1 6412 188 THE SPECTRUM OF FUNDAMENTAL BASIC SCIENCE DISCOVERIES CONTRIBUTING TO ORGANISMAL AGING. AGING RESEARCH HAS UNDERGONE UNPRECEDENTED ADVANCES AT AN ACCELERATING RATE IN RECENT YEARS, LEADING TO EXCITEMENT IN THE FIELD AS WELL AS OPPORTUNITIES FOR IMAGINATION AND INNOVATION. NOVEL INSIGHTS INDICATE THAT, RATHER THAN RESULTING FROM A PREPROGRAMMED SERIES OF EVENTS, THE AGING PROCESS IS PREDOMINANTLY DRIVEN BY FUNDAMENTAL NON-ADAPTIVE MECHANISMS THAT ARE INTERCONNECTED, LINKED, AND OVERLAP. TO VARYING DEGREES, THESE MECHANISMS ALSO MANIFEST WITH AGING IN BONE WHERE THEY CAUSE SKELETAL FRAGILITY. BECAUSE THESE MECHANISMS OF AGING CAN BE MANIPULATED, IT MIGHT BE POSSIBLE TO SLOW, DELAY, OR ALLEVIATE MULTIPLE AGE-RELATED DISEASES AND THEIR COMPLICATIONS BY TARGETING CONSERVED GENETIC SIGNALING PATHWAYS, CONTROLLED FUNCTIONAL NETWORKS, AND BASIC BIOCHEMICAL PROCESSES. INDEED, FINDINGS IN VARIOUS MAMMALIAN SPECIES SUGGEST THAT TARGETING FUNDAMENTAL AGING MECHANISMS (EG, VIA EITHER LOSS-OF-FUNCTION OR GAIN-OF-FUNCTION MUTATIONS OR ADMINISTRATION OF PHARMACOLOGICAL THERAPIES) CAN EXTEND HEALTHSPAN; IE, THE HEALTHY PERIOD OF LIFE FREE OF CHRONIC DISEASES. IN THIS REVIEW, WE SUMMARIZE THE EVIDENCE SUPPORTING THE ROLE OF THE SPECTRUM OF FUNDAMENTAL BASIC SCIENCE DISCOVERIES CONTRIBUTING TO ORGANISMAL AGING, WITH EMPHASIS ON MAMMALIAN STUDIES AND IN PARTICULAR AGING MECHANISMS IN BONE THAT DRIVE SKELETAL FRAGILITY. THESE MECHANISMS OR AGING HALLMARKS INCLUDE: GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DEREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION. BECAUSE THESE MECHANISMS ARE LINKED, INTERVENTIONS THAT AMELIORATE ONE HALLMARK CAN IN THEORY AMELIORATE OTHERS. IN THE FIELD OF BONE AND MINERAL RESEARCH, CURRENT CHALLENGES INCLUDE DEFINING THE RELATIVE CONTRIBUTIONS OF EACH AGING HALLMARK TO THE NATURAL SKELETAL AGING PROCESS, BETTER UNDERSTANDING THE COMPLEX INTERCONNECTIONS AMONG THE HALLMARKS, AND IDENTIFYING THE MOST EFFECTIVE THERAPEUTIC STRATEGIES TO SAFELY TARGET MULTIPLE HALLMARKS. BASED ON THEIR INTERCONNECTIONS, IT MAY BE FEASIBLE TO SIMULTANEOUSLY INTERFERE WITH SEVERAL FUNDAMENTAL AGING MECHANISMS TO ALLEVIATE A WIDE SPECTRUM OF AGE-RELATED CHRONIC DISEASES, INCLUDING OSTEOPOROSIS. (C) 2018 AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH. 2018 2 285 51 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 3 3102 63 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 4 5945 61 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 4122 47 MECHANISMS OF DEVELOPMENT OF MULTIMORBIDITY IN THE ELDERLY. IN