1 5685 138 SHOULD WE INVEST IN BIOLOGICAL AGE PREDICTORS TO TREAT COLORECTAL CANCER IN OLDER ADULTS? COLORECTAL CANCER (CRC) IS A CHRONIC DISEASE OF THE OLD POPULATION WITH SLOW DEVELOPMENT PROGRESSING INTO CLINICAL SIGNS AND SYMPTOMS. BIOLOGICAL AGING IS CHARACTERIZED BY E.G. MITOCHONDRIAL DYSFUNCTION AND EPIGENETIC ALTERATIONS (E.G. METHYLATION) - MECHANISMS THAT ARE ALSO IMPORTANT IN CANCER DEVELOPMENT. FOR CRC, SPECIFIC TYPES OF TUMORS ARE DISTINGUISHABLE BY THEIR METHYLATION PATTERNS AND SEVERAL DETECTION METHODS USING DIFFERENT EPIGENETIC MARKS HAVE BEEN DEVELOPED AS SIGNATURES FOR THE DISEASE. BIOLOGICAL AGE ASSESSED BY DNA METHYLATION PATTERNS FROM BLOOD, I.E. THE EPIGENETIC CLOCK, IS HIGHER IN CRC PATIENTS COMPARED TO CONTROLS, AND MAY BE A TOOL FOR IDENTIFYING INDIVIDUALS AT INCREASED RISK FOR CRC. OTHER TYPES OF BIOMARKERS OF AGING ARE USEFUL TO CALCULATE BIOLOGICAL AGE, SUCH AS METABOLITES, PROTEIN LEVELS, INFLAMMATORY MARKERS AND CLINICAL BIOMARKERS, WHERE COMPOSITE SCORES OF BIOMARKERS HAVE BEEN USED TO ASSESS THE RISK OF CRC AND COLORECTAL ADENOMAS. CLINICAL ASSESSMENTS OF BIOLOGICAL AGING INCLUDES FRAILTY, WHICH IS A GERIATRIC SYNDROME CHARACTERIZED BY INCREASED VULNERABILITY TO ADVERSE OUTCOMES. MORE THAN HALF OF THE CRC PATIENTS ARE ESTIMATED TO BE FRAIL OR PRE-FRAIL, AND THESE INDIVIDUALS ARE AT INCREASED RISK OF POSTOPERATIVE COMPLICATIONS, POORER PROGNOSIS, TREATMENT INTOLERANCE AND DEATH. HENCE, CONSIDERING FRAILTY AS PART OF BIOLOGICAL AGE IN CRC PATIENTS MAY HELP IDENTIFYING THOSE AT NEED OF CLOSE MONITORING. IN SUMMARY, FUTURE SCREENING PROGRAMS FOR CRC MAY MAKE USE OF BIOLOGICAL AGE ASSESSMENTS, E.G. BY EPIGENETIC CLOCK OR COMPOSITE SCORES. MONITORING DISEASE RELAPSE AND TREATMENT RESPONSE SHOULD BE ENHANCED IN FRAIL INDIVIDUALS FOR BETTER PROGNOSIS. 2020 2 1958 41 EPIGENETIC AGING AND COLORECTAL CANCER: STATE OF THE ART AND PERSPECTIVES FOR FUTURE RESEARCH. ALTHOUGH TRANSLATIONAL RESEARCH HAS IDENTIFIED A LARGE NUMBER OF POTENTIAL BIOMARKERS INVOLVED IN COLORECTAL CANCER (CRC) CARCINOGENESIS, A BETTER UNDERSTANDING OF THE MOLECULAR PATHWAYS ASSOCIATED WITH BIOLOGICAL AGING IN COLORECTAL CELLS AND TISSUES IS NEEDED. HERE, WE AIM TO SUMMARIZE THE STATE OF THE ART ABOUT THE ROLE OF AGE ACCELERATION, DEFINED AS THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE, IN THE DEVELOPMENT AND PROGRESSION OF CRC. SOME STUDIES HAVE SHOWN THAT ACCELERATED BIOLOGICAL AGING IS POSITIVELY ASSOCIATED WITH THE RISK OF CANCER AND DEATH IN GENERAL. IN LINE WITH THESE FINDINGS, OTHER STUDIES HAVE SHOWN HOW THE ASSESSMENT OF EPIGENETIC AGE IN PEOPLE AT RISK FOR CRC COULD BE HELPFUL FOR MONITORING THE MOLECULAR RESPONSE TO PREVENTIVE INTERVENTIONS. MOREOVER, IT WOULD BE INTERESTING TO INVESTIGATE WHETHER ABERRANT EPIGENETIC AGING COULD HELP IDENTIFY CRC PATIENTS WITH A HIGH RISK OF RECURRENCE AND A WORST PROGNOSIS, AS WELL AS THOSE WHO RESPOND POORLY TO TREATMENT. YET, THE APPLICATION OF THIS NOVEL CONCEPT IS STILL IN ITS INFANCY, AND FURTHER RESEARCH SHOULD BE ENCOURAGED IN ANTICIPATION OF FUTURE APPLICATIONS IN CLINICAL PRACTICE. 