1 2916 128 GENE VARIANTS AS DETERMINANTS OF LONGEVITY: FOCUS ON THE INFLAMMATORY FACTORS. HUMAN LONGEVITY IS AN EXTREMELY COMPLEX TRAIT WITH VARIOUS GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS ACTING UPON THE LONGEVITY PHENOTYPE. IT IS NOW BECOMING EVIDENT THAT WHILST THE GENETIC DIFFERENCES CONTRIBUTE ONLY MODESTLY TO LIFE EXPECTANCY BEFORE THE AGE OF 60 YEARS, THEIR IMPACT ON SURVIVAL BECOMES MORE PROMINENT AT THE EXTREME AGES. SEVERAL LONGEVITY GENE CANDIDATES HAVE EMERGED DURING THE PAST DECADE; THE MAJORITY OF THEM ARE RELATED EITHER TO INFLAMMATORY FUNCTIONS, STRESS RESPONSE OR TO LIPID AND GLUCOSE METABOLISM. THE VARIANTS OF INFLAMMATORY AND IMMUNE RESPONSE GENES ARE OF SPECIAL INTEREST SINCE ADVANCING AGES IS ACCOMPANIED BY A DECLINE IN SEVERAL IMMUNE FUNCTIONS--A PHENOMENON CALLED IMMUNOSENESCENCE. PARADOXICALLY, AGEING IS ALSO CHARACTERISED BY CHRONIC LOW-GRADE INFLAMMATION TERMED "INFLAMMAGING", WHICH MANIFESTS AS A TWO- TO FOURFOLD INCREASE IN THE PRODUCTION OF PROINFLAMMATORY CYTOKINES AND ACUTE PHASE PROTEINS. THESE CONTRASTING PHENOMENA PROVIDE A FUNCTIONAL RATIONALE OF HOW THE GENETIC DIFFERENCES IN INFLAMMATORY MEDIATORS MAY MODIFY THE LIFE SPAN OF THE ELDERLY. BESIDES DESCRIBING THE PRE-EXISTING INFLAMMATORY AND IMMUNE-RELATED LONGEVITY GENE VARIANTS, IN THIS REVIEW, WE ALSO EXPLAIN SOME OF THE THEORETICAL AND PRACTICAL CHALLENGES THAT GENETIC LONGEVITY STUDIES OFTEN ENCOUNTER. 2010 2 6034 42 THE CHALLENGE BY MULTIPLE ENVIRONMENTAL AND BIOLOGICAL FACTORS INDUCE INFLAMMATION IN AGING: THEIR ROLE IN THE PROMOTION OF CHRONIC DISEASE. THE AGING PROCESS IS DRIVEN BY MULTIPLE MECHANISMS THAT LEAD TO CHANGES IN ENERGY PRODUCTION, OXIDATIVE STRESS, HOMEOSTATIC DYSREGULATION AND EVENTUALLY TO LOSS OF FUNCTIONALITY AND INCREASED DISEASE SUSCEPTIBILITY. MOST AGED INDIVIDUALS DEVELOP CHRONIC LOW-GRADE INFLAMMATION, WHICH IS AN IMPORTANT RISK FACTOR FOR MORBIDITY, PHYSICAL AND COGNITIVE IMPAIRMENT, FRAILTY, AND DEATH. AT ANY AGE, CHRONIC INFLAMMATORY DISEASES ARE MAJOR CAUSES OF MORBIMORTALITY, AFFECTING UP TO 5-8% OF THE POPULATION OF INDUSTRIALIZED COUNTRIES. SEVERAL ENVIRONMENTAL FACTORS CAN PLAY AN IMPORTANT ROLE FOR MODIFYING THE INFLAMMATORY STATE. GENETICS ACCOUNTS FOR ONLY A SMALL FRACTION OF CHRONIC-INFLAMMATORY DISEASES, WHEREAS ENVIRONMENTAL FACTORS APPEAR TO PARTICIPATE, EITHER WITH A CAUSATIVE OR A PROMOTIONAL ROLE IN 50% TO 75% OF PATIENTS. SEVERAL OF THOSE CHANGES DEPEND ON EPIGENETIC CHANGES THAT WILL FURTHER MODIFY THE INDIVIDUAL RESPONSE TO ADDITIONAL STIMULI. THE INTERACTION BETWEEN INFLAMMATION AND THE ENVIRONMENT OFFERS IMPORTANT INSIGHTS ON AGING AND HEALTH. THESE CONDITIONS, OFTEN DEPENDING ON THE INDIVIDUAL'S SEX, APPEAR TO LEAD TO DECREASED LONGEVITY AND PHYSICAL AND COGNITIVE DECLINE. IN ADDITION TO BIOLOGICAL FACTORS, THE ENVIRONMENT IS ALSO INVOLVED IN THE GENERATION OF PSYCHOLOGICAL AND SOCIAL CONTEXT LEADING TO STRESS. POOR PSYCHOLOGICAL ENVIRONMENTS AND OTHER SOURCES OF STRESS ALSO RESULT IN INCREASED INFLAMMATION. HOWEVER, THE MECHANISMS UNDERLYING THE ROLE OF ENVIRONMENTAL AND PSYCHOSOCIAL FACTORS AND NUTRITION ON THE REGULATION OF INFLAMMATION, AND HOW THE RESPONSE ELICITED FOR THOSE FACTORS INTERACT AMONG THEM, ARE POORLY UNDERSTOOD. WHEREAS CERTAIN DELETERIOUS ENVIRONMENTAL FACTORS RESULT IN THE GENERATION OF OXIDATIVE STRESS DRIVEN BY AN INCREASED PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES, ENDOPLASMIC RETICULUM STRESS, AND INFLAMMATION, OTHER FACTORS, INCLUDING NUTRITION (POLYUNSATURATED FATTY ACIDS) AND BEHAVIORAL FACTORS (EXERCISE) CONFER PROTECTION AGAINST INFLAMMATION, OXIDATIVE AND ENDOPLASMIC RETICULUM STRESS, AND THUS AMELIORATE THEIR DELETERIOUS EFFECT. HERE, WE DISCUSS PROCESSES AND MECHANISMS OF INFLAMMATION ASSOCIATED WITH ENVIRONMENTAL FACTORS AND BEHAVIOR, THEIR LINKS TO SEX AND GENDER, AND THEIR OVERALL IMPACT ON AGING. 