAPOLATION OF THE LNT MODEL. ALTHOUGH A RECENT DELINEATION OF "HALLMARKS" OF THE CANCER PROCESS HAS HELPED TO FOCUS ON HOW IONIZING RADIATION MIGHT CONTRIBUTE TO THE INDUCTION OF CANCERS, SEVERAL OTHER HALLMARKS, PREVIOUSLY IGNORED--NAMELY, THE STEM CELLS IN TISSUES AS TARGETS FOR CARCINOGENESIS AND THE ROLE OF CELL-CELL COMMUNICATION PROCESSES IN MODULATING THE RADIATION EFFECTS ON THE TARGET CELL--MUST BE CONSIDERED, PARTICULARLY FOR THE ADAPTIVE RESPONSE, BYSTANDER EFFECTS, AND GENOMIC INSTABILITY PHENOMENA. 2005 8 6169 27 THE GUT MICROBIOTA AND HEALTHY AGING: A MINI-REVIEW. THE GUT MICROBIOTA SHOWS A WIDE INTER-INDIVIDUAL VARIATION, BUT ITS WITHIN-INDIVIDUAL VARIATION IS RELATIVELY STABLE OVER TIME. A FUNCTIONAL CORE MICROBIOME, PROVIDED BY ABUNDANT BACTERIAL TAXA, SEEMS TO BE COMMON TO VARIOUS HUMAN HOSTS REGARDLESS OF THEIR GENDER, GEOGRAPHIC LOCATION, AND AGE. WITH ADVANCING CHRONOLOGICAL AGE, THE GUT MICROBIOTA BECOMES MORE DIVERSE AND VARIABLE. HOWEVER, WHEN MEASURES OF BIOLOGICAL AGE ARE USED WITH ADJUSTMENT FOR CHRONOLOGICAL AGE, OVERALL RICHNESS DECREASES, WHILE A CERTAIN GROUP OF BACTERIA ASSOCIATED WITH FRAILTY INCREASES. THIS HIGHLIGHTS THE IMPORTANCE OF CONSIDERING BIOLOGICAL OR FUNCTIONAL MEASURES OF AGING. STUDIES USING MODEL ORGANISMS INDICATE THAT AGE-RELATED GUT DYSBIOSIS MAY CONTRIBUTE TO UNHEALTHY AGING AND REDUCED LONGEVITY. THE GUT MICROBIOME DEPENDS ON THE HOST NUTRIENT SIGNALING PATHWAYS FOR ITS BENEFICIAL EFFECTS ON HOST HEALTH AND LIFESPAN, AND GUT DYSBIOSIS DISRUPTING THE INTERDEPENDENCE MAY DIMINISH THE BENEFICIAL EFFECTS OR EVEN HAVE REVERSE EFFECTS. GUT DYSBIOSIS CAN TRIGGER THE INNATE IMMUNE RESPONSE AND CHRONIC LOW-GRADE INFLAMMATION, LEADING TO MANY AGE-RELATED DEGENERATIVE PATHOLOGIES AND UNHEALTHY AGING. THE GUT MICROBIOTA COMMUNICATES WITH THE HOST THROUGH VARIOUS BIOMOLECULES, NUTRIENT SIGNALING-INDEPENDENT PATHWAYS, AND EPIGENETIC MECHANISMS. DISTURBANCE OF THESE COMMUNICATIONS BY AGE-RELATED GUT DYSBIOSIS CAN AFFECT THE HOST HEALTH AND LIFESPAN. THIS MAY EXPLAIN THE IMPACT OF THE GUT MICROBIOME ON HEALTH AND AGING. 