1 5919 136 TARGETING CELLULAR SENESCENCE FOR AGE-RELATED DISEASES: PATH TO CLINICAL TRANSLATION. BEYOND THE PALLIATIVE REACH OF TODAY'S MEDICINES, MEDICAL THERAPIES OF TOMORROW AIM TO TREAT THE ROOT CAUSE OF AGE-RELATED DISEASES BY TARGETING FUNDAMENTAL AGING MECHANISMS. PILLARS OF AGING INCLUDE, AMONG OTHERS, GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DYSREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION. THE UNITARY THEORY OF FUNDAMENTAL AGING PROCESSES POSITS THAT BY TARGETING ONE FUNDAMENTAL AGING PROCESS, IT MAY BE FEASIBLE TO IMPACT SEVERAL OR ALL OTHERS GIVEN ITS INTERDEPENDENCE. INDEED, PATHOLOGIC ACCUMULATION OF SENESCENT CELLS IS IMPLICATED IN CHRONIC DISEASES AND AGE-ASSOCIATED MORBIDITIES, SUGGESTING THAT SENESCENT CELLS ARE A GOOD TARGET FOR WHOLE-BODY AGING INTERVENTION. PRECLINICAL STUDIES USING SENOLYTICS, AGENTS THAT SELECTIVELY ELIMINATE SENESCENT CELLS, AND SENOMORPHICS, AGENTS THAT INHIBIT PRODUCTION OR RELEASE OF SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE FACTORS, SHOW PROMISE IN SEVERAL AGING AND DISEASE PRECLINICAL MODELS. EARLY CLINICAL TRIALS USING A SENOLYTIC COMBINATION (DASATINIB AND QUERCETIN), AND OTHER SENOLYTICS INCLUDING FLAVONOID, FISETIN, AND BCL-XL INHIBITORS, ILLUSTRATE THE POTENTIAL OF SENOLYTICS TO ALLEVIATE AGE-RELATED DYSFUNCTION AND DISEASES INCLUDING WOUND HEALING. TRANSLATION INTO CLINICAL APPLICATIONS REQUIRES PARALLEL CLINICAL TRIALS ACROSS INSTITUTIONS TO VALIDATE SENOTHERAPEUTICS AS A VANGUARD FOR DELAYING, PREVENTING, OR TREATING AGE-RELATED DISORDERS AND AESTHETIC AGING. 2022 2 5588 50 ROLE OF SENESCENCE IN THE CHRONIC HEALTH CONSEQUENCES OF COVID-19. WHILE THE FULL IMPACT OF COVID-19 IS NOT YET CLEAR, EARLY STUDIES HAVE INDICATED THAT UPWARDS OF 10% OF PATIENTS EXPERIENCE COVID-19 SYMPTOMS LONGER THAN 3 WEEKS, KNOWN AS LONG-HAULER'S SYNDROME OR PACS (POSTACUTE SEQUELAE OF SARS-COV-2 INFECTION). THERE IS LITTLE KNOWN ABOUT RISK FACTORS OR PREDICTORS OF SUSCEPTIBILITY FOR LONG-HAULER'S SYNDROME, BUT OLDER ADULTS ARE AT GREATER RISK FOR SEVERE OUTCOMES AND MORTALITY FROM COVID-19. THE PILLARS OF AGING (INCLUDING CELLULAR SENESCENCE, TELOMERE DYSFUNCTION, IMPAIRED PROTEOSTASIS, MITOCHONDRIAL DYSFUNCTION, DEREGULATED NUTRIENT SENSING, GENOMIC INSTABILITY, PROGENITOR CELL EXHAUSTION, ALTERED INTERCELLULAR COMMUNICATION, AND EPIGENETIC ALTERATIONS) THAT CONTRIBUTE TO AGE-RELATED DYSFUNCTION AND CHRONIC DISEASES (THE "GEROSCIENCE HYPOTHESIS") MAY INTERFERE WITH DEFENSES AGAINST VIRAL INFECTION AND CONSEQUENCES OF THESE INFECTIONS. HEIGHTENING OF THE LOW-GRADE INFLAMMATION THAT IS ASSOCIATED WITH AGING MAY GENERATE AN EXAGGERATED RESPONSE TO AN ACUTE COVID-19 INFECTION. INNATE IMMUNE SYSTEM DYSFUNCTION THAT LEADS TO DECREASED SENESCENT CELL REMOVAL AND/OR INCREASED SENESCENT CELL FORMATION COULD CONTRIBUTE TO ACCUMULATION OF SENESCENT CELLS WITH BOTH AGING AND VIRAL INFECTIONS. THESE PROCESSES MAY CONTRIBUTE TO INCREASED RISK FOR LONG-TERM COVID-19 SEQUELAE IN OLDER OR CHRONICALLY ILL PATIENTS. HENCE, SENOLYTICS AND OTHER GEROSCIENCE INTERVENTIONS THAT MAY PROLONG HEALTHSPAN AND ALLEVIATE CHRONIC DISEASES AND MULTIMORBIDITY LINKED TO FUNDAMENTAL AGING PROCESSES MIGHT BE AN OPTION FOR DELAYING, PREVENTING, OR ALLEVIATING LONG-HAULER'S SYNDROME. 