1 375 91 AN ENERGETIC VIEW OF STRESS: FOCUS ON MITOCHONDRIA. ENERGY IS REQUIRED TO SUSTAIN LIFE AND ENABLE STRESS ADAPTATION. AT THE CELLULAR LEVEL, ENERGY IS LARGELY DERIVED FROM MITOCHONDRIA - UNIQUE MULTIFUNCTIONAL ORGANELLES WITH THEIR OWN GENOME. FOUR MAIN ELEMENTS CONNECT MITOCHONDRIA TO STRESS: (1) ENERGY IS REQUIRED AT THE MOLECULAR, (EPI)GENETIC, CELLULAR, ORGANELLAR, AND SYSTEMIC LEVELS TO SUSTAIN COMPONENTS OF STRESS RESPONSES; (2) GLUCOCORTICOIDS AND OTHER STEROID HORMONES ARE PRODUCED AND METABOLIZED BY MITOCHONDRIA; (3) RECIPROCALLY, MITOCHONDRIA RESPOND TO NEUROENDOCRINE AND METABOLIC STRESS MEDIATORS; AND (4) EXPERIMENTALLY MANIPULATING MITOCHONDRIAL FUNCTIONS ALTERS PHYSIOLOGICAL AND BEHAVIORAL RESPONSES TO PSYCHOLOGICAL STRESS. THUS, MITOCHONDRIA ARE ENDOCRINE ORGANELLES THAT PROVIDE BOTH THE ENERGY AND SIGNALS THAT ENABLE AND DIRECT STRESS ADAPTATION. NEURAL CIRCUITS REGULATING SOCIAL BEHAVIOR - AS WELL AS PSYCHOPATHOLOGICAL PROCESSES - ARE ALSO INFLUENCED BY MITOCHONDRIAL ENERGETICS. AN INTEGRATIVE VIEW OF STRESS AS AN ENERGY-DRIVEN PROCESS OPENS NEW OPPORTUNITIES TO STUDY MECHANISMS OF ADAPTATION AND REGULATION ACROSS THE LIFESPAN. 2018 2 4376 19 MITOCHONDRIAL (DYS) FUNCTION IN INFLAMMAGING: DO MITOMIRS INFLUENCE THE ENERGETIC, OXIDATIVE, AND INFLAMMATORY STATUS OF SENESCENT CELLS? A RELEVANT FEATURE OF AGING IS CHRONIC LOW-GRADE INFLAMMATION, TERMED INFLAMMAGING, A KEY PROCESS PROMOTING THE DEVELOPMENT OF ALL MAJOR AGE-RELATED DISEASES. SENESCENT CELLS CAN ACQUIRE THE SENESCENCE-ASSOCIATED (SA) SECRETORY PHENOTYPE (SASP), CHARACTERIZED BY THE SECRETION OF PROINFLAMMATORY FACTORS FUELLING INFLAMMAGING. CELLULAR SENESCENCE IS ALSO ACCOMPANIED BY A DEEP RESHAPING OF MICRORNA EXPRESSION AND BY THE MODULATION OF MITOCHONDRIA ACTIVITY, BOTH MASTER REGULATORS OF THE SASP. HERE, WE SYNTHESIZE NOVEL FINDINGS REGARDING THE ROLE OF MITOCHONDRIA IN THE SASP AND IN THE INFLAMMAGING PROCESS AND PROPOSE A NETWORK LINKING NUCLEAR-ENCODED SA-MIRNAS TO MITOCHONDRIAL GENE REGULATION AND FUNCTION IN AGING CELLS. IN THIS CONCEPTUAL STRUCTURE, SA-MIRNAS CAN TRANSLOCATE TO MITOCHONDRIA (SA-MITOMIRS) AND MAY AFFECT THE ENERGETIC, OXIDATIVE, AND INFLAMMATORY STATUS OF SENESCENT CELLS. WE DISCUSS THE POTENTIAL ROLE OF SEVERAL OF SA-MITOMIRS (I.E., LET-7B, MIR-1, MIR-130A-3P, MIR-133A, MIR-146A-5P, MIR-181C-5P, AND MIR-378-5P), USING MIR-146A AS A PROOF-OF-PRINCIPLE MODEL. FINALLY, WE PROPOSE A COMPREHENSIVE, METABOLIC, AND EPIGENETIC VIEW OF THE SENESCENCE PROCESS, IN ORDER TO AMPLIFY THE RANGE OF POSSIBLE APPROACHES TO TARGET INFLAMMAGING, WITH THE ULTIMATE GOAL OF DECELERATING THE AGING RATE, POSTPONING OR BLUNTING THE DEVELOPMENT OF AGE-RELATED DISEASES. 