1 6708 140 VIRAL INDUCED EFFECTS ON A VULNERABLE EPITHELIUM; LESSONS LEARNED FROM PAEDIATRIC ASTHMA AND EOSINOPHILIC OESOPHAGITIS. THE EPITHELIUM IS INTEGRAL TO THE PROTECTION OF MANY DIFFERENT BIOLOGICAL SYSTEMS AND FOR THE MAINTENANCE OF BIOCHEMICAL HOMEOSTASIS. EMERGING EVIDENCE SUGGESTS THAT PARTICULAR CHILDREN HAVE EPITHELIAL VULNERABILITIES LEADING TO DYSREGULATED BARRIER FUNCTION AND INTEGRITY, THAT RESULTANTLY CONTRIBUTES TO DISEASE PATHOGENESIS. THESE EPITHELIAL VULNERABILITIES LIKELY DEVELOP IN UTERO OR IN EARLY LIFE DUE TO VARIOUS GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. ALTHOUGH VARIOUS EPITHELIA ARE UNIQUELY STRUCTURED WITH SPECIFIC FUNCTION, PREVALENT ALLERGIC-TYPE EPITHELIAL DISEASES IN CHILDREN POTENTIALLY HAVE COMMON OR PARALLEL DISEASE PROCESSES. THESE INCLUDE INFLAMMATION AND IMMUNE RESPONSE DYSREGULATION STEMMING FROM ATYPICAL EPITHELIAL BARRIER FUNCTION AND INTEGRITY. TWO DISEASES WHERE AETIOLOGY AND PATHOGENESIS ARE POTENTIALLY LINKED TO EPITHELIAL VULNERABILITIES INCLUDE PAEDIATRIC ASTHMA AND EOSINOPHILIC OESOPHAGITIS (EOE). FOR EXAMPLE, RHINOVIRUS C (RV-C) IS A KNOWN RISK FACTOR FOR PAEDIATRIC ASTHMA DEVELOPMENT AND IS KNOWN TO DISRUPT RESPIRATORY EPITHELIAL BARRIER FUNCTION CAUSING ACUTE INFLAMMATION. IN ADDITION, EOE, A PREVALENT ATOPIC CONDITION OF THE OESOPHAGEAL EPITHELIUM, IS CHARACTERISED BY SIMILAR INNATE IMMUNE AND EPITHELIAL RESPONSES TO VIRAL INJURY. THIS REVIEW EXAMINES THE CURRENT LITERATURE AND IDENTIFIES THE GAPS IN THE FIELD DEFINING VIRAL-INDUCED EFFECTS ON A VULNERABLE RESPIRATORY EPITHELIUM AND RESULTING CHRONIC INFLAMMATION, DRAWING FROM KNOWLEDGE GENERATED IN ACUTE WHEEZING ILLNESS, PAEDIATRIC ASTHMA AND EOE. BESIDES HIGHLIGHTING THE IMPORTANCE OF EPITHELIAL STRUCTURE AND BARRIER FUNCTION IN ALLERGIC DISEASE PATHOGENESIS REGARDLESS OF SPECIFIC EPITHELIAL SUB-TYPES, THIS REVIEW FOCUSES ON THE IMPORTANCE OF EXAMINING OTHER PARALLEL ALLERGIC-TYPE DISEASE PROCESSES THAT MAY UNCOVER COMMONALITIES DRIVING DISEASE PATHOGENESIS. THIS IN TURN MAY BE BENEFICIAL IN THE DEVELOPMENT OF COMMON THERAPEUTICS FOR CURRENT CLINICAL MANAGEMENT AND DISEASE PREVENTION IN THE FUTURE. 2021 2 327 37 ALLERGIC INFLAMMATORY MEMORY IN HUMAN RESPIRATORY EPITHELIAL PROGENITOR CELLS. BARRIER TISSUE DYSFUNCTION IS A FUNDAMENTAL FEATURE OF CHRONIC HUMAN INFLAMMATORY DISEASES(1). SPECIALIZED SUBSETS OF EPITHELIAL CELLS-INCLUDING SECRETORY AND CILIATED CELLS-DIFFERENTIATE FROM BASAL STEM CELLS TO COLLECTIVELY PROTECT THE UPPER AIRWAY(2-4). ALLERGIC INFLAMMATION CAN DEVELOP FROM PERSISTENT ACTIVATION(5) OF TYPE 2 IMMUNITY(6) IN THE UPPER AIRWAY, RESULTING IN CHRONIC RHINOSINUSITIS, WHICH RANGES IN SEVERITY FROM RHINITIS TO SEVERE NASAL POLYPS(7). BASAL CELL HYPERPLASIA IS A HALLMARK OF SEVERE DISEASE(7-9), BUT IT IS NOT KNOWN HOW THESE PROGENITOR CELLS(2,10,11) CONTRIBUTE TO CLINICAL PRESENTATION AND BARRIER TISSUE DYSFUNCTION IN HUMANS. HERE WE PROFILE PRIMARY HUMAN SURGICAL CHRONIC RHINOSINUSITIS SAMPLES (18,036 CELLS, N = 12) THAT SPAN THE DISEASE SPECTRUM USING SEQ-WELL FOR MASSIVELY PARALLEL SINGLE-CELL RNA SEQUENCING(12), REPORT TRANSCRIPTOMES FOR HUMAN RESPIRATORY EPITHELIAL, IMMUNE AND STROMAL CELL TYPES AND SUBSETS FROM A TYPE 2 INFLAMMATORY DISEASE, AND MAP KEY MEDIATORS. BY COMPARISON WITH NASAL SCRAPINGS (18,704 CELLS, N = 9), WE DEFINE SIGNATURES OF CORE, HEALTHY, INFLAMED AND POLYP SECRETORY CELLS. WE REVEAL MARKED DIFFERENCES BETWEEN THE EPITHELIAL COMPARTMENTS OF THE NON-POLYP AND POLYP CELLULAR ECOSYSTEMS, IDENTIFYING AND VALIDATING A GLOBAL REDUCTION IN CELLULAR DIVERSITY OF POLYPS CHARACTERIZED BY BASAL CELL HYPERPLASIA, CONCOMITANT DECREASES IN GLANDULAR CELLS, AND PHENOTYPIC SHIFTS IN SECRETORY CELL ANTIMICROBIAL EXPRESSION. WE DETECT AN ABERRANT BASAL PROGENITOR DIFFERENTIATION TRAJECTORY IN POLYPS, AND PROPOSE CELL-INTRINSIC(13), EPIGENETIC(14,15) AND EXTRINSIC FACTORS(11,16,17) THAT LOCK POLYP BASAL