1 6188 110 THE IMPACT OF INSOMNIA ON FRAILTY AND THE HALLMARKS OF AGING. THROUGHOUT THE COURSE OF LIFE, THERE ARE AGE-RELATED CHANGES IN SLEEP. DESPITE THESE NORMAL CHANGES, THERE IS A HIGH PERCENTAGE OF OLDER ADULTS THAT REPORT SLEEP DISSATISFACTION WITH A HIGH PERVASIVENESS OF CHRONIC INSOMNIA, THE MOST COMMON SLEEP DISORDER WORLDWIDE, WITH ITS PREVALENCE BEING EXPECTED TO CONTINUOUSLY INCREASE DUE TO THE GROWING RATES OF AGING AND OBESITY. THIS CAN HAVE DIFFERENT ADVERSE HEALTH OUTCOMES, ESPECIALLY BY PROMOTING BOTH PHYSICAL AND COGNITIVE DECLINE, WHICH ULTIMATELY MAY AGGRAVATE FRAILTY IN OLDER ADULTS. MOREOVER, AGE-RELATED FRAILTY AND SLEEP DYSFUNCTION MAY HAVE A COMMON MECHANISM RELATED TO THE HALLMARKS OF CELLULAR AGING. CELLULAR AGING WAS CATEGORIZED INTO NINE HALLMARKS, SUCH AS DNA DAMAGE, TELOMERE ATTRITION AND EPIGENETIC CHANGES. IN THE CONTEXT OF GERIATRIC AND CHRONIC INSOMNIA RESEARCH, THIS REVIEW AIMS AT DISCUSSING THE CURRENT EVIDENCE FROM BOTH ANIMAL MODELS AND HUMAN COHORTS ADDRESSING THE LINK BETWEEN CHRONIC INSOMNIA, THE HALLMARKS OF AGING AND THEIR IMPACT ON FRAILTY. MOREOVER, THE MOST RECENT RESEARCH ABOUT THE PUTATIVE EFFECT OF INSOMNIA THERAPEUTIC APPROACHES ON HALLMARKS OF AGING WILL BE ALSO HIGHLIGHTED. 2023 2 5263 35 PROMISING BIOMARKERS OF HUMAN AGING: IN SEARCH OF A MULTI-OMICS PANEL TO UNDERSTAND THE AGING PROCESS FROM A MULTIDIMENSIONAL PERSPECTIVE. THE AGING PROCESS HAS BEEN LINKED TO THE OCCURRENCE OF CHRONIC DISEASES AND FUNCTIONAL IMPAIRMENTS, INCLUDING CANCER, SARCOPENIA, FRAILTY, METABOLIC, CARDIOVASCULAR, AND NEURODEGENERATIVE DISEASES. NONETHELESS, AGING IS HIGHLY VARIABLE AND HETEROGENEOUS AND REPRESENTS A CHALLENGE FOR ITS CHARACTERIZATION. IN THIS SENSE, INTRINSIC CAPACITY (IC) STANDS AS A NOVEL PERSPECTIVE BY THE WORLD HEALTH ORGANIZATION, WHICH INTEGRATES THE INDIVIDUAL WELLBEING, ENVIRONMENT, AND RISK FACTORS TO UNDERSTAND AGING. HOWEVER, THERE IS A LACK OF QUANTITATIVE AND QUALITATIVE ATTRIBUTES TO DEFINE IT OBJECTIVELY. THEREFORE, IN THIS REVIEW WE ATTEMPT TO SUMMARIZE THE MOST RELEVANT AND PROMISING BIOMARKERS DESCRIBED IN CLINICAL STUDIES AT DATE OVER DIFFERENT MOLECULAR LEVELS, INCLUDING EPIGENOMICS, TRANSCRIPTOMICS, PROTEOMICS, METABOLOMICS, AND THE MICROBIOME. TO AID GERONTOLOGISTS, GERIATRICIANS, AND BIOMEDICAL RESEARCHERS TO UNDERSTAND THE AGING PROCESS THROUGH THE IC. AGING BIOMARKERS REFLECT THE PHYSIOLOGICAL STATE OF INDIVIDUALS AND THE UNDERLYING MECHANISMS RELATED TO HOMEOSTATIC CHANGES THROUGHOUT AN INDIVIDUAL LIFESPAN; THEY DEMONSTRATED THAT AGING COULD BE MEASURED INDEPENDENTLY OF TIME (THAT MAY EXPLAIN ITS HETEROGENEITY) AND TO BE HELPFUL TO PREDICT AGE-RELATED SYNDROMES AND MORTALITY. IN SUMMARY, WE HIGHLIGHT THE AREAS OF OPPORTUNITY AND GAPS OF KNOWLEDGE THAT MUST BE ADDRESSED TO FULLY INTEGRATE BIOMEDICAL FINDINGS INTO CLINICALLY USEFUL TOOLS AND INTERVENTIONS. 