1 3807 149 INTRACELLULAR PROTONS ACCELERATE AGING AND SWITCH ON AGING HALLMARKS IN MICE. DIET-INDUCED METABOLIC ACIDOSIS IS ASSOCIATED WITH THE IMPAIRMENT OF BONE METABOLISM AND AN INCREASED RISK OF A NUMBER OF CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS TYPE 2 DIABETES MELLITUS AND HYPERTENSION. THE SERUM BICARBONATE LEVEL IS AN INDEPENDENT PREDICTOR OF CHRONIC KIDNEY DISEASE PROGRESSION. WE INVESTIGATED WHETHER PROTON ACCELERATES AGING BY ANALYZING BOTH COUPLING FACTOR 6-OVEREXPRESSING TRANSGENIC (TG) AND HIGH SALT-FED MICE WHICH DISPLAY SUSTAINED INTRACELLULAR ACIDOSIS, DUE TO ENHANCED PROTON IMPORT THROUGH ECTO-F(1) F(O) COMPLEX AND/OR REDUCED PROTON EXPORT THROUGH NA(+) -K(+) ATPASE INHIBITION. BOTH TYPES OF MICE DISPLAYED SHORTENED LIFESPAN AND EARLY SENESCENCE-ASSOCIATED PHENOTYPES SUCH AS SIGNS OF HAIR GREYING AND ALOPECIA, WEIGHT LOSS, AND/OR REDUCED ORGAN MASS. IN CHRONIC INTRACELLULAR ACIDOSIS MICE, AUTOPHAGY WAS IMPAIRED BY REGRESSION OF ATG7, AN INCREASE IN NUCLEAR ACETYLATED LC3 II, AND ACETYLATION OF ATG7. THE INCREASE IN HISTONE 3 TRIMETHYLATION AT LYSINE 4 (H3K4ME3) AND H4K20ME3 AND THE DECREASE IN H3K9ME3 AND H3K27ME3 WERE OBSERVED IN THE HEART AND KIDNEY OBTAINED FROM BOTH TG AND HIGH SALT-FED MICE. THE DECREASE IN LAMIN A/C, EMERIN, AND HETEROCHROMATIN PROTEIN 1ALPHA WITHOUT CHANGES IN BARRIER-TO-AUTOINTEGRATION FACTOR AND HIGH-MOBILITY GROUP BOX 1 WAS CONFIRMED IN TG AND HIGH SALT-FED MICE. SUPPRESSION OF NUCLEAR HISTONE DEACETYLASE 3-EMERIN SYSTEM IS ATTRIBUTABLE TO EPIGENETIC REGRESSION OF ATG7 AND H4K5 ACETYLATION. THESE FINDINGS WILL SHED LIGHT ON NOVEL AGING AND IMPAIRED AUTOPHAGY MECHANISM, AND PROVIDE IMPLICATIONS IN A TARGET FOR ANTIAGING THERAPY. 2018 2 4731 103 NOVEL ANTI-AGING GENE NM_026333 CONTRIBUTES TO PROTON-INDUCED AGING VIA NCX1-PATHWAY. DIET-INDUCED METABOLIC ACIDOSIS IS ASSOCIATED WITH THE IMPAIRMENT OF BONE METABOLISM AND AN INCREASED RISK OF A NUMBER OF CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS TYPE 2 DIABETES MELLITUS AND HYPERTENSION. LOW SERUM BICARBONATE IS ASSOCIATED WITH HIGH MORTALITY IN HEALTHY OLDER INDIVIDUALS. RECENTLY, WE DEMONSTRATED THAT BOTH COUPLING FACTOR 6 (CF6)-OVEREXPRESSING TRANSGENIC (TG) AND HIGH SALT-FED MICE WHICH HAD SUSTAINED INTRACELLULAR ACIDOSIS, DUE TO ENHANCED PROTON IMPORT THROUGH ECTO-F(1)F(O) COMPLEX AND/OR REDUCED PROTON EXPORT THROUGH NA(+)-K(+) ATPASE INHIBITION, DISPLAYED SHORTENED LIFESPAN AND EARLY SENESCENCE-ASSOCIATED PHENOTYPES SUCH AS SIGNS OF HAIR GREYING AND ALOPECIA, WEIGHT LOSS, AND/OR REDUCED ORGAN MASS. IN THIS STUDY, WE SEARCHED CAUSATIVE GENES OF PROTON-INDUCED AGING IN CF6-OVEREXPRESSING TG AND HIGH SALT-FED MICE. WE DISCOVERED NM_026333 AS A NOVEL ANTI-AGING GENE WHICH WAS DOWNREGULATED IN THE HEART AND KIDNEY IN BOTH TYPES OF MICE. NM_026333 PROTEIN CONSISTS OF 269 AMINO ACIDS WITH TRANSMEMBRANE REGION (90-193AA). INDUCTION OF NM_026333 OR RECOMBINANT PROTEIN RESCUED TG CELLS AND CF6-TREATED HUMAN CELLS FROM AGING HALLMARKS OF IMPAIRED AUTOPHAGY, GENOMIC INSTABILITY, AND EPIGENETIC ALTERATION. NM_026333 PROTEIN DIRECTLY BOUND PLASMA MEMBRANE NA(+)-CA(2+) EXCHANGER 1 (NCX1) TO SUPPRESS ITS REVERSE MODE, AND CANCELLED PROTON-INDUCED EPIGENETIC REGRESSION OF ATG7 THAT WAS CAUSED BY H3K4 AND H4K20 TRI-METHYLATION VIA SUPPRESSION OF DEMETHYLASE AND H4K5 ACETYLATION VIA SUPPRESSION OF NUCLEAR HDAC3-HDAC4-EMERIN SYSTEM. NM_026333 ALSO ATTENUATED PROTON-INDUCED IMPAIRED FORMATION OF AUTOLYSOSOME, AN INCREASE IN NUCLEAR ACETYLATED LC3 II, AND ACETYLATION OF ATG7. THESE EFFECTS REAPPEARED BY NCX1 INHIBITOR. FURTHERMORE, NCX1 INHIBITOR EXTENDED LIFESPAN COMPARED WITH VEHICLE-TREATMENT IN TG MICE. THIS STUDY WILL SHED LIGHT ON NOVEL AGING MECHANISM AND PROVIDE IMPLICATIONS IN A TARGET FOR ANTI-AGING THERAPY. 