2018 9 4663 34 NEW HORIZONS: NOVEL APPROACHES TO ENHANCE HEALTHSPAN THROUGH TARGETING CELLULAR SENESCENCE AND RELATED AGING MECHANISMS. THE ELDERLY POPULATION IS INCREASING FASTER THAN OTHER SEGMENTS OF THE POPULATION THROUGHOUT THE WORLD. AGE IS THE LEADING PREDICTOR FOR MOST CHRONIC DISEASES AND DISORDERS, MULTIMORBIDITY, GERIATRIC SYNDROMES, AND IMPAIRED ABILITY TO RECOVER FROM ACCIDENTS OR ILLNESSES. ENHANCING THE DURATION OF HEALTH AND INDEPENDENCE, TERMED HEALTHSPAN, WOULD BE MORE DESIRABLE THAN EXTENDING LIFESPAN MERELY BY PROLONGING THE PERIOD OF MORBIDITY TOWARD THE END OF LIFE. THE GEROSCIENCE HYPOTHESIS POSITS THAT HEALTHSPAN CAN BE EXTENDED BY TARGETING FUNDAMENTAL AGING MECHANISMS, RATHER THAN ATTEMPTING TO ADDRESS EACH AGE-RELATED DISEASE ONE AT A TIME, ONLY SO THE AFFLICTED INDIVIDUAL SURVIVES DISABLED AND DIES SHORTLY AFTERWARD OF ANOTHER AGE-RELATED DISEASE. THESE FUNDAMENTAL AGING MECHANISMS INCLUDE, AMONG OTHERS, CHRONIC INFLAMMATION, FIBROSIS, STEM CELL/ PROGENITOR DYSFUNCTION, DNA DAMAGE, EPIGENETIC CHANGES, METABOLIC SHIFTS, DESTRUCTIVE METABOLITE GENERATION, MITOCHONDRIAL DYSFUNCTION, MISFOLDED OR AGGREGATED PROTEIN ACCUMULATION, AND CELLULAR SENESCENCE. THESE PROCESSES APPEAR TO BE TIGHTLY INTERLINKED, AS TARGETING ANY ONE APPEARS TO AFFECT MANY OF THE REST, UNDERLYING OUR UNITARY THEORY OF FUNDAMENTAL AGING MECHANISMS. INTERVENTIONS TARGETING MANY FUNDAMENTAL AGING PROCESSES ARE BEING DEVELOPED, INCLUDING DIETARY MANIPULATIONS, METFORMIN, MTOR (MECHANISTIC TARGET OF RAPAMYCIN) INHIBITORS, AND SENOLYTICS, WHICH ARE IN EARLY HUMAN TRIALS. THESE INTERVENTIONS COULD LEAD TO GREATER HEALTHSPAN BENEFITS THAN TREATING AGE-RELATED DISEASES ONE AT A TIME. TO ILLUSTRATE THESE POINTS, WE FOCUS ON CELLULAR SENESCENCE AND THERAPIES IN DEVELOPMENT TO TARGET SENESCENT CELLS. COMBINING INTERVENTIONS TARGETING AGING MECHANISMS WITH DISEASE-SPECIFIC DRUGS COULD RESULT IN MORE THAN ADDITIVE BENEFITS FOR CURRENTLY DIFFICULT-TO-TREAT OR INTRACTABLE DISEASES. MORE RESEARCH ATTENTION NEEDS TO BE DEVOTED TO TARGETING FUNDAMENTAL AGING PROCESSES. 2021 10 2731 28 EXPLORING THE COMPLEX RELATIONSHIP BETWEEN MICROBIOTA AND SYSTEMIC LUPUS ERYTHEMATOSUS. PURPOSE OF REVIEW: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY VARIOUS AUTOANTIBODIES AND MULTI-ORGAN. MICROBIOTA DYSBIOSIS IN THE GUT, SKIN, ORAL, AND OTHER SURFACES HAS A SIGNIFICANT IMPACT ON SLE DEVELOPMENT. THIS ARTICLE SUMMARIZES RELEVANT RESEARCH AND PROVIDES NEW MICROBIOME-RELATED STRATEGIES FOR EXPLORING THE MECHANISMS AND TREATING PATIENTS WITH SLE. RECENT FINDINGS: SLE PATIENTS HAVE DISRUPTIONS IN MULTIPLE MICROBIOMES, WITH THE GUT MICROBIOTA (BACTERIA, VIRUSES, AND FUNGI) AND THEIR METABOLITES BEING