2020 3 3676 42 INFLAMMATION AND NEUTROPHIL IMMUNOSENESCENCE IN HEALTH AND DISEASE: TARGETED TREATMENTS TO IMPROVE CLINICAL OUTCOMES IN THE ELDERLY. DESPITE INCREASING LONGEVITY, MANY OLD PEOPLE ARE NOT IN GOOD HEALTH. THERE HAS BEEN AN INCREASE IN THE PREVALENCE OF AGE-ASSOCIATED MULTI-MORBIDITY (TWO OR MORE CHRONIC CONDITIONS IN THE SAME PERSON). ALSO, SEVERE INFECTIONS, SUCH AS PNEUMONIA, REMAIN SIGNIFICANT CAUSES OF MORTALITY AND MORBIDITY IN THIS AGING GROUP. MANY CHRONIC HEALTH CONDITIONS SHARE RISK FACTORS SUCH AS INCREASING AGE, SMOKING, A SEDENTARY LIFE STYLE AND BEING PART OF A LOWER SOCIOECONOMIC GROUP. HOWEVER, DESPITE THIS, MULTI-MORBIDITIES OFTEN CO-OCCUR MORE COMMONLY THAN WOULD BE PREDICTED. THIS HAS LED TO THE HYPOTHESIS THAT THEY SHARE COMMON UNDERLYING MECHANISMS. THIS IS AN IMPORTANT CONCEPT, FOR IF IT WERE TRUE, TREATMENTS COULD BE DEVISED WHICH TARGET THESE COMMON PATHWAYS AND IMPROVE A NUMBER OF AGE-ASSOCIATED HEALTH CONDITIONS. MANY CHRONIC ILLNESSES ASSOCIATED WITH MULTI-MORBIDITY AND SEVERE INFECTIONS ARE CHARACTERIZED BY AN ABNORMAL AND SUSTAINED INFLAMMATORY RESPONSE, WITH NEUTROPHILS BEING KEY EFFECTOR CELLS IN THE PATHOLOGICAL PROCESS. STUDIES HAVE DESCRIBED ABERRANT NEUTROPHIL FUNCTIONS ACROSS THESE CONDITIONS, AND SOME HAVE HIGHLIGHTED POTENTIAL MECHANISMS FOR ALTERED CELL BEHAVIOURS WHICH APPEAR SHARED ACROSS DISEASE STATES. IT HAS BEEN SUGGESTED THAT ALTERED FUNCTIONS MAY REPRESENT NEUTROPHIL "SENESCENCE". THIS REVIEW CONSIDERS HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE CELL AGES, AND HOW AND WHY NEUTROPHIL FUNCTIONS CHANGE AS THE HOST AGES IN HEALTH AND DISEASE AND DISCUSSES WHETHER NEUTROPHIL FUNCTIONS COULD BE TARGETED TO IMPROVE HEALTH OUTCOMES IN OLDER ADULTS. 2018 4 2855 46 FROM INFLAMMAGING TO HEALTHY AGING BY DIETARY LIFESTYLE CHOICES: IS EPIGENETICS THE KEY TO PERSONALIZED NUTRITION? THE PROGRESSIVELY OLDER POPULATION IN DEVELOPED COUNTRIES IS REFLECTED IN AN INCREASE IN THE NUMBER OF PEOPLE SUFFERING FROM AGE-RELATED CHRONIC INFLAMMATORY DISEASES SUCH AS METABOLIC SYNDROME, DIABETES, HEART AND LUNG DISEASES, CANCER, OSTEOPOROSIS, ARTHRITIS, AND DEMENTIA. THE HETEROGENEITY IN BIOLOGICAL AGING, CHRONOLOGICAL AGE, AND AGING-ASSOCIATED DISORDERS IN HUMANS HAVE BEEN ASCRIBED TO DIFFERENT GENETIC AND ENVIRONMENTAL FACTORS (I.E., DIET, POLLUTION, STRESS) THAT ARE CLOSELY LINKED TO SOCIOECONOMIC FACTORS. THE COMMON DENOMINATOR OF THESE FACTORS IS THE INFLAMMATORY RESPONSE. CHRONIC LOW-GRADE SYSTEMIC INFLAMMATION DURING PHYSIOLOGICAL AGING AND IMMUNOSENESCENCE ARE INTERTWINED IN THE PATHOGENESIS OF PREMATURE AGING ALSO DEFINED AS 'INFLAMMAGING.' THE LATTER HAS BEEN ASSOCIATED WITH FRAILTY, MORBIDITY, AND MORTALITY IN ELDERLY SUBJECTS. HOWEVER, IT IS UNKNOWN TO WHAT EXTENT INFLAMMAGING OR LONGEVITY IS CONTROLLED BY EPIGENETIC EVENTS IN EARLY LIFE. TODAY, HUMAN DIET IS BELIEVED TO HAVE A MAJOR INFLUENCE ON BOTH THE DEVELOPMENT AND PREVENTION OF AGE-RELATED DISEASES. MOST PLANT-DERIVED DIETARY PHYTOCHEMICALS AND MACRO- AND MICRONUTRIENTS MODULATE OXIDATIVE STRESS AND INFLAMMATORY SIGNALING AND REGULATE METABOLIC PATHWAYS AND BIOENERGETICS THAT CAN BE TRANSLATED INTO STABLE EPIGENETIC PATTERNS OF GENE EXPRESSION. THEREFORE, DIET INTERVENTIONS DESIGNED FOR HEALTHY AGING HAVE BECOME A HOT TOPIC IN NUTRITIONAL EPIGENOMIC RESEARCH. INCREASING