2018 3 2772 28 EXTRACELLULAR ATP AND NEURODEGENERATION. ATP IS A POTENT SIGNALING MOLECULE ABUNDANTLY PRESENT IN THE CNS. IT ELICITS A WIDE ARRAY OF PHYSIOLOGICAL EFFECTS AND IS REGARDED AS THE PHYLOGENETICALLY MOST ANCIENT EPIGENETIC FACTOR PLAYING CRUCIAL BIOLOGICAL ROLES IN SEVERAL DIFFERENT TISSUES. THESE CAN RANGE FROM NEUROTRANSMISSION, SMOOTH MUSCLE CONTRACTION, CHEMOSENSORY SIGNALING, SECRETION AND VASODILATATION, TO MORE COMPLEX PHENOMENA SUCH AS IMMUNE RESPONSES, PAIN, MALE REPRODUCTION, FERTILIZATION AND EMBRYONIC DEVELOPMENT. ATP IS RELEASED INTO THE EXTRACELLULAR SPACE EITHER EXOCYTOTICALLY OR FROM DAMAGED AND DYING CELLS. IT IS OFTEN CO-RELEASED WITH OTHER NEUROTRANSMITTERS AND IT CAN INTERACT WITH GROWTH FACTORS AT BOTH RECEPTOR- AND/OR SIGNAL TRANSDUCTION-LEVEL. ONCE IN THE EXTRACELLULAR ENVIRONMENT, ATP BINDS TO SPECIFIC RECEPTORS TERMED P2. BASED ON PHARMACOLOGICAL PROFILES, ON SELECTIVITY OF COUPLING TO SECOND-MESSENGER PATHWAYS AND ON MOLECULAR CLONING, TWO MAIN SUBCLASSES WITH MULTIPLE SUBTYPES HAVE BEEN DISTINGUISHED. THEY ARE P2X, I.E. FAST CATION-SELECTIVE RECEPTOR CHANNELS (NA+, K+, CA2+), POSSESSING LOW AFFINITY FOR ATP AND RESPONSIBLE FOR FAST EXCITATORY NEUROTRANSMISSION, AND P2Y, I.E. SLOW G PROTEIN-COUPLED METABOTROPIC RECEPTORS, POSSESSING HIGHER AFFINITY FOR THE LIGAND. IN THE NERVOUS SYSTEM, THEY ARE BROADLY EXPRESSED IN BOTH NEURONS AND GLIAL CELLS AND CAN MEDIATE DUAL EFFECTS: SHORT-TERM SUCH AS NEUROTRANSMISSION, AND LONG-TERM SUCH AS TROPHIC ACTIONS. SINCE MASSIVE EXTRACELLULAR RELEASE OF ATP OFTEN OCCURS AFTER METABOLIC STRESS, BRAIN ISCHEMIA AND TRAUMA, PURINERGIC MECHANISMS ARE ALSO CORRELATED TO AND INVOLVED IN THE ETIOPATHOLOGY OF MANY NEURODEGENERATIVE CONDITIONS. FURTHERMORE, EXTRACELLULAR ATP PER SE IS TOXIC FOR PRIMARY NEURONAL DISSOCIATED AND ORGANOTYPIC CNS CULTURES FROM CORTEX, STRIATUM AND CEREBELLUM AND P2 RECEPTORS CAN MEDIATE AND AGGRAVATE HYPOXIC SIGNALING IN MANY CNS NEURONS. CONVERSELY, SEVERAL P2 RECEPTOR ANTAGONISTS ABOLISH THE CELL DEATH FATE OF PRIMARY NEURONAL CULTURES EXPOSED TO EXCESSIVE GLUTAMATE, SERUM/POTASSIUM DEPRIVATION, HYPOGLYCEMIA AND CHEMICAL HYPOXIA. IN PARALLEL WITH THESE DETRIMENTAL EFFECTS, ALSO TROPHIC FUNCTIONS HAVE BEEN EXTENSIVELY DESCRIBED FOR EXTRACELLULAR PURINES (BOTH FOR NEURONAL AND NON-NEURONAL CELLS), BUT THESE MIGHT EITHER AGGRAVATE OR AMELIORATE THE NORMAL CELLULAR CONDITIONS. IN SUMMARY, EXTRACELLULAR ATP PLAYS A VERY COMPLEX ROLE NOT ONLY IN THE REPAIR, REMODELING AND SURVIVAL OCCURRING IN THE NERVOUS SYSTEM, BUT EVEN IN CELL DEATH AND THIS CAN OCCUR EITHER AFTER NORMAL DEVELOPMENTAL CONDITIONS, AFTER INJURY, OR ACUTE AND CHRONIC DISEASES. 2003 4 2361 25 EPIGENETIC REGULATION OF SKELETAL TISSUE INTEGRITY AND OSTEOPOROSIS DEVELOPMENT. BONE TURNOVER IS SOPHISTICATEDLY BALANCED BY A DYNAMIC COUPLING OF BONE FORMATION AND RESORPTION AT VARIOUS RATES. THE ORCHESTRATION OF THIS CONTINUOUS REMODELING OF THE SKELETON FURTHER AFFECTS OTHER SKELETAL TISSUES THROUGH ORGAN CROSSTALK. CHRONIC EXCESSIVE BONE RESORPTION COMPROMISES BONE MASS AND ITS POROUS MICROSTRUCTURE AS WELL AS PROPER BIOMECHANICS. THIS ACCELERATES THE DEVELOPMENT OF OSTEOPOROTIC DISORDERS, A LEADING CAUSE OF SKELETAL DEGENERATION-ASSOCIATED DISABILITY AND PREMATURE DEATH. BONE-FORMING CELLS PLAY IMPORTANT ROLES IN MAINTAINING BONE DEPOSIT AND OSTEOCLASTIC RESORPTION. A POOR ORGANELLE MACHINERY, SUCH AS MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS, AND DEFECTIVE AUTOPHAGY, ETC., DYSREGULATES GROWTH FACTOR SECRETION, MINERALIZATION MATRIX PRODUCTION, OR OSTEOCLAST-REGULATORY CAPACITY IN OSTEOBLASTIC CELLS. A PLETHORA OF EPIGENETIC PATHWAYS REGULATE BONE FORMATION, SKELETAL INTEGRITY, AND THE DEVELOPMENT OF OSTEOPOROSIS. MICRORNAS INHIBIT PROTEIN TRANSLATION BY BINDING THE 3'-UNTRANSLATED REGION OF MRNAS OR PROMOTE TRANSLATION THROUGH POST-TRANSCRIPTIONAL PATHWAYS. DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATION OF HISTONES ALTER THE CHROMATIN STRUCTURE, HINDERING HISTONE ENRICHMENT IN PROMOTER REGIONS. MICRORNA-PROCESSING ENZYMES AND DNA AS WELL AS HISTONE MODIFICATION ENZYMES CATALYZE THESE MODIFYING REACTIONS. GAIN AND LOSS OF THESE EPIGENETIC MODIFIERS IN BONE-FORMING CELLS AFFECT THEIR EPIGENETIC LANDSCAPES, INFLUENCING BONE HOMEOSTASIS, MICROARCHITECTURAL INTEGRITY, AND OSTEOPOROTIC CHANGES. THIS ARTICLE CONVEYS PRODUCTIVE INSIGHTS INTO BIOLOGICAL ROLES OF DNA METHYLATION, MICRORNA, AND HISTONE MODIFICATION AND HIGHLIGHTS THEIR INTERACTIONS DURING SKELETAL DEVELOPMENT AND BONE LOSS UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. 