THE MOST THOROUGHLY RESEARCHED. THIS DYSBIOSIS CAN PROMOTE SLE PROGRESSION THROUGH MECHANISMS SUCH AS THE LEAKY GUT, MOLECULAR MIMICRY, AND EPIGENETIC REGULATION. NOTWITHSTANDING STUDY CONSTRAINTS ON THE RELATIONSHIP BETWEEN MICROBIOTA AND SLE, SPECIFIC INTERVENTIONS TARGETING THE GUT MICROBIOTA, SUCH AS PROBIOTICS, DIETARY MANAGEMENT, AND FECAL MICROBIOTA TRANSPLANTATION, HAVE EMERGED AS PROMISING SLE THERAPEUTICS. 2023 11 3464 45 HYPOTHESIS. BYSTANDERS OR BAD SEEDS? MANY AUTOIMMUNE-TARGET CELLS MAY BE TRANSFORMING TO CANCER AND SIGNALLING "DANGER" TO THE IMMUNE SYSTEM. AUTOIMMUNE-TARGET CELLS IN AUTOIMMUNE DISEASE (AID) ARE USUALLY CONSTRUED AS CONSTITUTIONALLY NORMAL HEALTHY CELLS. A RELATED ASSUMPTION IS THAT OTHER CELLS IN THE BODY OF AID PATIENTS, EXCEPT FOR CERTAIN IMMUNOCYTES, ARE HEALTHY CELLS. AN IMPLICATION OF THAT VIEW IS THAT ANY SYSTEMIC PATHOLOGY IN ORGAN-SPECIFIC AID IS RELATED TO METABOLIC DERANGEMENTS SECONDARY TO TISSUE DESTRUCTION. HOWEVER, MUCH DATA ON TARGET AND OTHER CELLS IN AID SUGGEST WIDESPREAD PRIMARY CELLULAR DEFECTS. IN INSULIN-DEPENDENT DIABETES MELLITUS (IDDM), FOR EXAMPLE, MANY "COMPLICATIONS" SUCH AS ATHEROSCLEROSIS, PREMATURE ARTERIAL STIFFENING, SENESCENCE OF FIBROBLASTS IN VITRO, AND EXUBERANT GROWTH OF SMOOTH MUSCLE AND MESANGIAL CELLS IN VIVO ARE NOT STRICTLY ATTRIBUTABLE TO GLUCOSE ELEVATION. ALSO UNEXPLAINED IS THE SIMILAR APPEARANCE OF IDDM BETA-CELLS AND CELLS FROM INSULINOMA AND WHY THE PRODROMAL PHASE OF IDDM HAS MANY INSULINOMA-LIKE FEATURES. WHILE AID TARGET CELLS HAVE OFTEN BEEN LIKENED TO NEOPLASTIC CELLS, INVESTIGATORS HAVE RARELY EXPLORED THE POSSIBILITY THAT AUTOIMMUNITY IN AID IS FUNDAMENTALLY ANTINEOPLASTIC. THIS IS LIKELY BECAUSE THE DOMINANT IDEAS IN ONCOLOGY AND IMMUNOLOGY-SOMATIC MUTATION AND CLONAL DELETION, RESPECTIVELY-HAVE PREVENTED EXPLANATIONS FOR HOW NORMAL IMMUNITY COULD DETECT TRANSFORMING CELLS NOT EXPRESSING NON-SELF ANTIGENS. NEW AND LESS CONVENTIONAL THEORIES OF CANCER AND IMMUNITY HAVE FACILITATED SUCH AN EXPLANATION. I USE RUBIN'S "EPIGENETIC" AGING MODEL OF CARCINOGENESIS AND MATZINGER'S "DANGER" MODEL OF IMMUNITY TO INTEGRATE THE IMMUNOLOGICAL AND ONCOLOGICAL SIDES OF AID. IN PARTICULAR, I POSTULATE THAT INDIVIDUALS SUFFERING FROM AID HAVE INHERITED MANY FOCI OF PREMATURELY AGING CELLS. THOSE INHERENTLY DAMAGED CELLS ADAPT TO IN VIVO CHALLENGES BY BEGINNING TO TRANSFORM INTO CANCER