EVIDENCE HAS REVEALED THAT COMPLEX INTERACTIONS BETWEEN FOOD COMPONENTS AND HISTONE MODIFICATIONS, DNA METHYLATION, NON-CODING RNA EXPRESSION, AND CHROMATIN REMODELING FACTORS INFLUENCE THE INFLAMMAGING PHENOTYPE AND AS SUCH MAY PROTECT OR PREDISPOSE AN INDIVIDUAL TO MANY AGE-RELATED DISEASES. REMARKABLY, HUMANS PRESENT A BROAD RANGE OF RESPONSES TO SIMILAR DIETARY CHALLENGES DUE TO BOTH GENETIC AND EPIGENETIC MODULATIONS OF THE EXPRESSION OF TARGET PROTEINS AND KEY GENES INVOLVED IN THE METABOLISM AND DISTRIBUTION OF THE DIETARY CONSTITUENTS. HERE, WE WILL SUMMARIZE THE EPIGENETIC ACTIONS OF DIETARY COMPONENTS, INCLUDING PHYTOCHEMICALS, AND MACRO- AND MICRONUTRIENTS AS WELL AS METABOLITES, THAT CAN ATTENUATE INFLAMMAGING. WE WILL DISCUSS THE CHALLENGES FACING PERSONALIZED NUTRITION TO TRANSLATE HIGHLY VARIABLE INTERINDIVIDUAL EPIGENETIC DIET RESPONSES TO POTENTIAL INDIVIDUAL HEALTH BENEFITS/RISKS RELATED TO AGING DISEASE. 2015 5 4273 33 MICROBIOTA AND EPIGENETICS: HEALTH IMPACT. EPIGENETIC CHANGES ASSOCIATED WITH DISEASE DEVELOPMENT AND PROGRESSIONS ARE OF INCREASING IMPORTANCE BECAUSE OF THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. SEVERAL EPIGENETIC CHANGES ASSOCIATED WITH CHRONIC METABOLIC DISORDERS HAVE BEEN STUDIED IN VARIOUS DISEASES. EPIGENETIC CHANGES ARE MOSTLY MODULATED BY ENVIRONMENTAL FACTORS, INCLUDING THE HUMAN MICROBIOTA LIVING IN DIFFERENT PARTS OF OUR BODIES. THE MICROBIAL STRUCTURAL COMPONENTS AND THE MICROBIALLY DERIVED METABOLITES DIRECTLY INTERACT WITH HOST CELLS, THEREBY MAINTAINING HOMEOSTASIS. MICROBIOME DYSBIOSIS, ON THE OTHER HAND, IS KNOWN TO PRODUCE ELEVATED LEVELS OF DISEASE-LINKED METABOLITES, WHICH MAY DIRECTLY AFFECT A HOST METABOLIC PATHWAY OR INDUCE EPIGENETIC CHANGES THAT CAN LEAD TO DISEASE DEVELOPMENT. DESPITE THEIR IMPORTANT ROLE IN HOST PHYSIOLOGY AND SIGNAL TRANSDUCTION, THERE HAS BEEN LITTLE RESEARCH INTO THE MECHANICS AND PATHWAYS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. THIS CHAPTER FOCUSES ON THE RELATIONSHIP BETWEEN MICROBES AND THEIR EPIGENETIC EFFECTS IN DISEASED PATHOLOGY, AS WELL AS ON THE REGULATION AND METABOLISM OF THE DIETARY OPTIONS AVAILABLE TO THE MICROBES. FURTHERMORE, THIS CHAPTER ALSO PROVIDES A PROSPECTIVE LINK BETWEEN THESE TWO IMPORTANT PHENOMENA, TERMED "MICROBIOME AND EPIGENETICS." 2023 6 6629 25 UNDERSTANDING THE HUMAN AGING PROTEOME USING EPIDEMIOLOGICAL MODELS. HUMAN AGING IS A COMPLEX MULTIFACTORIAL PROCESS ASSOCIATED WITH A DECLINE OF PHYSICAL AND COGNITIVE FUNCTION AND HIGH SUSCEPTIBILITY TO CHRONIC DISEASES, INFLUENCED BY GENETIC, EPIGENETIC, ENVIRONMENTAL, AND DEMOGRAPHIC FACTORS. THIS CHAPTER WILL PROVIDE AN OVERVIEW ON THE USE OF EPIDEMIOLOGICAL MODELS WITH PROTEOMICS DATA AS A METHOD THAT CAN BE USED TO IDENTIFY FACTORS THAT MODULATE THE AGING PROCESS IN HUMANS. THIS IS DEMONSTRATED WITH PROTEOMICS DATA FROM HUMAN PLASMA AND SKELETAL MUSCLE, WHERE THE COMBINATION WITH EPIDEMIOLOGICAL MODELS IDENTIFIED A SET OF MITOCHONDRIAL, SPLICEOSOME, AND SENESCENCE PROTEINS AS WELL AS THE ROLE OF ENERGETIC PATHWAYS SUCH AS GLYCOLYSIS, AND ELECTRON TRANSPORT PATHWAYS THAT REGULATE THE AGING PROCESS. 