2020 3 6189 37 THE IMPACT OF LIFE STRESS ON HALLMARKS OF AGING AND ACCELERATED SENESCENCE: CONNECTIONS IN SICKNESS AND IN HEALTH. CHRONIC STRESS IS A RISK FACTOR FOR NUMEROUS AGING-RELATED DISEASES AND HAS BEEN SHOWN TO SHORTEN LIFESPAN IN HUMANS AND OTHER SOCIAL MAMMALS. YET HOW LIFE STRESS CAUSES SUCH A VAST RANGE OF DISEASES IS STILL LARGELY UNCLEAR. IN RECENT YEARS, THE IMPACT OF STRESS ON HEALTH AND AGING HAS BEEN INCREASINGLY ASSOCIATED WITH THE DYSREGULATION OF THE SO-CALLED HALLMARKS OF AGING. THESE ARE BASIC BIOLOGICAL MECHANISMS THAT INFLUENCE INTRINSIC CELLULAR FUNCTIONS AND WHOSE ALTERATION CAN LEAD TO ACCELERATED AGING. HERE, WE REVIEW CORRELATIONAL AND EXPERIMENTAL LITERATURE (PRIMARILY FOCUSING ON EVIDENCE FROM HUMANS AND MURINE MODELS) ON THE CONTRIBUTION OF LIFE STRESS - PARTICULARLY STRESS DERIVED FROM ADVERSE SOCIAL ENVIRONMENTS - TO TRIGGER HALLMARKS OF AGING, INCLUDING CELLULAR SENESCENCE, STERILE INFLAMMATION, TELOMERE SHORTENING, PRODUCTION OF REACTIVE OXYGEN SPECIES, DNA DAMAGE, AND EPIGENETIC CHANGES. WE ALSO EVALUATE THE VALIDITY OF STRESS-INDUCED SENESCENCE AND ACCELERATED AGING AS AN ETIOPATHOLOGICAL PROPOSITION. FINALLY, WE HIGHLIGHT CURRENT GAPS OF KNOWLEDGE AND FUTURE DIRECTIONS FOR THE FIELD, AND DISCUSS PERSPECTIVES FOR TRANSLATIONAL GEROSCIENCE. 2023 4 5945 32 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 5 6109 33 THE EPIGENETIC AGING, OBESITY, AND LIFESTYLE. THE PREVALENCE OF OBESITY HAS DRAMATICALLY INCREASED WORLDWIDE OVER THE PAST DECADES. AGING-RELATED CHRONIC CONDITIONS, SUCH AS TYPE 2 DIABETES AND CARDIOVASCULAR DISEASE, ARE MORE PREVALENT IN INDIVIDUALS WITH OBESITY, THUS REDUCING THEIR LIFESPAN. EPIGENETIC CLOCKS, THE NEW METRICS OF BIOLOGICAL AGE BASED ON DNA METHYLATION PATTERNS, COULD BE CONSIDERED A REFLECTION OF THE STATE OF ONE'S HEALTH. SEVERAL ENVIRONMENTAL EXPOSURES AND LIFESTYLE FACTORS CAN INDUCE EPIGENETIC AGING ACCELERATIONS, INCLUDING OBESITY, THUS LEADING TO AN INCREASED RISK OF AGE-RELATED DISEASES. THE INSIGHT INTO THE COMPLEX LINK BETWEEN OBESITY AND AGING MIGHT HAVE SIGNIFICANT IMPLICATIONS FOR THE PROMOTION OF HEALTH AND THE MITIGATION OF FUTURE DISEASE RISK. THE PRESENT NARRATIVE REVIEW TAKES INTO ACCOUNT THE INTERACTION BETWEEN EPIGENETIC AGING AND OBESITY, SUGGESTING THAT EPIGENOME MAY BE AN INTRIGUING TARGET FOR AGE-RELATED PHYSIOLOGICAL CHANGES AND THAT ITS MODIFICATION COULD INFLUENCE AGING AND PROLONG A HEALTHY LIFESPAN. THEREFORE, WE HAVE FOCUSED ON DNA METHYLATION AGE AS A CLINICAL BIOMARKER, AS WELL AS ON THE POTENTIAL REVERSAL OF EPIGENETIC AGE USING A PERSONALIZED DIET- AND LIFESTYLE-BASED INTERVENTION. 2022 6 739 31 CANCER TREATMENT-INDUCED ACCELERATED AGING IN CANCER SURVIVORS: BIOLOGY AND ASSESSMENT. RAPID IMPROVEMENTS IN CANCER SURVIVAL LED TO THE REALIZATION THAT MANY MODALITIES USED TO TREAT OR CONTROL CANCER MAY CAUSE ACCELERATED AGING IN CANCER SURVIVORS. CLINICALLY, "ACCELERATED AGING" PHENOTYPES IN CANCER SURVIVORS INCLUDE SECONDARY CANCERS, FRAILTY, CHRONIC ORGAN DYSFUNCTION, AND COGNITIVE IMPAIRMENT, ALL OF WHICH CAN IMPACT LONG-TERM HEALTH AND QUALITY OF