AGEING POPULATIONS MANY PATIENTS HAVE MULTIPLE DISEASES CHARACTERISED BY ACCELERATION OF THE NORMAL AGEING PROCESS. BETTER UNDERSTANDING OF THE SIGNALLING PATHWAYS AND CELLULAR EVENTS INVOLVED IN AGEING SHOWS THAT THESE ARE CHARACTERISTIC OF MANY CHRONIC DEGENERATIVE DISEASES, SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), CHRONIC CARDIOVASCULAR AND METABOLIC DISEASES, AND NEURODEGENERATION. COMMON MECHANISMS HAVE NOW BEEN IDENTIFIED IN THESE DISEASES, WHICH SHOW EVIDENCE OF CELLULAR SENESCENCE WITH TELOMERE SHORTENING, ACTIVATION OF PI3K-AKT-MTOR SIGNALLING, IMPAIRED AUTOPHAGY, MITOCHONDRIAL DYSFUNCTION, STEM CELL EXHAUSTION, EPIGENETIC CHANGES, ABNORMAL MICRORNA PROFILES, IMMUNOSENESCENCE AND LOW GRADE CHRONIC INFLAMMATION ("INFLAMMAGING"). MANY OF THESE PATHWAYS ARE DRIVEN BY CHRONIC OXIDATIVE STRESS. THERE IS ALSO A REDUCTION IN ANTI-AGEING MOLECULES, SUCH AS SIRTUINS AND KLOTHO, WHICH FURTHER ACCELERATES THE AGEING PROCESS. UNDERSTANDING THESE MOLECULAR MECHANISMS HAS IDENTIFIED SEVERAL NOVEL THERAPEUTIC TARGETS AND SEVERAL DRUGS HAVE ALREADY BEEN DEVELOPED THAT MAY SLOW THE AGEING PROCESS, AS WELL AS LIFESTYLE INTERVENTIONS, SUCH AS DIET AND PHYSICAL ACTIVITY. THIS INDICATES THAT IN THE FUTURE NEW TREATMENT APPROACHES MAY TARGET THE COMMON PATHWAYS INVOLVED IN MULTIMORBIDITY AND THIS AREA OF RESEARCH SHOULD BE GIVEN HIGH PRIORITY. THUS, COPD SHOULD BE CONSIDERED AS A COMPONENT OF MULTIMORBIDITY AND COMMON DISEASE PATHWAYS, PARTICULARLY ACCELERATED AGEING, SHOULD BE TARGETED. 2015 6 6629 33 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 6189 44 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 8 115 31 A STEM CELL AGING FRAMEWORK, FROM MECHANISMS TO INTERVENTIONS. STEM CELLS PLAY CENTRAL ROLES IN TISSUE DEVELOPMENT, HOMEOSTASIS, AND REGENERATION. DECADES OF SCIENTIFIC RESEARCH HAVE UNCOVERED PROCESSES OF STEM CELL DECLINE IN TISSUE AND ORGANISMAL AGING, AND MORE RECENTLY, PIONEERING TECHNOLOGIES PERMIT THE DISSECTION OF ITS UNDERLYING MECHANISMS AND INFORM THERAPEUTIC DEVELOPMENT FOR AGING AND AGING-ASSOCIATED DISORDERS. IN THIS REVIEW, WE ELUCIDATE AGING-RELATED FEATURES ACROSS DIFFERENT SOMATIC STEM CELL TYPES, WITH A SPECIFIC FOCUS ON EPIGENETIC CHANGES, LOSS OF PROTEIN HOMEOSTASIS, AND SYSTEMIC INFLUENCING FACTORS, INCLUDING CHRONIC INFLAMMATION, CIRCADIAN RHYTHM DYSREGULATION, AND METABOLIC DISORDER. OUR SURVEY OF ORGANISMAL STEM CELL AGING SUMMARIZES ITS UNDERLYING BIOLOGICAL IMPLICATIONS, POINTS TO POTENTIAL BIOMARKERS OF STEM CELL AGING, AND DISCUSSES STEM CELL-BASED THERAPEUTIC STRATEGIES WITH THE POTENTIAL FOR PROMOTING HEALTHY AGING AND COMBATING AGING AND AGE-RELATED DISEASES. 