2022 7 3706 33 INFLUENCE OF GENETICS ON DISEASE SUSCEPTIBILITY AND PROGRESSION. FOR MANY CHRONIC DISEASES, THE INFLUENCE OF GENETICS IS COMPLEX AND PHENOTYPES DO NOT CONFORM TO SIMPLE MENDELIAN PATTERNS OF INHERITANCE. DISCUSSED HERE ARE TWO TYPES OF GENETIC INFLUENCES ON HEALTHY AGING. THE FIRST INVOLVES VARIATION IN THE GENE SEQUENCE ITSELF AND HOW THIS MAY INFLUENCE DISEASE SUSCEPTIBILITY, PROGRESSION, AND SEVERITY, INTERACTING WITH OTHER RECOGNIZED RISK FACTORS. THE SECOND INVOLVES EPIGENETIC REGULATORY MECHANISMS THAT MAY POTENTIALLY PROVIDE INSIGHT INTO HOW ENVIRONMENTAL INFLUENCES AFFECT THE EXPRESSED GENOME, THUS IMPROVING OUR UNDERSTANDING OF THE GENETIC MECHANISMS UNDERLYING MULTIFACTORIAL DISEASES. THE INTERLEUKIN-1 FAMILY OF CYTOKINES CAN BE USED TO ILLUSTRATE HOW GENETIC SEQUENCE VARIATION MAY AFFECT SUCH DISEASES. THIS CYTOKINE FAMILY PLAYS A KEY ROLE IN MEDIATING INFLAMMATION, WHICH IS NOW UNDERSTOOD TO BE A CENTRAL COMPONENT OF A GROWING NUMBER OF CHRONIC DISEASES. RECENT WORK HAS REVEALED MANY SEQUENCE VARIATIONS IN THE REGULATORY DNA OF GENES ENCODING IMPORTANT MEMBERS OF THE INTERLEUKIN-1 FAMILY, AND THESE VARIATIONS ARE ASSOCIATED WITH DIFFERENTIAL EFFECTS ON THE INFLAMMATORY RESPONSE. THE INTERACTIONS OF ENVIRONMENTAL FACTORS WITH BOTH DNA SEQUENCE VARIATIONS AND EPIGENETIC MODIFICATIONS ARE LIKELY TO DETERMINE THE PHENOTYPES OF MULTIFACTORIAL DISEASES OF AGING AS WELL AS THE PHENOTYPE OF HEALTHY AGING. 2007 8 6135 33 THE EPIGENETICS OF INFLAMMAGING: THE CONTRIBUTION OF AGE-RELATED HETEROCHROMATIN LOSS AND LOCUS-SPECIFIC REMODELLING AND THE MODULATION BY ENVIRONMENTAL STIMULI. A GROWING AMOUNT OF EVIDENCES INDICATES THAT INFLAMMAGING - THE CHRONIC, LOW GRADE INFLAMMATION STATE CHARACTERISTIC OF THE ELDERLY - IS THE RESULT OF GENETIC AS WELL AS ENVIRONMENTAL OR STOCHASTIC FACTORS. SOME OF THESE, SUCH AS THE ACCUMULATION OF SENESCENT CELLS THAT ARE PERSISTENT DURING AGING OR ACCOMPANY ITS PROGRESSION, SEEM TO BE SUFFICIENT TO INITIATE THE AGING PROCESS AND TO FUEL IT. OTHERS, LIKE EXPOSURE TO ENVIRONMENTAL COMPOUNDS OR INFECTIONS, ARE TEMPORARY AND RESOLVE WITHIN A (RELATIVELY) SHORT TIME. IN BOTH CASES, HOWEVER, A CELLULAR MEMORY OF THE EVENT CAN BE ESTABLISHED BY MEANS OF EPIGENETIC MODULATION OF THE GENOME. IN THIS REVIEW WE WILL SPECIFICALLY DISCUSS THE RELATIONSHIP BETWEEN EPIGENETICS AND INFLAMMAGING. IN PARTICULAR, WE WILL SHOW HOW AGE-ASSOCIATED EPIGENETIC MODIFICATIONS CONCERNED WITH HETEROCHROMATIN LOSS AND GENE-SPECIFIC REMODELLING, CAN PROMOTE INFLAMMAGING. FURTHERMORE, WE WILL RECALL HOW THE EXPOSURE TO SPECIFIC NUTRITIONAL, ENVIRONMENTAL AND MICROBIAL STIMULI CAN AFFECT THE RATE OF INFLAMMAGING THROUGH EPIGENETIC MECHANISMS, TOUCHING ALSO ON THE RECENT INSIGHT GIVEN BY THE CONCEPT OF TRAINED IMMUNITY. 2018 9 4425 37 MOLECULAR BASIS OF AGEING IN CHRONIC METABOLIC DISEASES. AIM: OVER THE LAST DECADES, THE SHIFT IN AGE DISTRIBUTION TOWARDS OLDER AGES AND THE PROGRESSIVE AGEING WHICH HAS OCCURRED IN MOST POPULATIONS HAVE BEEN PARALLELED BY A GLOBAL EPIDEMIC OF OBESITY AND ITS RELATED METABOLIC DISORDERS, PRIMARILY, TYPE 2 DIABETES (T2D). DYSFUNCTION OF THE ADIPOSE TISSUE (AT) IS WIDELY RECOGNIZED AS A SIGNIFICANT HALLMARK OF THE AGEING PROCESS THAT, IN TURN, RESULTS IN SYSTEMIC METABOLIC ALTERATIONS. THESE INCLUDE INSULIN RESISTANCE, ACCUMULATION OF ECTOPIC LIPIDS AND CHRONIC INFLAMMATION, WHICH ARE RESPONSIBLE FOR AN ELEVATED RISK OF OBESITY AND T2D ONSET ASSOCIATED TO AGEING. ON THE OTHER HAND, OBESITY AND T2D, THE PARADIGMS OF AT DYSFUNCTION, SHARE MANY PHYSIOLOGICAL CHARACTERISTICS WITH THE AGEING PROCESS, SUCH AS AN INCREASED BURDEN OF SENESCENT CELLS AND EPIGENETIC ALTERATIONS. THUS, THESE CHRONIC METABOLIC DISORDERS MAY REPRESENT A STATE OF ACCELERATED AGEING. MATERIALS AND METHODS: A MORE PRECISE EXPLANATION OF THE FUNDAMENTAL AGEING MECHANISMS THAT OCCUR IN AT AND A DEEPER UNDERSTANDING OF THEIR ROLE IN THE INTERPLAY BETWEEN ACCELERATED AGEING AND AT DYSFUNCTION CAN BE A FUNDAMENTAL LEAP TOWARDS NOVEL THERAPIES THAT ADDRESS THE CAUSES, NOT JUST THE SYMPTOMS, OF OBESITY AND T2D, UTILIZING STRATEGIES THAT TARGET EITHER SENESCENT CELLS OR DNA METHYLATION. RESULTS: IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE PATHWAYS THAT LEAD TO AT DYSFUNCTION IN THE CHRONOLOGICAL AGEING PROCESS AS WELL AS THE PATHOPHYSIOLOGY OF OBESITY AND T2D, EMPHASIZING THE CRITICAL ROLE OF CELLULAR SENESCENCE AND DNA METHYLATION. CONCLUSION: FINALLY, WE HIGHLIGHT THE NEED FOR FURTHER RESEARCH FOCUSED ON TARGETING THESE MECHANISMS. 