2020 5 1490 26 DNA DIRECTED PRO-DOPAMINE REGULATION COUPLING SUBLUXATION REPAIR, H-WAVE((R)) AND OTHER NEUROBIOLOGICALLY BASED MODALITIES TO ADDRESS COMPLEXITIES OF CHRONIC PAIN IN A FEMALE DIAGNOSED WITH REWARD DEFICIENCY SYNDROME (RDS): EMERGENCE OF INDUCTION OF "DOPAMINE HOMEOSTASIS" IN THE FACE OF THE OPIOID CRISIS. ADDICTION IS A COMPLEX MULTIFACTORIAL CONDITION. ESTABLISHED GENETIC FACTORS CAN PROVIDE CLEAR GUIDANCE IN ASSESSING THE RISK OF ADDICTION TO SUBSTANCES AND BEHAVIORS. CHRONIC STRESS CAN ACCUMULATE, FORMING DIFFICULT TO RECOGNIZE ADDICTION PATTERNS FROM BOTH GENETIC AND EPIGENETIC (ENVIRONMENTAL) FACTORS. FURTHERMORE, PSYCHOLOGICAL/PHYSICAL/CHEMICAL STRESSORS ARE TYPICALLY CATEGORIZED LINEARLY, DELAYING IDENTIFICATION AND TREATMENT. THE PATIENT IN THIS CASE REPORT IS A CAUCASIAN FEMALE, AGED 36, WHO PRESENTED WITH CHRONIC PAIN AND PARTIAL DISABILITY FOLLOWING A SURGICALLY REPAIRED TRIMALLEOLAR FRACTURE. THE PATIENT HAD A HISTORY OF UNRESOLVED ATTENTION DEFICIT DISORDER AND AN MRI SCAN OF HER BRAIN REVEALED ATROPHY AND FUNCTIONAL ASYMMETRY. IN 2018, THE PATIENT ENTERED THE BAJAJ CHIROPRACTIC CLINIC, WHERE INITIAL TREATMENT FOCUSED ON RE-ESTABLISHING INTEGRITY OF THE SPINE AND LOWER EXTREMITY BIOMECHANICS AND GRADUATED INTO COGNITIVE BEHAVIOR STABILIZATION ASSISTED BY DNA PRO-DOPAMINE REGULATION GUIDED BY GENETIC ADDICTION RISK SEVERITY TESTING. DURING TREATMENT (2018-2021), PROGRESS ACHIEVED INCLUDED: IMPROVED COGNITIVE CLARITY, FOCUS, SLEEP, ANXIETY, AND EMOTIONAL STABILITY IN ADDITION TO PAIN REDUCTION (75%); ELIMINATION OF POWERFUL ANALGESICS; AND REDUCED INTAKE OF PREVIOUSLY UNADDRESSED ALCOHOLISM. TO HELP REDUCE HEDONIC ADDICTIVE BEHAVIORS AND PAIN, COUPLING OF H-WAVE WITH CORRECTIVE CHIROPRACTIC CARE SEEMS PRUDENT. WE EMPHASIZE THE IMPORTANCE OF GENETIC ASSESSMENT ALONG WITH ATTEMPTS AT INDUCING REQUIRED DOPAMINERGIC HOMEOSTASIS VIA PRECISION KB220PAM. IT IS HYPOTHESIZED THAT FROM PREVENTIVE CARE MODELS, A NEW STANDARD IS EMERGING INCLUDING SELF-AWARENESS AND ACCOUNTABILITY FOR REWARD DEFICIENCY AS A FUNCTION OF HYPODOPAMINERGIA. THIS CASE STUDY DOCUMENTS THE PROGRESSION OF A PATIENT DEALING WITH THE COMPLEXITIES OF AN INJURY, PAIN MANAGEMENT, COGNITIVE IMPAIRMENT, ANXIETY, DEPRESSION, AND THE APPLICATION OF UNIVERSAL HEALTH PRINCIPLES TOWARDS CORRECTION VERSUS PALLIATIVE CARE. 2022 6 5735 24 SMALL VESSEL DISEASE-RELATED DEMENTIA: AN INVALID NEUROVASCULAR COUPLING? THE ARTERIOSCLEROSIS-DEPENDENT ALTERATION OF BRAIN PERFUSION IS ONE OF THE MAJOR DETERMINANTS IN SMALL VESSEL DISEASE, SINCE SMALL VESSELS HAVE A PIVOTAL ROLE IN THE BRAIN'S AUTOREGULATION. NEVERTHELESS, AS FAR AS WE KNOW, ENDOTHELIUM DISTRESS CAN POTENTIATE THE FLOW DYSREGULATION AND LEAD TO SUBCORTICAL VASCULAR DEMENTIA THAT IS RELATED TO SMALL VESSEL DISEASE (SVD), ALSO BEING DEFINED AS SUBCORTICAL VASCULAR DEMENTIA (SVAD), AS WELL AS MICROGLIA ACTIVATION, CHRONIC HYPOXIA AND HYPOPERFUSION, VESSEL-TONE DYSREGULATION, ALTERED ASTROCYTES, AND PERICYTES FUNCTIONING BLOOD-BRAIN BARRIER DISRUPTION. THE MOLECULAR BASIS OF THIS PATHOLOGY REMAINS CONTROVERSIAL. THE APPARENT CONSEQUENCE (OR A FIRST EVENT, TOO) IS THE MACROSCOPIC ALTERATION OF THE NEUROVASCULAR COUPLING. HERE, WE EXAMINED THE POSSIBLE MECHANISMS THAT LEAD A HEALTHY AGING PROCESS TOWARDS SUBCORTICAL DEMENTIA. WE REMARKED THAT SVD AND WHITE MATTER ABNORMALITIES RELATED TO AGE COULD BE ACCELERATED AND POTENTIATED BY DIFFERENT VASCULAR RISK FACTORS. VASCULAR FUNCTION CHANGES CAN BE HEAVILY INFLUENCED BY GENETIC AND EPIGENETIC FACTORS, WHICH ARE, TO THE BEST OF OUR KNOWLEDGE, MOSTLY UNKNOWN. METABOLIC DEMANDS, ACTIVE NEUROVASCULAR COUPLING, CORRECT GLYMPHATIC PROCESS, AND ADEQUATE OXIDATIVE AND INFLAMMATORY RESPONSES COULD BE BULWARKS IN DEFENSE OF THE CORRECT AGING PROCESS; THEIR IMPAIRMENTS LEAD TO A POTENTIALLY CATASTROPHIC AND NON-REVERSIBLE CONDITION. 2020 7 5889 27 SYSTEMS APPROACHES TO MODELING CHRONIC MUCOSAL INFLAMMATION. THE RESPIRATORY MUCOSA IS A MAJOR COORDINATOR OF THE INFLAMMATORY RESPONSE IN CHRONIC AIRWAY DISEASES, INCLUDING ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). SIGNALS PRODUCED BY THE CHRONIC INFLAMMATORY PROCESS INDUCE EPITHELIAL MESENCHYMAL TRANSITION (EMT) THAT DRAMATICALLY ALTERS THE EPITHELIAL CELL PHENOTYPE. THE EFFECTS OF EMT ON EPIGENETIC REPROGRAMMING AND THE ACTIVATION OF TRANSCRIPTIONAL NETWORKS ARE KNOWN, ITS EFFECTS ON THE INNATE INFLAMMATORY RESPONSE ARE UNDEREXPLORED. WE USED A MULTIPLEX GENE EXPRESSION PROFILING PLATFORM TO INVESTIGATE THE PERTURBATIONS OF THE INNATE PATHWAYS INDUCED BY TGF BETA IN A PRIMARY AIRWAY