LIFE IN CANCER SURVIVORS. THE TREATMENT-INDUCED ACCELERATED AGING IN CANCER SURVIVORS COULD BE EXPLAINED BY TELOMERE ATTRITION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, DNA DAMAGE, AND EPIGENETIC ALTERATIONS. SEVERAL AGING CLOCKS AND BIOMARKERS OF AGING HAVE BEEN PROPOSED TO BE POTENTIALLY USEFUL IN ESTIMATING BIOLOGICAL AGE, WHICH CAN PROVIDE SPECIFIC INFORMATION ABOUT HOW OLD AN INDIVIDUAL IS BIOLOGICALLY INDEPENDENT OF CHRONOLOGICAL AGE. MEASURING BIOLOGICAL AGE IN CANCER SURVIVORS MAY BE IMPORTANT FOR TWO REASONS. FIRST, IT CAN BETTER PREDICT THE RISK OF CANCER TREATMENT-RELATED COMORBIDITIES THAN CHRONOLOGICAL AGE. SECOND, BIOLOGICAL AGE MAY PROVIDE ADDITIONAL VALUE IN EVALUATING THE EFFECTS OF TREATMENTS AND PERSONALIZING CANCER THERAPIES TO MAXIMIZE EFFICACY OF TREATMENT. A DEEPER UNDERSTANDING OF TREATMENT-INDUCED ACCELERATED AGING IN INDIVIDUALS WITH CANCER MAY LEAD TO NOVEL STRATEGIES THAT REDUCE THE ACCELERATED AGING AND IMPROVE THE QUALITY OF LIFE IN CANCER SURVIVORS. 2021 7 4985 40 PATHWAYS TO AGING: THE MITOCHONDRION AT THE INTERSECTION OF BIOLOGICAL AND PSYCHOSOCIAL SCIENCES. COMPELLING EVIDENCE SUGGESTS THAT BOTH BIOLOGICAL AND PSYCHOSOCIAL FACTORS IMPACT THE PROCESS OF AGING. HOWEVER, OUR UNDERSTANDING OF THE DYNAMIC INTERPLAY AMONG BIOLOGICAL AND PSYCHOSOCIAL FACTORS ACROSS THE LIFE COURSE IS STILL FRAGMENTARY. FOR EXAMPLE, IT NEEDS TO BE ESTABLISHED HOW THE INTERACTION OF INDIVIDUAL FACTORS (E.G., GENETIC AND EPIGENETIC ENDOWMENT AND PERSONALITY), BEHAVIORAL FACTORS (E.G., PHYSICAL ACTIVITY, DIET, AND STRESS MANAGEMENT), AND PSYCHOSOCIAL EXPERIENCES (E.G., SOCIAL SUPPORT, WELL-BEING, SOCIOECONOMIC STATUS, AND MARRIAGE) IN PERINATAL, CHILDHOOD, AND ADULTHOOD INFLUENCE HEALTH ACROSS THE AGING CONTINUUM. THIS PAPER AIMS TO OUTLINE POTENTIAL INTERSECTION POINTS SERVING AS AN INTERFACE BETWEEN BIOLOGICAL AND PSYCHOSOCIAL FACTORS, WITH AN EMPHASIS ON THE MITOCHONDRION. MITOCHONDRIA ARE CELLULAR ORGANELLES WHICH PLAY A CRITICAL ROLE IN CELLULAR SENESCENCE. BOTH CHRONIC EXPOSURE TO PSYCHOSOCIAL STRESS AND GENETIC-BASED MITOCHONDRIAL DYSFUNCTION HAVE STRIKINGLY SIMILAR BIOLOGICAL CONSEQUENCES; BOTH PREDISPOSE INDIVIDUALS TO ADVERSE AGE-RELATED HEALTH DISORDERS AND EARLY MORTALITY. EXPLORING THE INTERACTIVE NATURE OF THE FACTORS RESULTING IN PATHWAYS TO NORMAL HEALTHY AGING, AS WELL AS THOSE LEADING TO MORBIDITY AND EARLY MORTALITY, WILL CONTINUE TO ENHANCE OUR ABILITY TO TRANSLATE RESEARCH INTO EFFECTIVE PRACTICES THAT CAN BE IMPLEMENTED THROUGHOUT THE LIFE COURSE TO OPTIMISE THE AGING PROCESS. 