2020 3 1516 42 DNA METHYLATION AS A BIOMARKER OF AGING IN EPIDEMIOLOGIC STUDIES. CANCER IS LARGELY AN AGING DISEASE. ACCELERATED BIOLOGICAL AGING MAY BE THE STRONGEST PREDICTOR OF CANCER AND OTHER CHRONIC DISEASE RISKS. IN THE ABSENCE OF RELIABLE AND QUANTIFIABLE BIOMARKERS OF AGING TO DATE, IT HAS LONG BEEN OBSERVED THAT TUMORIGENESIS SHARES DISTINCT EPIGENETIC ALTERATIONS WITH THE AGING PROCESS. RECENTLY, EPIGENETIC AGE ESTIMATES HAVE BEEN DEVELOPED BASED ON THE AVAILABILITY OF GENOME-WIDE DNA METHYLATION PROFILES, BY APPLYING IN THE PREDICTION FORMULA THE METHYLATION LEVEL AT A SUBSET OF HIGHLY PREDICTIVE METHYLATION SITES, CALLED EPIGENETIC CLOCK. THESE DNA METHYLATION AGE ESTIMATES HAVE PRODUCED REMARKABLY STRONG CORRELATIONS WITH CHRONOLOGICAL AGE, WITH A SMALL DEVIATION AND HIGH REPRODUCIBILITY ACROSS DIFFERENT AGE GROUPS AND STUDY POPULATIONS. MOREOVER, AN INCREASING NUMBER OF EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED AN INDEPENDENT ASSOCIATION OF DNA METHYLATION AGE OR THE EXTENT OF ACCELERATION WITH MORTALITY AND VARIOUS AGING-RELATED CONDITIONS, EVEN AFTER ACCOUNTING FOR DIFFERENCES IN CHRONOLOGICAL AGE AND OTHER RISK FACTORS. ALTHOUGH EPIGENETIC PROFILES ARE KNOWN TO BE TISSUE-SPECIFIC, BOTH TARGET TISSUE- AND MULTIPLE TISSUE-DERIVED ESTIMATES APPEAR TO PERFORM WELL TO CAPTURE WHAT IS THOUGHT TO BE THE CUMULATIVE EPIGENETIC DRIFT THAT REPRESENTS A MULTIFACTORIAL DEGENERATIVE PROCESS ACROSS TISSUES AND ORGANISMS. FURTHER REFINEMENT OF THE EPIGENETIC AGE ESTIMATES IS ANTICIPATED OVER TIME TO ACCOMMODATE A BETTER TECHNOLOGICAL COVERAGE OF THE METHYLOME AND A BETTER UNDERSTANDING OF THE BIOLOGY UNDERLYING PREDICTIVE REGIONS. EPIDEMIOLOGIC PRINCIPLES WILL REMAIN CRITICAL FOR THE EVALUATION OF RESEARCH FINDINGS INVOLVING, FOR EXAMPLE, DIFFERENT STUDY POPULATIONS, DESIGN, FOLLOW-UP TIME, AND QUALITY OF COVARIATE DATA. OVERALL, THE EPIGENETIC AGE ESTIMATES ARE AN EXCITING DEVELOPMENT WITH USEFUL IMPLICATIONS FOR BIOMEDICAL RESEARCH OF HEALTHY AGING AND DISEASE PREVENTION AND CONTROL. 