2022 3 6738 26 WHAT'S YOUR CUP OF TEA? THE ROLE OF HERBAL COMPOUNDS IN THE MANAGEMENT OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS A CHRONIC, INFLAMMATORY, NEURODEGENERATIVE DISEASE THAT IS CHARACTERIZED BY A COMPLEX ETIOLOGY. EFFORTS TOWARDS THE MANAGEMENT OF MS HAVE LONG BEEN DIRECTED TOWARDS SYMPTOMATIC RELIEF, AS WELL AS THE USE OF IMMUNE-MODULATORY, DISEASE MODIFYING THERAPIES; HOWEVER, INCONSISTENT TREATMENT RESPONSES STILL PREVAIL, INCREASING THE RISK FOR DISEASE PROGRESSION. WHILE A GREAT DEAL OF RESEARCH ATTEMPTED TO UNRAVEL THE COMPLEXITY OF TREATMENT RESPONSES IN LIGHT OF EPIGENETIC VARIABILITY, PARALLEL EFFORTS IN THE DIRECTION OF ALTERNATIVE MEDICINE MAY BE AS PARAMOUNT. HERBAL COMPOUNDS HAVE LONG BEEN REGARDED AS SAFE AND VERSATILE OPTIONS FOR AIDING IN VARIOUS DISORDERS, INCLUDING NEURODEGENERATIVE CONDITIONS LIKE MS. NUMEROUS STUDIES HAVE TAKEN INTEREST IN A MYRIAD OF HERBAL PLANTS FOR THEIR POTENTIAL BENEFIT IN ALLEVIATING SOME OF THE MOST COMMON MS SYMPTOMS SUCH AS SPASTICITY AND FATIGUE, DELAYING THE PROGRESSION OF THE DISEASE, AS WELL AS INFLUENCING THE OVERALL QUALITY OF LIFE FOR MS PATIENTS. THIS REVIEW AIMS TO PROVIDE A COMPREHENSIVE OVERVIEW OF RECENT CLINICAL STUDIES EXAMINING THE EFFECTS OF VARIOUS HERBAL PLANTS ON DIFFERENT ASPECTS OF MS, IN AN ATTEMPT TO SHED LIGHT ON AN IMPORTANT TOOL FOR AIDING IN THE MANAGEMENT OF THIS COMPLEX AND MULTIFACTORIAL DISEASE. 2023 4 5634 48 SENOLYTICS AND SENOMORPHICS: NATURAL AND SYNTHETIC THERAPEUTICS IN THE TREATMENT OF AGING AND CHRONIC DISEASES. CELLULAR SENESCENCE IS A HETEROGENEOUS PROCESS GUIDED BY GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS, CHARACTERIZING MANY TYPES OF SOMATIC CELLS. IT HAS BEEN SUGGESTED AS AN AGING HALLMARK THAT IS BELIEVED TO CONTRIBUTE TO AGING AND CHRONIC DISEASES. SENESCENT CELLS (SC) EXHIBIT A SPECIFIC SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP), MAINLY CHARACTERIZED BY THE PRODUCTION OF PROINFLAMMATORY AND MATRIX-DEGRADING MOLECULES. WHEN SC ACCUMULATE, A CHRONIC, SYSTEMIC, LOW-GRADE INFLAMMATION, KNOWN AS INFLAMMAGING, IS INDUCED. IN TURN, THIS CHRONIC IMMUNE SYSTEM ACTIVATION RESULTS IN REDUCED SC CLEARANCE THUS ESTABLISHING A VICIOUS CIRCLE THAT FUELS INFLAMMAGING. SC ACCUMULATION REPRESENTS A CAUSAL FACTOR FOR VARIOUS AGE-RELATED PATHOLOGIES. TARGETING OF SEVERAL AGING HALLMARKS HAS BEEN SUGGESTED AS A STRATEGY TO AMELIORATE HEALTHSPAN AND POSSIBLY LIFESPAN. CONSEQUENTLY, SC AND SASP ARE VIEWED AS POTENTIAL THERAPEUTIC TARGETS EITHER THROUGH THE SELECTIVE KILLING OF SC OR THE SELECTIVE SASP BLOCKAGE, THROUGH NATURAL OR SYNTHETIC COMPOUNDS. THESE COMPOUNDS ARE MEMBERS OF A FAMILY OF AGENTS CALLED SENOTHERAPEUTICS DIVIDED INTO SENOLYTICS AND SENOMORPHICS. FEW OF THEM ARE ALREADY IN CLINICAL TRIALS, POSSIBLY REPRESENTING A FUTURE TREATMENT OF AGE-RELATED PATHOLOGIES INCLUDING DISEASES SUCH AS ATHEROSCLEROSIS, OSTEOARTHRITIS, OSTEOPOROSIS, CANCER, DIABETES, NEURODEGENERATIVE DISEASES SUCH AS ALZHEIMER'S DISEASE, CARDIOVASCULAR DISEASES, HEPATIC STEATOSIS, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, IDIOPATHIC PULMONARY FIBROSIS AND AGE-RELATED MACULAR DEGENERATION. IN THIS REVIEW, WE PRESENT THE ALREADY IDENTIFIED SENOLYTICS AND SENOMORPHICS FOCUSING ON THEIR REDOX-SENSITIVE PROPERTIES. WE DESCRIBE THE STUDIES THAT REVEALED THEIR EFFECTS ON CELLULAR SENESCENCE AND ENABLED THEIR NOMINATION AS NOVEL ANTI-AGING AGENTS. WE REFER TO THE SENOLYTICS THAT ARE ALREADY IN CLINICAL TRIALS AND WE PRESENT VARIOUS ADVERSE EFFECTS EXHIBITED BY SENOTHERAPEUTICS SO FAR. FINALLY, WE DISCUSS ASPECTS OF THE SENOTHERAPEUTICS THAT NEED IMPROVEMENT AND WE SUGGEST THE DESIGN OF FUTURE