2022 9 2855 49 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 10 1112 48 COMMON PATHOGENETIC MECHANISMS UNDERLYING AGING AND TUMOR AND MEANS OF INTERVENTIONS. RECENTLY, THERE HAS BEEN AN INCREASE IN THE INCIDENCE OF MALIGNANT TUMORS AMONG THE OLDER POPULATION. MOREOVER, THERE IS AN ASSOCIATION BETWEEN AGING AND CANCER. DURING THE PROCESS OF SENESCENCE, THE HUMAN BODY SUFFERS FROM A SERIES OF IMBALANCES, WHICH HAVE BEEN SHOWN TO FURTHER ACCELERATE AGING, TRIGGER TUMORIGENESIS, AND FACILITATE CANCER PROGRESSION. THEREFORE, EXPLORING THE JUNCTIONS OF AGING AND CANCER AND SEARCHING FOR NOVEL METHODS TO RESTORE THE JUNCTIONS IS OF GREAT IMPORTANCE TO INTERVENE AGAINST AGING-RELATED CANCERS. IN THIS REVIEW, WE HAVE IDENTIFIED THE UNDERLYING PATHOGENETIC MECHANISMS OF AGING-RELATED CANCERS BY COMPARING ALTERATIONS IN THE HUMAN BODY CAUSED BY AGING AND THE FACTORS THAT TRIGGER CANCERS. WE FOUND THAT THE COMMON MECHANISMS OF AGING AND CANCER INCLUDE CELLULAR SENESCENCE, ALTERATIONS IN PROTEOSTASIS, MICROBIOTA DISORDERS (DECREASED PROBIOTICS AND INCREASED PERNICIOUS BACTERIA), PERSISTENT CHRONIC INFLAMMATION, EXTENSIVE IMMUNOSENESCENCE, INORDINATE ENERGY METABOLISM, ALTERED MATERIAL METABOLISM, ENDOCRINE DISORDERS, ALTERED GENETIC EXPRESSION, AND EPIGENETIC MODIFICATION. FURTHERMORE, WE HAVE PROPOSED THAT AGING AND CANCER HAVE COMMON MEANS OF INTERVENTION, INCLUDING NOVEL USES OF COMMON MEDICINE (METFORMIN, RESVERATROL, AND RAPAMYCIN), DIETARY RESTRICTION, AND ARTIFICIAL MICROBIOTA INTERVENTION OR SELECTIVELY REPLENISHING SCARCE METABOLITES. IN ADDITION, WE HAVE SUMMARIZED THE RESEARCH PROGRESS OF EACH INTERVENTION AND REVEALED THEIR BIDIRECTIONAL EFFECTS ON CANCER PROGRESSION TO COMPARE THEIR RELIABILITY AND FEASIBILITY. THEREFORE, THE STUDY FINDINGS PROVIDE VITAL INFORMATION FOR ADVANCED RESEARCH STUDIES ON AGE-RELATED CANCERS. HOWEVER, THERE IS A NEED FOR FURTHER OPTIMIZATION OF THE DESCRIBED METHODS AND MORE SUITABLE METHODS FOR COMPLICATED CLINICAL PRACTICES. IN CONCLUSION, TARGETING AGING MAY HAVE POTENTIAL THERAPEUTIC EFFECTS ON AGING-RELATED CANCERS. 2022 11 3922 48 LIPIDS AND THE HALLMARKS OF AGEING: FROM PATHOLOGY TO INTERVENTIONS. LIPIDS ARE CRITICAL STRUCTURAL AND FUNCTIONAL ARCHITECTS OF CELLULAR HOMEOSTASIS. CHANGE IN SYSTEMIC LIPID PROFILE IS A CLINICAL INDICATOR OF UNDERLYING METABOLIC PATHOLOGIES, AND EMERGING EVIDENCE IS NOW DEFINING NOVEL ROLES OF LIPIDS IN MODULATING ORGANISMAL AGEING. CHARACTERISTIC ALTERATIONS IN LIPID METABOLISM CORRELATE