2017 3 788 26 CELLULAR ALLOSTATIC LOAD IS LINKED TO INCREASED ENERGY EXPENDITURE AND ACCELERATED BIOLOGICAL AGING. STRESS TRIGGERS ANTICIPATORY PHYSIOLOGICAL RESPONSES THAT PROMOTE SURVIVAL, A PHENOMENON TERMED ALLOSTASIS. HOWEVER, THE CHRONIC ACTIVATION OF ENERGY-DEPENDENT ALLOSTATIC RESPONSES RESULTS IN ALLOSTATIC LOAD, A DYSREGULATED STATE THAT PREDICTS FUNCTIONAL DECLINE, ACCELERATES AGING, AND INCREASES MORTALITY IN HUMANS. THE ENERGETIC COST AND CELLULAR BASIS FOR THE DAMAGING EFFECTS OF ALLOSTATIC LOAD HAVE NOT BEEN DEFINED. HERE, BY LONGITUDINALLY PROFILING THREE UNRELATED PRIMARY HUMAN FIBROBLAST LINES ACROSS THEIR LIFESPAN, WE FIND THAT CHRONIC GLUCOCORTICOID EXPOSURE INCREASES CELLULAR ENERGY EXPENDITURE BY APPROXIMATELY 60%, ALONG WITH A METABOLIC SHIFT FROM GLYCOLYSIS TO MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION (OXPHOS). THIS STATE OF STRESS-INDUCED HYPERMETABOLISM IS LINKED TO MTDNA INSTABILITY, NON-LINEARLY AFFECTS AGE-RELATED CYTOKINES SECRETION, AND ACCELERATES CELLULAR AGING BASED ON DNA METHYLATION CLOCKS, TELOMERE SHORTENING RATE, AND REDUCED LIFESPAN. PHARMACOLOGICALLY NORMALIZING OXPHOS ACTIVITY WHILE FURTHER INCREASING ENERGY EXPENDITURE EXACERBATES THE ACCELERATED AGING PHENOTYPE, POINTING TO TOTAL ENERGY EXPENDITURE AS A POTENTIAL DRIVER OF AGING DYNAMICS. TOGETHER, OUR FINDINGS DEFINE BIOENERGETIC AND MULTI-OMIC RECALIBRATIONS OF STRESS ADAPTATION, UNDERSCORING INCREASED ENERGY EXPENDITURE AND ACCELERATED CELLULAR AGING AS INTERRELATED FEATURES OF CELLULAR ALLOSTATIC LOAD. 2023 4 1960 18 EPIGENETIC AGING IN CHILDREN FROM A SMALL-SCALE FARMING SOCIETY IN THE CONGO BASIN: ASSOCIATIONS WITH CHILD GROWTH AND FAMILY CONFLICT. DEVELOPMENTAL ENVIRONMENTS INFLUENCE INDIVIDUALS' LONG-TERM HEALTH TRAJECTORIES, AND THERE IS INCREASING EMPHASIS ON UNDERSTANDING THE BIOLOGICAL PATHWAYS THROUGH WHICH THIS OCCURS. EPIGENETIC AGING EVALUATES DNA METHYLATION AT A SUITE OF DISTINCT CPG SITES IN THE GENOME, AND EPIGENETIC AGE ACCELERATION (EAA) IS LINKED TO HEIGHTENED CHRONIC MORBIDITY AND MORTALITY RISKS IN ADULTS. CONSEQUENTLY, EAA PROVIDES INSIGHTS ON TRAJECTORIES OF BIOLOGICAL AGING, WHICH EARLY LIFE EXPERIENCES MAY HELP SHAPE. HOWEVER, FEW STUDIES HAVE MEASURED CORRELATES OF CHILDREN'S EPIGENETIC AGING, ESPECIALLY OUTSIDE OF THE U.S. AND EUROPE. IN PARTICULAR, LITTLE IS KNOWN ABOUT HOW CHILDREN'S GROWTH AND DEVELOPMENT RELATE TO EAA IN ECOLOGIES IN WHICH ENERGETIC AND PATHOGENIC STRESSORS ARE COMMONPLACE. WE STUDIED EAA FROM DRIED BLOOD SPOTS AMONG BONDONGO CHILDREN (N = 54) RESIDING IN A SMALL-SCALE, FISHER-FARMER SOCIETY IN A REMOTE REGION OF THE REPUBLIC