SENOTHERAPEUTICS TO TARGET SPECIFIC REDOX-REGULATED SIGNALING PATHWAYS IMPLICATED EITHER IN THE REGULATION OF SASP OR IN THE ELIMINATION OF SC. 2021 5 6342 36 THE ROLE OF EPIGENETIC REGULATOR SIRT1 IN BALANCING THE HOMEOSTASIS AND PREVENTING THE FORMATION OF SPECIFIC "SOIL" OF METABOLIC DISORDERS AND RELATED CANCERS. SIRT1 WAS DISCOVERED IN 1979 BUT GROWING INTEREST IN THIS PROTEIN OCCURRED ONLY 20 YEARS LATER WHEN ITS OVEREXPRESSION WAS REPORTED TO PROLONG THE LIFESPAN OF YEAST. SINCE THEN, SEVERAL STUDIES HAVE SHOWN THE BENEFITS OF ITS INCREASED EXPRESSION IN PREVENTING OR DELAYING OF MANY DISEASES. SIRT1, AS A HISTONE DEACETYLASE, IS AN EPIGENETIC REGULATOR BUT IT HAS WIDE RANGE OF NON-HISTONE TARGETS WHICH ARE INVOLVED IN METABOLISM, ENERGY SENSING PATHWAYS, CIRCADIAN MACHINERY AND IN INFLAMMATORY REGULATION. DISTURBANCES IN THESE INTERCONNECTED PROCESSES CAUSE DIFFERENT DISEASES, HOWEVER IT SEEMS THEY HAVE COMMON ROOTS IN UNBALANCED INFLAMMATORY PROCESSES AND LOWER LEVEL OR INACTIVATION OF SIRT1. SIRT1 INACTIVATION WAS IMPLICATED IN CORONAVIRUS DISEASE (COVID-19) SEVERITY AS WELL AND ITS LOW LEVEL COUNTED AS A PREDICTOR OF UNCONTROLLED COVID-19. SEVERAL OTHER DISEASES SUCH AS METABOLIC DISEASE, OBESITY, DIABETES, ALZHEIMER'S DISEASE, CARDIOVASCULAR DISEASE OR DEPRESSION ARE RELATED TO CHRONIC INFLAMMATION AND SIMILARLY SHOW DECREASED SIRT1 LEVEL. IT HAS RECENTLY BEEN KNOWN THAT SIRT1 IS INDUCIBLE BY CALORIE RESTRICTION/PROPER DIET, PHYSICAL ACTIVITY AND APPROPRIATE EMOTIONAL STATE. INDEED, A HEALTHIER METABOLIC STATE BELONGS TO HIGHER LEVEL OF SIRT1 EXPRESSION. THESE SUGGEST THAT APPROPRIATE LIFESTYLE AS NON-PHARMACOLOGICAL TREATMENT MAY BE A BENEFICIAL TOOL IN THE PREVENTION OF INFLAMMATION OR METABOLIC DISTURBANCE-RELATED DISEASES AS WELL AS COULD BE A PART OF THE COMPLEMENTARY THERAPY IN MEDICAL PRACTICE TO REACH BETTER THERAPEUTIC RESPONSE AND QUALITY OF LIFE. WE AIMED IN THIS REVIEW TO LINK THE BENEFICIAL EFFECT OF SIRT1 WITH THOSE DISEASES, WHERE ITS LEVEL DECREASED. MOREOVER, WE AIMED TO COLLECT EVIDENCES OF INTERVENTIONS OR TREATMENTS, WHICH INCREASE SIRT1 EXPRESSION AND THUS, OPEN THE POSSIBILITY TO USE THEM AS PREVENTIVE OR COMPLEMENTARY THERAPIES IN MEDICAL PRACTICE. 2022 6 1398 35 DIET, GUT MICROBIOME AND EPIGENETICS: EMERGING LINKS WITH INFLAMMATORY BOWEL DISEASES AND PROSPECTS FOR MANAGEMENT AND PREVENTION. INFLAMMATORY BOWEL DISEASES (IBD) REPRESENT A GROWING PUBLIC HEALTH CONCERN DUE TO INCREASING INCIDENCE WORLDWIDE. THE CURRENT NOTION ON THE PATHOGENESIS OF IBD IS THAT GENETICALLY SUSCEPTIBLE INDIVIDUALS DEVELOP INTOLERANCE TO DYSREGULATED GUT MICROFLORA (DYSBIOSIS) AND CHRONIC INFLAMMATION DEVELOPS AS A RESULT OF ENVIRONMENTAL TRIGGERS. AMONG THE ENVIRONMENTAL FACTORS ASSOCIATED WITH IBD, DIET PLAYS AN IMPORTANT ROLE IN MODULATING THE GUT MICROBIOME, INFLUENCING EPIGENETIC CHANGES, AND, THEREFORE, COULD BE APPLIED AS A THERAPEUTIC TOOL TO IMPROVE THE DISEASE COURSE. NEVERTHELESS, THE CURRENT DIETARY RECOMMENDATIONS FOR DISEASE PREVENTION AND MANAGEMENT ARE SCARCE AND HAVE WEAK EVIDENCE. THIS REVIEW SUMMARISES THE CURRENT KNOWLEDGE ON THE COMPLEX INTERACTIONS BETWEEN DIET, MICROBIOME AND EPIGENETICS IN IBD. WHEREAS AN OVERABUNDANCE OF CALORIES AND SOME MACRONUTRIENTS INCREASE GUT INFLAMMATION, SEVERAL MICRONUTRIENTS HAVE THE POTENTIAL TO MODULATE IT. IMMUNONUTRITION HAS EMERGED AS A NEW CONCEPT PUTTING FORWARD THE IMPORTANCE OF VITAMINS SUCH AS VITAMINS A, C, E, AND D, FOLIC ACID, BETA