CELLS INTO THIS UNCOMMITTED STATE. FINALLY, WE FUNCTIONALLY DEMONSTRATE THAT EX VIVO CULTURED BASAL CELLS RETAIN INTRINSIC MEMORY OF IL-4/IL-13 EXPOSURE, AND TEST THE POTENTIAL FOR CLINICAL BLOCKADE OF THE IL-4 RECEPTOR ALPHA-SUBUNIT TO MODIFY BASAL AND SECRETORY CELL STATES IN VIVO. OVERALL, WE FIND THAT REDUCED EPITHELIAL DIVERSITY STEMMING FROM FUNCTIONAL SHIFTS IN BASAL CELLS IS A KEY CHARACTERISTIC OF TYPE 2 IMMUNE-MEDIATED BARRIER TISSUE DYSFUNCTION. OUR RESULTS DEMONSTRATE THAT EPITHELIAL STEM CELLS MAY CONTRIBUTE TO THE PERSISTENCE OF HUMAN DISEASE BY SERVING AS REPOSITORIES FOR ALLERGIC MEMORIES. 2018 3 2566 29 EPIGENETICS MECHANISMS IN RENAL DEVELOPMENT. APPRECIATION FOR THE ROLE OF EPIGENETIC MODIFICATIONS IN THE DIAGNOSIS AND TREATMENT OF DISEASES IS FAST GAINING ATTENTION. TREATMENT OF CHRONIC KIDNEY DISEASE STEMMING FROM DIABETES OR HYPERTENSION AS WELL AS WILMS TUMOR WILL ALL PROFIT FROM KNOWLEDGE OF THE CHANGES IN THE EPIGENOMIC LANDSCAPES. TO DO SO, IT IS ESSENTIAL TO CHARACTERIZE THE EPIGENOMIC MODIFIERS AND THEIR MODIFICATIONS UNDER NORMAL PHYSIOLOGICAL CONDITIONS. THE TRANSCRIPTION FACTOR PAX2 WAS IDENTIFIED AS A MAJOR EPIGENETIC PLAYER IN THE EARLY SPECIFICATION OF THE KIDNEY. NOTABLY, THE PROGENITORS OF ALL NEPHRONS THAT RESIDE IN THE CAP MESENCHYME DISPLAY A UNIQUE BIVALENT HISTONE SIGNATURE (EXPRESSING REPRESSIVE EPIGENETIC MARKS ALONGSIDE ACTIVATION MARKS) ON LINEAGE-SPECIFIC GENES. THESE CELLS ARE DEEMED POISED FOR DIFFERENTIATION AND COMMITMENT TO THE NEPHROGENIC LINEAGE. IN RESPONSE TO THE APPROPRIATE INDUCING SIGNAL, THESE GENES LOSE THEIR REPRESSIVE HISTONE MARKS, WHICH ALLOW FOR THEIR EXPRESSION IN NASCENT NEPHRON PRECURSORS. SUCH KNOWLEDGE OF THE EPIGENETIC LANDSCAPE AND THE RESULTANT CELL FATE OR BEHAVIOR IN THE DEVELOPING KIDNEY WILL GREATLY IMPROVE THE OVERALL SUCCESS IN DESIGNING REGENERATIVE STRATEGIES AND TISSUE REPROGRAMMING METHODOLOGIES FROM PLURIPOTENT CELLS. 2016 4 5630 33 SENESCENCE IN PULMONARY FIBROSIS: BETWEEN AGING AND EXPOSURE. TO DATE, CHRONIC PULMONARY PATHOLOGIES REPRESENT THE THIRD LEADING CAUSE OF DEATH IN THE ELDERLY POPULATION. EVIDENCE-BASED PROJECTIONS SUGGEST THAT >65 (YEARS OLD) INDIVIDUALS WILL ACCOUNT FOR APPROXIMATELY A QUARTER OF THE WORLD POPULATION BEFORE THE TURN OF THE CENTURY. GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DEREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION, ARE DESCRIBED AS THE NINE "HALLMARKS" THAT GOVERN CELLULAR FITNESS. ANY DEVIATION FROM THE NORMAL PATTERN INITIATES A COMPLEX CASCADE OF EVENTS CULMINATING TO A DISEASE STATE. THIS BLUEPRINT, ORIGINALLY EMPLOYED TO DESCRIBE ABERRANT CHANGES IN CANCER CELLS, CAN BE ALSO USED TO DESCRIBE AGING AND FIBROSIS. PULMONARY FIBROSIS (PF) IS THE RESULT OF A PROGRESSIVE DECLINE IN INJURY RESOLUTION PROCESSES STEMMING FROM ENDOGENOUS (PHYSIOLOGICAL DECLINE OR SOMATIC MUTATIONS) OR EXOGENOUS STRESS. ENVIRONMENTAL, DIETARY OR OCCUPATIONAL EXPOSURE ACCELERATES THE PATHOGENESIS OF A SENESCENT PHENOTYPE BASED ON (1) WINDOW OF EXPOSURE; (2) DOSE, DURATION, RECURRENCE; AND (3) CELLS TYPE BEING TARGETED. AS THE LUNG AGES, THE THRESHOLD TO GENERATE AN IRREVERSIBLY SENESCENT PHENOTYPE IS LOWERED. HOWEVER, WE DO NOT HAVE SUFFICIENT KNOWLEDGE TO MAKE ACCURATE PREDICTIONS. IN THIS REVIEW, WE PROVIDE AN ASSESSMENT OF THE LITERATURE THAT INTERROGATES LUNG EPITHELIAL, MESENCHYMAL, AND IMMUNE SENESCENCE AT THE INTERSECTION OF AGING, ENVIRONMENTAL EXPOSURE AND PULMONARY FIBROSIS. 