2018 4 739 43 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 5 640 54 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 6 560 38 BACK TO THE FUTURE: EPIGENETIC CLOCK PLASTICITY TOWARDS HEALTHY AGING. AGING IS THE MOST IMPORTANT RISK FACTOR FOR MAJOR HUMAN LIFESTYLE DISEASES, INCLUDING CANCER, NEUROLOGICAL AND CARDIOMETABOLIC DISORDERS. DUE TO THE COMPLEX INTERPLAY BETWEEN GENETICS, LIFESTYLE AND ENVIRONMENTAL FACTORS, SOME INDIVIDUALS SEEM TO AGE FASTER THAN OTHERS, WHEREAS CENTENARIANS SEEM TO HAVE A SLOWER AGING PROCESS. THEREFORE, A BIOCHEMICAL BIOMARKER REFLECTING THE RELATIVE BIOLOGICAL AGE WOULD BE HELPFUL TO PREDICT AN INDIVIDUAL'S HEALTH STATUS AND AGING DISEASE RISK. ALTHOUGH IT IS ALREADY KNOWN FOR YEARS THAT CUMULATIVE EPIGENETIC CHANGES OCCUR UPON AGING, DNA METHYLATION PATTERNS WERE ONLY RECENTLY USED TO CONSTRUCT AN EPIGENETIC CLOCK PREDICTOR FOR BIOLOGICAL AGE, WHICH IS A MEASURE OF HOW WELL YOUR BODY FUNCTIONS COMPARED TO YOUR CHRONOLOGICAL AGE. MOREOVER, THE EPIGENETIC DNA METHYLATION CLOCK SIGNATURE IS INCREASINGLY APPLIED AS A BIOMARKER TO ESTIMATE AGING DISEASE SUSCEPTIBILITY AND MORTALITY RISK. FINALLY, THE EPIGENETIC CLOCK SIGNATURE COULD BE USED AS A LIFESTYLE MANAGEMENT TOOL TO MONITOR HEALTHY AGING, TO EVALUATE PREVENTIVE INTERVENTIONS AGAINST CHRONIC AGING DISORDERS AND TO EXTEND HEALTHY LIFESPAN. DISSECTING THE MECHANISM OF THE EPIGENETIC AGING CLOCK WILL YIELD VALUABLE INSIGHTS INTO THE AGING PROCESS AND HOW IT CAN BE MANIPULATED TO IMPROVE HEALTH SPAN. 2018 7 5959 35 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 8 3676 43 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 9 1206 30 COUNTERACTING AGED DNA METHYLATION STATES TO COMBAT AGEING AND AGE-RELATED DISEASES. DNA METHYLATION (DNAM) OVERWRITES INFORMATION ABOUT MULTIPLE EXTRINSIC FACTORS ON THE GENOME. AGE IS ONE OF THESE FACTORS. AGE CAUSES CHARACTERISTIC DNAM CHANGES THAT ARE THOUGHT TO BE NOT ONLY MAJOR DRIVERS OF NORMAL AGEING BUT ALSO PRECURSORS TO DISEASES, CANCER BEING ONE OF THESE. ALTHOUGH THERE IS STILL MUCH TO LEARN ABOUT THE RELATIONSHIP BETWEEN AGEING, AGE-RELATED DISEASES AND DNAM, WE NOW KNOW HOW TO INTERPRET SOME OF THE EFFECTS CAUSED BY AGE IN THE FORM OF CHANGES IN METHYLATION MARKS AT SPECIFIC LOCI. IN FACT, THESE CHANGES FORM THE BASIS OF THE SO CALLED "EPIGENETIC CLOCKS", WHICH TRANSLATE THE GENOMIC METHYLATION PROFILE INTO AN "EPIGENETIC AGE". EPIGENETIC AGE DOES NOT ONLY ESTIMATE CHRONOLOGICAL AGE BUT CAN ALSO PREDICT THE RISK OF CHRONIC DISEASES AND MORTALITY. EPIGENETIC AGE IS BELIEVED TO BE ONE OF THE MOST ACCURATE METRICS OF BIOLOGICAL AGE. INITIAL EVIDENCE HAS RECENTLY BEEN GATHERED POINTING TO THE POSSIBILITY THAT THE RATE OF EPIGENETIC AGEING CAN BE SLOWED DOWN OR EVEN REVERSED. IN THIS REVIEW, WE DISCUSS SOME OF THE MOST RELEVANT ADVANCES IN THIS FIELD. EXPECTED OUTCOME IS THAT THIS APPROACH CAN PROVIDE INSIGHTS INTO HOW TO PRESERVE HEALTH AND REDUCE THE IMPACT OF AGEING DISEASES IN HUMANS. 