2020 10 1360 33 DEVELOPMENTAL ASPECTS OF A LIFE COURSE APPROACH TO HEALTHY AGEING. WE EXAMINE THE MECHANISTIC BASIS AND WIDER IMPLICATIONS OF ADOPTING A DEVELOPMENTAL PERSPECTIVE ON HUMAN AGEING. PREVIOUS MODELS OF AGEING HAVE CONCENTRATED ON ITS GENETIC BASIS, OR THE DETRIMENTAL EFFECTS OF ACCUMULATED DAMAGE, BUT ALSO HAVE RAISED ISSUES ABOUT WHETHER AGEING CAN BE VIEWED AS ADAPTIVE ITSELF, OR IS A CONSEQUENCE OF OTHER ADAPTIVE PROCESSES, FOR EXAMPLE IF MAINTENANCE AND REPAIR PROCESSES IN THE PERIOD UP TO REPRODUCTION ARE TRADED OFF AGAINST LATER DECLINE IN FUNCTION. A LIFE COURSE MODEL PLACES AGEING IN THE CONTEXT OF THE ATTAINMENT OF PEAK CAPACITY FOR A BODY SYSTEM, STARTING IN EARLY DEVELOPMENT WHEN PLASTICITY PERMITS CHANGES IN STRUCTURE AND FUNCTION INDUCED BY A RANGE OF ENVIRONMENTAL STIMULI, FOLLOWED BY A PERIOD OF DECLINE, THE RATE OF WHICH DEPENDS ON THE PEAK ATTAINED AS WELL AS THE LATER LIFE CONDITIONS. SUCH PATH DEPENDENCY IN THE RATE OF AGEING MAY OFFER NEW INSIGHTS INTO ITS MODIFICATION. FOCUSING ON MUSCULOSKELETAL AND CARDIOVASCULAR FUNCTION, WE DISCUSS THIS MODEL AND THE POSSIBLE UNDERLYING MECHANISMS, INCLUDING ENDOTHELIAL FUNCTION, OXIDATIVE STRESS, STEM CELLS AND NUTRITIONAL FACTORS SUCH AS VITAMIN D STATUS. EPIGENETIC CHANGES INDUCED DURING DEVELOPMENTAL PLASTICITY, AND IMMUNE FUNCTION MAY PROVIDE A COMMON MECHANISTIC PROCESS UNDERLYING A LIFE COURSE MODEL OF AGEING. THE LIFE COURSE TRAJECTORY DIFFERS IN HIGH AND LOW RESOURCE SETTINGS. NEW INSIGHTS INTO THE DEVELOPMENTAL COMPONENTS OF THE LIFE COURSE MODEL OF AGEING MAY LEAD TO THE DESIGN OF BIOMARKERS OF LATER CHRONIC DISEASE RISK AND TO NEW INTERVENTIONS TO PROMOTE HEALTHY AGEING, WITH IMPORTANT IMPLICATIONS FOR PUBLIC HEALTH. 2016 11 625 28 BIOLOGICAL AGE AND ENVIRONMENTAL RISK FACTORS FOR DEMENTIA AND STROKE: MOLECULAR MECHANISMS. SINCE THE DEVELOPMENT OF ANTIBIOTICS AND VACCINATION, AS WELL AS MAJOR IMPROVEMENTS IN PUBLIC HYGIENE, THE MAIN RISK FACTORS FOR MORBIDITY AND MORTALITY ARE AGE AND CHRONIC EXPOSURE TO ENVIRONMENTAL FACTORS, BOTH OF WHICH CAN INTERACT WITH GENETIC PREDISPOSITIONS. AS THE AVERAGE AGE OF THE POPULATION INCREASES, THE PREVALENCE AND COSTS OF CHRONIC DISEASES, ESPECIALLY NEUROLOGICAL CONDITIONS, ARE RAPIDLY INCREASING. THE DELETERIOUS EFFECTS OF AGE AND ENVIRONMENTAL RISK FACTORS, DEVELOP CHRONICALLY OVER RELATIVELY LONG PERIODS OF TIME, IN CONTRAST TO THE RELATIVELY RAPID DELETERIOUS EFFECTS OF INFECTIOUS DISEASES OR ACCIDENTS. OF PARTICULAR INTEREST IS THE HYPOTHESIS THAT THE DELETERIOUS EFFECTS OF ENVIRONMENTAL FACTORS MAY BE MEDIATED BY ACCELERATION OF BIOLOGICAL AGE. THIS HYPOTHESIS IS SUPPORTED BY EVIDENCE THAT DIETARY RESTRICTION, WHICH UNIVERSALLY DELAYS AGE-RELATED DISEASES, ALSO AMELIORATES DELETERIOUS EFFECTS OF ENVIRONMENTAL FACTORS. CONVERSELY, BOTH AGE AND ENVIRONMENTAL RISK FACTORS ARE ASSOCIATED WITH THE ACCUMULATION OF SOMATIC MUTATIONS IN MITOTIC CELLS AND EPIGENETIC MODIFICATIONS THAT ARE A MEASURE OF "BIOLOGICAL AGE", A BETTER PREDICTOR OF AGE-RELATED MORBIDITY AND MORTALITY THAN CHRONOLOGICAL AGE. HERE WE REVIEW EVIDENCE THAT ENVIRONMENTAL RISK FACTORS SUCH AS SMOKING AND AIR POLLUTION MAY ALSO DRIVE NEUROLOGICAL CONDITIONS, INCLUDING ALZHEIMER'S DISEASE, BY THE ACCELERATION OF BIOLOGICAL AGE, MEDIATED BY CUMULATIVE AND PERSISTENT EPIGENETIC EFFECTS AS WELL AS SOMATIC MUTATIONS. ELUCIDATION OF SUCH MECHANISMS COULD PLAUSIBLY ALLOW THE DEVELOPMENT OF INTERVENTIONS WHICH DELAY DELETERIOUS EFFECTS OF BOTH AGING AND ENVIRONMENTAL RISK FACTORS. 