OF THE CONGO. HERE, INFECTIOUS DISEASE BURDENS AND THEIR RESULTANT ENERGY DEMANDS ARE HIGH. CHILDREN WHO WERE HEAVIER FOR HEIGHT OR TALLER FOR AGE, RESPECTIVELY, EXHIBITED GREATER EAA, INCLUDING INTRINSIC EAA, WHICH IS CONSIDERED TO MEASURE EAA INTERNAL TO CELLS. FURTHERMORE, WE FOUND THAT CHILDREN IN FAMILIES WITH MORE CONFLICT BETWEEN PARENTS HAD GREATER INTRINSIC EAA. THESE RESULTS SUGGEST THAT IN CONTEXTS IN WHICH LIMITED ENERGY MUST BE ALLOCATED TO COMPETING DEMANDS, MORE INVESTMENT IN GROWTH MAY COINCIDE WITH GREATER EAA, WHICH PARALLELS FINDINGS IN EUROPEAN CHILDREN WHO DO NOT FACE SIMILAR ENERGETIC CONSTRAINTS. OUR FINDINGS ALSO INDICATE THAT ASSOCIATIONS BETWEEN ADVERSE FAMILY ENVIRONMENTS AND GREATER INTRINSIC EAA WERE NONETHELESS OBSERVABLE BUT ONLY AFTER ADJUSTMENT FOR COVARIATES RELEVANT TO THE ENERGETICALLY AND IMMUNOLOGICALLY DEMANDING NATURE OF THE LOCAL ECOLOGY. 2020 5 5948 13 TARGETING THE MOLECULAR & CELLULAR PILLARS OF HUMAN AGING WITH EXERCISE. BIOLOGICAL AGING IS THE MAIN DRIVER OF AGE-ASSOCIATED CHRONIC DISEASES. IN 2014, THE UNITED STATES NATIONAL INSTITUTE OF AGING (NIA) SPONSORED A MEETING BETWEEN SEVERAL INVESTIGATORS IN THE FIELD OF AGING BIOLOGY, WHO IDENTIFIED SEVEN BIOLOGICAL PILLARS OF AGING AND A CONSENSUS REVIEW, "GEROSCIENCE: LINKING AGING TO CHRONIC DISEASE," WAS PUBLISHED. THE PILLARS OF AGING DEMONSTRATED THE CONSERVATION OF AGING PATHWAYS IN DIVERSE MODEL ORGANISMS AND THUS REPRESENT A USEFUL FRAMEWORK WITH WHICH TO STUDY HUMAN AGING. IN THIS PRESENT REVIEW, WE REVISIT THE SEVEN PILLARS OF AGING FROM THE PERSPECTIVE OF EXERCISE AND DISCUSS HOW REGULAR PHYSICAL EXERCISE CAN MODULATE THESE PILLARS TO STAVE OFF AGE-RELATED CHRONIC DISEASES AND MAINTAIN FUNCTIONAL CAPACITY. 2023 6 3881 25 KETOGENIC DIETS AND THE NERVOUS SYSTEM: A SCOPING REVIEW OF NEUROLOGICAL OUTCOMES FROM NUTRITIONAL KETOSIS IN ANIMAL STUDIES. OBJECTIVES: KETOGENIC DIETS HAVE REPORTED EFFICACY FOR NEUROLOGICAL DYSFUNCTIONS; HOWEVER, THERE ARE LIMITED PUBLISHED HUMAN CLINICAL TRIALS ELUCIDATING THE MECHANISMS BY WHICH NUTRITIONAL KETOSIS PRODUCES THERAPEUTIC EFFECTS. THE PURPOSE OF THIS PRESENT STUDY WAS TO INVESTIGATE ANIMAL MODELS THAT REPORT VARIATIONS IN NERVOUS SYSTEM FUNCTION BY CHANGING FROM A STANDARD ANIMAL DIET TO A KETOGENIC DIET, SYNTHESISE THESE INTO BROAD THEMES, AND COMPARE THESE WITH MECHANISMS REPORTED AS TARGETS IN PAIN NEUROSCIENCE TO INFORM HUMAN CHRONIC PAIN TRIALS. METHODS: AN ELECTRONIC SEARCH OF SEVEN DATABASES WAS CONDUCTED IN JULY 2020. TWO INDEPENDENT REVIEWERS SCREENED STUDIES FOR ELIGIBILITY, AND DESCRIPTIVE OUTCOMES RELATING TO NERVOUS SYSTEM FUNCTION WERE EXTRACTED FOR A THEMATIC