EPITHELIAL CELL MODEL OF EMT. EMT HAD DRAMATIC EFFECTS ON THE INDUCTION OF THE INNATE PATHWAY AND THE COUPLING INTERVAL OF THE CANONICAL AND NONCANONICAL NF- KAPPA B PATHWAYS. SIMULATION EXPERIMENTS DEMONSTRATE THAT RAPID, COORDINATED CAP-INDEPENDENT TRANSLATION OF TRAF-1 AND NF- KAPPA B2 IS REQUIRED TO REDUCE THE NONCANONICAL PATHWAY COUPLING INTERVAL. EXPERIMENTS USING AMANTADINE CONFIRMED THE PREDICTION THAT TRAF-1 AND NF- KAPPA B2/P100 PRODUCTION IS MEDIATED BY AN IRES-DEPENDENT MECHANISM. THESE DATA INDICATE THAT THE EPIGENETIC CHANGES PRODUCED BY EMT INDUCE DYNAMIC STATE CHANGES OF THE INNATE SIGNALING PATHWAY. FURTHER APPLICATIONS OF SYSTEMS APPROACHES WILL PROVIDE UNDERSTANDING OF THIS COMPLEX PHENOTYPE THROUGH DETERMINISTIC MODELING AND MULTIDIMENSIONAL (GENOMIC AND PROTEOMIC) PROFILING. 2013 8 1900 30 ENERGY SENSING PATHWAYS: BRIDGING TYPE 2 DIABETES AND COLORECTAL CANCER? THE RECENTLY RAPID INCREASE OF OBESITY AND TYPE 2 DIABETES MELLITUS HAS CAUSED GREAT BURDEN TO OUR SOCIETY. A POSITIVE ASSOCIATION BETWEEN TYPE 2 DIABETES AND RISK OF COLORECTAL CANCER HAS BEEN REPORTED BY INCREASING EPIDEMIOLOGICAL STUDIES. THE MOLECULAR MECHANISM OF THIS CONNECTION REMAINS ELUSIVE. HOWEVER, TYPE 2 DIABETES MAY RESULT IN ABNORMAL CARBOHYDRATE AND LIPID METABOLISM, HIGH LEVELS OF CIRCULATING INSULIN, INSULIN GROWTH FACTOR-1, AND ADIPOCYTOKINES, AS WELL AS CHRONIC INFLAMMATION. ALL THESE FACTORS COULD LEAD TO THE ALTERATION OF ENERGY SENSING PATHWAYS SUCH AS THE AMP ACTIVATED KINASE (PRKA), MECHANISTIC (MAMMALIAN) TARGET OF RAPAMYCIN (MTOR), SIRT1, AND AUTOPHAGY SIGNALING PATHWAYS. THE RESULTED IMPAIRED SIRT1 AND AUTOPHAGY SIGNALING PATHWAY COULD INCREASE THE RISK OF GENE MUTATION AND CANCER GENESIS BY DECREASING GENETIC STABILITY AND DNA MISMATCH REPAIR. THE DYSREGULATED MTOR AND PRKA PATHWAY COULD REMODEL CELL METABOLISM DURING THE GROWTH AND METASTASIS OF CANCER IN ORDER FOR THE CANCER CELL TO SURVIVE THE UNFAVORABLE MICROENVIRONMENT SUCH AS HYPOXIA AND LOW BLOOD SUPPLY. MOREOVER, THESE PATHWAYS MAY BE COUPLING METABOLIC AND EPIGENETIC ALTERATIONS THAT ARE CENTRAL TO ONCOGENIC TRANSFORMATION. FURTHER RESEARCHES INCLUDING MOLECULAR PATHOLOGIC EPIDEMIOLOGIC STUDIES ARE WARRANTED TO BETTER ADDRESS THE PRECISE LINKS BETWEEN THESE TWO IMPORTANT DISEASES. 2017 9 4344 27 MINIREVIEW: TRANSLATIONAL ANIMAL MODELS OF HUMAN MENOPAUSE: CHALLENGES AND EMERGING OPPORTUNITIES. INCREASING IMPORTANCE IS PLACED ON THE TRANSLATIONAL VALIDITY OF ANIMAL MODELS OF HUMAN MENOPAUSE TO DISCERN RISK VS. BENEFIT FOR PREDICTION OF OUTCOMES AFTER THERAPEUTIC INTERVENTIONS AND TO DEVELOP NEW THERAPEUTIC STRATEGIES TO PROMOTE HEALTH. BASIC DISCOVERY RESEARCH CONDUCTED OVER MANY DECADES HAS BUILT AN EXTENSIVE BODY OF KNOWLEDGE REGARDING REPRODUCTIVE SENESCENCE ACROSS MAMMALIAN SPECIES UPON WHICH TO ADVANCE ANIMAL MODELS OF HUMAN MENOPAUSE. MODIFICATIONS TO EXISTING ANIMAL MODELS COULD RAPIDLY ADDRESS TRANSLATIONAL GAPS RELEVANT TO CLINICAL ISSUES IN HUMAN MENOPAUSAL HEALTH, WHICH INCLUDE THE IMPACT OF 1) CHRONIC OVARIAN HORMONE DEPRIVATION AND HORMONE THERAPY, 2) CLINICALLY RELEVANT HORMONE THERAPY REGIMENS (CYCLIC VS. CONTINUOUS COMBINED), 3) CLINICALLY RELEVANT HORMONE THERAPY FORMULATIONS, AND 4) WINDOWS OF OPPORTUNITY AND OPTIMAL DURATION OF INTERVENTIONS. MODIFICATIONS IN EXISTING ANIMAL MODELS TO MORE ACCURATELY REPRESENT HUMAN MENOPAUSE AND CLINICAL INTERVENTIONS COULD RAPIDLY PROVIDE PRECLINICAL TRANSLATIONAL DATA TO PREDICT OUTCOMES REGARDING UNRESOLVED CLINICAL ISSUES RELEVANT TO WOMEN'S MENOPAUSAL HEALTH. DEVELOPMENT OF THE NEXT GENERATION OF ANIMAL MODELS OF HUMAN MENOPAUSE COULD LEVERAGE ADVANCES IN IDENTIFYING GENOTYPIC VARIATIONS IN ESTROGEN AND PROGESTERONE RECEPTORS TO DEVELOP PERSONALIZED MENOPAUSAL CARE AND TO PREDICT OUTCOMES OF INTERVENTIONS FOR PROTECTION AGAINST OR VULNERABILITY TO DISEASE. KEY TO THE SUCCESS OF THESE MODELS IS THE CLOSE COUPLING BETWEEN THE TRANSLATIONAL TARGET AND THE RANGE OF PREDICTIVE VALIDITY. PRECLINICAL TRANSLATIONAL ANIMAL MODELS OF HUMAN MENOPAUSE NEED TO KEEP PACE WITH CHANGES IN CLINICAL PRACTICE. WITH FOCUS ON PREDICTIVE VALIDITY AND STRATEGIC USE OF ADVANCES IN GENETIC AND EPIGENETIC SCIENCE, NEW ANIMAL MODELS OF HUMAN MENOPAUSE HAVE THE OPPORTUNITY TO SET NEW DIRECTIONS FOR MENOPAUSAL CLINICAL CARE FOR WOMEN WORLDWIDE. 