2011 8 625 29 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 9 3102 46 GENOMIC INSTABILITIES, CELLULAR SENESCENCE, AND AGING: IN VITRO, IN VIVO AND AGING-LIKE HUMAN SYNDROMES. AS AVERAGE LIFE SPAN AND ELDERLY PEOPLE PREVALENCE IN THE WESTERN WORLD POPULATION IS GRADUALLY INCREASING, THE INCIDENCE OF AGE-RELATED DISEASES SUCH AS CANCER, HEART DISEASES, DIABETES, AND DEMENTIA IS INCREASING, BEARING SOCIAL AND ECONOMIC CONSEQUENCES WORLDWIDE. UNDERSTANDING THE MOLECULAR BASIS OF AGING-RELATED PROCESSES CAN HELP EXTEND THE ORGANISM'S HEALTH SPAN, I.E., THE LIFE PERIOD IN WHICH THE ORGANISM IS FREE OF CHRONIC DISEASES OR DECREASE IN BASIC BODY FUNCTIONS. DURING THE LAST FEW DECADES, IMMENSE PROGRESS WAS MADE IN THE UNDERSTANDING OF MAJOR COMPONENTS OF AGING AND HEALTHY AGING BIOLOGY, INCLUDING GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC CHANGES, PROTEOSTASIS, NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND INTRACELLULAR COMMUNICATIONS. THIS PROGRESS HAS BEEN MADE BY THREE SPEAR-HEADED STRATEGIES: IN VITRO (CELL AND TISSUE CULTURE FROM VARIOUS SOURCES), IN VIVO (INCLUDES DIVERSE MODEL AND NON-MODEL ORGANISMS), BOTH CAN BE MANIPULATED AND TRANSLATED TO HUMAN BIOLOGY, AND THE STUDY OF AGING-LIKE HUMAN SYNDROMES AND HUMAN POPULATIONS. HEREIN, WE WILL FOCUS ON CURRENT REPOSITORY OF GENOMIC "SENESCENCE" STAGE OF AGING, WHICH INCLUDES HEALTH DECLINE, STRUCTURAL CHANGES OF THE GENOME, FAULTY DNA DAMAGE RESPONSE AND DNA DAMAGE, TELOMERE SHORTENING, AND EPIGENETIC ALTERATIONS. ALTHOUGH AGING IS A COMPLEX PROCESS, MANY OF THE "HALLMARKS" OF AGING ARE DIRECTLY RELATED TO DNA STRUCTURE AND FUNCTION. THIS REVIEW WILL ILLUSTRATE THE VARIETY OF THESE STUDIES, DONE IN IN VITRO, IN VIVO AND HUMAN LEVELS, AND HIGHLIGHT THE UNIQUE POTENTIAL AND CONTRIBUTION OF EACH RESEARCH LEVEL AND EVENTUALLY THE LINK BETWEEN THEM. 2018 10 5185 44 PREMATURE PHYSIOLOGIC AGING AS A PARADIGM FOR UNDERSTANDING INCREASED RISK OF ADVERSE HEALTH ACROSS THE LIFESPAN OF SURVIVORS OF CHILDHOOD CANCER. THE IMPROVEMENT IN SURVIVAL OF CHILDHOOD CANCER OBSERVED ACROSS THE PAST 50 YEARS HAS RESULTED IN A GROWING ACKNOWLEDGMENT THAT SIMPLY EXTENDING THE LIFESPAN OF SURVIVORS IS NOT ENOUGH. IT IS INCUMBENT ON BOTH THE CANCER RESEARCH AND THE CLINICAL CARE COMMUNITIES TO ALSO IMPROVE THE HEALTH SPAN OF SURVIVORS. IT IS WELL ESTABLISHED THAT AGING ADULT SURVIVORS OF CHILDHOOD CANCER ARE AT INCREASED RISK OF CHRONIC HEALTH CONDITIONS, RELATIVE TO THE GENERAL POPULATION. HOWEVER, AS THE FIRST GENERATION OF SURVIVORS AGE INTO THEIR 50S AND 60S, IT HAS BECOME INCREASINGLY EVIDENT THAT THIS POPULATION IS ALSO AT RISK OF EARLY ONSET OF PHYSIOLOGIC AGING. GERIATRIC MEASURES HAVE UNCOVERED EVIDENCE OF REDUCED STRENGTH AND SPEED AND INCREASED FATIGUE, ALL COMPONENTS OF FRAILTY, AMONG SURVIVORS WITH A MEDIAN AGE OF 33 YEARS, WHICH IS SIMILAR TO ADULTS OLDER THAN 65 YEARS OF AGE IN THE GENERAL POPULATION. FURTHERMORE, FRAILTY IN SURVIVORS INDEPENDENTLY INCREASED THE RISK OF MORBIDITY AND MORTALITY. ALTHOUGH THERE HAS BEEN A PAUCITY OF RESEARCH INVESTIGATING THE UNDERLYING BIOLOGIC MECHANISMS FOR ADVANCED PHYSIOLOGIC AGE IN SURVIVORS, RESULTS FROM GERIATRIC POPULATIONS SUGGEST FIVE BIOLOGICALLY PLAUSIBLE MECHANISMS THAT MAY BE POTENTIATED BY EXPOSURE TO CANCER THERAPIES: INCREASED CELLULAR SENESCENCE, REDUCED TELOMERE LENGTH, EPIGENETIC MODIFICATIONS, SOMATIC MUTATIONS, AND MITOCHONDRIAL DNA INFIDELITY. THERE IS NOW A CRITICAL NEED FOR RESEARCH TO ELUCIDATE THE BIOLOGIC MECHANISMS OF PREMATURE AGING IN SURVIVORS OF CHILDHOOD CANCER. THIS RESEARCH COULD PAVE THE WAY FOR NEW FRONTIERS IN THE PREVENTION OF THESE LIFE-CHANGING OUTCOMES. 