ANALYSIS, THEN SYNTHESISED INTO BROAD THEMES. RESULTS: IN TOTAL, 170 STUDIES FROM EIGHTEEN DIFFERENT DISEASE MODELS WERE IDENTIFIED AND GROUPED INTO FOURTEEN BROAD THEMES: ALTERATIONS IN CELLULAR ENERGETICS AND METABOLISM, BIOCHEMICAL, CORTICAL EXCITABILITY, EPIGENETIC REGULATION, MITOCHONDRIAL FUNCTION, NEUROINFLAMMATION, NEUROPLASTICITY, NEUROPROTECTION, NEUROTRANSMITTER FUNCTION, NOCICEPTION, REDOX BALANCE, SIGNALLING PATHWAYS, SYNAPTIC TRANSMISSION AND VASCULAR SUPPLY. DISCUSSION: THE MECHANISMS PRESENTED CENTRED AROUND THE REDUCTION OF INFLAMMATION AND OXIDATIVE STRESS AS WELL AS A REDUCTION IN NERVOUS SYSTEM EXCITABILITY. GIVEN THE MULTIPLE POTENTIAL MECHANISMS PRESENTED, IT IS LIKELY THAT MANY OF THESE ARE INVOLVED SYNERGISTICALLY AND UNDERGO ADAPTIVE PROCESSES WITHIN THE HUMAN BODY, AND CONTROLLED ANIMAL MODELS THAT LIMIT THE INVESTIGATION TO A PARTICULAR PATHWAY IN ISOLATION MAY REACH DIFFERING CONCLUSIONS. ATTENTION IS REQUIRED WHEN TRANSLATING THIS INFORMATION TO HUMAN CHRONIC PAIN POPULATIONS OWING TO THE LIMITATIONS OUTLINED FROM THE ANIMAL RESEARCH. 2022 7 5879 20 SYNTHETIC MITOCHONDRIA AS THERAPEUTICS AGAINST SYSTEMIC AGING: A HYPOTHESIS. WE HYPOTHESIZE HEREIN THAT SYNTHETIC MITOCHONDRIA, ENGINEERED, OR REPROGRAMMED TO BE MORE ENERGETICALLY EFFICIENT AND TO HAVE MILDLY ELEVATED LEVELS OF REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, WOULD BE AN EFFECTIVE FORM OF THERAPEUTICS AGAINST SYSTEMIC AGING. THE FREE RADICAL AND MITOCHONDRIA THEORIES OF AGING HOLD THAT MITOCHONDRIA-GENERATED ROS UNDERLIES CHRONIC ORGANELLE, CELL AND TISSUES DAMAGES THAT CONTRIBUTE TO SYSTEMIC AGING. MORE RECENT FINDINGS, HOWEVER, COLLECTIVELY SUGGEST THAT WHILE ACUTE AND MASSIVE ROS GENERATION DURING EVENTS SUCH AS TISSUE INJURY IS INDEED DETRIMENTAL, SUBACUTE STRESSES, AND CHRONIC ELEVATION IN ROS PRODUCTION MAY INSTEAD INDUCE A STATE OF MITOCHONDRIAL HORMESIS (OR "MITOHORMESIS") THAT COULD EXTEND LIFESPAN. MITOHORMESIS APPEARS TO BE A CONVERGENT MECHANISM FOR SEVERAL KNOWN ANTI-AGING SIGNALING PATHWAYS. IMPORTANTLY, MITOHORMETIC SIGNALING COULD ALSO OCCUR IN A NON-CELL AUTONOMOUS MANNER, WITH ITS INDUCTION IN NEURONS AFFECTING GUT CELLS, FOR EXAMPLE. TECHNOLOGIES ARE OUTLINED THAT COULD LEAD TOWARDS TESTING OF THE HYPOTHESIS, WHICH INCLUDE GENETIC AND EPIGENETIC ENGINEERING OF THE MITOCHONDRIA, AS WELL AS INTERCELLULAR TRANSFER OF MITOCHONDRIA FROM TRANSPLANTED HELPER CELLS TO TARGET TISSUES. 