2022 12 5069 23 PHYSICAL ACTIVITY IN THE PREVENTION OF HUMAN DISEASES: ROLE OF EPIGENETIC MODIFICATIONS. EPIGENETIC MODIFICATION REFERS TO HERITABLE CHANGES IN GENE FUNCTION THAT CANNOT BE EXPLAINED BY ALTERATIONS IN THE DNA SEQUENCE. THE CURRENT LITERATURE CLEARLY DEMONSTRATES THAT THE EPIGENETIC RESPONSE IS HIGHLY DYNAMIC AND INFLUENCED BY DIFFERENT BIOLOGICAL AND ENVIRONMENTAL FACTORS SUCH AS AGING, NUTRIENT AVAILABILITY AND PHYSICAL EXERCISE. AS SUCH, IT IS WELL ACCEPTED THAT PHYSICAL ACTIVITY AND EXERCISE CAN MODULATE GENE EXPRESSION THROUGH EPIGENETIC ALTERNATIONS ALTHOUGH THE TYPE AND DURATION OF EXERCISE ELICITING SPECIFIC EPIGENETIC EFFECTS THAT CAN RESULT IN HEALTH BENEFITS AND PREVENT CHRONIC DISEASES REMAINS TO BE DETERMINED. THIS REVIEW HIGHLIGHTS THE MOST SIGNIFICANT FINDINGS FROM EPIGENETIC STUDIES INVOLVING PHYSICAL ACTIVITY/EXERCISE INTERVENTIONS KNOWN TO BENEFIT CHRONIC DISEASES SUCH AS METABOLIC SYNDROME, DIABETES, CANCER, CARDIOVASCULAR AND NEURODEGENERATIVE DISEASES. 2017 13 6812 32 [EPIGENETICS, INTERFACE BETWEEN ENVIRONMENT AND GENES: ROLE IN COMPLEX DISEASES]. EPIGENETICS IS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION OR CELLULAR PHENOTYPE CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE. EPIGENETICS IS ONE OF THE MAJOR MECHANISMS EXPLAINING THE "DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASES" (DOHAD). BESIDES GENETIC BACKGROUND INHERITED FROM PARENTS, WHICH CONFERS SUSCEPTIBILITY TO CERTAIN PATHOLOGIES, EPIGENETIC CHANGES CONSTITUTE THE MEMORY OF PREVIOUS EVENTS, EITHER POSITIVE OR NEGATIVE, ALONG THE LIFE CYCLE, INCLUDING AT THE IN UTERO STAGE. THE LATER EXPOSITION TO HOSTILE ENVIRONMENT MAY REVEAL SUCH SUSCEPTIBILITY, WITH THE DEVELOPMENT OF VARIOUS PATHOLOGIES, AMONG THEM NUMEROUS CHRONIC COMPLEX DISEASES. THE DEMONSTRATION OF SUCH A SEQUENCE OF EVENTS HAS BEEN SHOWN FOR METABOLIC DISEASES AS OBESITY, METABOLIC SYNDROME AND TYPE 2 DIABETES, CARDIOVASCULAR DISEASE AND CANCER. IN CONTRAST TO GENETIC PREDISPOSITION, WHICH IS IRREVERSIBLE, EPIGENETIC CHANGES ARE POTENTIALLY REVERSIBLE, THUS GIVING TARGETS NOT ONLY FOR PREVENTION, BUT POSSIBLY ALSO FOR THE TREATMENT OF CERTAIN COMPLEX DISEASES. 2012 14 3402 36 HOW DOES AGE DETERMINE THE DEVELOPMENT OF HUMAN IMMUNE-MEDIATED ARTHRITIS? DOES AGE SUBSTANTIALLY AFFECT THE EMERGENCE OF HUMAN IMMUNE-MEDIATED ARTHRITIS? CHILDREN DO NOT USUALLY DEVELOP IMMUNE-MEDIATED ARTICULAR INFLAMMATION DURING THEIR FIRST YEAR OF LIFE. IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS, THIS APPARENT 'IMMUNE PRIVILEGE' DISINTEGRATES, AND CHRONIC INFLAMMATION IS ASSOCIATED WITH VARIABLE AUTOANTIBODY SIGNATURES AND PATTERNS OF DISEASE THAT RESEMBLE ADULT ARTHRITIS PHENOTYPES. NUMEROUS MECHANISMS MIGHT BE INVOLVED IN THIS SHIFT, INCLUDING GENETIC AND EPIGENETIC PREDISPOSING FACTORS, MATURATION OF THE IMMUNE SYSTEM WITH A PROGRESSIVE MODULATION OF PUTATIVE TOLEROGENIC CONTROLS, PARALLEL DEVELOPMENT OF MICROBIAL DYSBIOSIS, ACCUMULATION OF A PRO-INFLAMMATORY BURDEN DRIVEN BY ENVIRONMENTAL EXPOSURES (THE EXPOSOME) AND COMORBIDITY-RELATED DRIVERS. BY EXPLORING THESE MECHANISMS, WE EXPAND THE DISCUSSION OF THREE (NOT MUTUALLY EXCLUSIVE) HYPOTHESES ON HOW THESE FACTORS CAN CONTRIBUTE TO THE DIFFERENCES