CELLS. HOWEVER, AS LONG AS THOSE STRESSED CELLS HAVE NOT FULLY TRANSFORMED, THEY WILL CONTINUE TO SIGNAL "DANGER" TO THE INNATE IMMUNE SYSTEM. THE CLINICAL OUTCOME OF THAT STRUGGLE BETWEEN INCIPIENT NEOPLASIA AND IMMUNITY WILL VARY DEPENDING UPON THE DEGREE OF TUMOR-PRONENESS AND RESISTANCE OF THE INDIVIDUAL. BORROWING FROM CANCER GENETICIST HENRY LYNCH, I POSTULATE THAT TUMOR-RESISTANCE IS INHERITED AS A QUANTITATIVE POLYGENIC TRAIT IN DIRECT PROPORTION TO TUMOR-PRONENESS. I FURTHER CONTEND THAT TUMOR-PRONENESS AND IMMUNITY ARE LINKED POLYGENIC TRAITS SUCH THAT THE GREATER ONE'S TUMOR-PRONENESS, THE MORE POWERFUL HIS/HER ANTITUMOR IMMUNITY. I POINT TO THE SHARED DNA REPAIR DEFICIENCY OF CERTAIN CANCER-PRONE SYNDROMES AND HLA-LINKED AID, THEIR OCCASIONAL CO-OCCURRENCE, AND THEIR DEMONSTRABLY EXCEPTIONAL IMMUNITY AGAINST SOLID TUMORS. I PROPOSE THAT HLA-LINKED AID CONSTITUTE "CHRONIC HYPERSENSITIVITY SYNDROMES" DUE TO IMMUNITY'S LARGELY HIDDEN BATTLE TO SUPPRESS MULTIPLE INCIPIENT NEOPLASTIC MICROFOCI. MUCH OF THE PHYSIOPATHOLOGY OF AID IS EXPLICABLE AS A SUSTAINED SYSTEMIC RESPONSE TO THREATENED NEOPLASTIC TRANSFORMATION. 2001 12 303 35 AIR POLLUTION STRESS AND THE AGING PHENOTYPE: THE TELOMERE CONNECTION. AGING IS A COMPLEX PHYSIOLOGICAL PHENOMENON. THE QUESTION WHY SOME SUBJECTS GROW OLD WHILE REMAINING FREE FROM DISEASE WHEREAS OTHERS PREMATURELY DIE REMAINS LARGELY UNANSWERED. WE FOCUS HERE ON THE ROLE OF AIR POLLUTION IN BIOLOGICAL AGING. HALLMARKS OF AGING CAN BE GROUPED INTO THREE MAIN CATEGORIES: GENOMIC INSTABILITY, TELOMERE ATTRITION, AND EPIGENETIC ALTERATIONS LEADING TO ALTERED MITOCHONDRIAL FUNCTION AND CELLULAR SENESCENCE. AT BIRTH, THE INITIAL TELOMERE LENGTH OF A PERSON IS LARGELY DETERMINED BY ENVIRONMENTAL FACTORS. TELOMERE LENGTH SHORTENS WITH EACH CELL DIVISION AND EXPOSURE TO AIR POLLUTION AS WELL AS LOW RESIDENTIAL GREENS SPACE EXPOSURE IS ASSOCIATED WITH SHORTER TELOMERE LENGTH. RECENT STUDIES SHOW THAT THE ESTIMATED EFFECTS OF PARTICULATE AIR POLLUTION EXPOSURE ON THE TELOMERE MITOCHONDRIAL AXIS OF AGING MAY PLAY AN IMPORTANT ROLE IN CHRONIC HEALTH EFFECTS OF AIR POLLUTION. THE EXPOSOME ENCOMPASSES ALL EXPOSURES OVER AN ENTIRE LIFE. AS TELOMERES CAN BE CONSIDERED AS THE CELLULAR MEMORIES OF EXPOSURE TO OXIDATIVE STRESS AND INFLAMMATION, TELOMERE MAINTENANCE MAY BE A PROXY FOR ASSESSING THE "EXPOSOME". IF TELOMERES ARE CAUSALLY RELATED TO THE AGING PHENOTYPE AND ENVIRONMENTAL AIR POLLUTION IS AN IMPORTANT DETERMINANT OF TELOMERE LENGTH, THIS MIGHT PROVIDE NEW AVENUES FOR FUTURE PREVENTIVE STRATEGIES. 