2022 10 728 37 CAN WE IDENTIFY PATIENTS WITH HIGH RISK OF OSTEOARTHRITIS PROGRESSION WHO WILL RESPOND TO TREATMENT? A FOCUS ON BIOMARKERS AND FRAILTY. OSTEOARTHRITIS (OA), A DISEASE AFFECTING DIFFERENT PATIENT PHENOTYPES, APPEARS AS AN OPTIMAL CANDIDATE FOR PERSONALIZED HEALTHCARE. THE AIM OF THE DISCUSSIONS OF THE EUROPEAN SOCIETY FOR CLINICAL AND ECONOMIC ASPECTS OF OSTEOPOROSIS AND OSTEOARTHRITIS (ESCEO) WORKING GROUP WAS TO EXPLORE THE VALUE OF MARKERS OF DIFFERENT SOURCES IN DEFINING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. THE ESCEO ORGANIZED A SERIES OF MEETINGS TO EXPLORE THE POSSIBILITY OF IDENTIFYING PATIENTS WHO WOULD MOST BENEFIT FROM TREATMENT FOR OA, ON THE BASIS OF RECENT DATA AND EXPERT OPINION. IN THE FIRST MEETING, PATIENT PHENOTYPES WERE IDENTIFIED ACCORDING TO THE NUMBER OF AFFECTED JOINTS, BIOMECHANICAL FACTORS, AND THE PRESENCE OF LESIONS IN THE SUBCHONDRAL BONE. IN THE SECOND MEETING, SUMMARIZED IN THE PRESENT ARTICLE, THE WORKING GROUP EXPLORED OTHER MARKERS INVOLVED IN OA. PROFILES OF PATIENTS MAY BE DEFINED ACCORDING TO THEIR LEVEL OF PAIN, FUNCTIONAL LIMITATION, AND PRESENCE OF COEXISTENT CHRONIC CONDITIONS INCLUDING FRAILTY STATUS. A CONSIDERABLE AMOUNT OF DATA SUGGESTS THAT MAGNETIC RESONANCE IMAGING MAY ALSO ASSIST IN DELINEATING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. AMONG MULTIPLE BIOCHEMICAL BIOMARKERS IDENTIFIED, NONE IS SUFFICIENTLY VALIDATED AND RECOGNIZED TO IDENTIFY PATIENTS WHO SHOULD BE TREATED. CONSIDERABLE EFFORTS ARE ALSO BEING MADE TO IDENTIFY GENETIC AND EPIGENETIC FACTORS INVOLVED IN OA, BUT RESULTS ARE STILL LIMITED. THE MANY POTENTIAL BIOMARKERS THAT COULD BE USED AS POTENTIAL STRATIFIERS ARE PROMISING, BUT MORE RESEARCH IS NEEDED TO CHARACTERIZE AND QUALIFY THE EXISTING BIOMARKERS AND TO IDENTIFY NEW CANDIDATES. 2015 11 5183 42 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 12 625 34 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 13 456 49 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 3577 39 IMPACT OF NUTRITION ON TELOMERE HEALTH: SYSTEMATIC REVIEW OF OBSERVATIONAL COHORT STUDIES AND RANDOMIZED CLINICAL TRIALS. DIET, PHYSICAL ACTIVITY, AND OTHER LIFESTYLE FACTORS HAVE BEEN IMPLICATED IN THE PATHOPHYSIOLOGY OF SEVERAL CHRONIC DISEASES, BUT ALSO IN A LOWER TOTAL MORTALITY AND LONGER LIFE EXPECTANCY. ONE OF THE MECHANISMS IN WHICH DIET CAN REDUCE THE RISK OF DISEASE IS WITH REGARD TO ITS IMPACT ON TELOMERES. TELOMERE LENGTH (TL) IS HIGHLY CORRELATED TO CHRONOLOGICAL AGE AND METABOLIC STATUS. INDIVIDUALS WITH SHORTER TELOMERES ARE AT HIGHER RISK OF CHRONIC DISEASES AND MORTALITY. DIET MAY INFLUENCE TL BY SEVERAL MECHANISMS SUCH AS REGULATING OXIDATIVE STRESS AND INFLAMMATION OR MODULATING EPIGENETIC REACTIONS. THE PRESENT SYSTEMATIC REVIEW AIMS TO EXAMINE THE RESULTS FROM EPIDEMIOLOGIC AND CLINICAL TRIALS CONDUCTED IN HUMANS EVALUATING THE ROLE OF NUTRIENTS, FOOD GROUPS, AND DIETARY PATTERNS ON TL. WE ALSO