AND SIMILARITIES BETWEEN THE LOSS OF IMMUNE TOLERANCE IN CHILDREN AND THE DEVELOPMENT OF ESTABLISHED IMMUNE-MEDIATED ARTHRITIS IN ADULTS. THESE THREE HYPOTHESES RELATE TO A CRITICAL WINDOW IN GENETICS AND EPIGENETICS, IMMUNE MATURATION, AND THE ACCUMULATION OF BURDEN. THE VARIED MANIFESTATION OF THE UNDERLYING MECHANISMS AMONG INDIVIDUALS IS ONLY BEGINNING TO BE CLARIFIED, BUT THE ESTABLISHMENT OF A FRAMEWORK CAN FACILITATE THE DEVELOPMENT OF AN INTEGRATED UNDERSTANDING OF THE PATHOGENESIS OF ARTHRITIS ACROSS ALL AGES. 2022 15 4393 29 MODIFIABLE RISK FACTORS IN PERIODONTITIS: AT THE INTERSECTION OF AGING AND DISEASE. CHRONIC INFLAMMATION IS A PROMINENT FEATURE OF AGING AND OF COMMON AGE-RELATED DISEASES, INCLUDING ATHEROSCLEROSIS, CANCER AND PERIODONTITIS. THIS VOLUME EXAMINES MODIFIABLE RISK FACTORS FOR PERIODONTITIS AND OTHER CHRONIC INFLAMMATORY DISEASES. ORAL BACTERIAL COMMUNITIES AND VIRAL INFECTIONS, PARTICULARLY WITH CYTOMEGALOVIRUS AND OTHER HERPESVIRUSES, ELICIT DISTINCT IMMUNE RESPONSES AND ARE CENTRAL IN THE INITIATION OF PERIODONTAL DISEASES. RISK OF DISEASE IS DYNAMIC AND CHANGES IN RESPONSE TO COMPLEX INTERACTIONS OF GENETIC, ENVIRONMENTAL AND STOCHASTIC FACTORS OVER THE LIFESPAN. MANY MODIFIABLE RISK FACTORS, SUCH AS SMOKING AND EXCESS CALORIC INTAKE, CONTRIBUTE TO INCREASES IN SYSTEMIC MARKERS OF INFLAMMATION AND CAN MODIFY GENE REGULATION THROUGH A VARIETY OF BIOLOGIC MECHANISMS (E.G. EPIGENETIC MODIFICATIONS). PERIODONTITIS AND OTHER COMMON CHRONIC INFLAMMATORY DISEASES SHARE MULTIPLE MODIFIABLE RISK FACTORS, SUCH AS TOBACCO SMOKING, PSYCHOLOGICAL STRESS AND DEPRESSION, ALCOHOL CONSUMPTION, OBESITY, DIABETES, METABOLIC SYNDROME AND OSTEOPOROSIS. INTERVENTIONS THAT TARGET MODIFIABLE RISK FACTORS HAVE THE POTENTIAL TO IMPROVE RISK PROFILES FOR PERIODONTITIS AS WELL AS FOR OTHER COMMON CHRONIC DISEASES. 2014 16 3404 28 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 17 6187 31 THE IMPACT OF IMMUNOSENESCENCE ON PULMONARY DISEASE. THE GLOBAL POPULATION IS AGING WITH SIGNIFICANT GAINS IN LIFE EXPECTANCY PARTICULARLY IN THE DEVELOPED WORLD. CONSEQUENTLY, GREATER FOCUS ON UNDERSTANDING THE PROCESSES THAT UNDERLIE PHYSIOLOGICAL AGING HAS OCCURRED. KEY FACETS OF ADVANCING AGE INCLUDE GENOMIC INSTABILITY, TELOMERE SHORTENING, EPIGENETIC CHANGES, AND DECLINES IN IMMUNE FUNCTION TERMED IMMUNOSENESCENCE. IMMUNOSENESCENCE AND ITS ASSOCIATED CHRONIC LOW GRADE SYSTEMIC "INFLAMM-AGING" CONTRIBUTE TO THE DEVELOPMENT AND PROGRESSION OF PULMONARY DISEASE IN OLDER INDIVIDUALS. THESE PHYSIOLOGICAL PROCESSES PREDISPOSE TO PULMONARY INFECTION AND CONFER SPECIFIC AND UNIQUE CLINICAL PHENOTYPES OBSERVED IN CHRONIC RESPIRATORY DISEASE INCLUDING LATE-ONSET ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND PULMONARY FIBROSIS. EMERGING CONCEPTS OF THE GUT AND AIRWAY MICROBIOME FURTHER COMPLICATE THE INTERRELATIONSHIP BETWEEN HOST AND MICROORGANISM PARTICULARLY FROM AN IMMUNOLOGICAL PERSPECTIVE AND ESPECIALLY SO IN THE SETTING OF IMMUNOSENESCENCE. THIS REVIEW FOCUSES ON OUR CURRENT UNDERSTANDING OF THE AGING PROCESS, IMMUNOSENESCENCE, AND HOW IT CAN POTENTIALLY IMPACT ON VARIOUS PULMONARY DISEASES AND THE HUMAN MICROBIOME. 