CAROTENE AND TRACE ELEMENTS SUCH AS ZINC, SELENIUM, MANGANESE AND IRON. HOWEVER, WHEN ASSESSED IN CLINICAL TRIALS, SPECIFIC MICRONUTRIENTS EXERTED A LIMITED BENEFIT. BEYOND NUTRIENTS, AN ANTI-INFLAMMATORY DIETARY PATTERN AS A COMPLEX INTERVENTION APPROACH HAS BECOME POPULAR IN RECENT YEARS. HENCE, EXCLUSIVE ENTERAL NUTRITION IN PAEDIATRIC CROHN'S DISEASE IS THE ONLY NUTRITIONAL INTERVENTION CURRENTLY RECOMMENDED AS A FIRST-LINE THERAPY. OTHER NUTRITIONAL INTERVENTIONS OR SPECIFIC DIETS INCLUDING THE SPECIFIC CARBOHYDRATE DIET (SCD), THE LOW FERMENTABLE OLIGOSACCHARIDES, DISACCHARIDES, MONOSACCHARIDES, AND POLYOL (FODMAP) DIET AND, MOST RECENTLY, THE MEDITERRANEAN DIET HAVE SHOWN STRONG ANTI-INFLAMMATORY PROPERTIES AND SHOW PROMISE FOR IMPROVING DISEASE SYMPTOMS. MORE WORK IS REQUIRED TO EVALUATE THE ROLE OF INDIVIDUAL FOOD COMPOUNDS AND COMPLEX NUTRITIONAL INTERVENTIONS WITH THE POTENTIAL TO DECREASE INFLAMMATION AS A MEANS OF PREVENTION AND MANAGEMENT OF IBD. 2017 7 1394 29 DIET AND AGING. NUTRITION HAS IMPORTANT LONG-TERM CONSEQUENCES FOR HEALTH THAT ARE NOT ONLY LIMITED TO THE INDIVIDUAL BUT CAN BE PASSED ON TO THE NEXT GENERATION. IT CAN CONTRIBUTE TO THE DEVELOPMENT AND PROGRESSION OF CHRONIC DISEASES THUS EFFECTING LIFE SPAN. CALORIC RESTRICTION (CR) CAN EXTEND THE AVERAGE AND MAXIMUM LIFE SPAN AND DELAY THE ONSET OF AGE-ASSOCIATED CHANGES IN MANY ORGANISMS. CR ELICITS COORDINATED AND ADAPTIVE STRESS RESPONSES AT THE CELLULAR AND WHOLE-ORGANISM LEVEL BY MODULATING EPIGENETIC MECHANISMS (E.G., DNA METHYLATION, POSTTRANSLATIONAL HISTONE MODIFICATIONS), SIGNALING PATHWAYS THAT REGULATE CELL GROWTH AND AGING (E.G., TOR, AMPK, P53, AND FOXO), AND CELL-TO-CELL SIGNALING MOLECULES (E.G., ADIPONECTIN). THE OVERALL EFFECT OF THESE ADAPTIVE STRESS RESPONSES IS AN INCREASED RESISTANCE TO SUBSEQUENT STRESS, THUS DELAYING AGE-RELATED CHANGES AND PROMOTING LONGEVITY. IN HUMAN, CR COULD DELAY MANY DISEASES ASSOCIATED WITH AGING INCLUDING CANCER, DIABETES, ATHEROSCLEROSIS, CARDIOVASCULAR DISEASE, AND NEURODEGENERATIVE DISEASES. AS AN ALTERNATIVE TO CR, SEVERAL CR MIMETICS HAVE BEEN TESTED ON ANIMALS AND HUMANS. AT PRESENT, THE MOST PROMISING ALTERNATIVES TO THE USE OF CR IN HUMANS SEEM TO BE EXERCISE, ALONE OR IN COMBINATION WITH REDUCED CALORIE INTAKE, AND THE USE OF PLANT-DERIVED POLYPHENOL RESVERATROL AS A FOOD SUPPLEMENT. 2012 8 5986 32 TFEB IS A CENTRAL REGULATOR OF THE AGING PROCESS AND AGE-RELATED DISEASES. OLD AGE IS ASSOCIATED WITH A GREATER BURDEN OF DISEASE, INCLUDING NEURODEGENERATIVE DISORDERS SUCH AS ALZHEIMER'S DISEASE AND PARKINSON'S DISEASE, AS WELL AS OTHER CHRONIC DISEASES. COINCIDENTALLY, POPULAR LIFESTYLE INTERVENTIONS, SUCH AS CALORIC RESTRICTION, INTERMITTENT FASTING, AND REGULAR EXERCISE, IN ADDITION TO PHARMACOLOGICAL INTERVENTIONS INTENDED TO PROTECT AGAINST AGE-RELATED DISEASES, INDUCE TRANSCRIPTION FACTOR EB (TFEB) AND AUTOPHAGY. IN THIS REVIEW, WE SUMMARIZE EMERGING DISCOVERIES THAT POINT TO TFEB ACTIVITY AFFECTING THE HALLMARKS OF AGING, INCLUDING INHIBITING DNA DAMAGE AND EPIGENETIC MODIFICATIONS, INDUCING AUTOPHAGY AND CELL CLEARANCE TO PROMOTE PROTEOSTASIS, REGULATING MITOCHONDRIAL QUALITY CONTROL, LINKING NUTRIENT-SENSING TO ENERGY METABOLISM, REGULATING PRO- AND ANTI-INFLAMMATORY PATHWAYS, INHIBITING SENESCENCE AND PROMOTING CELL REGENERATIVE CAPACITY. FURTHERMORE, THE THERAPEUTIC IMPACT OF TFEB ACTIVATION ON NORMAL AGING AND TISSUE-SPECIFIC DISEASE DEVELOPMENT IS ASSESSED IN THE CONTEXTS OF NEURODEGENERATION AND NEUROPLASTICITY, STEM CELL DIFFERENTIATION, IMMUNE RESPONSES, MUSCLE ENERGY ADAPTATION, ADIPOSE TISSUE BROWNING, HEPATIC FUNCTIONS, BONE REMODELING, AND CANCER. SAFE AND EFFECTIVE STRATEGIES OF ACTIVATING TFEB HOLD PROMISE AS A THERAPEUTIC STRATEGY FOR MULTIPLE AGE-ASSOCIATED DISEASES AND FOR EXTENDING LIFESPAN. 