2020 5 2444 29 EPIGENETIC STATES OF NEPHRON PROGENITORS AND EPITHELIAL DIFFERENTIATION. IN MAMMALS, FORMATION OF NEW NEPHRONS ENDS PERINATALLY DUE TO CONSUMPTION OF MESENCHYMAL PROGENITOR CELLS. PREMATURE DEPLETION OF PROGENITORS DUE TO PREMATURITY OR POSTNATAL LOSS OF NEPHRONS DUE TO INJURY CAUSES CHRONIC KIDNEY DISEASE AND HYPERTENSION. INTENSIVE EFFORTS ARE CURRENTLY INVESTED IN DESIGNING REGENERATIVE STRATEGIES TO FORM NEW NEPHRON PROGENITORS FROM PLURIPOTENT CELLS, WHICH UPON FURTHER DIFFERENTIATION PROVIDE A POTENTIAL SOURCE OF NEW NEPHRONS. TO KNOW IF REPROGRAMED RENAL CELLS CAN MAINTAIN THEIR IDENTITY AND FATE REQUIRES KNOWLEDGE OF THE EPIGENETIC STATES OF NATIVE NEPHRON PROGENITORS AND THEIR PROGENY. IN THIS ARTICLE, WE SUMMARIZE CURRENT KNOWLEDGE AND GAPS IN THE EPIGENOMIC LANDSCAPE OF THE DEVELOPING KIDNEY. WE NOW KNOW THAT PAX2/PTIP/H3K4 METHYLTRANSFERASE ACTIVITY PROVIDES THE INITIAL EPIGENETIC SPECIFICATION SIGNAL TO THE METANEPHRIC MESENCHYME. DURING NEPHROGENESIS, THE CAP MESENCHYME HOUSING NEPHRON PROGENITORS IS ENRICHED IN BIVALENT CHROMATIN MARKS; AS TUBULOGENESIS PROCEEDS, THE TUBULAR EPITHELIUM ACQUIRES H3K79ME2. THE LATTER MARK IS UNIQUELY INDUCED DURING EPITHELIAL DIFFERENTIATION. ANALYSIS OF HISTONE LANDSCAPES IN CLONAL METANEPHRIC MESENCHYME CELL LINES AND IN WILMS TUMOR AND NORMAL FETAL KIDNEY HAS REVEALED THAT PROMOTERS OF POISED NEPHROGENESIS GENES CARRY BIVALENT HISTONE SIGNATURES IN PROGENITORS. DIFFERENTIATION OR STIMULATION OF WNT SIGNALING PROMOTES RESOLUTION OF BIVALENCY; THIS DOES NOT OCCUR IN WILMS TUMOR CELLS CONSISTENT WITH THEIR DEVELOPMENTAL ARREST. THE USE OF SMALL CELL NUMBER CHIP-SEQ SHOULD FACILITATE THE CHARACTERIZATION OF THE CHROMATIN LANDSCAPE OF THE METANEPHRIC MESENCHYME AND VARIOUS NEPHRON COMPARTMENTS DURING NEPHROGENESIS. ONLY THEN WE WILL KNOW IF STEM AND SOMATIC CELL REPROGRAMMING INTO KIDNEY PROGENITORS RECAPITULATES NORMAL DEVELOPMENT. 2015 6 3596 37 IMPLICATIONS OF SPHINGOLIPIDS ON AGING AND AGE-RELATED DISEASES. AGING IS A PROCESS LEADING TO A PROGRESSIVE LOSS OF PHYSIOLOGICAL INTEGRITY AND HOMEOSTASIS, AND A PRIMARY RISK FACTOR FOR MANY LATE-ONSET CHRONIC DISEASES. THE MECHANISMS UNDERLYING AGING HAVE LONG PIQUED THE CURIOSITY OF SCIENTISTS. HOWEVER, THE IDEA THAT AGING IS A BIOLOGICAL PROCESS SUSCEPTIBLE TO GENETIC MANIPULATION WAS NOT WELL ESTABLISHED UNTIL THE DISCOVERY THAT THE INHIBITION OF INSULIN/IGF-1 SIGNALING EXTENDED THE LIFESPAN OF C. ELEGANS. ALTHOUGH AGING IS A COMPLEX MULTISYSTEM PROCESS, LOPEZ-OTIN ET AL. DESCRIBED AGING IN REFERENCE TO NINE HALLMARKS OF AGING. THESE NINE HALLMARKS INCLUDE: GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DEREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION. DUE TO RECENT ADVANCES IN LIPIDOMIC, INVESTIGATION INTO THE ROLE OF LIPIDS IN BIOLOGICAL AGING HAS INTENSIFIED, PARTICULARLY THE ROLE OF SPHINGOLIPIDS (SL). SLS ARE A DIVERSE GROUP OF LIPIDS ORIGINATING FROM THE ENDOPLASMIC RETICULUM (ER) AND CAN BE MODIFIED TO CREATE A VASTLY DIVERSE GROUP OF BIOACTIVE METABOLITES THAT REGULATE ALMOST EVERY MAJOR CELLULAR PROCESS, INCLUDING CELL CYCLE REGULATION, SENESCENCE, PROLIFERATION, AND APOPTOSIS. ALTHOUGH SL BIOLOGY REACHES ALL NINE HALLMARKS OF AGING, ITS CONTRIBUTION TO EACH HALLMARK IS DISPROPORTIONATE. IN THIS REVIEW, WE WILL DISCUSS IN DETAIL THE MAJOR CONTRIBUTIONS OF SLS TO THE HALLMARKS OF AGING AND AGE-RELATED DISEASES WHILE ALSO SUMMARIZING THE IMPORTANCE OF THEIR OTHER MINOR BUT INTEGRAL CONTRIBUTIONS. 2021 7 2600 23 EPIGENETICS REGULATION DURING VIRUS-HOST INTERACTION AND THEIR EFFECTS ON THE VIRUS AND HOST CELL. EPIGENETICS, A FIELD OF STUDY FOCUSED ON CELLULAR GENE REGULATION INDEPENDENT OF DNA SEQUENCE ALTERATIONS, ENCOMPASSES DNA METHYLATION, HISTONE MODIFICATION AND MICRORNA MODIFICATION. EPIGENETICS PROCESSES PLAY A PIVOTAL ROLE IN GOVERNING THE LIFE CYCLES OF VIRUSES, ENABLING THEIR TRANSMISSION, PERSISTENCE, AND MAINTENANCE WITH IN HOST ORGANISMS. THIS REVIEW EXAMINES THE EPIGENETICS REGULATION OF DIVERSE VIRUS INCLUDING ORTHOMOXYVIRUSES, CORONAVIRUS, RETROVIRIDAE, MONONEGAVIRALES, AND POXVIRUSES AMONG OTHERS. THE INVESTIGATION ENCOMPASSES TEN REPRESENTATIVE VIRUSES FROM THESE FAMILIES. DETAILED EXPLORATION OF THE EPIGENETIC MECHANISMS UNDERLYING EACH VIRUS TYPE, INVOLVING MIRNA MODIFICATION, HISTONE MODIFICATION AND DNA METHYLATION, SHEDS LIGHT ON THE INTRICATE AND MULTIFACETED EPIGENETIC INTERPLAY BETWEEN VIRUSES AND THEIR HOSTS. FURTHERMORE, THIS REVIEW INVESTIGATES THE INFLUENCE OF THESE EPIGENETIC PROCESSES ON INFECTION CYCLES, EMPHASIZING THE UTILIZATION OF EPIGENETICS BY VIRUSES SUCH AS EPSTEIN-BARR VIRUS AND HUMAN IMMUNODEFICIENCY VIRUS (HIV) TO REGULATE GENE EXPRESSION DURING CHRONIC OR LATENT INFECTIONS, CONTROL LATENCY, AND TRANSITION TO LYTIC INFECTION. FINALLY, THE PAPER EXPLORES THE NOVEL TREATMENTS POSSIBILITIES STEMMING FROM THIS EPIGENETIC UNDERSTANDING. 