WITH AGE, AND IMPAIRED SYSTEMIC LIPID PROFILE CAN ALSO ACCELERATE THE DEVELOPMENT OF AGEING PHENOTYPE. THE PRESENT WORK PROVIDES A COMPREHENSIVE REVIEW OF THE EXTENT OF LIPIDS AS REGULATORS OF THE MODERN HALLMARKS OF AGEING VIZ., CELLULAR SENESCENCE, CHRONIC INFLAMMATION, GUT DYSBIOSIS, TELOMERE ATTRITION, GENOME INSTABILITY, PROTEOSTASIS AND AUTOPHAGY, EPIGENETIC ALTERATIONS, AND STEM CELLS DYSFUNCTIONS. CURRENT EVIDENCE ON THE MODULATION OF EACH OF THESE HALLMARKS HAS BEEN DISCUSSED WITH EMPHASIS ON INHERENT AGE-DEPENDENT DEFICIENCIES IN LIPID METABOLISM AS WELL AS EXOGENOUS LIPID CHANGES. THERE APPEARS TO BE SUFFICIENT EVIDENCE TO CONSIDER IMPAIRED LIPID METABOLISM AS KEY DRIVER OF THE AGEING PROCESS ALTHOUGH MUCH OF KNOWLEDGE IS YET FRAGMENTED. CONSIDERING DIETARY LIPIDS, THE TYPE AND QUANTITY OF LIPIDS IN THE DIET IS A SIGNIFICANT, BUT OFTEN OVERLOOKED DETERMINANT THAT GOVERNS THE EFFECTS OF LIPIDS ON AGEING. FURTHER RESEARCH USING INTEGRATIVE APPROACHES AMIDST THE KNOWN AGING HALLMARKS IS HIGHLY DESIRABLE FOR UNDERSTANDING THE THERAPEUTICS OF LIPIDS ASSOCIATED WITH AGEING. 2023 12 4425 54 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 13 5630 58 SENESCENCE IN PULMONARY FIBROSIS: BETWEEN AGING AND EXPOSURE. TO DATE, CHRONIC PULMONARY PATHOLOGIES REPRESENT THE THIRD LEADING CAUSE OF DEATH IN THE ELDERLY POPULATION. EVIDENCE-BASED PROJECTIONS SUGGEST THAT >65 (YEARS OLD) INDIVIDUALS WILL ACCOUNT FOR APPROXIMATELY A QUARTER OF THE WORLD POPULATION BEFORE THE TURN OF THE CENTURY. GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DEREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION, ARE DESCRIBED AS THE NINE "HALLMARKS" THAT GOVERN CELLULAR FITNESS. ANY DEVIATION FROM THE NORMAL PATTERN INITIATES A COMPLEX CASCADE OF EVENTS CULMINATING TO A DISEASE STATE. THIS BLUEPRINT, ORIGINALLY EMPLOYED TO DESCRIBE ABERRANT CHANGES IN CANCER CELLS, CAN BE ALSO USED TO DESCRIBE AGING AND FIBROSIS. PULMONARY FIBROSIS (PF) IS THE RESULT OF A PROGRESSIVE DECLINE IN INJURY RESOLUTION PROCESSES STEMMING FROM ENDOGENOUS (PHYSIOLOGICAL DECLINE OR SOMATIC MUTATIONS) OR EXOGENOUS STRESS. ENVIRONMENTAL, DIETARY OR OCCUPATIONAL EXPOSURE ACCELERATES THE PATHOGENESIS OF A SENESCENT PHENOTYPE BASED ON (1) WINDOW OF EXPOSURE; (2) DOSE, DURATION, RECURRENCE; AND (3) CELLS TYPE BEING TARGETED. AS THE LUNG AGES, THE THRESHOLD TO GENERATE AN IRREVERSIBLY SENESCENT PHENOTYPE IS LOWERED. HOWEVER, WE DO NOT HAVE SUFFICIENT KNOWLEDGE TO MAKE ACCURATE PREDICTIONS. IN THIS REVIEW, WE PROVIDE AN ASSESSMENT OF THE LITERATURE THAT INTERROGATES LUNG EPITHELIAL, MESENCHYMAL, AND IMMUNE SENESCENCE AT THE INTERSECTION OF AGING, ENVIRONMENTAL EXPOSURE AND PULMONARY FIBROSIS. 