2023 9 4663 52 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 1490 27 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 11 2770 34 EXTENDING INJURY- AND DISEASE-RESISTANT CNS PHENOTYPES BY REPETITIVE EPIGENETIC CONDITIONING. SIGNIFICANT REDUCTIONS IN THE EXTENT OF ACUTE INJURY IN THE CNS CAN BE ACHIEVED BY EXPOSURE TO DIFFERENT PRECONDITIONING STIMULI, BUT THE DURATION OF THE INDUCED PROTECTIVE PHENOTYPE IS TYPICALLY SHORT-LASTING, AND THUS IS DEEMED AS LIMITING ITS CLINICAL APPLICABILITY. EXTENDING THE PERIOD OVER WHICH SUCH ADAPTIVE EPIGENETIC CHANGES PERSIST - IN EFFECT, EXPANDING CONDITIONING'S "THERAPEUTIC WINDOW" - WOULD SIGNIFICANTLY BROADEN THE POTENTIAL APPLICATIONS OF SUCH A TREATMENT APPROACH IN PATIENTS. THE FREQUENCY OF THE CONDITIONING STIMULUS MAY HOLD THE KEY. WHILE TRANSIENT (1-3 DAYS) PROTECTION AGAINST CNS ISCHEMIC INJURY IS WELL ESTABLISHED PRECLINICALLY FOLLOWING A SINGLE PRECONDITIONING STIMULUS, REPETITIVELY PRESENTING PRECONDITIONING STIMULI EXTENDS THE DURATION OF ISCHEMIC TOLERANCE BY MANY WEEKS. MOREOVER, REPETITIVE INTERMITTENT POSTCONDITIONING ENHANCES POST-ISCHEMIC RECOVERY METRICS AND IMPROVES LONG-TERM SURVIVAL. INTERMITTENT CONDITIONING IS ALSO EFFICACIOUS FOR PREVENTING OR DELAYING INJURY IN PRECLINICAL MODELS OF CHRONIC NEURODEGENERATIVE DISEASE, AND FOR PROMOTING LONG-LASTING FUNCTIONAL IMPROVEMENTS IN A NUMBER OF OTHER PATHOLOGIES AS WELL. ALTHOUGH THE DETAILED MECHANISMS UNDERLYING THESE PROTRACTED KINDS OF NEUROPLASTICITY REMAIN LARGELY UNSTUDIED, ACCUMULATING EMPIRICAL EVIDENCE SUPPORTS THE CONTENTION THAT ALL OF THESE ADAPTIVE PHENOTYPES ARE EPIGENETICALLY MEDIATED. GOING FORWARD, ADDITIONAL PRECLINICAL DEMONSTRATIONS OF THE ABILITY TO INDUCE SUSTAINED BENEFICIAL PHENOTYPES THAT REDUCE THE BURDEN OF ACUTE AND CHRONIC NEURODEGENERATION, AND EXPERIMENTAL INTERROGATIONS OF THE REGULATORY CONSTRUCTS RESPONSIBLE FOR THESE EPIGENETIC RESPONSES, WILL ACCELERATE THE IDENTIFICATION OF NOT ONLY EFFICACIOUS BUT ALSO PRACTICAL, ADAPTIVE EPIGENETICS-BASED TREATMENTS FOR INDIVIDUALS WITH NEUROLOGICAL DISEASE. 2015 12 4794 22 NUTRITIONAL GENOMIC APPROACHES TO CANCER PREVENTION RESEARCH. A WEALTH OF EVIDENCE POINTS TO THE DIET AS ONE OF THE MOST IMPORTANT MODIFIABLE DETERMINANTS OF THE RISK OF DEVELOPING CANCER, BUT A GREATER UNDERSTANDING OF THE INTERACTION BETWEEN DIET AND GENES MAY HELP DISTINGUISH WHO WILL AND WILL NOT RESPOND TO DIETARY INTERVENTIONS. THE TERM NUTRIGENOMICS OR NUTRITIONAL GENOMICS REFERS TO THE BIDIRECTIONAL INTERACTIONS BETWEEN GENES AND DIET. NUTRITIONAL GENOMICS ENCOMPASSES AN UNDERSTANDING ABOUT HOW THE RESPONSE TO BIOACTIVE FOOD COMPONENTS DEPENDS ON AN INDIVIDUAL'S GENETIC BACKGROUND (NUTRIGENETICS), NUTRIENT INDUCED CHANGES IN DNA METHYLATION, HISTONE POSTTRANSLATIONAL MODIFICATIONS, AND OTHER CHROMATIN ALTERATIONS (NUTRITIONAL EPIGENETICS), AND NUTRIENT INDUCED CHANGES IN GENE EXPRESSION (NUTRITIONAL TRANSCRIPTOMICS). THESE APPROACHES TO THE STUDY OF NUTRITION WILL ASSIST IN UNDERSTANDING HOW GENETIC VARIATION, EPIGENETIC EVENTS, AND REGULATION OF GENE EXPRESSION ALTER REQUIREMENTS FOR, AND RESPONSES TO, NUTRIENTS. RECOGNITION OF THE INTERPLAY BETWEEN GENES AND DIET COULD ULTIMATELY HELP IDENTIFY MODIFIABLE MOLECULAR TARGETS FOR PREVENTING, DELAYING, OR REDUCING THE SYMPTOMS OF CANCER AND OTHER CHRONIC DISEASES. 