2012 10 2500 19 EPIGENETICS AND IMPRINTED GENES: INSIGHTS FROM THE IMPRINTED GNAS LOCUS. THE HALLMARKS OF EPIGENETICS--THE MEMORY OF DEFINING EARLIER DEVELOPMENTAL EVENTS AND THE DISTINCTION OF ACTIVE AND INACTIVE GENES--ARE EXEMPLIFIED BY IMPRINTED GENES. IN THIS ARTICLE, I SHALL CONSIDER THE IMPRINTED GNAS LOCUS IN SOME DETAIL. GNAS ENCODES THE STIMULATORY G-PROTEIN SUBUNIT, GSALPHA, AN ESSENTIAL INTERMEDIATE BETWEEN RECEPTOR COUPLING AND CYCLIC ADENOSINE MONOPHOSPHATE GENERATION. IT PROVIDES AN EXCELLENT ILLUSTRATION OF THE PLEIOTROPIC EFFECTS OF IMPRINTED GENES, PARTICULARLY ON SKELETAL GROWTH AND METABOLISM, AND IS A POWERFUL EXAMPLE OF THE CONFLICTING EFFECTS OF IMPRINTED GENES WITH OPPOSING PATTERNS OF IMPRINTING. I SHALL DESCRIBE THE EFFECTS OF GSALPHA DEFICIENCY IN HUMANS AND THE KNOWLEDGE GAINED FROM GENETIC MANIPULATION IN THE MOUSE. FINALLY, GIVEN THE PERVASIVE EFFECTS OF IMPRINTED GENES, I SHALL DISCUSS THE LIKELIHOOD THAT EPIGENETIC DEREGULATION, FOR EXAMPLE OF IMPRINTED GENES, COULD CONTRIBUTE TO THE DEVELOPMENTAL PROGRAMMING OF CHRONIC ADULT DISEASES. 2009 11 3848 30 IS EPIGENETICS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE? BACKGROUND: EPIGENETIC MECHANISMS PROVIDE ONE POTENTIAL EXPLANATION FOR HOW ENVIRONMENTAL INFLUENCES IN EARLY LIFE CAUSE LONG-TERM CHANGES IN CHRONIC DISEASE SUSCEPTIBILITY. WHEREAS EPIGENETIC DYSREGULATION IS INCREASINGLY IMPLICATED IN VARIOUS RARE DEVELOPMENTAL SYNDROMES AND CANCER, THE ROLE OF EPIGENETICS IN COMPLEX CHRONIC DISEASES, SUCH AS CARDIOVASCULAR DISEASE, TYPE 2 DIABETES AND OBESITY, REMAINS LARGELY UNCHARACTERIZED. EXTENSIVE WORK IN ANIMAL MODELS IS REQUIRED TO DEVELOP SPECIFIC HYPOTHESES THAT CAN BE PRACTICABLY TESTED IN HUMANS. ANIMAL MODELS: WE HAVE DEVELOPED A MOUSE MODEL SHOWING THAT METHYL DONOR SUPPLEMENTATION PREVENTS TRANSGENERATIONAL AMPLIFICATION OF OBESITY, SUGGESTING A ROLE FOR DNA METHYLATION IN THE DEVELOPMENTAL ESTABLISHMENT OF BODY WEIGHT REGULATION. CONCLUSIONS: COUPLING SUCH MODELS WITH RECENTLY DEVELOPED EPIGENOMIC TECHNOLOGIES SHOULD ULTIMATELY ENABLE US TO DETERMINE IF EPIGENETICS IS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE. 2009 12 621 35 BIOENERGETIC EVOLUTION EXPLAINS PREVALENCE OF LOW NEPHRON NUMBER AT BIRTH: RISK FACTOR FOR CKD. THERE IS GREATER THAN TENFOLD VARIATION IN NEPHRON NUMBER OF THE HUMAN KIDNEY AT BIRTH. ALTHOUGH LOW NEPHRON NUMBER IS A RECOGNIZED RISK FACTOR FOR CKD, ITS DETERMINANTS ARE POORLY UNDERSTOOD. EVOLUTIONARY MEDICINE REPRESENTS A NEW DISCIPLINE THAT SEEKS EVOLUTIONARY EXPLANATIONS FOR DISEASE, BROADENING PERSPECTIVES ON RESEARCH AND PUBLIC HEALTH INITIATIVES. EVOLUTION OF THE KIDNEY, AN ORGAN RICH IN MITOCHONDRIA, HAS BEEN DRIVEN BY NATURAL SELECTION FOR REPRODUCTIVE FITNESS CONSTRAINED BY ENERGY AVAILABILITY. OVER THE PAST 2 MILLION YEARS, RAPID GROWTH OF AN ENERGY-DEMANDING BRAIN IN HOMO SAPIENS ENABLED HOMINID ADAPTATION TO ENVIRONMENTAL EXTREMES THROUGH SELECTION FOR MUTATIONS IN MITOCHONDRIAL AND NUCLEAR DNA EPIGENETICALLY REGULATED BY ALLOCATION OF ENERGY TO DEVELOPING ORGANS. MATERNAL UNDERNUTRITION OR HYPOXIA RESULTS IN INTRAUTERINE GROWTH RESTRICTION OR PRETERM BIRTH, RESULTING IN LOW BIRTH WEIGHT AND LOW NEPHRON NUMBER. REGULATED THROUGH PLACENTAL TRANSFER, ENVIRONMENTAL OXYGEN AND NUTRIENTS SIGNAL NEPHRON PROGENITOR CELLS TO REPROGRAM METABOLISM FROM GLYCOLYSIS TO OXIDATIVE PHOSPHORYLATION. THESE PROCESSES ARE MODULATED BY COUNTERBALANCING ANABOLIC AND CATABOLIC METABOLIC PATHWAYS THAT EVOLVED FROM PROKARYOTE HOMOLOGS AND BY HYPOXIA-DRIVEN AND AUTOPHAGY PATHWAYS THAT EVOLVED IN EUKARYOTES. REGULATION OF NEPHRON DIFFERENTIATION BY HISTONE MODIFICATIONS AND DNA METHYLTRANSFERASES PROVIDE EPIGENETIC CONTROL OF NEPHRON NUMBER IN RESPONSE TO ENERGY AVAILABLE TO THE FETUS. DEVELOPMENTAL PLASTICITY OF NEPHROGENESIS REPRESENTS AN EVOLVED LIFE HISTORY STRATEGY THAT PRIORITIZES ENERGY TO EARLY BRAIN GROWTH WITH ADEQUATE KIDNEY FUNCTION THROUGH REPRODUCTIVE YEARS, THE TRADE-OFF BEING INCREASING PREVALENCE OF CKD DELAYED UNTIL LATER ADULTHOOD. THE RESEARCH IMPLICATIONS OF THIS EVOLUTIONARY ANALYSIS ARE TO IDENTIFY REGULATORY PATHWAYS OF ENERGY ALLOCATION DIRECTING NEPHROGENESIS WHILE ACCOUNTING FOR THE DIFFERENT LIFE HISTORY STRATEGIES OF ANIMAL MODELS SUCH AS THE MOUSE. THE CLINICAL IMPLICATIONS ARE TO OPTIMIZE NUTRITION AND MINIMIZE HYPOXIC/TOXIC STRESSORS IN CHILDBEARING WOMEN AND CHILDREN IN EARLY POSTNATAL DEVELOPMENT. 