2023 8 4116 46 MECHANISMS OF AIRWAY EPITHELIAL INJURY AND ABNORMAL REPAIR IN ASTHMA AND COPD. THE AIRWAY EPITHELIUM COMPRISES OF DIFFERENT CELL TYPES AND ACTS AS A PHYSICAL BARRIER PREVENTING PATHOGENS, INCLUDING INHALED PARTICLES AND MICROBES, FROM ENTERING THE LUNGS. GOBLET CELLS AND SUBMUCOSAL GLANDS PRODUCE MUCUS THAT TRAPS PATHOGENS, WHICH ARE EXPELLED FROM THE RESPIRATORY TRACT BY CILIATED CELLS. BASAL CELLS ACT AS PROGENITOR CELLS, DIFFERENTIATING INTO DIFFERENT EPITHELIAL CELL TYPES, TO MAINTAIN HOMEOSTASIS FOLLOWING INJURY. ADHERENS AND TIGHT JUNCTIONS BETWEEN CELLS MAINTAIN THE EPITHELIAL BARRIER FUNCTION AND REGULATE THE MOVEMENT OF MOLECULES ACROSS IT. IN THIS REVIEW WE DISCUSS HOW ABNORMAL EPITHELIAL STRUCTURE AND FUNCTION, CAUSED BY CHRONIC INJURY AND ABNORMAL REPAIR, DRIVES AIRWAY DISEASE AND SPECIFICALLY ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). IN BOTH DISEASES, INHALED ALLERGENS, POLLUTANTS AND MICROBES DISRUPT JUNCTIONAL COMPLEXES AND PROMOTE CELL DEATH, IMPAIRING THE BARRIER FUNCTION AND LEADING TO INCREASED PENETRATION OF PATHOGENS AND A CONSTANT AIRWAY IMMUNE RESPONSE. IN ASTHMA, THE INFLAMMATORY RESPONSE PRECIPITATES THE EPITHELIAL INJURY AND DRIVES ABNORMAL BASAL CELL DIFFERENTIATION. THIS LEADS TO REDUCED CILIATED CELLS, GOBLET CELL HYPERPLASIA AND INCREASED EPITHELIAL MESENCHYMAL TRANSITION, WHICH CONTRIBUTE TO IMPAIRED MUCOCILIARY CLEARANCE AND AIRWAY REMODELLING. IN COPD, CHRONIC OXIDATIVE STRESS AND INFLAMMATION TRIGGER PREMATURE EPITHELIAL CELL SENESCENCE, WHICH CONTRIBUTES TO LOSS OF EPITHELIAL INTEGRITY AND AIRWAY INFLAMMATION AND REMODELLING. INCREASED NUMBERS OF BASAL CELLS SHOWING DEREGULATED DIFFERENTIATION, CONTRIBUTES TO CILIARY DYSFUNCTION AND MUCOUS HYPERPRODUCTION IN COPD AIRWAYS. DEFECTIVE ANTIOXIDANT, ANTIVIRAL AND DAMAGE REPAIR MECHANISMS, POSSIBLY DUE TO GENETIC OR EPIGENETIC FACTORS, MAY CONFER SUSCEPTIBILITY TO AIRWAY EPITHELIAL DYSFUNCTION IN THESE DISEASES. THE CURRENT EVIDENCE SUGGESTS THAT A CONSTANT CYCLE OF INJURY AND ABNORMAL REPAIR OF THE EPITHELIUM DRIVES CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA AND COPD. MECHANISTIC UNDERSTANDING OF INJURY SUSCEPTIBILITY AND DAMAGE RESPONSE MAY LEAD TO IMPROVED THERAPIES FOR THESE DISEASES. 2023 9 3181 19 HALLMARKS OF AGING: AN EXPANDING UNIVERSE. AGING IS DRIVEN BY HALLMARKS FULFILLING THE FOLLOWING THREE PREMISES: (1) THEIR AGE-ASSOCIATED MANIFESTATION, (2) THE ACCELERATION OF AGING BY EXPERIMENTALLY ACCENTUATING THEM, AND (3) THE OPPORTUNITY TO DECELERATE, STOP, OR REVERSE AGING BY THERAPEUTIC INTERVENTIONS ON THEM. WE PROPOSE THE FOLLOWING TWELVE HALLMARKS OF AGING: GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DISABLED MACROAUTOPHAGY, DEREGULATED NUTRIENT-SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, ALTERED INTERCELLULAR COMMUNICATION, CHRONIC INFLAMMATION, AND DYSBIOSIS. THESE HALLMARKS ARE INTERCONNECTED AMONG EACH OTHER, AS WELL AS TO THE RECENTLY PROPOSED HALLMARKS OF HEALTH, WHICH INCLUDE ORGANIZATIONAL FEATURES OF SPATIAL COMPARTMENTALIZATION, MAINTENANCE OF HOMEOSTASIS, AND ADEQUATE RESPONSES TO STRESS. 