2007 13 1836 19 EFFECTS OF NUTRIENT AND BIOACTIVE FOOD COMPONENTS ON ALZHEIMER'S DISEASE AND EPIGENETIC. ALZHEIMER'S DISEASE (AD) IS THE MOST COMMON FORM OF DEMENTIA IN THE ELDERLY AND IS A CHRONIC NEURODEGENERATIVE DISEASE THAT IS BECOMING WIDESPREAD. FOR THIS REASON, IN RECENT YEARS FACTORS AFFECTING THE DEVELOPMENT, PROGRESSION AND COGNITIVE FUNCTION OF THE AD HAVE BEEN EMPHASIZED. NUTRIENTS AND OTHER BIOACTIVE NUTRIENTS ARE AMONG THE FACTORS THAT ARE EFFECTIVE IN AD. IN PARTICULAR, VITAMINS A, C AND E, VITAMINS B(1), B(6) AND B(12), FOLATE, MAGNESIUM, CHOLINE, INOSITOL, ANTHOCYANINS, ISOFLAVONES ETC. NUTRIENTS AND BIOACTIVE NUTRIENTS ARE KNOWN TO BE EFFECTIVE IN THE DEVELOPMENT OF AD. NUTRIENTS AND NUTRIENT COMPONENTS MAY ALSO HAVE AN EPIGENETIC EFFECT ON AD. AT THE SAME TIME, NUTRIENTS AND BIOACTIVE FOOD COMPONENTS SLOW DOWN THE PROGRESSION OF THE DISEASE. FOR THIS REASON, THE EFFECT OF NUTRIENTS AND FOOD COMPONENTS ON AD WAS EXAMINED IN THIS REVIEW. 2019 14 5948 18 TARGETING THE MOLECULAR & CELLULAR PILLARS OF HUMAN AGING WITH EXERCISE. BIOLOGICAL AGING IS THE MAIN DRIVER OF AGE-ASSOCIATED CHRONIC DISEASES. IN 2014, THE UNITED STATES NATIONAL INSTITUTE OF AGING (NIA) SPONSORED A MEETING BETWEEN SEVERAL INVESTIGATORS IN THE FIELD OF AGING BIOLOGY, WHO IDENTIFIED SEVEN BIOLOGICAL PILLARS OF AGING AND A CONSENSUS REVIEW, "GEROSCIENCE: LINKING AGING TO CHRONIC DISEASE," WAS PUBLISHED. THE PILLARS OF AGING DEMONSTRATED THE CONSERVATION OF AGING PATHWAYS IN DIVERSE MODEL ORGANISMS AND THUS REPRESENT A USEFUL FRAMEWORK WITH WHICH TO STUDY HUMAN AGING. IN THIS PRESENT REVIEW, WE REVISIT THE SEVEN PILLARS OF AGING FROM THE PERSPECTIVE OF EXERCISE AND DISCUSS HOW REGULAR PHYSICAL EXERCISE CAN MODULATE THESE PILLARS TO STAVE OFF AGE-RELATED CHRONIC DISEASES AND MAINTAIN FUNCTIONAL CAPACITY. 2023 15 3181 36 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 16 4808 27 OBESITY MANAGEMENT: AT THE FOREFRONT AGAINST DISEASE STIGMA AND THERAPEUTIC INERTIA. OBESITY IS A COMPLEX CHRONIC RELAPSING DISEASE, RESULTING FROM THE INTERACTION BETWEEN MULTIPLE ENVIRONMENTAL, GENETIC AND EPIGENETIC CAUSES, AND SUPPORTED BY CHANGES IN THE NEUROENDOCRINE MECHANISMS REGULATING ENERGY BALANCE AND BODY WEIGHT. ADIPOSE TISSUE DYSFUNCTION CONTRIBUTES TO OBESITY-RELATED COMPLICATIONS. HOWEVER, THE PREVALENT NARRATIVE ABOUT THE CAUSES AND MECHANISMS OF OBESITY REMAINS A MUCH MORE SIMPLISTIC ONE, BASED ON THE FALSE ASSUMPTION THAT INDIVIDUALS CAN FULLY CONTROL THEIR BODY WEIGHT THROUGH APPROPRIATE BEHAVIOURAL CHOICES. ACCORDING TO THIS NARRATIVE, OBESITY IS SIMPLY REVERSIBLE "PERSUADING" THE PATIENT TO FOLLOW HEALTHIER AND MORE VIRTUOUS INDIVIDUAL BEHAVIOURS (MORAL JUDGEMENT). THIS PERSISTENT NARRATIVE FORMS THE DEEP ROOT OF THE STIGMATISATION OF PEOPLE WITH OBESITY AT THE INDIVIDUAL LEVEL AND CREATES A CLEAR DISCREPANCY ON HOW OBESITY PREVENTION AND CURE ARE DESIGNED IN COMPARISON WITH THE CASE OF OTHER NON-COMMUNICABLE CHRONIC DISEASES (CLINICAL STIGMA). THE PROMOTION OF SYSTEMIC PREVENTIVE MEASURES AGAINST OBESITY IS NOT SUPPORTED AT A POLITICAL AND SOCIAL LEVEL BY THE PERSISTENCE OF A NARRATIVE OF OBESITY AS THE SIMPLE CONSEQUENCE OF INDIVIDUAL FAILURES AND LACK OF WILLPOWER. THE SIMPLISTIC NARRATIVE OF OBESITY AS A SELF-IMPOSED