2020 13 5600 23 ROLES OF VOLTAGE-DEPENDENT SODIUM CHANNELS IN NEURONAL DEVELOPMENT, PAIN, AND NEURODEGENERATION. BESIDES INITIATING AND PROPAGATING ACTION POTENTIALS IN ESTABLISHED NEURONAL CIRCUITS, VOLTAGE-DEPENDENT SODIUM CHANNELS SCULPT AND BOLSTER THE FUNCTIONAL NEURONAL NETWORK FROM EARLY IN EMBRYONIC DEVELOPMENT THROUGH ADULTHOOD (E.G., DIFFERENTIATION OF OLIGODENDROCYTE PRECURSOR CELLS INTO OLIGODENDROCYTES, MYELINATING AXON; COMPETITION BETWEEN NEIGHBORING EQUIPOTENTIAL NEURITES FOR DEVELOPMENT INTO A SINGLE AXON; ENHANCING AND OPPOSING FUNCTIONAL INTERACTIONS WITH ATTRACTIVE AND REPULSIVE MOLECULES FOR AXON PATHFINDING; EXTENDING AND RETRACTING TERMINAL ARBORIZATION OF AXON FOR CORRECT SYNAPSE FORMATION; EXPERIENCE-DRIVEN COGNITION; NEURONAL SURVIVAL; AND REMYELINATION OF DEMYELINATED AXONS). SURPRISINGLY, DIFFERENT PATTERNS OF ACTION POTENTIALS DIRECT HOMEOSTASIS-BASED EPIGENETIC SELECTION FOR NEUROTRANSMITTER PHENOTYPE, THUS EXCITABILITY BY SODIUM CHANNELS SPECIFYING EXPRESSION OF INHIBITORY NEUROTRANSMITTERS. MECHANISMS FOR THESE PLEIOTROPIC EFFECTS OF SODIUM CHANNELS INCLUDE RECIPROCAL INTERACTIONS BETWEEN NEURONS AND GLIA VIA NEUROTRANSMITTERS, GROWTH FACTORS, AND CYTOKINES AT SYNAPSES AND AXONS. SODIUM CHANNELOPATHIES CAUSING PAIN (E.G., ALLODYNIA) AND NEURODEGENERATION (E.G., MULTIPLE SCLEROSIS) DERIVE FROM 1) ELECTROPHYSIOLOGICAL DISTURBANCES BY INSULTS (E.G., ISCHEMIA/HYPOXIA, TOXINS, AND ANTIBODIES); 2) LOSS-OF-PHYSIOLOGICAL FUNCTION OR GAIN-OF-PATHOLOGICAL FUNCTION OF MUTANT SODIUM CHANNEL PROTEINS; 3) SPATIOTEMPORAL INAPPROPRIATE EXPRESSION OF NORMAL SODIUM CHANNEL PROTEINS; OR 4) DE-REPRESSED EXPRESSION OF OTHERWISE SILENT SODIUM CHANNEL GENES. NA(V)1.7 PROVED TO ACCOUNT FOR PAIN IN HUMAN ERYTHERMALGIA AND INFLAMMATION, BEING THE CONVINCING MOLECULAR TARGET OF PAIN TREATMENT. 2006 14 4459 27 MOLECULAR MECHANISMS OF DIABETIC VASCULAR COMPLICATIONS. DIABETIC COMPLICATIONS ARE THE MAJOR CAUSES OF MORBIDITY AND MORTALITY IN PATIENTS WITH DIABETES. MICROVASCULAR COMPLICATIONS INCLUDE RETINOPATHY, NEPHROPATHY AND NEUROPATHY, WHICH ARE LEADING CAUSES OF BLINDNESS, END-STAGE RENAL DISEASE AND VARIOUS PAINFUL NEUROPATHIES; WHEREAS MACROVASCULAR COMPLICATIONS INVOLVE ATHEROSCLEROSIS RELATED DISEASES, SUCH AS CORONARY ARTERY DISEASE, PERIPHERAL VASCULAR DISEASE AND STROKE. DIABETIC COMPLICATIONS ARE THE RESULT OF INTERACTIONS AMONG SYSTEMIC METABOLIC CHANGES, SUCH AS HYPERGLYCEMIA, LOCAL TISSUE RESPONSES TO TOXIC METABOLITES FROM GLUCOSE METABOLISM, AND GENETIC AND EPIGENETIC MODULATORS. CHRONIC HYPERGLYCEMIA IS RECOGNIZED AS A MAJOR INITIATOR OF DIABETIC COMPLICATIONS. MULTIPLE MOLECULAR MECHANISMS HAVE BEEN PROPOSED TO MEDIATE HYPERGLYCEMIA'S ADVERSE EFFECTS ON VASCULAR TISSUES. THESE INCLUDE INCREASED POLYOL PATHWAY, ACTIVATION OF THE DIACYLGLYCEROL/PROTEIN KINASE C PATHWAY, INCREASED OXIDATIVE STRESS, OVERPRODUCTION AND ACTION OF ADVANCED GLYCATION END PRODUCTS, AND INCREASED HEXOSAMINE PATHWAY. IN ADDITION, THE ALTERATIONS OF SIGNAL TRANSDUCTION PATHWAYS INDUCED BY HYPERGLYCEMIA OR TOXIC METABOLITES CAN ALSO LEAD TO CELLULAR DYSFUNCTIONS AND DAMAGE VASCULAR TISSUES BY ALTERING GENE EXPRESSION AND PROTEIN FUNCTION. LESS STUDIED THAN THE TOXIC MECHANISMS, HYPERGLYCEMIA MIGHT ALSO INHIBIT THE ENDOGENOUS VASCULAR PROTECTIVE FACTORS SUCH AS INSULIN, VASCULAR ENDOTHELIAL GROWTH FACTOR, PLATELET-DERIVED GROWTH FACTOR AND ACTIVATED PROTEIN C, WHICH PLAY IMPORTANT ROLES IN MAINTAINING VASCULAR HOMEOSTASIS. THUS, EFFECTIVE THERAPIES FOR DIABETIC COMPLICATIONS NEED TO INHIBIT MECHANISMS INDUCED BY HYPERGLYCEMIA'S TOXIC EFFECTS AND ALSO ENHANCE THE ENDOGENOUS PROTECTIVE FACTORS. THE PRESENT REVIEW SUMMARIZES THESE MULTIPLE BIOCHEMICAL PATHWAYS ACTIVATED BY HYPERGLYCEMIA AND THE POTENTIAL THERAPEUTIC INTERVENTIONS THAT MIGHT PREVENT DIABETIC COMPLICATIONS. (J DIABETES INVEST, DOI: 10.1111/J.2040-1124.2010.00018.X, 2010). 