2023 10 3183 29 HALLMARKS OF T CELL AGING. THE AGED ADAPTIVE IMMUNE SYSTEM IS CHARACTERIZED BY PROGRESSIVE DYSFUNCTION AS WELL AS INCREASED AUTOIMMUNITY. THIS DECLINE IS RESPONSIBLE FOR ELEVATED SUSCEPTIBILITY TO INFECTION AND CANCER, AS WELL AS DECREASED VACCINATION EFFICACY. RECENT EVIDENCE INDICATES THAT CD4(+) T CELL-INTRINSIC ALTERATINS CONTRIBUTE TO CHRONIC INFLAMMATION AND ARE SUFFICIENT TO ACCELERATE AN ORGANISM-WIDE AGING PHENOTYPE, SUPPORTING THE IDEA THAT T CELL AGING PLAYS A MAJOR ROLE IN BODY-WIDE DETERIORATION. IN THIS REVIEW, WE PROPOSE TEN MOLECULAR HALLMARKS TO REPRESENT COMMON DENOMINATORS OF T CELL AGING. THESE HALLMARKS ARE GROUPED INTO FOUR PRIMARY HALLMARKS (THYMIC INVOLUTION, MITOCHONDRIAL DYSFUNCTION, GENETIC AND EPIGENETIC ALTERATIONS, AND LOSS OF PROTEOSTASIS) AND FOUR SECONDARY HALLMARKS (REDUCTION OF THE TCR REPERTOIRE, NAIVE-MEMORY IMBALANCE, T CELL SENESCENCE, AND LACK OF EFFECTOR PLASTICITY), AND TOGETHER THEY EXPLAIN THE MANIFESTATION OF THE TWO INTEGRATIVE HALLMARKS (IMMUNODEFICIENCY AND INFLAMMAGING). A MAJOR CHALLENGE NOW IS WEIGHING THE RELATIVE IMPACT OF THESE HALLMARKS ON T CELL AGING AND UNDERSTANDING THEIR INTERCONNECTIONS, WITH THE FINAL GOAL OF DEFINING MOLECULAR TARGETS FOR INTERVENTIONS IN THE AGING PROCESS. 2021 11 4674 25 NEW INSIGHTS INTO THE ROLE AND MECHANISM OF PARTIAL EPITHELIAL-MESENCHYMAL TRANSITION IN KIDNEY FIBROSIS. EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IS DESCRIBED AS THE PROCESS IN WHICH INJURED RENAL TUBULAR EPITHELIAL CELLS UNDERGO A PHENOTYPE CHANGE, ACQUIRING MESENCHYMAL CHARACTERISTICS AND MORPHING INTO FIBROBLASTS. INITIALLY, IT WAS WIDELY THOUGHT OF AS A CRITICAL MECHANISM OF FIBROGENESIS UNDERLYING CHRONIC KIDNEY DISEASE. HOWEVER, EVIDENCE THAT RENAL TUBULAR EPITHELIAL CELLS CAN CROSS THE BASEMENT MEMBRANE AND BECOME FIBROBLASTS IN THE RENAL INTERSTITIUM IS RARE, LEADING TO DEBATE ABOUT THE EXISTENCE OF EMT. RECENT RESEARCH HAS DEMONSTRATED THAT AFTER INJURY, RENAL TUBULAR EPITHELIAL CELLS ACQUIRE MESENCHYMAL CHARACTERISTICS AND THE ABILITY TO PRODUCE A VARIETY OF PROFIBROTIC FACTORS AND CYTOKINES, BUT REMAIN ATTACHED TO THE BASEMENT MEMBRANE. ON THIS BASIS, A NEW CONCEPT OF "PARTIAL EPITHELIAL-MESENCHYMAL TRANSITION (PEMT)" WAS PROPOSED TO EXPLAIN THE CONTRIBUTION OF RENAL EPITHELIAL CELLS TO RENAL FIBROGENESIS. IN THIS REVIEW, WE DISCUSS THE CONCEPT OF PEMT AND THE MOST RECENT FINDINGS RELATED TO THIS PROCESS, INCLUDING CELL CYCLE ARREST, METABOLIC ALTERNATION OF EPITHELIAL CELLS, INFILTRATION OF IMMUNE CELLS, EPIGENETIC REGULATION AS WELL AS THE NOVEL SIGNALING PATHWAYS THAT MEDIATE THIS DISTURBED EPITHELIAL-MESENCHYMAL COMMUNICATION. A DEEPER UNDERSTANDING OF THE ROLE AND THE MECHANISM OF PEMT MAY HELP IN DEVELOPING NOVEL THERAPIES TO PREVENT AND HALT FIBROSIS IN KIDNEY DISEASE. 2020 12 4872 42 OUTSIDE-IN HYPOTHESIS REVISITED: THE ROLE OF MICROBIAL, EPITHELIAL, AND IMMUNE INTERACTIONS. OBJECTIVE: OUR UNDERSTANDING OF THE ORIGIN OF ALLERGIC DISEASES HAS INCREASED IN RECENT YEARS, HIGHLIGHTING THE IMPORTANCE OF MICROBIAL DYSBIOSIS AND EPITHELIAL BARRIER DYSFUNCTION IN AFFECTED TISSUES. EXPLORING THE MICROBIAL-EPITHELIAL-IMMUNE CROSSTALK UNDERLYING THE MECHANISMS OF ALLERGIC DISEASES WILL ALLOW THE DEVELOPMENT OF NOVEL PREVENTION AND TREATMENT STRATEGIES FOR ALLERGIC DISEASES. DATA SOURCES: THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN MICROBIAL, EPITHELIAL, AND IMMUNE INTERACTIONS IN ATOPIC DERMATITIS, ALLERGIC RHINITIS, CHRONIC RHINOSINUSITIS, AND ASTHMA. STUDY SELECTIONS: WE PERFORMED A LITERATURE SEARCH, IDENTIFYING RELEVANT RECENT PRIMARY ARTICLES AND REVIEW ARTICLES. RESULTS: DYNAMIC CROSSTALK BETWEEN THE ENVIRONMENTAL FACTORS AND MICROBIAL, EPITHELIAL, AND IMMUNE CELLS IN THE DEVELOPMENT OF ATOPIC DERMATITIS, ALLERGIC RHINITIS, CHRONIC RHINOSINUSITIS, AND ASTHMA UNDERLIES THE PATHOGENESIS OF THESE DISEASES. THERE IS SUBSTANTIAL EVIDENCE IN THE LITERATURE SUGGESTING THAT ENVIRONMENTAL FACTORS DIRECTLY AFFECT BARRIER FUNCTION OF THE EPITHELIUM. IN ADDITION, T-HELPER 2 (T(H)2) CELLS, TYPE 2 INNATE LYMPHOID CELLS, AND THEIR CYTOKINE INTERLEUKIN 13 (IL-13) DAMAGE SKIN AND LUNG BARRIERS. THE EFFECTS OF ENVIRONMENTAL FACTORS