DISCUSS THE POSSIBLE MECHANISMS OF ACTION THAT INFLUENCE THIS PROCESS, WITH THE PERSPECTIVE THAT TL COULD BE A NOVEL BIOMARKER INDICATING THE RISK OF METABOLIC DISTURBANCES AND AGE-RELATED DISEASES. THE AVAILABLE EVIDENCE SUGGESTS THAT SOME ANTIOXIDANT NUTRIENTS, THE CONSUMPTION OF FRUITS AND VEGETABLES, AND MEDITERRANEAN DIET ARE MAINLY ASSOCIATED WITH LONGER TELOMERES. HOWEVER, MOST OF THE EVIDENCE IS BASED ON HIGH HETEROGENIC OBSERVATIONAL STUDIES AND VERY FEW RANDOMIZED CLINICAL TRIALS (RCTS). THEREFORE, THE ASSOCIATIONS SUMMARIZED IN THE PRESENT REVIEW NEED TO BE CONFIRMED WITH LARGER PROSPECTIVE COHORT STUDIES AND BETTER-DESIGNED RCTS. 2020 15 777 39 CELL-FREE CIRCULATING EPIGENOMIC SIGNATURES: NON-INVASIVE BIOMARKER FOR CARDIOVASCULAR AND OTHER AGE-RELATED CHRONIC DISEASES. THE BURDEN OF CARDIO-VASCULAR AND OTHER AGE-RELATED NON-COMMUNICABLE DISEASES ARE RAPIDLY INCREASING WORLDWIDE. MAJORITY OF THESE CHRONIC AILMENTS ARE CURABLE, IF DIAGNOSED AT EARLY STAGES. CANDIDATE BIOMARKERS OF EARLY DETECTION ARE THEREFORE ESSENTIAL FOR IDENTIFICATION OF HIGH-RISK INDIVIDUALS, PROMPT AND ACCURATE DISEASE DIAGNOSIS, AND TO MONITOR THERAPEUTIC RESPONSE. THE FUNCTIONAL SIGNIFICANCE OF CIRCULATING NUCLEIC ACIDS THAT RECAPITULATE SPECIFIC DISEASE PROFILES IS NOW WELL ESTABLISHED. BUT SUBTLE CHANGES IN DNA SEQUENCE MAY NOT SOLELY REFLECT THE DIFFERENTIATION OF GENE EXPRESSION PATTERNS OBSERVED IN DIVERSE SET OF DISEASES AS EPIGENETIC PHENOMENA PLAY A LARGER ROLE IN AETIOLOGY AND PATHO-PHYSIOLOGY. UNLIKE GENETIC MARKERS, KNOWLEDGE ABOUT THE DIAGNOSTIC UTILITY OF CIRCULATING EPIGENETIC SIGNATURES: METHYLATED DNA; MICRO RNA AND MODIFIED HISTONES ARE DEFICIENT. CHARACTERIZATION OF THESE NOVEL ENTITIES THROUGH OMICS-BASED MOLECULAR TECHNOLOGIES MIGHT PROMPT DEVELOPMENT OF A RANGE OF LABORATORY-BASED STRATEGIES, THEREBY ACCELERATING THEIR BROADER TRANSLATIONAL PURPOSE FOR EARLY DISEASE DIAGNOSIS, MONITORING THERAPEUTIC RESPONSE AND DRUG RESISTANCE. HOWEVER, LARGEST OPPORTUNITY FOR INNOVATION LIES IN DEVELOPING POINT-OF-CARE TESTS WITH ACCURATE DIAGNOSTIC AND HIGHER PROGNOSTIC SCORE THAT IS APPLICABLE FOR SCREENING OF HIGH-RISK POPULATIONS. 2017 16 1168 45 CONTRIBUTION OF EPITHELIAL AND GUT MICROBIOME INFLAMMATORY BIOMARKERS TO THE IMPROVEMENT OF COLORECTAL CANCER PATIENTS' STRATIFICATION. IN ORDER TO ENSURE THAT PRIMARY ENDPOINTS OF CLINICAL STUDIES ARE ATTAINED, THE PATIENTS' STRATIFICATION IS AN IMPORTANT ASPECT. SELECTION CRITERIA INCLUDE AGE, GENDER, AND ALSO SPECIFIC BIOMARKERS, SUCH AS INFLAMMATION SCORES. THESE CRITERIA ARE NOT SUFFICIENT TO ACHIEVE A STRAIGHTFORWARD SELECTION, HOWEVER, IN CASE OF MULTIFACTORIAL DISEASES, WITH UNKNOWN OR PARTIALLY IDENTIFIED MECHANISMS, OCCASIONALLY INCLUDING HOST FACTORS, AND THE MICROBIOME. IN