2010 15 375 22 AN ENERGETIC VIEW OF STRESS: FOCUS ON MITOCHONDRIA. ENERGY IS REQUIRED TO SUSTAIN LIFE AND ENABLE STRESS ADAPTATION. AT THE CELLULAR LEVEL, ENERGY IS LARGELY DERIVED FROM MITOCHONDRIA - UNIQUE MULTIFUNCTIONAL ORGANELLES WITH THEIR OWN GENOME. FOUR MAIN ELEMENTS CONNECT MITOCHONDRIA TO STRESS: (1) ENERGY IS REQUIRED AT THE MOLECULAR, (EPI)GENETIC, CELLULAR, ORGANELLAR, AND SYSTEMIC LEVELS TO SUSTAIN COMPONENTS OF STRESS RESPONSES; (2) GLUCOCORTICOIDS AND OTHER STEROID HORMONES ARE PRODUCED AND METABOLIZED BY MITOCHONDRIA; (3) RECIPROCALLY, MITOCHONDRIA RESPOND TO NEUROENDOCRINE AND METABOLIC STRESS MEDIATORS; AND (4) EXPERIMENTALLY MANIPULATING MITOCHONDRIAL FUNCTIONS ALTERS PHYSIOLOGICAL AND BEHAVIORAL RESPONSES TO PSYCHOLOGICAL STRESS. THUS, MITOCHONDRIA ARE ENDOCRINE ORGANELLES THAT PROVIDE BOTH THE ENERGY AND SIGNALS THAT ENABLE AND DIRECT STRESS ADAPTATION. NEURAL CIRCUITS REGULATING SOCIAL BEHAVIOR - AS WELL AS PSYCHOPATHOLOGICAL PROCESSES - ARE ALSO INFLUENCED BY MITOCHONDRIAL ENERGETICS. AN INTEGRATIVE VIEW OF STRESS AS AN ENERGY-DRIVEN PROCESS OPENS NEW OPPORTUNITIES TO STUDY MECHANISMS OF ADAPTATION AND REGULATION ACROSS THE LIFESPAN. 2018 16 6374 33 THE ROLE OF MITOCHONDRIA IN MYOCARDIAL DAMAGE CAUSED BY ENERGY METABOLISM DISORDERS: FROM MECHANISMS TO THERAPEUTICS. MYOCARDIAL DAMAGE IS THE MOST SERIOUS PATHOLOGICAL CONSEQUENCE OF CARDIOVASCULAR DISEASES AND AN IMPORTANT REASON FOR THEIR HIGH MORTALITY. IN RECENT YEARS, BECAUSE OF THE HIGH PREVALENCE OF SYSTEMIC ENERGY METABOLISM DISORDERS (E.G., OBESITY, DIABETES MELLITUS, AND METABOLIC SYNDROME), COMPLICATIONS OF MYOCARDIAL DAMAGE CAUSED BY THESE DISORDERS HAVE ATTRACTED WIDESPREAD ATTENTION. ENERGY METABOLISM DISORDERS ARE INDEPENDENT OF TRADITIONAL INJURY-RELATED RISK FACTORS, SUCH AS ISCHEMIA, HYPOXIA, TRAUMA, AND INFECTION. AN IMBALANCE OF MYOCARDIAL METABOLIC FLEXIBILITY AND MYOCARDIAL ENERGY DEPLETION ARE USUALLY THE INITIAL CHANGES OF MYOCARDIAL INJURY CAUSED BY ENERGY METABOLISM DISORDERS, AND ABNORMAL MORPHOLOGY AND FUNCTIONAL DESTRUCTION OF THE MITOCHONDRIA ARE THEIR IMPORTANT FEATURES. SPECIFICALLY, MITOCHONDRIA ARE THE CENTERS OF ENERGY METABOLISM, AND RECENT EVIDENCE HAS SHOWN THAT DECREASED MITOCHONDRIAL FUNCTION, CAUSED BY AN IMBALANCE IN MITOCHONDRIAL QUALITY CONTROL, MAY PLAY A KEY ROLE IN MYOCARDIAL INJURY CAUSED BY ENERGY METABOLISM DISORDERS. UNDER CHRONIC ENERGY STRESS, MITOCHONDRIA UNDERGO PATHOLOGICAL FISSION, WHILE MITOPHAGY, MITOCHONDRIAL FUSION, AND BIOGENESIS ARE INHIBITED, AND MITOCHONDRIAL PROTEIN BALANCE AND TRANSFER ARE DISTURBED, RESULTING IN THE ACCUMULATION OF NONFUNCTIONAL AND DAMAGED MITOCHONDRIA. CONSEQUENTLY, DAMAGED MITOCHONDRIA LEAD TO MYOCARDIAL ENERGY DEPLETION AND THE ACCUMULATION OF LARGE AMOUNTS OF REACTIVE OXYGEN SPECIES, FURTHER AGGRAVATING THE IMBALANCE IN MITOCHONDRIAL QUALITY CONTROL AND FORMING A VICIOUS CYCLE. IN ADDITION, IMPAIRED MITOCHONDRIA COORDINATE CALCIUM HOMEOSTASIS IMBALANCE, AND EPIGENETIC ALTERATIONS PARTICIPATE IN THE PATHOGENESIS OF MYOCARDIAL DAMAGE. THESE PATHOLOGICAL CHANGES INDUCE RAPID PROGRESSION OF MYOCARDIAL DAMAGE, EVENTUALLY LEADING TO HEART FAILURE OR SUDDEN CARDIAC DEATH. TO INTERVENE MORE SPECIFICALLY IN THE MYOCARDIAL DAMAGE CAUSED BY METABOLIC DISORDERS, WE NEED TO UNDERSTAND THE SPECIFIC ROLE OF MITOCHONDRIA IN THIS CONTEXT IN DETAIL. ACCORDINGLY, PROMISING THERAPEUTIC STRATEGIES HAVE BEEN PROPOSED. WE ALSO SUMMARIZE THE EXISTING THERAPEUTIC STRATEGIES TO PROVIDE A REFERENCE FOR CLINICAL TREATMENT AND DEVELOPING NEW THERAPIES. 2023 17 5025 28 PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS. PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS (CVD), ALSO REFERRED TO AS PERSONALIZED OR PRECISION CARDIOLOGY IN ACCORDANCE WITH GENERAL PRINCIPLES OF PERSONALIZED MEDICINE, IS SELECTION OF THE BEST TREATMENT FOR AN INDIVIDUAL PATIENT. IT INVOLVES THE INTEGRATION OF VARIOUS "OMICS" TECHNOLOGIES SUCH AS GENOMICS AND PROTEOMICS AS WELL AS OTHER NEW TECHNOLOGIES SUCH AS NANOBIOTECHNOLOGY. MOLECULAR DIAGNOSTICS AND BIOMARKERS ARE IMPORTANT FOR LINKING DIAGNOSIS WITH THERAPY AND MONITORING THERAPY. BECAUSE CVD INVOLVE PERTURBATIONS OF LARGE COMPLEX BIOLOGICAL NETWORKS, A SYSTEMS BIOLOGY APPROACH TO CVD RISK STRATIFICATION MAY BE USED FOR IMPROVING RISK-ESTIMATING ALGORITHMS, AND MODELING OF PERSONALIZED BENEFIT OF TREATMENT MAY BE HELPFUL FOR GUIDING THE CHOICE OF INTERVENTION. BIOINFORMATICS TOOLS ARE HELPFUL IN ANALYZING AND INTEGRATING LARGE AMOUNTS OF DATA FROM VARIOUS SOURCES. PERSONALIZED THERAPY IS CONSIDERED DURING DRUG DEVELOPMENT, INCLUDING METHODS OF TARGETED DRUG DELIVERY AND CLINICAL TRIALS. INDIVIDUALIZED