CONDITION WITH AN EASY WAY-OUT ("EAT LESS AND MOVE MORE") CREATES A CLEAR DISCREPANCY ON HOW OBESITY IS MANAGED BY HEALTH CARE SYSTEMS IN COMPARISON WITH OTHER NCDS. THE OVER-ESTIMATION OF THE EFFICACY OF THERAPEUTIC INTERVENTION SOLELY BASED ON PATIENTS EDUCATION AND LIFESTYLE MODIFICATION IS RESPONSIBLE OF THERAPEUTIC INERTIA IN HEALTH CARE PROFESSIONALS AND IN CLINICAL GUIDELINES, LIMITING OR DELAYING THE ADOPTION OF MORE EFFECTIVE THERAPEUTIC STRATEGIES, LIKE ANTI-OBESITY MEDICATIONS AND BARIATRIC SURGERY. IN CONCLUSION, THE PERSISTENCE OF A NARRATIVE DESCRIBING OBESITY AS A SELF-INDUCED EASILY REVERSIBLE CONDITION HAS PROFOUND CONSEQUENCES ON HOW OBESITY PREVENTION AND MANAGEMENT ARE BUILD, INCLUDING THE DESIGN AND IMPLEMENTATION OF OBESITY MANAGEMENT GUIDELINES AND A TENDENCY TO THERAPEUTIC INERTIA.LEVEL OF EVIDENCE: NO LEVEL OF EVIDENCE. 2022 17 380 23 AN EPIGENETIC PERSPECTIVE ON LIFESTYLE MEDICINE FOR DEPRESSION: IMPLICATIONS FOR PRIMARY CARE PRACTICE. DEPRESSION IS THE MOST COMMON PRESENTING MENTAL HEALTH DISORDER IN PRIMARY CARE. IT IS ALSO A MAJOR CONTRIBUTOR TO SOMATIC COMPLAINTS, WORSENING OF CHRONIC MEDICAL CONDITIONS, POOR QUALITY OF LIFE, AND SUICIDE. CURRENT PHARMACOLOGIC AND PSYCHOTHERAPEUTIC APPROACHES AVERT LESS THAN HALF OF DEPRESSION'S CUMULATIVE BURDEN ON SOCIETY. HOWEVER, THERE IS A GROWING BODY OF RESEARCH DESCRIBING BOTH HOW MALADAPTIVE LIFESTYLE CHOICES CONTRIBUTE TO THE DEVELOPMENT AND WORSENING OF DEPRESSION AND HOW LIFESTYLE-ORIENTED MEDICAL INTERVENTIONS CAN REDUCE THE INCIDENCE AND SEVERITY OF DEPRESSION. THIS RESEARCH, LARGELY DERIVED FROM AN EMERGING FIELD CALLED EPIGENETICS, ELUCIDATES THE INTERACTIONS BETWEEN OUR LIFESTYLE CHOICES AND THOSE EPIGENETIC FACTORS WHICH MEDIATE OUR TENDENCIES TOWARD EITHER HEALTH, OR THE ONSET, IF NOT WORSENING OF DISEASE. THE PRESENT REVIEW HIGHLIGHTS HOW LIFESTYLE CHOICES INVOLVING DIET, PHYSICAL ACTIVITY, SLEEP, SOCIAL RELATIONSHIPS, AND STRESS INFLUENCE EPIGENETIC PROCESSES POSITIVELY OR NEGATIVELY, AND THEREBY PLAY A SIGNIFICANT ROLE IN DETERMINING WHETHER ONE DOES OR DOES NOT SUFFER FROM DEPRESSION. THE AUTHORS PROPOSE THAT MEDICAL TRAINING PROGRAMS CONSIDER AND ADOPT LIFESTYLE MEDICINE ORIENTED INSTRUCTIONAL INITIATIVES THAT WILL ENABLE TOMORROW'S PRIMARY CARE PROVIDERS TO MORE EFFECTIVELY IDENTIFY AND THERAPEUTICALLY INTERVENE IN THE MALADAPTIVE CHOICES CONTRIBUTING TO THEIR PATIENTS' DEPRESSION. 2022 18 285 40 AGING AND AGING-RELATED DISEASES: FROM MOLECULAR MECHANISMS TO INTERVENTIONS AND TREATMENTS. AGING IS A GRADUAL AND IRREVERSIBLE PATHOPHYSIOLOGICAL PROCESS. IT PRESENTS WITH DECLINES IN TISSUE AND CELL FUNCTIONS AND SIGNIFICANT INCREASES IN THE RISKS OF VARIOUS AGING-RELATED DISEASES, INCLUDING NEURODEGENERATIVE DISEASES, CARDIOVASCULAR DISEASES, METABOLIC DISEASES, MUSCULOSKELETAL DISEASES, AND IMMUNE SYSTEM DISEASES. ALTHOUGH THE DEVELOPMENT OF MODERN MEDICINE HAS PROMOTED HUMAN HEALTH AND GREATLY EXTENDED LIFE EXPECTANCY, WITH THE AGING OF SOCIETY, A VARIETY OF CHRONIC DISEASES HAVE GRADUALLY BECOME THE MOST IMPORTANT CAUSES OF DISABILITY AND DEATH IN ELDERLY INDIVIDUALS. CURRENT RESEARCH ON AGING FOCUSES ON ELUCIDATING HOW VARIOUS ENDOGENOUS AND EXOGENOUS STRESSES (SUCH AS GENOMIC INSTABILITY, TELOMERE DYSFUNCTION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, COMPROMISE OF AUTOPHAGY, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, ALTERED INTERCELLULAR COMMUNICATION, DEREGULATED NUTRIENT SENSING) PARTICIPATE IN THE