2016 13 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 14 6030 39 THE BURGEONING CARDIOVASCULAR DISEASE EPIDEMIC IN INDIANS - PERSPECTIVES ON CONTEXTUAL FACTORS AND POTENTIAL SOLUTIONS. CARDIOVASCULAR DISEASES (CVD) ARE THE LEADING CAUSE OF DEATH AND DISABILITY IN INDIA. THE CVD EPIDEMIC IN INDIANS IS CHARACTERIZED BY A HIGHER RELATIVE RISK BURDEN, AN EARLIER AGE OF ONSET, HIGHER CASE FATALITY AND HIGHER PREMATURE DEATHS. FOR DECADES, RESEARCHERS HAVE BEEN TRYING TO UNDERSTAND THE REASON FOR THIS INCREASED BURDEN AND PROPENSITY OF CVD AMONG INDIANS. IT CAN PARTLY BE EXPLAINED BY POPULATION-LEVEL CHANGES AND THE REMAINING BY INCREASED INHERENT BIOLOGICAL RISK. WHILE INCREASED BIOLOGICAL RISK CAN BE ATTRIBUTED TO PHENOTYPIC CHANGES CAUSED BY EARLY LIFE INFLUENCES, SIX MAJOR TRANSITIONS CAN BE CONSIDERED LARGELY RESPONSIBLE FOR THE POPULATION-LEVEL CHANGES IN INDIA-EPIDEMIOLOGICAL, DEMOGRAPHIC, NUTRITIONAL, ENVIRONMENTAL, SOCIAL-CULTURAL AND ECONOMIC. ALTHOUGH CONVENTIONAL RISK FACTORS EXPLAIN SUBSTANTIAL POPULATION ATTRIBUTABLE RISK, THE THRESHOLDS AT WHICH THESE RISK FACTORS OPERATE ARE DIFFERENT AMONG INDIANS COMPARED WITH OTHER POPULATIONS. THEREFORE, ALTERNATE EXPLANATIONS FOR THESE ECOLOGICAL DIFFERENCES HAVE BEEN SOUGHT AND MULTIPLE HYPOTHESES HAVE BEEN PROPOSED OVER THE YEARS. PRENATAL FACTORS THAT INCLUDE MATERNAL AND PATERNAL INFLUENCES ON THE OFFSPRING, AND POSTNATAL FACTORS, RANGING FROM BIRTH THROUGH CHILDHOOD, ADOLESCENCE AND YOUNG ADULTHOOD, AS WELL AS INTER-GENERATIONAL INFLUENCES HAVE BEEN EXPLORED USING THE LIFE COURSE APPROACH TO CHRONIC DISEASE. IN ADDITION TO THIS, RECENT RESEARCH HAS ILLUSTRATED THE IMPORTANCE OF THE ROLE OF INHERENT BIOLOGICAL DIFFERENCES IN LIPID METABOLISM, GLUCOSE METABOLISM, INFLAMMATORY STATES, GENETIC PREDISPOSITIONS AND EPIGENETIC INFLUENCES FOR THE INCREASED RISK. A MULTIFACETED AND HOLISTIC APPROACH TO CVD PREVENTION THAT TAKES INTO CONSIDERATION POPULATION-LEVEL AS WELL AS BIOLOGICAL RISK FACTORS WOULD BE NEEDED TO CONTROL THE BURGEONING CVD EPIDEMIC AMONG INDIANS. 