2015 8 6629 20 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 9 4985 24 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 10 1372 22 DEVELOPMENTAL ORIGINS OF METABOLIC DISEASES. ALMOST 2 BILLION ADULTS IN THE WORLD ARE OVERWEIGHT, AND MORE THAN HALF OF THEM ARE CLASSIFIED AS OBESE, WHILE NEARLY ONE-THIRD OF CHILDREN GLOBALLY EXPERIENCE POOR GROWTH AND DEVELOPMENT. GIVEN THE VAST AMOUNT OF KNOWLEDGE THAT HAS BEEN GLEANED FROM DECADES OF RESEARCH ON GROWTH AND DEVELOPMENT, A NUMBER OF QUESTIONS REMAIN AS TO WHY THE WORLD IS NOW IN THE MIDST OF A GLOBAL EPIDEMIC OF OBESITY ACCOMPANIED BY THE "DOUBLE BURDEN OF MALNUTRITION," WHERE OVERWEIGHT COEXISTS WITH UNDERWEIGHT AND MICRONUTRIENT DEFICIENCIES. THIS CHALLENGE TO THE HUMAN CONDITION CAN BE ATTRIBUTED TO NUTRITIONAL AND ENVIRONMENTAL EXPOSURES DURING PREGNANCY THAT MAY PROGRAM A FETUS TO HAVE A HIGHER RISK OF CHRONIC DISEASES IN ADULTHOOD. TO EXPLORE THIS CONCEPT, FREQUENTLY CALLED THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD), THIS REVIEW CONSIDERS A HOST OF FACTORS AND PHYSIOLOGICAL MECHANISMS THAT DRIVE A FETUS OR CHILD TOWARD A HIGHER RISK OF OBESITY, FATTY LIVER DISEASE, HYPERTENSION, AND/OR TYPE 2 DIABETES (T2D). TO THAT END, THIS REVIEW EXPLORES THE EPIDEMIOLOGY OF DOHAD WITH DISCUSSIONS FOCUSED ON ADAPTATIONS TO HUMAN ENERGETICS, PLACENTAL DEVELOPMENT, DYSMETABOLISM, AND KEY ENVIRONMENTAL EXPOSURES THAT ACT TO PROMOTE CHRONIC DISEASES IN ADULTHOOD. THESE AREAS ARE COMPLEMENTARY AND ADDITIVE IN UNDERSTANDING HOW PROVIDING THE BEST CONDITIONS FOR OPTIMAL GROWTH CAN CREATE THE BEST POSSIBLE CONDITIONS FOR LIFELONG HEALTH. MOREOVER, UNDERSTANDING BOTH PHYSIOLOGICAL AS WELL AS EPIGENETIC AND MOLECULAR MECHANISMS FOR DOHAD IS VITAL TO MOST FULLY ADDRESS THE GLOBAL ISSUES OF OBESITY AND OTHER CHRONIC DISEASES. 2021 11 3181 22 HALLMARKS OF AGING: AN EXPANDING UNIVERSE. AGING IS DRIVEN BY HALLMARKS FULFILLING THE FOLLOWING THREE PREMISES: (1) THEIR AGE-ASSOCIATED MANIFESTATION, (2) THE ACCELERATION OF AGING BY EXPERIMENTALLY ACCENTUATING THEM, AND (3) THE OPPORTUNITY TO DECELERATE, STOP, OR REVERSE AGING BY THERAPEUTIC INTERVENTIONS ON THEM. WE PROPOSE THE FOLLOWING TWELVE HALLMARKS OF AGING: GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DISABLED MACROAUTOPHAGY, DEREGULATED NUTRIENT-SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, ALTERED INTERCELLULAR COMMUNICATION, CHRONIC INFLAMMATION, AND DYSBIOSIS. THESE HALLMARKS ARE INTERCONNECTED AMONG EACH OTHER, AS WELL AS TO THE RECENTLY PROPOSED HALLMARKS OF HEALTH, WHICH INCLUDE ORGANIZATIONAL FEATURES OF SPATIAL COMPARTMENTALIZATION, MAINTENANCE OF HOMEOSTASIS, AND ADEQUATE RESPONSES TO STRESS. 2023 12 6189 25 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 13 627 24 BIOLOGICAL AGING PROCESSES UNDERLYING COGNITIVE DECLINE AND NEURODEGENERATIVE DISEASE. ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (ADRD) ARE AMONG THE TOP CONTRIBUTORS TO DISABILITY AND MORTALITY IN LATER LIFE. AS WITH MANY CHRONIC CONDITIONS, AGING IS THE SINGLE MOST INFLUENTIAL FACTOR IN THE DEVELOPMENT OF ADRD. EVEN AMONG OLDER ADULTS WHO REMAIN FREE OF DEMENTIA THROUGHOUT THEIR LIVES, COGNITIVE DECLINE AND NEURODEGENERATIVE CHANGES ARE APPRECIABLE WITH ADVANCING AGE, SUGGESTING SHARED PATHOPHYSIOLOGICAL MECHANISMS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF CHANGES IN COGNITION, BRAIN MORPHOLOGY, AND NEUROPATHOLOGICAL PROTEIN ACCUMULATION ACROSS THE LIFESPAN IN HUMANS, WITH COMPLEMENTARY AND MECHANISTIC EVIDENCE FROM ANIMAL MODELS. NEXT, WE HIGHLIGHT SELECTED AGING PROCESSES THAT ARE DIFFERENTIALLY REGULATED IN NEURODEGENERATIVE DISEASE, INCLUDING ABERRANT AUTOPHAGY, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, EPIGENETIC CHANGES, CEREBROVASCULAR DYSFUNCTION, INFLAMMATION, AND LIPID DYSREGULATION. WE SUMMARIZE RESEARCH ACROSS CLINICAL AND TRANSLATIONAL STUDIES TO LINK BIOLOGICAL AGING PROCESSES TO UNDERLYING ADRD PATHOGENESIS. TARGETING FUNDAMENTAL PROCESSES UNDERLYING BIOLOGICAL AGING MAY REPRESENT A YET RELATIVELY UNEXPLORED AVENUE TO ATTENUATE BOTH AGE-RELATED COGNITIVE DECLINE AND ADRD. COLLABORATION ACROSS THE FIELDS OF GEROSCIENCE AND NEUROSCIENCE, COUPLED WITH THE DEVELOPMENT OF NEW TRANSLATIONAL ANIMAL MODELS THAT MORE CLOSELY ALIGN WITH HUMAN DISEASE PROCESSES, IS NECESSARY TO ADVANCE NOVEL THERAPEUTIC DISCOVERY IN THIS REALM. 2022 14 3116 17 GEROSCIENCE: ADDRESSING THE MISMATCH BETWEEN ITS EXCITING RESEARCH OPPORTUNITIES, ITS ECONOMIC IMPERATIVE AND ITS CURRENT FUNDING CRISIS. THERE IS AT PRESENT A HUGE DISCONNECT BETWEEN LEVELS OF FUNDING FOR BASIC RESEARCH ON FUNDAMENTAL MECHANISMS OF BIOLOGICAL AGING AND, GIVEN DEMOGRAPHIC PROJECTIONS, THE ANTICIPATED ENORMOUS SOCIAL AND ECONOMIC IMPACTS OF A LITANY OF CHRONIC DISEASES FOR WHICH AGING IS BY FAR THE MAJOR RISK FACTOR: ONE VALUABLE APPROACH, RECENTLY INSTIGATED BY FELIPE SIERRA & COLLEAGUES AT THE US NATIONAL INSTITUTE ON AGING, IS THE DEVELOPMENT OF A GEROSCIENCE INTEREST GROUP AMONG VIRTUALLY ALL OF THE NIH INSTITUTES. A COMPLEMENTARY APPROACH WOULD BE TO SEEK MAJOR ESCALATIONS OF PRIVATE FUNDING. THE AMERICAN FEDERATION FOR AGING RESEARCH, THE PAUL GLENN FOUNDATION AND THE ELLISON MEDICAL FOUNDATION PIONEERED EFFORTS BY THE PRIVATE SECTOR TO PROVIDE SUBSTANTIAL SUPPLEMENTS TO PUBLIC SOURCES OF FUNDING. IT IS TIME FOR OUR COMMUNITY TO ORGANIZE EFFORTS TOWARDS THE ENHANCEMENTS OF SUCH CRUCIAL CONTRIBUTIONS, ESPECIALLY IN SUPPORT OF THE EMERGING GENERATION OF YOUNG INVESTIGATORS, MANY OF WHOM ARE LEAVING OUR RANKS TO SEEK ALTERNATIVE EMPLOYMENT. TO DO SO, WE MUST PROVIDE POTENTIAL DONORS WITH STRONG ECONOMIC, HUMANITARIAN AND SCIENTIFIC RATIONALES. AN INITIAL APPROACH TO SUCH EFFORTS IS BRIEFLY OUTLINED IN THIS MANUSCRIPT AS A BASIS FOR WIDER DISCUSSIONS WITHIN OUR COMMUNITY. 