REGULATION OF AGING. FURTHERMORE, THOROUGH RESEARCH ON THE PATHOGENESIS OF AGING TO IDENTIFY INTERVENTIONS THAT PROMOTE HEALTH AND LONGEVITY (SUCH AS CALORIC RESTRICTION, MICROBIOTA TRANSPLANTATION, AND NUTRITIONAL INTERVENTION) AND CLINICAL TREATMENT METHODS FOR AGING-RELATED DISEASES (DEPLETION OF SENESCENT CELLS, STEM CELL THERAPY, ANTIOXIDATIVE AND ANTI-INFLAMMATORY TREATMENTS, AND HORMONE REPLACEMENT THERAPY) COULD DECREASE THE INCIDENCE AND DEVELOPMENT OF AGING-RELATED DISEASES AND IN TURN PROMOTE HEALTHY AGING AND LONGEVITY. 2022 19 4396 19 MODULATION OF CHRONIC INFLAMMATION BY QUERCETIN: THE BENEFICIAL EFFECTS ON OBESITY. OBESITY HAS BECOME A MAJOR RISK FACTOR FOR THE DEVELOPMENT OF CHRONIC DISEASES SUCH AS INSULIN RESISTANCE, TYPE 2 DIABETES MELLITUS, AND CARDIOVASCULAR DISEASE. MOREOVER, OBESITY INDUCES CHRONIC INFLAMMATION IN ADIPOSE TISSUE, LIVER, SKELETAL MUSCLE, AND THE VASCULAR SYSTEM. QUERCETIN IS THE MAJOR REPRESENTATIVE OF THE FLAVONOID SUBCLASS OF FLAVONOLS, WHICH IS UBIQUITOUSLY CONTAINED WITHIN NATURAL PLANTS SUCH AS GREEN TEA, AND VEGETABLES, INCLUDING ONIONS AND APPLES. RESEARCHERS HAVE FOCUSED GREATER ATTENTION TO THE BENEFICIAL PHYSIOLOGICAL ROLES OF QUERCETIN, WHICH HAS ANTI-OXIDATIVE, ANTI-INFLAMMATORY, AND ANTI-FIBROTIC EFFECTS ON INSULIN RESISTANCE AND ATHEROSCLEROSIS IN OBESITY-RELATED DISEASES. ALSO, THE ANTI-INFLAMMATORY EFFECTS OF QUERCETIN ON INTESTINAL MICROBIOTA HAVE BEEN DEMONSTRATED IN OBESITY. IN ADDITION, THERE IS INCREASING EVIDENCE THAT QUERCETIN IS ASSOCIATED WITH EPIGENETIC ACTIVITIES IN CANCER, AND IN MATERNAL UNDERNUTRITION DURING GESTATION AND LACTATION. IN THIS REVIEW, WE FOCUS ON THE CHEMICAL PROPERTIES OF QUERCETIN, ITS DIETARY SOURCES IN OBESITY, AND ITS ANTI-INFLAMMATORY EFFECTS ON INSULIN RESISTANCE, ATHEROSCLEROSIS, INTESTINAL MICROBIOTA, AND MATERNAL UNDER-NUTRITION WITH EPIGENETIC ACTIVITY. 2020 20 5945 49 TARGETING THE "HALLMARKS OF AGING" TO SLOW AGING AND TREAT AGE-RELATED DISEASE: FACT OR FICTION? AGING IS A MAJOR RISK FACTOR FOR A NUMBER OF CHRONIC DISEASES, INCLUDING NEURODEGENERATIVE AND CEREBROVASCULAR DISORDERS. AGING PROCESSES HAVE THEREFORE BEEN DISCUSSED AS POTENTIAL TARGETS FOR THE DEVELOPMENT OF NOVEL AND BROADLY EFFECTIVE PREVENTATIVES OR THERAPEUTICS FOR AGE-RELATED DISEASES, INCLUDING THOSE AFFECTING THE BRAIN. MECHANISMS THOUGHT TO CONTRIBUTE TO AGING HAVE BEEN SUMMARIZED UNDER THE TERM THE "HALLMARKS OF AGING" AND INCLUDE A LOSS OF PROTEOSTASIS, MITOCHONDRIAL DYSFUNCTION, ALTERED NUTRIENT SENSING, TELOMERE ATTRITION, GENOMIC INSTABILITY, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, EPIGENETIC ALTERATIONS AND ALTERED INTERCELLULAR COMMUNICATION. WE HERE EXAMINE KEY CLAIMS ABOUT THE "HALLMARKS OF AGING". OUR ANALYSIS REVEALS IMPORTANT WEAKNESSES THAT PRECLUDE STRONG AND DEFINITIVE CONCLUSIONS CONCERNING A POSSIBLE ROLE OF THESE PROCESSES IN SHAPING ORGANISMAL AGING RATE. SIGNIFICANT AMBIGUITY ARISES FROM THE OVERRELIANCE ON LIFESPAN AS A PROXY MARKER FOR AGING, THE USE OF MODELS WITH UNCLEAR RELEVANCE FOR ORGANISMAL AGING, AND THE USE OF STUDY DESIGNS THAT DO NOT ALLOW TO PROPERLY ESTIMATE INTERVENTION EFFECTS ON AGING RATE. WE ALSO DISCUSS FUTURE RESEARCH DIRECTIONS THAT SHOULD BE TAKEN TO CLARIFY IF AND TO WHAT EXTENT PUTATIVE AGING REGULATORS DO IN FACT INTERACT WITH AGING. THESE INCLUDE MULTIDIMENSIONAL ANALYTICAL FRAMEWORKS AS WELL AS DESIGNS THAT FACILITATE THE PROPER ASSESSMENT OF INTERVENTION EFFECTS ON AGING RATE. 2023