2023 15 292 32 AGING AND SUSCEPTIBILITY TO PULMONARY DISEASE. THE LUNGS ARE CONTINUALLY SUBJECTED TO NOXIOUS AND INERT SUBSTANCES, ARE IMMUNOLOGICALLY ACTIVE, AND ARE IN A CONSTANT STATE OF DAMAGE AND REPAIR. THIS MAKES THE PULMONARY SYSTEM PARTICULARLY VULNERABLE TO DISEASES OF AGING. AGING CAN BE UNDERSTOOD AS RANDOM MOLECULAR DAMAGE THAT IS UNREPAIRED AND ACCUMULATES OVER TIME, RESULTING IN CELLULAR DEFECTS AND TISSUE DYSFUNCTION. THE BREAKDOWN OF CELLULAR MECHANISMS, INCLUDING STEM CELL EXHAUSTION, GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATION, LOSS OF PROTEOSTASIS, DEREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, ALTERED INTERCELLULAR COMMUNICATION, AND CHANGES IN THE EXTRACELLULAR MATRIX IS THOUGHT TO ADVANCE THE AGING PROCESS ITSELF. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), IDIOPATHIC PULMONARY FIBROSIS (IPF), AND CANCERS ILLUSTRATE A PATHOLOGIC BREAKDOWN IN THESE MECHANISMS BEYOND NORMAL AGING. THE IMMUNE SYSTEM BECOMES LESS EFFECTIVE WITH ADVANCING AGE. THERE IS A LOW-LEVEL STATE OF CHRONIC INFLAMMATION TERMED INFLAMMAGING WHICH IS THOUGHT TO BE DRIVEN BY IMMUNOSENESCENCE, THE CHANGES IN THE INNATE AND ADAPTIVE IMMUNE SYSTEMS WITH ADVANCING AGE THAT LEAD TO DYSREGULATION AND DECREASED EFFECTIVENESS OF THE IMMUNE SYSTEM. THESE PROCESSES OF AGING LEAD TO EXPECTED CHANGES IN THE FORM AND FUNCTION OF THE RESPIRATORY SYSTEM, MOST NOTABLY A LOSS OF LUNG ELASTICITY, DECREASE IN RESPIRATORY MUSCLE STRENGTH, INCREASE IN VENTILATION-PERFUSION MISMATCHING, AND STIFFENING OF THE VASCULATURE. THE ASTUTE CLINICIAN IS AWARE OF THESE EXPECTED FINDINGS AND DOES NOT OFTEN ATTRIBUTE DYSPNEA TO AGING ALONE. MAINTAINING A LOW THRESHOLD TO INVESTIGATE FOR COMORBID DISEASE AND UNDERSTANDING HOW PULMONARY DISEASE PRESENTS DIFFERENTLY IN THE ELDERLY THAN IN YOUNGER ADULTS CAN IMPROVE CLINICAL OUTCOMES. (C) 2022 AMERICAN PHYSIOLOGICAL SOCIETY. COMPR PHYSIOL 12:3509-3522, 2022. 2022 16 3551 39 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 17 3209 26 HEALTH DISPARITIES IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC MULTISYSTEM AUTOIMMUNE DISEASE CHARACTERIZED BY AUTOANTIBODY PRODUCTION AND DIVERSE CLINICAL MANIFESTATIONS. THE MANY COMPLEX, OVERLAPPING, AND CLOSELY ASSOCIATED FACTORS THAT INFLUENCE SLE SUSCEPTIBILITY AND OUTCOMES INCLUDE ETHNIC DISPARITIES, LOW ADHERENCE TO MEDICATIONS, AND POVERTY, AND GEOGRAPHY. EPIGENETIC MECHANISMS MAY PROVIDE THE LINK BETWEEN THESE ENVIRONMENTAL EXPOSURES AND BEHAVIORS AND THE DISPROPORTIONATE BURDEN OF SLE SEEN IN ETHNIC MINORITIES. ATTENTION TO THESE MODIFIABLE SOCIAL DETERMINANTS OF HEALTH WOULD NOT ONLY IMPROVE OUTCOMES FOR VULNERABLE PATIENTS WITH SLE BUT LIKELY REDUCE SUSCEPTIBILITY TO SLE AS WELL THROUGH EPIGENETIC CHANGES. 