RECOMMENDATIONS CONSIDER MULTIPLE FACTORS - GENETIC AS WELL AS EPIGENETIC - FOR PATIENTS' RISK OF HEART DISEASE. EXAMPLES OF PERSONALIZED TREATMENT ARE THOSE OF CHRONIC MYOCARDIAL ISCHEMIA, HEART FAILURE, AND HYPERTENSION. SIMILAR APPROACHES CAN BE USED FOR THE MANAGEMENT OF ATRIAL FIBRILLATION AND HYPERCHOLESTEROLEMIA, AS WELL AS THE USE OF ANTICOAGULANTS. PERSONALIZED MANAGEMENT INCLUDES PHARMACOTHERAPY, SURGERY, LIFESTYLE MODIFICATIONS, AND COMBINATIONS THEREOF. FURTHER PROGRESS IN UNDERSTANDING THE PATHOMECHANISM OF COMPLEX CARDIOVASCULAR DISEASES AND IDENTIFICATION OF CAUSATIVE FACTORS AT THE INDIVIDUAL PATIENT LEVEL WILL PROVIDE OPPORTUNITIES FOR THE DEVELOPMENT OF PERSONALIZED CARDIOLOGY. APPLICATION OF PRINCIPLES OF PERSONALIZED MEDICINE WILL IMPROVE THE CARE OF THE PATIENTS WITH CVD. 2017 18 5525 37 RNA BINDING PROTEINS IN SENESCENCE: A POTENTIAL COMMON LINKER FOR AGE-RELATED DISEASES? AGING REPRESENTS THE MAJOR RISK FACTOR FOR THE ONSET AND/OR PROGRESSION OF VARIOUS DISORDERS INCLUDING NEURODEGENERATIVE DISEASES, METABOLIC DISORDERS, AND BONE-RELATED DEFECTS. AS THE AVERAGE AGE OF THE POPULATION IS PREDICTED TO EXPONENTIALLY INCREASE IN THE COMING YEARS, UNDERSTANDING THE MOLECULAR MECHANISMS UNDERLYING THE DEVELOPMENT OF AGING-RELATED DISEASES AND THE DISCOVERY OF NEW THERAPEUTIC APPROACHES REMAIN PIVOTAL. WELL-REPORTED HALLMARKS OF AGING ARE CELLULAR SENESCENCE, GENOME INSTABILITY, AUTOPHAGY IMPAIRMENT, MITOCHONDRIA DYSFUNCTION, DYSBIOSIS, TELOMERE ATTRITION, METABOLIC DYSREGULATION, EPIGENETIC ALTERATIONS, LOW-GRADE CHRONIC INFLAMMATION, STEM CELL EXHAUSTION, ALTERED CELL-TO-CELL COMMUNICATION AND IMPAIRED PROTEOSTASIS. WITH FEW EXCEPTIONS, HOWEVER, MANY OF THE MOLECULAR PLAYERS IMPLICATED WITHIN THESE PROCESSES AS WELL AS THEIR ROLE IN DISEASE DEVELOPMENT REMAIN LARGELY UNKNOWN. RNA BINDING PROTEINS (RBPS) ARE KNOWN TO REGULATE GENE EXPRESSION BY DICTATING AT POST-TRANSCRIPTIONAL LEVEL THE FATE OF NASCENT TRANSCRIPTS. THEIR ACTIVITY RANGES FROM DIRECTING PRIMARY MRNA MATURATION AND TRAFFICKING TO MODULATION OF TRANSCRIPT STABILITY AND/OR TRANSLATION. ACCUMULATING EVIDENCE HAS SHOWN THAT RBPS ARE EMERGING AS KEY REGULATORS OF AGING AND AGING-RELATED DISEASES, WITH THE POTENTIAL TO BECOME NEW DIAGNOSTIC AND THERAPEUTIC TOOLS TO PREVENT OR DELAY AGING PROCESSES. IN THIS REVIEW, WE SUMMARIZE THE ROLE OF RBPS IN PROMOTING CELLULAR SENESCENCE AND WE HIGHLIGHT THEIR DYSREGULATION IN THE PATHOGENESIS AND PROGRESSION OF THE MAIN AGING-RELATED DISEASES, WITH THE AIM OF ENCOURAGING FURTHER INVESTIGATIONS THAT WILL HELP TO BETTER DISCLOSE THIS NOVEL AND CAPTIVATING MOLECULAR SCENARIO. 2023 19 6412 31 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 4974 29 PATHOPHYSIOLOGICAL MECHANISMS LEADING TO MUSCLE LOSS IN CHRONIC KIDNEY DISEASE. LOSS OF MUSCLE PROTEINS IS A DELETERIOUS CONSEQUENCE OF CHRONIC KIDNEY DISEASE (CKD) THAT CAUSES A DECREASE IN MUSCLE STRENGTH AND FUNCTION, AND CAN LEAD TO A REDUCTION IN QUALITY OF LIFE AND INCREASED RISK OF MORBIDITY AND MORTALITY. THE EFFECTIVENESS OF CURRENT TREATMENT STRATEGIES IN PREVENTING OR REVERSING MUSCLE PROTEIN LOSSES IS LIMITED. THE LIMITATIONS LARGELY STEM FROM THE SYSTEMIC NATURE OF DISEASES SUCH AS CKD, WHICH STIMULATE SKELETAL MUSCLE PROTEIN DEGRADATION PATHWAYS WHILE SIMULTANEOUSLY ACTIVATING MECHANISMS THAT IMPAIR MUSCLE PROTEIN SYNTHESIS AND REPAIR. STIMULI THAT INITIATE MUSCLE PROTEIN LOSS INCLUDE METABOLIC ACIDOSIS, INSULIN AND IGF1 RESISTANCE, CHANGES IN HORMONES, CYTOKINES, INFLAMMATORY PROCESSES AND DECREASED APPETITE. A GROWING BODY OF EVIDENCE SUGGESTS THAT SIGNALLING MOLECULES SECRETED FROM MUSCLE CAN ENTER THE CIRCULATION AND SUBSEQUENTLY INTERACT WITH RECIPIENT ORGANS, INCLUDING THE KIDNEYS, WHILE CONVERSELY, PATHOLOGICAL EVENTS IN THE KIDNEY CAN ADVERSELY INFLUENCE PROTEIN METABOLISM IN SKELETAL MUSCLE, DEMONSTRATING THE EXISTENCE OF CROSSTALK BETWEEN KIDNEY AND MUSCLE. TOGETHER, THESE SIGNALS, WHETHER DIRECT OR INDIRECT, INDUCE CHANGES IN THE LEVELS OF REGULATORY AND EFFECTOR PROTEINS VIA ALTERATIONS IN MRNAS, MICRORNAS AND CHROMATIN EPIGENETIC RESPONSES. ADVANCES IN OUR UNDERSTANDING OF THE SIGNALS AND PROCESSES THAT MEDIATE MUSCLE LOSS IN CKD AND OTHER MUSCLE WASTING CONDITIONS WILL SUPPORT THE FUTURE DEVELOPMENT OF THERAPEUTIC STRATEGIES TO REDUCE MUSCLE LOSS. 2022