2017 15 3818 21 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 16 929 12 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 17 5945 19 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 18 28 24 A BIOMIMETIC NATURAL SCIENCES APPROACH TO UNDERSTANDING THE MECHANISMS OF AGEING IN BURDEN OF LIFESTYLE DISEASES. THE WORLDWIDE LANDSCAPE OF AN AGEING POPULATION AND AGE-RELATED DISEASE BRINGS WITH IT HUGE SOCIO-ECONOMIC AND PUBLIC HEALTHCARE CONCERNS ACROSS NATIONS. CORRESPONDINGLY, MONUMENTAL HUMAN AND FINANCIAL RESOURCES HAVE BEEN INVESTED IN BIOMEDICAL RESEARCH, WITH A MISSION TO DECODE THE MECHANISMS OF AGEING AND HOW THESE CONTRIBUTE TO AGE-RELATED DISEASE. MULTIPLE HALLMARKS OF AGEING HAVE BEEN IDENTIFIED THAT ARE COMMON ACROSS TAXA, HIGHLIGHTING THEIR FUNDAMENTAL IMPORTANCE. THESE INCLUDE DYSREGULATED MITOCHONDRIAL METABOLISM AND TELOMERES BIOLOGY, EPIGENETIC MODIFICATIONS, CELL-MATRIX INTERACTIONS, PROTEOSTASIS, DYSREGULATED NUTRIENT SENSING, STEM CELL EXHAUSTION, INFLAMMAGEING AND IMMUNO-SENESCENCE. WHILE OUR UNDERSTANDING OF THE MOLECULAR BASIS OF AGEING IS IMPROVING, IT REMAINS A COMPLEX AND MULTIFACTORIAL PROCESS THAT REMAINS TO BE FULLY UNDERSTOOD. A KEY ASPECT OF THE SHORTFALL IN OUR UNDERSTANDING OF THE AGEING PROCESS LIES IN TRANSLATING DATA FROM STANDARD ANIMAL MODELS TO HUMANS. CONSEQUENTLY, WE SUGGEST THAT A 'BIOMIMETIC' AND COMPARATIVE APPROACH, INTEGRATING KNOWLEDGE FROM SPECIES IN THE WILD, AS OPPOSED TO INBRED GENETICALLY HOMOGENOUS LABORATORY ANIMALS, CAN PROVIDE POWERFUL INSIGHTS INTO HUMAN AGEING PROCESSES. HERE WE DISCUSS SOME PARTICULARITIES AND COMPARATIVE PATTERNS AMONG SEVERAL SPECIES FROM THE ANIMAL KINGDOM, ENDOWED WITH LONGEVITY OR SHORT LIFESPANS AND UNIQUE METABOLIC PROFILES THAT COULD BE POTENTIALLY EXPLOITED TO THE UNDERSTANDING OF AGEING AND AGE-RELATED DISEASES. BASED UPON LESSONS FROM NATURE, WE ALSO HIGHLIGHT SEVERAL AVENUES FOR RENEWED FOCUS IN THE PATHOPHYSIOLOGY OF AGEING AND AGE-RELATED DISEASE (I.E. DIET-MICROBIOME-HEALTH AXIS, OXIDATIVE PROTEIN DAMAGE, ADAPTIVE HOMOEOSTASIS AND PLANETARY HEALTH). WE PROPOSE THAT A BIOMIMETIC ALLIANCE WITH COLLABORATIVE RESEARCH FROM DIFFERENT DISCIPLINES CAN IMPROVE OUR UNDERSTANDING OF AGEING AND AGE-RELATED DISEASES WITH LONG-TERM SUSTAINABLE UTILITY. 