THESE CASES, THE EFFICACY OF INTERVENTIONS IS DIFFICULT TO PREDICT, AND AS A RESULT, THE SELECTION OF SUBJECTS IS OFTEN RANDOM. COLORECTAL CANCER (CRC) IS A HIGHLY HETEROGENEOUS DISEASE, WITH VARIABLE CLINICAL FEATURES, OUTCOMES, AND RESPONSE TO THERAPY; THE CRC ONSET AND PROGRESS INVOLVES MULTIPLE SEQUENTIAL STEPS WITH ACCUMULATION OF GENETIC ALTERATIONS, NAMELY, MUTATIONS, GENE AMPLIFICATION, AND EPIGENETIC CHANGES. THE GUT MICROBES, EITHER EUBIOTIC OR DYSBIOTIC, COULD INFLUENCE THE CRC EVOLUTION THROUGH A COMPLEX AND VERSATILE CROSSTALK WITH THE INTESTINAL AND IMMUNE CELLS, PERMANENTLY CHANGING THE TUMOR MICROENVIRONMENT. THERE HAVE BEEN SIGNIFICANT ADVANCES IN THE DEVELOPMENT OF PERSONALIZED APPROACHES FOR CRC SCREENING, TREATMENT, AND POTENTIAL PREVENTION. ADVANCES IN MOLECULAR TECHNIQUES BRING NEW CRITERIA FOR PATIENTS' STRATIFICATION-MUTATIONAL ANALYSIS AT THE TIME OF DIAGNOSIS TO GUIDE TREATMENT, FOR EXAMPLE. GUT MICROBIOME HAS EMERGED AS THE MAIN TRIGGER OF GUT MUCOSAL HOMEOSTASIS. THIS MAY IMPACT CANCER SUSCEPTIBILITY THROUGH MAINTENANCE OF THE EPITHELIAL/MUCUS BARRIER AND PRODUCTION OF PROTECTIVE METABOLITES, SUCH AS SHORT-CHAIN FATTY ACIDS (SCFAS) VIA INTERACTIONS WITH THE HOSTS' DIET AND METABOLISM. MICROBIOME DYSBIOSIS LEADS TO THE ENRICHMENT OF CANCER-PROMOTING BACTERIAL POPULATIONS, LOSS OF PROTECTIVE POPULATIONS OR MAINTAINING AN INFLAMMATORY CHRONIC STATE, ALL OF WHICH CONTRIBUTE TO THE DEVELOPMENT AND PROGRESSION OF CRC. MEANWHILE, VARIATIONS IN PATIENT RESPONSES TO ANTI-CANCER IMMUNO- AND CHEMOTHERAPIES WERE ALSO LINKED TO INTER-INDIVIDUAL DIFFERENCES IN INTESTINE MICROBIOMES. THE AUTHORS AIM TO HIGHLIGHT THE CONTRIBUTION OF EPITHELIAL AND GUT MICROBIOME INFLAMMATORY BIOMARKERS IN THE IMPROVEMENT OF CRC PATIENTS' STRATIFICATION TOWARDS A PERSONALIZED APPROACH OF EARLY DIAGNOSIS AND TREATMENT. 2021 17 637 30 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 18 1385 45 DIABETES IN CHILDHOOD CANCER SURVIVORS: EMERGING CONCEPTS IN PATHOPHYSIOLOGY AND FUTURE DIRECTIONS. WITH ADVANCEMENTS IN CANCER TREATMENT AND SUPPORTIVE CARE, THERE IS A GROWING POPULATION OF CHILDHOOD CANCER SURVIVORS WHO EXPERIENCE A SUBSTANTIAL BURDEN OF COMORBIDITIES RELATED TO HAVING RECEIVED CANCER TREATMENT AT A YOUNG AGE. DESPITE AN OVERALL REDUCTION IN THE INCIDENCE OF MOST CHRONIC HEALTH CONDITIONS IN CHILDHOOD CANCER SURVIVORS OVER THE PAST SEVERAL DECADES, THE CUMULATIVE INCIDENCE OF CERTAIN LATE EFFECTS, IN PARTICULAR DIABETES MELLITUS (DM), HAS INCREASED. THE IMPLICATIONS ARE SIGNIFICANT, BECAUSE DM IS A KEY RISK FACTOR FOR CARDIOVASCULAR DISEASE, A LEADING CAUSE OF PREMATURE DEATH IN CHILDHOOD CANCER SURVIVORS. THE UNDERLYING PATHOPHYSIOLOGY OF DM IN CANCER SURVIVORS IS MULTIFACTORIAL. DM DEVELOPS AT YOUNGER AGES