2020 14 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 15 3818 31 INTRINSIC AND ENVIRONMENTAL BASIS OF AGING: A NARRATIVE REVIEW. LONGEVITY HAS BEEN A TOPIC OF INTEREST SINCE THE BEGINNINGS OF HUMANITY, YET ITS AETIOLOGY AND PRECISE MECHANISMS REMAIN TO BE ELUCIDATED. AGING IS CURRENTLY VIEWED AS A PHYSIOLOGICAL PHENOMENON CHARACTERIZED BY THE GRADUAL DEGENERATION OF ORGANIC PHYSIOLOGY AND MORPHOLOGY DUE TO THE PASSAGE OF TIME WHERE BOTH EXTERNAL AND INTERNAL STIMULI INTERVENE. THE INFLUENCE OF INTRINSIC FACTORS, SUCH AS PROGRESSIVE TELOMERE SHORTENING, GENOME INSTABILITY DUE TO MUTATION BUILDUP, THE DIRECT OR INDIRECT ACTIONS OF AGE-RELATED GENES, AND MARKED CHANGES IN EPIGENETIC, METABOLIC, AND MITOCHONDRIAL PATTERNS CONSTITUTE A BIG PART OF ITS UNDERLYING ENDOGENOUS MECHANISMS. ON THE OTHER HAND, SEVERAL PSYCHOSOCIAL AND DEMOGRAPHIC FACTORS, SUCH AS DIET, PHYSICAL ACTIVITY, SMOKING, AND DRINKING HABITS, MAY HAVE AN EVEN MORE SIGNIFICANT IMPACT ON SHAPING THE AGING PROCESS. CONSEQUENTIALLY, IMPLEMENTING DIETARY AND EXERCISE PATTERNS HAS BEEN PROPOSED AS THE MOST VIABLE ALTERNATIVE STRATEGY FOR ATTENUATING THE MOST TYPICAL DEGENERATIVE AGING CHANGES, THUS INCREASING THE LIKELIHOOD OF PROLONGING LIFESPAN AND ACHIEVING SUCCESSFUL AGING. 2023 16 5263 40 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 17 290 50 AGING AND PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS IS A CHRONIC, PROGRESSIVE, AND USUALLY FATAL LUNG DISORDER OF UNKNOWN ETIOLOGY. THE DISEASE LIKELY RESULTS FROM THE INTERACTION OF GENETIC SUSCEPTIBILITY ARCHITECTURE, ENVIRONMENTAL FACTORS SUCH AS SMOKING, AND AN ABNORMAL EPIGENETIC REPROGRAMMING THAT LEADS TO A COMPLEX PATHOGENESIS. IDIOPATHIC PULMONARY FIBROSIS OCCURS IN MIDDLE-AGED AND MAINLY ELDERLY ADULTS, AND IN THIS CONTEXT AGE HAS EMERGED AS ITS STRONGEST RISK FACTOR. HOWEVER, THE MECHANISMS LINKING IT TO AGING ARE UNCERTAIN. RECENTLY, NINE MOLECULAR AND CELLULAR HALLMARKS OF AGING HAVE BEEN PROPOSED: GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DEREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THESE MOLECULAR MECHANISMS AND THEIR INVOLVEMENT IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS, WHILE EMPHASIZING THAT THE STUDIES ON THIS DISEASE ARE FEW AND THE FINDINGS ARE NOT DEFINITIVE. 