2021 19 4067 14 MATERNAL AND PEDIATRIC HEALTH AND DISEASE: INTEGRATING BIOPSYCHOSOCIAL MODELS AND EPIGENETICS. THE CONCEPTS OF ALLOSTASIS (STABILITY THROUGH ADAPTATION) AND ACCUMULATED LIFE STRESS (MCEWEN'S ALLOSTATIC LOAD) AIM TO UNDERSTAND CHILDHOOD AND ADULT OUTCOMES. CHRONIC MALNUTRITION, CHANGES IN SOCIAL CONDITION, AND ADVERSE EARLY-LIFE EXPERIENCES MAY PROGRAM PHENOTYPES AND CONTRIBUTE TO LONG-LASTING DISEASE RISK. HOWEVER, INTEGRATION OF LIFE COURSE APPROACHES, SOCIAL AND ECONOMIC CONTEXTS, AND COMPARISON AMONG DIFFERENT BIOPSYCHOSOCIAL MODELS HAS NOT GENERALLY BEEN EXPLORED. THIS REVIEW CRITICALLY EXAMINES THE LITERATURE AND EVALUATES RECENT INSIGHTS INTO HOW ENVIRONMENTAL STRESS CAN ALTER LIFELONG HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND IMMUNE SYSTEM RESPONSIVENESS AND INDUCE METABOLIC AND NEURODEVELOPMENTAL MALADAPTATION. MODELS OF BIOPSYCHOSOCIAL STRESS OVERLAP BUT MAY CONSIDER DIFFERENT CONDITIONS. CONCEPTS INCLUDE ALLOSTASIS, WHICH INCORPORATES HORMONAL RESPONSES TO PREDICTABLE ENVIRONMENTAL CHANGES, AND GERONIMUS'S "WEATHERING," WHICH AIMS TO EXPLAIN HOW SOCIALLY STRUCTURED, REPEATED STRESS CAN ACCUMULATE AND INCREASE DISEASE VULNERABILITY. WEATHERING EMPHASIZES ROLES OF INTERNALIZED/INTERPERSONAL RACISM IN OUTCOMES DISPARITIES. FOR MEXICAN IMMIGRANTS AND MEXICAN AMERICANS, THE "ACCULTURATION" FRAMEWORK HAS PROVEN ESPECIALLY USEFUL TO EXPLORE DISPARITIES, INCLUDING PRETERM BIRTH AND NEUROPSYCHIATRIC RISKS IN CHILDHOOD. COMPLEXITIES OF STRESS ASSESSMENTS AND RECENT RESEARCH INTO EPIGENETIC MECHANISMS MEDIATING EFFECTS OF PHYSICAL, NUTRITIONAL, PSYCHOLOGICAL, AND SOCIAL STRESS ARE REVIEWED. 2016 20 2528 19 EPIGENETICS AS A KEY LINK BETWEEN PSYCHOSOCIAL STRESS AND AGING: CONCEPTS, EVIDENCE, MECHANISMS . PSYCHOSOCIAL STRESS-ESPECIALLY WHEN CHRONIC, EXCESSIVE, OR OCCURRING EARLY IN LIFE-HAS BEEN ASSOCIATED WITH ACCELERATED AGING AND INCREASED DISEASE RISK. WITH RAPID AGING OF THE WORLD POPULATION, THE NEED TO ELUCIDATE THE UNDERLYING MECHANISMS IS PRESSING, NOW MORE SO THAN EVER. AMONG MOLECULAR MECHANISMS LINKING STRESS AND AGING, THE PRESENT ARTICLE REVIEWS EVIDENCE ON THE ROLE OF EPIGENETICS, BIOCHEMICAL PROCESSES THAT CAN BE SET INTO MOTION BY STRESSORS AND IN TURN INFLUENCE GENOMIC FUNCTION AND COMPLEX PHENOTYPES, INCLUDING AGING-RELATED OUTCOMES. THE ARTICLE FURTHER PROVIDES A CONCEPTUAL MECHANISTIC FRAMEWORK ON HOW STRESS MAY DRIVE EPIGENETIC CHANGES AT SUSCEPTIBLE GENOMIC SITES, THEREBY EXERTING SYSTEMS-LEVEL EFFECTS ON THE AGING EPIGENOME WHILE ALSO REGULATING THE EXPRESSION OF MOLECULES IMPLICATED IN AGING-RELATED PROCESSES. THIS EMERGING EVIDENCE, TOGETHER WITH WORK EXAMINING RELATED BIOLOGICAL PROCESSES, BEGINS TO SHED LIGHT ON THE EPIGENETIC AND, MORE BROADLY, MOLECULAR UNDERPINNINGS OF THE LONG-HYPOTHESIZED CONNECTION BETWEEN STRESS AND AGING. . 2019