MAY AT LEAST IN PART BE MEDIATED BY EPIGENETIC MECHANISMS. HISTONE DEACETYLASE ACTIVATION BY TYPE 2 IMMUNE RESPONSE HAS A MAJOR EFFECT ON LEAKY BARRIERS AND BLOCKING OF HISTONE DEACETYLASE ACTIVITY CORRECTS THE DEFECTIVE BARRIER IN HUMAN AIR-LIQUID INTERFACE CULTURES AND MOUSE MODELS OF ALLERGIC ASTHMA WITH RHINITIS. WE ALSO PRESENT AND DISCUSS A NOVEL DEVICE TO DETECT AND MONITOR SKIN BARRIER DYSFUNCTION, WHICH PROVIDES AN OPPORTUNITY TO RAPIDLY AND ROBUSTLY ASSESS DISEASE SEVERITY. CONCLUSION: A COMPLEX INTERPLAY BETWEEN ENVIRONMENTAL FACTORS, EPITHELIUM, AND THE IMMUNE SYSTEM IS INVOLVED IN THE DEVELOPMENT OF SYSTEMIC ALLERGIC DISEASES. 2020 13 290 25 AGING AND PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS IS A CHRONIC, PROGRESSIVE, AND USUALLY FATAL LUNG DISORDER OF UNKNOWN ETIOLOGY. THE DISEASE LIKELY RESULTS FROM THE INTERACTION OF GENETIC SUSCEPTIBILITY ARCHITECTURE, ENVIRONMENTAL FACTORS SUCH AS SMOKING, AND AN ABNORMAL EPIGENETIC REPROGRAMMING THAT LEADS TO A COMPLEX PATHOGENESIS. IDIOPATHIC PULMONARY FIBROSIS OCCURS IN MIDDLE-AGED AND MAINLY ELDERLY ADULTS, AND IN THIS CONTEXT AGE HAS EMERGED AS ITS STRONGEST RISK FACTOR. HOWEVER, THE MECHANISMS LINKING IT TO AGING ARE UNCERTAIN. RECENTLY, NINE MOLECULAR AND CELLULAR HALLMARKS OF AGING HAVE BEEN PROPOSED: GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DEREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THESE MOLECULAR MECHANISMS AND THEIR INVOLVEMENT IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS, WHILE EMPHASIZING THAT THE STUDIES ON THIS DISEASE ARE FEW AND THE FINDINGS ARE NOT DEFINITIVE. 2016 14 6272 30 THE ORIGIN AND PATHOGENESIS OF ENDOMETRIOSIS. RECENT MOLECULAR GENETIC FINDINGS ON ENDOMETRIOSIS AND NORMAL ENDOMETRIUM SUGGEST A MODIFIED MODEL IN WHICH CIRCULATING EPITHELIAL PROGENITOR OR STEM CELLS INTENDED TO REGENERATE UTERINE ENDOMETRIUM AFTER MENSTRUATION MAY BECOME OVERREACTIVE AND TRAPPED OUTSIDE THE UTERUS. THESE TRAPPED EPITHELIUM-COMMITTED PROGENITOR CELLS FORM NASCENT GLANDS THROUGH CLONAL EXPANSION AND RECRUIT POLYCLONAL STROMAL CELLS, LEADING TO THE ESTABLISHMENT OF DEEP INFILTRATING ENDOMETRIOSIS. ONCE FORMED, THE ECTOPIC TISSUE BECOMES SUBJECT TO IMMUNE SURVEILLANCE, RESULTING IN CHRONIC INFLAMMATION. THE INFLAMMATORY RESPONSE ORCHESTRATED BY NUCLEAR FACTOR-KAPPAB SIGNALING IS EXACERBATED BY ABERRATIONS IN THE ESTROGEN RECEPTOR-BETA AND PROGESTERONE RECEPTOR PATHWAYS, WHICH ARE ALSO AFFECTED BY LOCAL INFLAMMATION, FORMING A DYSREGULATED INFLAMMATION-HORMONAL LOOP. GLANDULAR EPITHELIUM WITHIN ENDOMETRIOTIC TISSUE HARBORS CANCER-ASSOCIATED MUTATIONS THAT ARE FREQUENTLY DETECTED IN ENDOMETRIOSIS-RELATED OVARIAN CANCERS. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES THAT HAVE ILLUMINATED THE ORIGIN AND PATHOGENESIS OF ENDOMETRIOSIS AND HAVE PROVIDED NEW AVENUES FOR RESEARCH THAT PROMISE TO IMPROVE THE EARLY DIAGNOSIS AND MANAGEMENT OF ENDOMETRIOSIS. 2020 15 4186 25 METABOLIC AND EPIGENETIC REGULATION OF T-CELL EXHAUSTION. CURRENT IMMUNOTHERAPIES YIELD REMARKABLE CLINICAL OUTCOMES BY BOOSTING THE POWER OF HOST IMMUNITY IN CANCER CELL ELIMINATION AND VIRAL CLEARANCE. HOWEVER, AFTER PROLONGED ANTIGEN EXPOSURE, CD8(+) T CELLS DIFFERENTIATE INTO A SPECIAL DIFFERENTIATION STATE KNOWN AS T-CELL EXHAUSTION, WHICH POSES ONE OF THE MAJOR HURDLES TO ANTIVIRAL AND ANTITUMOR IMMUNITY DURING CHRONIC VIRAL INFECTION AND TUMOUR DEVELOPMENT. GROWING EVIDENCE INDICATES THAT EXHAUSTED T CELLS UNDERGO METABOLIC INSUFFICIENCY WITH ALTERED SIGNALLING CASCADES AND EPIGENETIC LANDSCAPES, WHICH DAMPEN EFFECTOR IMMUNITY AND CAUSE POOR RESPONSIVENESS TO IMMUNE-CHECKPOINT-BLOCKADE THERAPIES. HOW METABOLIC STRESS AFFECTS T-CELL EXHAUSTION REMAINS UNCLEAR; THEREFORE, IN THIS REVIEW, WE SUMMARIZE CURRENT KNOWLEDGE OF HOW T-CELL EXHAUSTION OCCURS, AND DISCUSS HOW METABOLIC INSUFFICIENCY AND PROLONGED STRESS RESPONSES MAY AFFECT SIGNALLING CASCADES AND EPIGENETIC REPROGRAMMING, THUS LOCKING T CELLS INTO AN EXHAUSTED STATE VIA SPECIALIZED DIFFERENTIATION PROGRAMMING. 