2016 18 5633 37 SENESCENT REMODELING OF THE INNATE AND ADAPTIVE IMMUNE SYSTEM IN THE ELDERLY MEN WITH PROSTATE CANCER. DESPITE YEARS OF INTENSIVE INVESTIGATION THAT HAS BEEN MADE IN UNDERSTANDING PROSTATE CANCER, IT REMAINS A MAJOR CAUSE OF DEATH IN MEN WORLDWIDE. PROSTATE CANCER EMERGES FROM MULTIPLE ALTERATIONS THAT INDUCE CHANGES IN EXPRESSION PATTERNS OF GENES AND PROTEINS THAT FUNCTION IN NETWORKS CONTROLLING CRITICAL CELLULAR EVENTS. BASED ON THE EXPONENTIAL AGING OF THE POPULATION AND THE INCREASING LIFE EXPECTANCY IN INDUSTRIALIZED WESTERN COUNTRIES, PROSTATE CANCER IN THE ELDERLY MEN IS BECOMING A DISEASE OF INCREASING SIGNIFICANCE. AGING IS A PROGRESSIVE DEGENERATIVE PROCESS STRICTLY INTEGRATED WITH INFLAMMATION. SEVERAL THEORIES HAVE BEEN PROPOSED THAT ATTEMPT TO DEFINE THE ROLE OF CHRONIC INFLAMMATION IN AGING INCLUDING REDOX STRESS, MITOCHONDRIAL DAMAGE, IMMUNOSENESCENCE, AND EPIGENETIC MODIFICATIONS. HERE, WE REVIEW THE INNATE AND ADAPTIVE IMMUNE SYSTEMS AND THEIR SENESCENT REMODELING IN ELDERLY MEN WITH PROSTATE CANCER. 2014 19 6656 44 UPDATED UNDERSTANDING OF CANCER AS A METABOLIC AND TELOMERE-DRIVEN DISEASE, AND PROPOSAL FOR COMPLEX PERSONALIZED TREATMENT, A HYPOTHESIS. IN THIS REVIEW, WE PROPOSE A HOLISTIC APPROACH TO UNDERSTANDING CANCER AS A METABOLIC DISEASE. OUR SEARCH FOR RELEVANT STUDIES IN MEDICAL DATABASES CONCLUDES THAT CANCER CELLS DO NOT EVOLVE DIRECTLY FROM NORMAL HEALTHY CELLS. WE HYPOTHESIZE THAT ABERRANT DNA DAMAGE ACCUMULATES OVER TIME-AVOIDING THE NATURAL DNA CONTROLS THAT OTHERWISE REPAIR OR REPLACE THE RAPIDLY REPLICATING CELLS. DNA DAMAGE STARTS TO ACCUMULATE IN NON-REPLICATING CELLS, LEADING TO SENESCENCE AND AGING. DNA DAMAGE IS LINKED WITH GENETIC AND EPIGENETIC FACTORS, BUT THE DEVELOPMENT OF CANCER IS FAVORED BY TELOMERASE ACTIVITY. EVIDENCE INDICATES THAT TELOMERE LENGTH IS AFFECTED BY CHRONIC INFLAMMATIONS, ALTERATIONS OF MITOCHONDRIAL DNA, AND VARIOUS ENVIRONMENTAL FACTORS. EMOTIONAL STRESS ALSO INFLUENCES TELOMERE LENGTH. CHRONIC INFLAMMATION CAN CAUSE OXIDATIVE DNA DAMAGE. OXIDATIVE STRESS, IN TURN, CAN TRIGGER MITOCHONDRIAL CHANGES, WHICH ULTIMATELY ALTER NUCLEAR GENE EXPRESSION. THIS VICIOUS CYCLE HAS LED SEVERAL SCIENTISTS TO VIEW CANCER AS A METABOLIC DISEASE. WE HAVE PROPOSED COMPLEX PERSONALIZED TREATMENTS THAT SEEK TO CORRECT MULTIPLE CHANGES SIMULTANEOUSLY USING A PSYCHOLOGICAL APPROACH TO REDUCE CHRONIC STRESS, IMMUNE CHECKPOINT THERAPY WITH REDUCED DOSES OF CHEMO AND RADIOTHERAPY, MINIMAL SURGICAL INTERVENTION, IF ANY, AND MITOCHONDRIAL METABOLIC REPROGRAMMING PROTOCOLS SUPPLEMENTED BY INTERMITTENT FASTING AND PERSONALIZED DIETARY PLANS WITHOUT INTERFERING WITH THE OTHER THERAPIES. 2020 20 6034 45 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