IN SURVIVORS COMPARED TO CONTROLS, WHICH MAY REFLECT AN "ACCELERATED AGING" PHENOTYPE IN THESE INDIVIDUALS. THE TREATMENT-RELATED EXPOSURES (I.E., CHEMOTHERAPY, RADIATION) THAT INCREASE RISK FOR DM IN CHILDHOOD CANCER SURVIVORS MAY BE MORE THAN ADDITIVE WITH ESTABLISHED DM RISK FACTORS (E.G., OLDER AGE, OBESITY, RACE, AND ETHNICITY). EMERGING RESEARCH ALSO POINTS TO PARALLELS IN CELLULAR PROCESSES IMPLICATED IN AGING- AND CANCER TREATMENT-RELATED DM. STILL, THERE REMAINS MARKED INTER-INDIVIDUAL VARIABILITY REGARDING RISK OF DM THAT IS NOT EXPLAINED BY DEMOGRAPHIC AND THERAPEUTIC RISK FACTORS ALONE. RECENT STUDIES HAVE HIGHLIGHTED THE ROLE OF GERMLINE GENETIC RISK FACTORS AND EPIGENETIC MODIFICATIONS THAT ARE ASSOCIATED WITH RISK OF DM IN BOTH THE GENERAL AND ONCOLOGY POPULATIONS. THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF RECOGNIZED RISK FACTORS FOR DM IN CHILDHOOD CANCER SURVIVORS TO HELP INFORM TARGETED APPROACHES FOR DISEASE SCREENING, PREVENTION, AND TREATMENT. FURTHERMORE, IT HIGHLIGHTS THE EXISTING SCIENTIFIC GAPS IN UNDERSTANDING THE RELATIVE CONTRIBUTIONS OF INDIVIDUAL THERAPEUTIC EXPOSURES AND THE MECHANISMS BY WHICH THEY EXERT THEIR EFFECTS THAT UNIQUELY PREDISPOSE THIS POPULATION TO DM FOLLOWING CANCER TREATMENT. 2023 19 822 37 CHARACTERIZATION OF BLOOD SURROGATE IMMUNE-METHYLATION BIOMARKERS FOR IMMUNE CELL INFILTRATION IN CHRONIC INFLAMMAGING DISORDERS. ALZHEIMER'S DISEASE (AD) AND ATHEROSCLEROSIS ARE BOTH CHRONIC AGE- AND INFLAMMATION-DEPENDENT DISEASES. IN ADDITION, ATHEROSCLEROSIS IS FREQUENTLY OBSERVED IN AD PATIENTS INDICATING COMMON INVOLVEMENT OF VASCULAR COMPONENTS IN BOTH DISEASE ETIOLOGIES. RECENTLY, EPIGENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED EPIGENETIC ALTERATIONS, AND IN PARTICULARLY DNA METHYLATION CHANGES FOR BOTH DISORDERS. WE HYPOTHESIZED THE EXISTENCE OF A COMMON DNA METHYLATION PROFILE IN ATHEROSCLEROSIS AND AD WHICH MAY BE VALUABLE AS A BLOOD-BASED DNA METHYLATION INFLAMMAGING BIOMARKER. USING PUBLICLY AVAILABLE 450K ILLUMINA METHYLATION DATASETS, WE IDENTIFIED A CO-METHYLATION NETWORK ASSOCIATED WITH BOTH ATHEROSCLEROSIS AND AD IN WHOLE BLOOD SAMPLES. THIS METHYLATION PROFILE APPEARED TO INDICATE SHIFTS IN BLOOD IMMUNE CELL TYPE DISTRIBUTION. REMARKABLY, SIMILAR METHYLATION CHANGES WERE ALSO DETECTED IN DISEASE TISSUES, INCLUDING AD BRAIN TISSUES, ATHEROSCLEROTIC PLAQUES, AND TUMORS AND WERE FOUND TO CORRELATE WITH IMMUNE CELL INFILTRATION. IN ADDITION, THIS IMMUNE-RELATED METHYLATION PROFILE COULD ALSO BE DETECTED IN OTHER INFLAMMAGING DISEASES, INCLUDING PARKINSON'S DISEASE AND OBESITY, BUT NOT IN MULTIPLE SCLEROSIS, SCHIZOPHRENIA, AND OSTEOPOROSIS. IN CONCLUSION, WE IDENTIFIED A BLOOD-BASED IMMUNE-RELATED DNA METHYLATION SIGNATURE IN MULTIPLE INFLAMMAGING DISEASES ASSOCIATED WITH CHANGES IN BLOOD IMMUNE CELL COUNTS AND PREDICTIVE FOR IMMUNE CELL INFILTRATION IN DISEASED TISSUES. IN ADDITION TO EPIGENETIC CLOCK MEASUREMENTS, THIS IMMUNE-METHYLATION SIGNATURE MAY BECOME A VALUABLE BLOOD-BASED BIOMARKER TO PREVENT CHRONIC INFLAMMATORY DISEASE DEVELOPMENT OR MONITOR LIFESTYLE INTERVENTION STRATEGIES WHICH PROMOTE HEALTHY AGING. 