2020 18 4799 31 OBESITY AND AGEING: TWO SIDES OF THE SAME COIN. CONDITIONS AND COMORBIDITIES OF OBESITY MIRROR THOSE OF AGEING AND AGE-RELATED DISEASES. OBESITY AND AGEING SHARE A SIMILAR SPECTRUM OF PHENOTYPES SUCH AS COMPROMISED GENOMIC INTEGRITY, IMPAIRED MITOCHONDRIAL FUNCTION, ACCUMULATION OF INTRACELLULAR MACROMOLECULES, WEAKENED IMMUNITY, SHIFTS IN TISSUE AND BODY COMPOSITION, AND ENHANCED SYSTEMIC INFLAMMATION. MOREOVER, IT HAS BEEN SHOWN THAT OBESITY REDUCES LIFE EXPECTANCY BY 5.8 YEARS IN MEN AND 7.1 YEARS IN WOMEN AFTER THE AGE OF 40. SHORTER LIFE EXPECTANCY COULD BE BECAUSE OBESITY HOLISTICALLY ACCELERATES AGEING AT MULTIPLE LEVELS. BESIDES JEOPARDIZING NUCLEAR DNA AND MITOCHONDRIAL DNA INTEGRITY, OBESITY MODIFIES THE DNA METHYLATION PATTERN, WHICH IS ASSOCIATED WITH EPIGENETIC AGEING IN DIFFERENT TISSUES. ADDITIONALLY, OTHER SIGNS OF AGEING ARE SEEN IN INDIVIDUALS WITH OBESITY INCLUDING TELOMERE SHORTENING, SYSTEMIC INFLAMMATION, AND FUNCTIONAL DECLINES. THIS REVIEW AIMS TO SHOW HOW OBESITY AND AGEING ARE "TWO SIDES OF THE SAME COIN" THROUGH DISCUSSING HOW OBESITY PREDISPOSES AN INDIVIDUAL TO AGE-RELATED CONDITIONS, ILLNESS, AND DISEASE. WE WILL FURTHER DEMONSTRATE HOW THE MECHANISMS THAT PERPETUATE THE EARLY-ONSET OF CHRONIC DISEASES IN OBESITY PARALLEL THOSE OF AGEING. 2020 19 601 27 BETA-GLUCAN "TRAINED IMMUNITY" IMMUNOMODULATORY PROPERTIES POTENTIATE TISSUE WOUND MANAGEMENT AND ACCELERATE FITNESS RECOVER. INTRODUCTION: IT IS WELL ESTABLISHED THAT MODERATE PHYSICAL ACTIVITY CAN IMPROVE THE IMMUNE STATUS, RATHER EXCESS OR HIGH-INTENSITY PHYSICAL EXERCISE CAN CAUSE DAMAGE TO THE IMMUNE SYSTEM. IN ADDITION, MUSCLE INJURIES RESULTING FROM INCREASED FREQUENCY AND INTENSITY OF EXERCISES COMPROMISE INNATE IMMUNE ACTIVITY AND MAY DECREASE TISSUE REGENERATION. THUS, BETA-GLUCANS, A NATURAL COMPOUND, MAY REPRESENT AN IMPORTANT SUBSTANCE WITH STRONG IMMUNOMODULATORY PROPERTIES ACTING AS AN IMMUNOSTIMULANT THERAPY KNOWN AS "TRAINED IMMUNITY". THIS IMMUNE STIMULATING THERAPEUTIC IS AN IMMUNOLOGICAL MEMORY PHENOMENON LINKED TO THE INNATE IMMUNE SYSTEM, TRIGGERING CELLULAR CHANGES AT EPIGENETIC, TRANSCRIPTIONAL, AND FUNCTIONAL LEVELS, TO REGULATE THE IMMUNE SYSTEM AND RECOVER ITS HOMEOSTASIS WITH CLINICAL BENEFITS. CONCLUSION: THIS NARRATIVE REVIEW WORKS WITH THE CURRENT EVIDENCE REGARDING BETA-GLUCANS AS A POSSIBLE ALTERNATIVE THERAPY FOR WOUND HEALING AND ITS SAFETY AND EFFICACY IN THE TREATMENT OF MUSCLE INJURIES AND PHYSICAL RECOVERY INCLUDING OTHER CHRONIC CONDITIONS AND DISEASES. 