2015 18 738 28 CANCER SUSCEPTIBILITY: EPIGENETIC MANIFESTATION OF ENVIRONMENTAL EXPOSURES. CANCER IS A DISEASE THAT RESULTS FROM BOTH GENETIC AND EPIGENETIC CHANGES. DISCORDANT PHENOTYPES AND VARYING INCIDENCES OF COMPLEX DISEASES SUCH AS CANCER IN MONOZYGOTIC TWINS AS WELL AS GENETICALLY IDENTICAL LABORATORY ANIMALS HAVE LONG BEEN ATTRIBUTED TO DIFFERENCES IN ENVIRONMENTAL EXPOSURES. ACCUMULATING EVIDENCE INDICATES, HOWEVER, THAT DISPARITIES IN GENE EXPRESSION RESULTING FROM VARIABLE MODIFICATIONS IN DNA METHYLATION AND CHROMATIN STRUCTURE IN RESPONSE TO THE ENVIRONMENT ALSO PLAY A ROLE IN DIFFERENTIAL SUSCEPTIBILITY TO DISEASE. DESPITE A GROWING CONSENSUS ON THE IMPORTANCE OF EPIGENETICS IN THE ETIOLOGY OF CHRONIC HUMAN DISEASES, THE GENES MOST PRONE TO EPIGENETIC DYSREGULATION ARE INCOMPLETELY DEFINED. MOREOVER, NEITHER THE ENVIRONMENTAL AGENTS MOST STRONGLY AFFECTING THE EPIGENOME NOR THE CRITICAL WINDOWS OF VULNERABILITY TO ENVIRONMENTALLY INDUCED EPIGENETIC ALTERATIONS ARE ADEQUATELY CHARACTERIZED. THESE MAJOR DEFICITS IN KNOWLEDGE MARKEDLY IMPAIR OUR ABILITY TO UNDERSTAND FULLY THE ETIOLOGY OF CANCER AND THE IMPORTANCE OF THE EPIGENOME IN DIAGNOSING AND PREVENTING THIS DEVASTATING DISEASE. 2007 19 5635 31 SEPTIC SHOCK AND THE AGING PROCESS: A MOLECULAR COMPARISON. AGING IS A CONTINUOUS PROCESS PROMOTED BY BOTH INTRINSIC AND EXTRINSIC FACTORS THAT EACH TRIGGER A MULTITUDE OF MOLECULAR EVENTS. INCREASING EVIDENCE SUPPORTS A CENTRAL ROLE FOR INFLAMMATION IN THIS PROGRESSION. HERE, WE DISCUSS HOW THE LOW-GRADE CHRONIC INFLAMMATION THAT CHARACTERIZES AGING IS TIGHTLY INTERCONNECTED WITH OTHER IMPORTANT ASPECTS OF THIS PROCESS, SUCH AS DNA DAMAGE, MITOCHONDRIAL DYSFUNCTION, AND EPIGENETIC CHANGES. SIMILARLY, INFLAMMATION ALSO PLAYS A CRITICAL ROLE IN MANY MORBID CONDITIONS THAT AFFECT PATIENTS WHO ARE ADMITTED TO INTENSIVE CARE. ALTHOUGH THE INFLAMMATORY RESPONSE IS LOW GRADE AND PERSISTENT IN HEALTHY AGING WHILE IT IS ACUTE AND SEVERE IN CRITICALLY ILL STATES, WE HYPOTHESIZE THAT BOTH SITUATIONS HAVE IMPORTANT INTERCONNECTIONS. HERE, WE PERFORMED AN EXTENSIVE REVIEW OF THE LITERATURE TO INVESTIGATE THIS POTENTIAL LINK. BECAUSE SEPSIS IS THE MOST EXTENSIVELY STUDIED DISEASE AND IS THE LEADING CAUSE OF DEATH IN CRITICAL CARE, WE FOCUS OUR DISCUSSION ON COMPARING THE INFLAMMATORY PROFILE OF HEALTHY OLDER PEOPLE WITH THAT OF PATIENTS IN SEPTIC SHOCK TO EXPLAIN WHY WE BELIEVE THAT BOTH SITUATIONS HAVE SYNERGISTIC EFFECTS, LEADING TO CRITICALLY ILL AGED PATIENTS HAVING A WORSE PROGNOSIS WHEN COMPARED WITH CRITICALLY ILL YOUNG PATIENTS. 2017 20 2346 30 EPIGENETIC REGULATION OF METABOLISM AND INFLAMMATION BY CALORIE RESTRICTION. CHRONIC CALORIC RESTRICTION (CR) WITHOUT MALNUTRITION IS KNOWN TO AFFECT DIFFERENT CELLULAR PROCESSES SUCH AS STEM CELL FUNCTION, CELL SENESCENCE, INFLAMMATION, AND METABOLISM. DESPITE THE DIFFERENCES IN THE IMPLEMENTATION OF CR, THE REDUCTION OF CALORIES PRODUCES A WIDESPREAD BENEFICIAL EFFECT IN NONCOMMUNICABLE CHRONIC DISEASES, WHICH CAN BE EXPLAINED BY IMPROVEMENTS IN IMMUNO-METABOLIC ADAPTATION. CELLULAR ADAPTATION THAT OCCURS IN RESPONSE TO DIETARY PATTERNS CAN BE EXPLAINED BY ALTERATIONS IN EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNA. IN THIS REVIEW, WE DEFINE THESE MODIFICATIONS AND SYSTEMATICALLY SUMMARIZE THE CURRENT EVIDENCE RELATED TO CR AND THE EPIGENOME. WE THEN EXPLAIN THE SIGNIFICANCE OF GENOME-WIDE EPIGENETIC MODIFICATIONS IN THE CONTEXT OF DISEASE DEVELOPMENT. ALTHOUGH SUBSTANTIAL EVIDENCE EXISTS FOR THE WIDESPREAD EFFECT OF CR ON LONGEVITY, THERE IS NO CONSENSUS REGARDING THE EPIGENETIC REGULATIONS OF THE UNDERLYING CELLULAR MECHANISMS THAT LEAD TO IMPROVED HEALTH. WE PROVIDE COMPELLING EVIDENCE THAT CR PRODUCES LONG-LASTING EPIGENETIC EFFECTS THAT MEDIATE EXPRESSION OF GENES RELATED TO IMMUNO-METABOLIC PROCESSES. EPIGENETIC REPROGRAMMING OF THE UNDERLYING CHRONIC LOW-GRADE INFLAMMATION BY CR CAN LEAD TO IMMUNO-METABOLIC ADAPTATIONS THAT ENHANCE QUALITY OF LIFE, EXTEND LIFESPAN, AND DELAY CHRONIC DISEASE ONSET. 2019