2019 20 6159 37 THE GENETICS AND EPIGENETICS OF FATIGUE. FATIGUE IS A COMMON SYMPTOM AND INCLUDES BOTH PHYSICAL AND MENTAL COMPONENTS. IT CAN BE ASSOCIATED WITH A VARIETY OF DIFFERENT SYNDROMES AND DISEASES, BUT IN MANY CASES IS NOT ASSOCIATED WITH OTHER COMORBID CONDITIONS. MOST HUMANS HAVE EXPERIENCED ACUTE FATIGUE IN RELATION TO DIFFERENT STRESSORS. ACUTE FATIGUE TYPICALLY DECREASES AS THE EFFECT OF THE TRIGGERING FACTOR IS REDUCED AND A NORMAL HOMEOSTATIC BALANCE IS RESTORED. FATIGUE THAT PERSISTS FOR 6 MONTHS OR MORE IS TERMED CHRONIC FATIGUE. CHRONIC FATIGUE (CF) IN COMBINATION WITH A MINIMUM OF 4 OF 8 SYMPTOMS AND THE ABSENCE OF DISEASES THAT COULD EXPLAIN THESE SYMPTOMS, CONSTITUTE THE CASE DEFINITION FOR CHRONIC FATIGUE SYNDROME. IN SPITE OF ITS PREVALENCE, THE BIOLOGY OF FATIGUE IS RELATIVELY POORLY UNDERSTOOD AND BIOLOGICAL MARKERS HAVE NOT YET BEEN IDENTIFIED. THIS LITERATURE SEARCH WAS PERFORMED IN PUBMED TO IDENTIFY RESEARCH ON THE GENETICS AND EPIGENETICS OF FATIGUE. PUBLICATIONS WERE INCLUDED IF FATIGUE WAS A MAJOR TOPIC AND THE TOPIC WAS COMBINED WITH GENETIC AND/OR EPIGENETIC MEASUREMENTS IN ADULT HUMANS. A TOTAL OF 40 PUBLICATIONS WERE IDENTIFIED. ALTHOUGH ALTERED FUNCTIONING IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, THE SEROTONERGIC SYSTEM, AND ASSOCIATIONS WITH INFECTIOUS AGENTS HAVE BEEN IDENTIFIED, THE SEARCH FOR GENETIC OR EPIGENETIC MARKERS OF FATIGUE, EITHER IN THE CONTEXT OF CF OR CHRONIC FATIGUE SYNDROME (CFS) HAS BEEN RELATIVELY UNPRODUCTIVE OR, IN THE CASE OF EPIGENETICS, NONEXISTENT. ALTHOUGH SEVERAL STUDIES, BOTH HYPOTHESIS-TESTING AND HYPOTHESIS-GENERATING, HAVE BEEN PERFORMED TO SEARCH FOR BIOMARKERS, THEY HAVE MOSTLY BEEN UNDERPOWERED, RESTRICTED BY THE HETEROGENEITY OF THE PHENOTYPE, OR LIMITED BY AN UNSYSTEMATIC STUDY DESIGN. TO BE ABLE TO CONFIRM THE HYPOTHESIS THAT RISK FOR, OR LEVELS OF, FATIGUE ARE INFLUENCED BY THE GENETIC OR EPIGENETIC BACKGROUND OF AN INDIVIDUAL, STUDIES NEED TO BE BASED ON LARGER SAMPLE SIZES WITH A MORE CLEARLY DEFINED PHENOTYPE. STUDIES NEED TO FOCUS NOT ONLY ON THE INFLUENCE OF A SINGLE ASPECT SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OR DIFFERENTIAL GENE EXPRESSION ON DISEASE RISK OR STATE, BUT ALSO ON THE SYSTEMS BIOLOGY BEHIND THE DISEASE IN COMBINATION WITH INFORMATION ON ENVIRONMENTAL INFLUENCES AND VALIDATION OF FINDINGS IN FUNCTIONAL STUDIES. 2010