2018 11 3676 37 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 12 285 28 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 13 456 41 APPLYING A LIFE COURSE BIOLOGICAL AGE FRAMEWORK TO IMPROVING THE CARE OF INDIVIDUALS WITH ADULT CANCERS: REVIEW AND RESEARCH RECOMMENDATIONS. IMPORTANCE: THE PRACTICE OF ONCOLOGY WILL INCREASINGLY INVOLVE THE CARE OF A GROWING POPULATION OF INDIVIDUALS WITH MIDLIFE AND LATE-LIFE CANCERS. MANAGING CANCER IN THESE INDIVIDUALS IS COMPLEX, BASED ON DIFFERENCES IN BIOLOGICAL AGE AT DIAGNOSIS. BIOLOGICAL AGE IS A MEASURE OF ACCUMULATED LIFE COURSE DAMAGE TO BIOLOGICAL SYSTEMS, LOSS OF RESERVE, AND VULNERABILITY TO FUNCTIONAL DETERIORATION AND DEATH. BIOLOGICAL AGE IS IMPORTANT BECAUSE IT AFFECTS THE ABILITY TO MANAGE THE RIGORS OF CANCER THERAPY, SURVIVORS' FUNCTION, AND CANCER PROGRESSION. HOWEVER, BIOLOGICAL AGE IS NOT ALWAYS CLINICALLY APPARENT. THIS REVIEW PRESENTS A CONCEPTUAL FRAMEWORK OF LIFE COURSE BIOLOGICAL AGING, SUMMARIZES CANDIDATE MEASURES, AND DESCRIBES A RESEARCH AGENDA TO FACILITATE CLINICAL TRANSLATION TO ONCOLOGY PRACTICE. OBSERVATIONS: MIDLIFE AND LATE-LIFE CANCERS ARE CHRONIC DISEASES THAT MAY ARISE FROM CUMULATIVE PATTERNS OF BIOLOGICAL AGING OCCURRING OVER THE LIFE COURSE. BEFORE DIAGNOSIS, EACH NEW PATIENT WAS ON A DISTINCT COURSE OF BIOLOGICAL AGING RELATED TO PAST EXPOSURES, LIFE EXPERIENCES, GENETICS, AND NONCANCER CHRONIC DISEASE. CANCER AND ITS TREATMENTS MAY ALSO BE ASSOCIATED WITH BIOLOGICAL AGING. SEVERAL MEASURES OF BIOLOGICAL AGE, INCLUDING P16INK4A, EPIGENETIC AGE, TELOMERE LENGTH, AND INFLAMMATORY AND BODY COMPOSITION MARKERS, HAVE BEEN USED IN ONCOLOGY RESEARCH. ONE OR MORE OF THESE MEASURES MAY BE USEFUL IN CANCER CARE, EITHER ALONE OR IN COMBINATION WITH CLINICAL HISTORY AND GERIATRIC ASSESSMENTS. HOWEVER, FURTHER RESEARCH WILL BE NEEDED BEFORE BIOLOGICAL AGE ASSESSMENT CAN BE RECOMMENDED IN ROUTINE PRACTICE, INCLUDING DETERMINATION OF SITUATIONS IN WHICH KNOWLEDGE ABOUT BIOLOGICAL AGE WOULD CHANGE TREATMENT, ASCERTAINING WHETHER TREATMENT EFFECTS ON BIOLOGICAL AGING ARE SHORT-LIVED OR PERSISTENT, AND TESTING INTERVENTIONS TO MODIFY BIOLOGICAL AGE, DECREASE TREATMENT TOXIC EFFECTS, AND MAINTAIN FUNCTIONAL ABILITIES. CONCLUSIONS AND RELEVANCE: UNDERSTANDING DIFFERENCES IN BIOLOGICAL AGING COULD ULTIMATELY ALLOW CLINICIANS TO BETTER PERSONALIZE TREATMENT AND SUPPORTIVE CARE, DEVELOP TAILORED SURVIVORSHIP CARE PLANS, AND PRESCRIBE PREVENTIVE OR AMELIORATIVE THERAPIES AND BEHAVIORS INFORMED BY AGING MECHANISMS. 