2022 20 1385 36 DIABETES IN CHILDHOOD CANCER SURVIVORS: EMERGING CONCEPTS IN PATHOPHYSIOLOGY AND FUTURE DIRECTIONS. WITH ADVANCEMENTS IN CANCER TREATMENT AND SUPPORTIVE CARE, THERE IS A GROWING POPULATION OF CHILDHOOD CANCER SURVIVORS WHO EXPERIENCE A SUBSTANTIAL BURDEN OF COMORBIDITIES RELATED TO HAVING RECEIVED CANCER TREATMENT AT A YOUNG AGE. DESPITE AN OVERALL REDUCTION IN THE INCIDENCE OF MOST CHRONIC HEALTH CONDITIONS IN CHILDHOOD CANCER SURVIVORS OVER THE PAST SEVERAL DECADES, THE CUMULATIVE INCIDENCE OF CERTAIN LATE EFFECTS, IN PARTICULAR DIABETES MELLITUS (DM), HAS INCREASED. THE IMPLICATIONS ARE SIGNIFICANT, BECAUSE DM IS A KEY RISK FACTOR FOR CARDIOVASCULAR DISEASE, A LEADING CAUSE OF PREMATURE DEATH IN CHILDHOOD CANCER SURVIVORS. THE UNDERLYING PATHOPHYSIOLOGY OF DM IN CANCER SURVIVORS IS MULTIFACTORIAL. DM DEVELOPS AT YOUNGER AGES IN SURVIVORS COMPARED TO CONTROLS, WHICH MAY REFLECT AN "ACCELERATED AGING" PHENOTYPE IN THESE INDIVIDUALS. THE TREATMENT-RELATED EXPOSURES (I.E., CHEMOTHERAPY, RADIATION) THAT INCREASE RISK FOR DM IN CHILDHOOD CANCER SURVIVORS MAY BE MORE THAN ADDITIVE WITH ESTABLISHED DM RISK FACTORS (E.G., OLDER AGE, OBESITY, RACE, AND ETHNICITY). EMERGING RESEARCH ALSO POINTS TO PARALLELS IN CELLULAR PROCESSES IMPLICATED IN AGING- AND CANCER TREATMENT-RELATED DM. STILL, THERE REMAINS MARKED INTER-INDIVIDUAL VARIABILITY REGARDING RISK OF DM THAT IS NOT EXPLAINED BY DEMOGRAPHIC AND THERAPEUTIC RISK FACTORS ALONE. RECENT STUDIES HAVE HIGHLIGHTED THE ROLE OF GERMLINE GENETIC RISK FACTORS AND EPIGENETIC MODIFICATIONS THAT ARE ASSOCIATED WITH RISK OF DM IN BOTH THE GENERAL AND ONCOLOGY POPULATIONS. THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF RECOGNIZED RISK FACTORS FOR DM IN CHILDHOOD CANCER SURVIVORS TO HELP INFORM TARGETED APPROACHES FOR DISEASE SCREENING, PREVENTION, AND TREATMENT. FURTHERMORE, IT HIGHLIGHTS THE EXISTING SCIENTIFIC GAPS IN UNDERSTANDING THE RELATIVE CONTRIBUTIONS OF INDIVIDUAL THERAPEUTIC EXPOSURES AND THE MECHANISMS BY WHICH THEY EXERT THEIR EFFECTS THAT UNIQUELY PREDISPOSE THIS POPULATION TO DM FOLLOWING CANCER TREATMENT. 2023