2020 16 182 22 ACCELERATED LUNG AGING AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE PREVALENCE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) INCREASES EXPONENTIALLY WITH AGING. ITS PATHOGENESIS, HOWEVER, IS NOT WELL KNOWN AND ASIDE FROM SMOKING CESSATION, THERE ARE NO DISEASE-MODIFYING TREATMENTS FOR THIS DISEASE. AREAS COVERED: COPD IS ASSOCIATED WITH ACCELERATING AGING AND AGING-RELATED DISEASES. IN THIS REVIEW, WE WILL DISCUSS THE HALLMARKS OF AGING INCLUDING GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATION, LOSS OF PROTEOSTASIS, MITOCHONDRIAL DYSFUNCTION, DEREGULATED NUTRIENT SENSING, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION, WHICH MAY BE INVOLVED IN COPD PATHOGENESIS. EXPERT COMMENTARY: COPD AND THE AGING PROCESS SHARE SIMILAR MOLECULAR AND CELLULAR CHANGES. AGING-RELATED MOLECULAR PATHWAYS MAY REPRESENT NOVEL THERAPEUTIC TARGETS AND BIOMARKERS FOR COPD. 2019 17 6189 37 THE IMPACT OF LIFE STRESS ON HALLMARKS OF AGING AND ACCELERATED SENESCENCE: CONNECTIONS IN SICKNESS AND IN HEALTH. CHRONIC STRESS IS A RISK FACTOR FOR NUMEROUS AGING-RELATED DISEASES AND HAS BEEN SHOWN TO SHORTEN LIFESPAN IN HUMANS AND OTHER SOCIAL MAMMALS. YET HOW LIFE STRESS CAUSES SUCH A VAST RANGE OF DISEASES IS STILL LARGELY UNCLEAR. IN RECENT YEARS, THE IMPACT OF STRESS ON HEALTH AND AGING HAS BEEN INCREASINGLY ASSOCIATED WITH THE DYSREGULATION OF THE SO-CALLED HALLMARKS OF AGING. THESE ARE BASIC BIOLOGICAL MECHANISMS THAT INFLUENCE INTRINSIC CELLULAR FUNCTIONS AND WHOSE ALTERATION CAN LEAD TO ACCELERATED AGING. HERE, WE REVIEW CORRELATIONAL AND EXPERIMENTAL LITERATURE (PRIMARILY FOCUSING ON EVIDENCE FROM HUMANS AND MURINE MODELS) ON THE CONTRIBUTION OF LIFE STRESS - PARTICULARLY STRESS DERIVED FROM ADVERSE SOCIAL ENVIRONMENTS - TO TRIGGER HALLMARKS OF AGING, INCLUDING CELLULAR SENESCENCE, STERILE INFLAMMATION, TELOMERE SHORTENING, PRODUCTION OF REACTIVE OXYGEN SPECIES, DNA DAMAGE, AND EPIGENETIC CHANGES. WE ALSO EVALUATE THE VALIDITY OF STRESS-INDUCED SENESCENCE AND ACCELERATED AGING AS AN ETIOPATHOLOGICAL PROPOSITION. FINALLY, WE HIGHLIGHT CURRENT GAPS OF KNOWLEDGE AND FUTURE DIRECTIONS FOR THE FIELD, AND DISCUSS PERSPECTIVES FOR TRANSLATIONAL GEROSCIENCE. 2023 18 1175 32 CONTRIBUTIONS OF AGE-RELATED THYMIC INVOLUTION TO IMMUNOSENESCENCE AND INFLAMMAGING. IMMUNE SYSTEM AGING IS CHARACTERIZED BY THE PARADOX OF IMMUNOSENESCENCE (INSUFFICIENCY) AND INFLAMMAGING (OVER-REACTION), WHICH INCORPORATE TWO SIDES OF THE SAME COIN, RESULTING IN IMMUNE DISORDER. IMMUNOSENESCENCE REFERS TO DISRUPTION IN THE STRUCTURAL ARCHITECTURE OF IMMUNE ORGANS AND DYSFUNCTION IN IMMUNE RESPONSES, RESULTING FROM BOTH AGED INNATE AND ADAPTIVE IMMUNITY. INFLAMMAGING, DESCRIBED AS A CHRONIC, STERILE, SYSTEMIC INFLAMMATORY CONDITION ASSOCIATED WITH ADVANCED AGE, IS MAINLY ATTRIBUTED TO SOMATIC CELLULAR SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) AND AGE-RELATED AUTOIMMUNE PREDISPOSITION. HOWEVER, THE INABILITY TO REDUCE SENESCENT SOMATIC CELLS (SSCS), BECAUSE OF IMMUNOSENESCENCE, EXACERBATES INFLAMMAGING. AGE-RELATED ADAPTIVE IMMUNE SYSTEM DEVIATIONS, PARTICULARLY ALTERED T CELL FUNCTION, ARE DERIVED FROM AGE-RELATED THYMIC ATROPHY OR INVOLUTION, A HALLMARK OF THYMIC AGING. RECENTLY, THERE HAVE BEEN MAJOR DEVELOPMENTS IN UNDERSTANDING HOW AGE-RELATED THYMIC INVOLUTION CONTRIBUTES TO INFLAMMAGING AND IMMUNOSENESCENCE AT THE CELLULAR AND MOLECULAR LEVELS, INCLUDING GENETIC AND EPIGENETIC REGULATION, AS WELL AS DEVELOPMENTS OF MANY POTENTIAL REJUVENATION STRATEGIES. HEREIN, WE DISCUSS THE RESEARCH PROGRESS UNCOVERING HOW AGE-RELATED THYMIC INVOLUTION CONTRIBUTES TO IMMUNOSENESCENCE AND INFLAMMAGING, AS WELL AS THEIR INTERSECTION. WE ALSO DESCRIBE HOW T CELL ADAPTIVE IMMUNITY MEDIATES INFLAMMAGING AND PLAYS A CRUCIAL ROLE IN THE PROGRESSION OF AGE-RELATED NEUROLOGICAL AND CARDIOVASCULAR DISEASES, AS WELL AS CANCER. WE THEN BRIEFLY OUTLINE THE UNDERLYING CELLULAR AND MOLECULAR MECHANISMS OF AGE-RELATED THYMIC INVOLUTION, AND FINALLY SUMMARIZE POTENTIAL REJUVENATION STRATEGIES TO RESTORE AGED THYMIC FUNCTION. 