2021 14 929 30 CHRONIC INFLAMMATION: ACCELERATOR OF BIOLOGICAL AGING. BIOLOGICAL AGING IS CHARACTERIZED BY A CHRONIC LOW-GRADE INFLAMMATION LEVEL. THIS CHRONIC PHENOMENON HAS BEEN NAMED "INFLAMM-AGING" AND IS A HIGHLY SIGNIFICANT RISK FACTOR FOR MORBIDITY AND MORTALITY IN THE OLDER PERSONS. THE MOST COMMON THEORIES OF INFLAMM-AGING INCLUDE REDOX STRESS, MITOCHONDRIAL DYSFUNCTION, GLYCATION, DEREGULATION OF THE IMMUNE SYSTEM, HORMONAL CHANGES, EPIGENETIC MODIFICATIONS, AND DYSFUNCTION TELOMERE ATTRITION. INFLAMM-AGING PLAYS A ROLE IN THE INITIATION AND PROGRESSION OF AGE-RELATED DISEASES SUCH AS TYPE II DIABETES, ALZHEIMER'S DISEASE, CARDIOVASCULAR DISEASE, FRAILTY, SARCOPENIA, OSTEOPOROSIS, AND CANCER. THIS REVIEW WILL COVER THE IDENTIFICATION OF PATHWAYS THAT CONTROL AGE-RELATED INFLAMMATION ACROSS MULTIPLE SYSTEMS AND ITS POTENTIAL CAUSAL ROLE IN CONTRIBUTING TO ADVERSE HEALTH OUTCOMES. 2017 15 5959 36 TELOMERE LENGTH AS A MARKER OF BIOLOGICAL AGE: STATE-OF-THE-ART, OPEN ISSUES, AND FUTURE PERSPECTIVES. TELOMERE SHORTENING IS A WELL-KNOWN HALLMARK OF BOTH CELLULAR SENESCENCE AND ORGANISMAL AGING. AN ACCELERATED RATE OF TELOMERE ATTRITION IS ALSO A COMMON FEATURE OF AGE-RELATED DISEASES. THEREFORE, TELOMERE LENGTH (TL) HAS BEEN RECOGNIZED FOR A LONG TIME AS ONE OF THE BEST BIOMARKERS OF AGING. RECENT RESEARCH FINDINGS, HOWEVER, INDICATE THAT TL PER SE CAN ONLY ALLOW A ROUGH ESTIMATE OF AGING RATE AND CAN HARDLY BE REGARDED AS A CLINICALLY IMPORTANT RISK MARKER FOR AGE-RELATED PATHOLOGIES AND MORTALITY. EVIDENCE IS OBTAINED THAT OTHER INDICATORS SUCH AS CERTAIN IMMUNE PARAMETERS, INDICES OF EPIGENETIC AGE, ETC., COULD BE STRONGER PREDICTORS OF THE HEALTH STATUS AND THE RISK OF CHRONIC DISEASE. HOWEVER, DESPITE THESE ISSUES AND LIMITATIONS, TL REMAINS TO BE VERY INFORMATIVE MARKER IN ACCESSING THE BIOLOGICAL AGE WHEN USED ALONG WITH OTHER MARKERS SUCH AS INDICES OF HOMEOSTATIC DYSREGULATION, FRAILTY INDEX, EPIGENETIC CLOCK, ETC. THIS REVIEW ARTICLE IS AIMED AT DESCRIBING THE CURRENT STATE OF THE ART IN THE FIELD AND AT DISCUSSING RECENT RESEARCH FINDINGS AND DIVERGENT VIEWPOINTS REGARDING THE USEFULNESS OF LEUKOCYTE TL FOR ESTIMATING THE HUMAN BIOLOGICAL AGE. 2020 16 637 34 BIOLOGY OF PREMATURE AGEING IN SURVIVORS OF CANCER. OVER 30 MILLION CANCER SURVIVORS EXIST WORLDWIDE. SURVIVORS HAVE AN EARLIER ONSET AND HIGHER INCIDENCE OF CHRONIC COMORBIDITIES, INCLUDING ENDOCRINOPATHIES, CARDIAC DYSFUNCTION, OSTEOPOROSIS, PULMONARY FIBROSIS, SECONDARY CANCERS AND FRAILTY THAN THE GENERAL POPULATION; HOWEVER, THE FUNDAMENTAL BASIS OF THESE CHANGES AT THE CELLULAR LEVEL IS UNKNOWN. AN ELECTRONIC SEARCH WAS PERFORMED ON EMBASE, MEDLINE IN-PROCESS & OTHER NON-INDEXED CITATIONS, AND THE COCHRANE CENTRAL REGISTER OF CONTROLLED TRIALS. ORIGINAL ARTICLES ADDRESSING THE CELLULAR BIOLOGY OF AGEING AND/OR THE MECHANISMS OF CANCER THERAPIES SIMILAR TO AGEING MECHANISMS WERE INCLUDED, AND REFERENCES OF THESE ARTICLES WERE REVIEWED FOR FURTHER SEARCH. WE FOUND MULTIPLE BIOLOGICAL PROCESS OF AGEING AT THE CELLULAR LEVEL AND THEIR ASSOCIATION WITH CANCER THERAPIES, AS WELL AS WITH CLINICAL EFFECTS. THE DIRECT EFFECTS OF VARIOUS CHEMOTHERAPIES AND RADIATION ON TELOMERE LENGTH, SENESCENT CELLS, EPIGENETIC MODIFICATIONS AND MICRORNA WERE FOUND. WE REVIEW THE EFFECTS OF CANCER THERAPIES ON RECOGNISED HALLMARKS OF AGEING. LONG-TERM COMORBIDITIES SEEN IN CANCER SURVIVORS MIMIC THE PHENOTYPES OF AGEING AND LIKELY RESULT FROM THE INTERACTION BETWEEN THERAPEUTIC EXPOSURES AND THE UNDERLYING BIOLOGY OF AGEING. LONG-TERM FOLLOW-UP OF CANCER SURVIVORS AND RESEARCH ON PREVENTION STRATEGIES SHOULD BE PURSUED TO INCREASE THE LENGTH AND QUALITY OF LIFE AMONG THE GROWING POPULATION OF CANCER SURVIVORS. 2017 17 640 36 BIOMARKERS OF AGING IN FRAILTY AND AGE-ASSOCIATED DISORDERS: STATE OF THE ART AND FUTURE PERSPECTIVE. ACCORDING TO THE GEROSCIENCE CONCEPT THAT ORGANISMAL AGING AND AGE-ASSOCIATED DISEASES SHARE THE SAME BASIC MOLECULAR MECHANISMS, THE IDENTIFICATION OF BIOMARKERS OF AGE THAT CAN EFFICIENTLY CLASSIFY PEOPLE AS BIOLOGICALLY OLDER (OR YOUNGER) THAN THEIR CHRONOLOGICAL (I.E. CALENDAR) AGE IS BECOMING OF PARAMOUNT IMPORTANCE. THESE PEOPLE WILL BE IN FACT AT HIGHER (OR LOWER) RISK FOR MANY DIFFERENT AGE-ASSOCIATED DISEASES, INCLUDING CARDIOVASCULAR DISEASES, NEURODEGENERATION, CANCER, ETC. IN TURN, PATIENTS SUFFERING FROM THESE DISEASES ARE BIOLOGICALLY OLDER THAN HEALTHY AGE-MATCHED INDIVIDUALS. MANY BIOMARKERS THAT CORRELATE WITH AGE HAVE BEEN DESCRIBED SO FAR. THE AIM OF THE PRESENT REVIEW IS TO DISCUSS THE USEFULNESS OF SOME OF THESE BIOMARKERS (ESPECIALLY SOLUBLE, CIRCULATING ONES) IN ORDER TO IDENTIFY FRAIL PATIENTS, POSSIBLY BEFORE THE APPEARANCE OF CLINICAL SYMPTOMS, AS WELL AS PATIENTS AT RISK FOR AGE-ASSOCIATED DISEASES. AN OVERVIEW OF SELECTED BIOMARKERS WILL BE DISCUSSED IN THIS REGARD, IN PARTICULAR WE WILL FOCUS ON BIOMARKERS RELATED TO METABOLIC STRESS RESPONSE, INFLAMMATION, AND CELL DEATH (IN PARTICULAR IN NEURODEGENERATION), ALL PHENOMENA CONNECTED TO INFLAMMAGING (CHRONIC, LOW-GRADE, AGE-ASSOCIATED INFLAMMATION). IN THE SECOND PART OF THE REVIEW, NEXT-GENERATION MARKERS SUCH AS EXTRACELLULAR VESICLES AND THEIR CARGOS, EPIGENETIC MARKERS AND GUT MICROBIOTA COMPOSITION, WILL BE DISCUSSED. SINCE RECENT PROGRESSES IN OMICS TECHNIQUES HAVE ALLOWED AN EXPONENTIAL INCREASE IN THE PRODUCTION OF LABORATORY DATA ALSO IN THE FIELD OF BIOMARKERS OF AGE, MAKING IT DIFFICULT TO EXTRACT BIOLOGICAL MEANING FROM THE HUGE MASS OF AVAILABLE DATA, ARTIFICIAL INTELLIGENCE (AI) APPROACHES WILL BE DISCUSSED AS AN INCREASINGLY IMPORTANT STRATEGY FOR EXTRACTING KNOWLEDGE FROM RAW DATA AND PROVIDING PRACTITIONERS WITH ACTIONABLE INFORMATION TO TREAT PATIENTS. 2023 18 5183 33 PREMATURE AGING IN CHILDHOOD CANCER SURVIVORS. PROGRESS IN MEDICINE HAS INCREASED THE SURVIVAL TIME OF CHILDREN SUFFERING FROM CANCER; >80% OF PATIENTS SURVIVE FOR AT LEAST 5 YEARS FROM THE END OF TREATMENT. HOWEVER, THERE ARE LATE EFFECTS OF ANTICANCER THERAPY, WHICH ACCOMPANY THIS SUCCESS. TWO-THIRDS OF CHILDHOOD CANCER SURVIVORS (CCSS) HAVE AT LEAST ONE LATE EFFECT (ANY SIDE EFFECTS OR COMPLICATIONS OF ANTICANCER TREATMENT THAT APPEAR MONTHS TO YEARS AFTER THE