2020 19 6412 42 THE SPECTRUM OF FUNDAMENTAL BASIC SCIENCE DISCOVERIES CONTRIBUTING TO ORGANISMAL AGING. AGING RESEARCH HAS UNDERGONE UNPRECEDENTED ADVANCES AT AN ACCELERATING RATE IN RECENT YEARS, LEADING TO EXCITEMENT IN THE FIELD AS WELL AS OPPORTUNITIES FOR IMAGINATION AND INNOVATION. NOVEL INSIGHTS INDICATE THAT, RATHER THAN RESULTING FROM A PREPROGRAMMED SERIES OF EVENTS, THE AGING PROCESS IS PREDOMINANTLY DRIVEN BY FUNDAMENTAL NON-ADAPTIVE MECHANISMS THAT ARE INTERCONNECTED, LINKED, AND OVERLAP. TO VARYING DEGREES, THESE MECHANISMS ALSO MANIFEST WITH AGING IN BONE WHERE THEY CAUSE SKELETAL FRAGILITY. BECAUSE THESE MECHANISMS OF AGING CAN BE MANIPULATED, IT MIGHT BE POSSIBLE TO SLOW, DELAY, OR ALLEVIATE MULTIPLE AGE-RELATED DISEASES AND THEIR COMPLICATIONS BY TARGETING CONSERVED GENETIC SIGNALING PATHWAYS, CONTROLLED FUNCTIONAL NETWORKS, AND BASIC BIOCHEMICAL PROCESSES. INDEED, FINDINGS IN VARIOUS MAMMALIAN SPECIES SUGGEST THAT TARGETING FUNDAMENTAL AGING MECHANISMS (EG, VIA EITHER LOSS-OF-FUNCTION OR GAIN-OF-FUNCTION MUTATIONS OR ADMINISTRATION OF PHARMACOLOGICAL THERAPIES) CAN EXTEND HEALTHSPAN; IE, THE HEALTHY PERIOD OF LIFE FREE OF CHRONIC DISEASES. IN THIS REVIEW, WE SUMMARIZE THE EVIDENCE SUPPORTING THE ROLE OF THE SPECTRUM OF FUNDAMENTAL BASIC SCIENCE DISCOVERIES CONTRIBUTING TO ORGANISMAL AGING, WITH EMPHASIS ON MAMMALIAN STUDIES AND IN PARTICULAR AGING MECHANISMS IN BONE THAT DRIVE SKELETAL FRAGILITY. THESE MECHANISMS OR AGING HALLMARKS INCLUDE: GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DEREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION. BECAUSE THESE MECHANISMS ARE LINKED, INTERVENTIONS THAT AMELIORATE ONE HALLMARK CAN IN THEORY AMELIORATE OTHERS. IN THE FIELD OF BONE AND MINERAL RESEARCH, CURRENT CHALLENGES INCLUDE DEFINING THE RELATIVE CONTRIBUTIONS OF EACH AGING HALLMARK TO THE NATURAL SKELETAL AGING PROCESS, BETTER UNDERSTANDING THE COMPLEX INTERCONNECTIONS AMONG THE HALLMARKS, AND IDENTIFYING THE MOST EFFECTIVE THERAPEUTIC STRATEGIES TO SAFELY TARGET MULTIPLE HALLMARKS. BASED ON THEIR INTERCONNECTIONS, IT MAY BE FEASIBLE TO SIMULTANEOUSLY INTERFERE WITH SEVERAL FUNDAMENTAL AGING MECHANISMS TO ALLEVIATE A WIDE SPECTRUM OF AGE-RELATED CHRONIC DISEASES, INCLUDING OSTEOPOROSIS. (C) 2018 AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH. 2018 20 4413 26 MOLECULAR AND CELLULAR INSIGHTS INTO THE DEVELOPMENT OF UTERINE FIBROIDS. UTERINE LEIOMYOMAS REPRESENT THE MOST COMMON BENIGN GYNECOLOGIC TUMOR. THESE HORMONE-DEPENDENT SMOOTH-MUSCLE FORMATIONS OCCUR WITH AN ESTIMATED PREVALENCE OF ~70% AMONG WOMEN OF REPRODUCTIVE AGE AND CAUSE SYMPTOMS INCLUDING PAIN, ABNORMAL UTERINE BLEEDING, INFERTILITY, AND RECURRENT ABORTION. DESPITE THE PREVALENCE AND PUBLIC HEALTH IMPACT OF UTERINE LEIOMYOMAS, AVAILABLE TREATMENTS REMAIN LIMITED. AMONG THE POTENTIAL CAUSES OF LEIOMYOMAS, EARLY HORMONAL EXPOSURE DURING PERIODS OF DEVELOPMENT MAY RESULT IN DEVELOPMENTAL REPROGRAMMING VIA EPIGENETIC CHANGES THAT PERSIST IN ADULTHOOD, LEADING TO DISEASE ONSET OR PROGRESSION. RECENT DEVELOPMENTS IN UNBIASED HIGH-THROUGHPUT SEQUENCING TECHNOLOGY ENABLE POWERFUL APPROACHES TO DETECT DRIVER MUTATIONS, YIELDING NEW INSIGHTS INTO THE GENOMIC INSTABILITY OF LEIOMYOMAS. CURRENT DATA ALSO SUGGEST THAT EACH LEIOMYOMA ORIGINATES FROM THE CLONAL EXPANSION OF A SINGLE TRANSFORMED SOMATIC STEM CELL OF THE MYOMETRIUM. IN THIS REVIEW, WE PROPOSE AN INTEGRATED CELLULAR AND MOLECULAR VIEW OF THE ORIGINS OF LEIOMYOMAS, AS WELL AS PARADIGM-SHIFTING STUDIES THAT WILL LEAD TO BETTER UNDERSTANDING AND THE FUTURE DEVELOPMENT OF NON-SURGICAL TREATMENTS FOR THESE HIGHLY FREQUENT TUMORS. 2021