COMPLETION OF TREATMENT), E.G. ENDOCRINOPATHIES, CARDIOVASCULAR DISEASES OR SUBSEQUENT CANCERS, AND HALF OF THESE LATE EFFECTS ARE SERIOUS OR LIFE THREATENING. THESE LATE CONSEQUENCES OF CHILDHOOD CANCER TREATMENT POSE A SERIOUS HEALTH, SOCIAL AND ECONOMIC PROBLEM. A COMMON MECHANISM FOR DEVELOPING A NUMBER OF LATE EFFECTS IS THE ONSET OF PREMATURE BIOLOGICAL AGING, WHICH IS ASSOCIATED WITH THE EARLY ONSET OF CHRONIC DISEASES AND DEATH. CELLULAR SENESCENCE IN CANCER SURVIVORS IS CAUSED BY THERAPY THAT CAN INDUCE CHROMOSOMAL ABERRATIONS, MUTATIONS, TELOMERE SHORTENING, EPIGENETIC ALTERATIONS AND MITOCHONDRIAL DYSFUNCTIONS. THE MECHANISMS OF ACCELERATED AGING IN CANCER SURVIVORS HAVE NOT YET BEEN FULLY CLARIFIED. THE MEASUREMENT OF BIOLOGICAL AGE IN SURVIVORS CAN HELP IMPROVE THE UNDERSTANDING OF AGING MECHANISMS AND IDENTIFY RISK FACTORS FOR PREMATURE AGING. HOWEVER, TO THE BEST OF OUR KNOWLEDGE, NO SINGLE MARKER FOR THE EVALUATION OF BIOLOGICAL OR FUNCTIONAL AGE IS KNOWN, SO IT IS THEREFORE NECESSARY TO MEASURE THE CONSEQUENCES OF ANTICANCER TREATMENT USING COMPLEX ASSESSMENTS. THE PRESENT REVIEW PRESENTS AN OVERVIEW OF PREMATURE AGING IN CCSS AND OF THE MECHANISMS INVOLVED IN ITS DEVELOPMENT, FOCUSING ON THE ASSOCIATION OF SENESCENCE AND LATE EFFECTS. 2023 19 6346 23 THE ROLE OF EPIGENETICS IN CARDIOVASCULAR HEALTH AND AGEING: A FOCUS ON PHYSICAL ACTIVITY AND NUTRITION. THE CARDIOVASCULAR SYSTEM IS RESPONSIBLE FOR TRANSPORT OF BLOOD AND NUTRIENTS TO TISSUES, AND IS PIVOTAL TO THE PHYSIOLOGICAL HEALTH AND LONGEVITY. EPIGENETIC MODIFICATION IS A NATURAL, AGE-ASSOCIATED PROCESS RESULTING IN HIGHLY CONTEXTUALISED GENE EXPRESSION WITH CLEAR IMPLICATIONS FOR CELL DIFFERENTIATION AND DISEASE ONSET. BIOLOGICAL/EPIGENETIC AGE IS INDEPENDENT OF CHRONOLOGICAL AGE, CONSTITUTING A HIGHLY REFLECTIVE SNAPSHOT OF AN INDIVIDUAL'S OVERALL HEALTH. ACCELERATED VASCULAR AGEING IS OF MAJOR CONCERN, EFFECTIVELY LOWERING DISEASE THRESHOLD. AGE-RELATED CHRONIC ILLNESS INVOLVES A COMPLEX INTERPLAY BETWEEN MANY BIOLOGICAL PROCESSES AND IS MODULATED BY NON-MODIFIABLE AND MODIFIABLE RISK FACTORS. THESE ALTER THE STATIC GENOME BY A NUMBER OF EPIGENETIC MECHANISMS, WHICH CHANGE GENE EXPRESSION IN AN AGE AND LIFESTYLE DEPENDENT MANNER. THIS 'EPIGENETIC DRIFT' IMPACTS HEALTH AND CONTRIBUTES TO THE ETIOLOGY OF CHRONIC ILLNESS. LIFESTYLE FACTORS MAY CAUSE ACCELERATION OF THIS EPIGENETIC "CLOCK", PRE-DISPOSING INDIVIDUALS TO CARDIOVASCULAR DISEASE. NUTRITION AND PHYSICAL ACTIVITY ARE MODIFIABLE LIFESTYLE CHOICES, SYNERGISTICALLY CONTRIBUTING TO CARDIOVASCULAR HEALTH. THEY REPRESENT A POWERFUL POTENTIAL EPIGENETIC INTERVENTION POINT FOR EFFECTIVE CARDIOVASCULAR PROTECTIVE AND MANAGEMENT STRATEGIES. THUS, TOGETHER WITH TRADITIONAL RISK FACTORS, MONITORING THE EPIGENETIC SIGNATURE OF AGEING MAY PROVE BENEFICIAL FOR TAILORING LIFESTYLE TO FIT BIOLOGY - SUPPORTING THE INCREASINGLY POPULAR CONCEPT OF "AGEING WELL". 2018 20 2855 43 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