1 6897 51 [TELOMERE-TELOMERASE SYSTEM IN AGING, NORM AND PATHOLOGY (LITERATURE REVIEW)]. THIS LITERATURE REVIEW PRESENTS RESULTS OF RESEARCH SHOWING ASSOCIATION BETWEEN FUNCTIONAL ACTIVITY OF THE TELOMERE-TELOMERASE SYSTEM AND MENTAL COGNITIVE AND EMOTIONAL PROCESSES IN NORMAL AND VARIOUS PATHOLOGICAL STATES: CHRONIC STRESS, DEPRESSION, BIPOLAR DISORDER, SCHIZOPHRENIA, MILD COGNITIVE IMPAIRMENT AND DEMENTIA IN AGING. IT ALSO REFERS TO AGE-SPECIFIC, PSYCHO-SOCIAL, ECONOMIC, IMMUNOLOGICAL, GENETIC AND EPIGENETIC FACTORS THAT INFLUENCE THESE RELATIONSHIPS. 2017 2 5280 20 PROMOTING SYMPATHOVAGAL BALANCE IN MULTIPLE SCLEROSIS; PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES. ACCUMULATED EVIDENCE SUGGESTS THAT CARDIOVASCULAR AUTONOMIC NERVOUS SYSTEM (ANS) DYSFUNCTION MAY BE THE UNDERLYING CAUSE OF MANY MS CLINICAL PRESENTATIONS, INCLUDING NEURODEGENERATION AND REDUCED RESPONSE TO IMMUNOMODULATORY THERAPIES, DEPRESSION, FATIGUE AND SLEEP DISORDERS, MIGRAINE, OSTEOPOROSIS, AND CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY, THE NEWER MS VASCULAR ETIOLOGY. WE HAVE RECENTLY DESCRIBED THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS WITH THE POTENTIAL INFLUENCING ANS ACTIVITY, AND THE INTERACTIONS AMONG THESE FACTORS. THIS REVIEW EXPANDS UPON PREVIOUS ONES, DESCRIBING THE PHARMACOLOGICAL, NON-PHARMACOLOGICAL, AND SURGICAL STRATEGIES THAT COULD BE ADOPTED TO PREVENT AND MINIMIZE THE DETERIORATION IN ANS FUNCTION, PROMOTING A STATE OF SYMPATHOVAGAL BALANCE. HOWEVER, THESE STRATEGIES SHOULD NOT BE APPLIED AS "ONE SIZE FITS ALL", BUT SHOULD TAKE INTO ACCOUNT THE NATURE AND THE DEGREE OF ANS DYSFUNCTION. THESE STRATEGIES WOULD BE EFFECTIVE IN IMPROVING ANS FUNCTION NOT ONLY IN MS, BUT ALSO IN OTHER AUTOIMMUNE AND NEURODEGENERATIVE DISEASES, WHERE THE DYSFUNCTION OF THIS SYSTEM PLAYS A ROLE. 2016 3 3181 10 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 4 929 14 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 5 285 16 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 6 3183 14 HALLMARKS OF T CELL AGING. THE AGED ADAPTIVE IMMUNE SYSTEM IS CHARACTERIZED BY PROGRESSIVE DYSFUNCTION AS WELL AS INCREASED AUTOIMMUNITY. THIS DECLINE IS RESPONSIBLE FOR ELEVATED SUSCEPTIBILITY TO INFECTION AND CANCER, AS WELL AS DECREASED VACCINATION EFFICACY. RECENT EVIDENCE INDICATES THAT CD4(+) T CELL-INTRINSIC ALTERATINS CONTRIBUTE TO CHRONIC INFLAMMATION AND ARE SUFFICIENT TO ACCELERATE AN ORGANISM-WIDE AGING PHENOTYPE, SUPPORTING THE IDEA THAT T CELL AGING PLAYS A MAJOR ROLE IN BODY-WIDE DETERIORATION. IN THIS REVIEW, WE PROPOSE TEN MOLECULAR HALLMARKS TO REPRESENT COMMON DENOMINATORS OF T CELL AGING. THESE HALLMARKS ARE GROUPED INTO FOUR PRIMARY HALLMARKS (THYMIC INVOLUTION, MITOCHONDRIAL DYSFUNCTION, GENETIC AND EPIGENETIC ALTERATIONS, AND LOSS OF PROTEOSTASIS) AND FOUR SECONDARY HALLMARKS (REDUCTION OF THE TCR REPERTOIRE, NAIVE-MEMORY IMBALANCE, T CELL SENESCENCE, AND LACK OF EFFECTOR PLASTICITY), AND TOGETHER THEY EXPLAIN THE MANIFESTATION OF THE TWO INTEGRATIVE HALLMARKS (IMMUNODEFICIENCY AND INFLAMMAGING). A MAJOR CHALLENGE NOW IS WEIGHING THE RELATIVE IMPACT OF THESE HALLMARKS ON T CELL AGING AND UNDERSTANDING THEIR INTERCONNECTIONS, WITH THE FINAL GOAL OF DEFINING MOLECULAR TARGETS FOR INTERVENTIONS IN THE AGING PROCESS. 2021 7 4503 15 MOSAIC AGING. ALTHOUGH ALL MULTICELLULAR ORGANISMS UNDERGO STRUCTURAL AND FUNCTIONAL DETERIORATION WITH AGE, SENESCENCE IS NOT A UNIFORM PROCESS. RATHER, EACH ORGANISM EXPERIENCES A CONSTELLATION OF CHANGES THAT REFLECT THE HETEROGENEOUS EFFECTS OF AGE ON MOLECULES, CELLS, ORGANS AND SYSTEMS, AN IDIOSYNCRATIC PATTERN THAT WE REFER TO AS MOSAIC AGING. VARYING GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS (LOCAL AND EXTRINSIC) CONTRIBUTE TO THE AGING PHENOTYPE IN A GIVEN INDIVIDUAL, AND THESE AGENTS INFLUENCE THE TYPE AND RATE OF FUNCTIONAL DECLINE, AS WELL AS THE LIKELIHOOD OF DEVELOPING AGE-ASSOCIATED AFFLICTIONS SUCH AS CARDIOVASCULAR DISEASE, ARTHRITIS, CANCER, AND NEURODEGENERATIVE DISORDERS. IDENTIFYING KEY FACTORS THAT DRIVE AGING, CLARIFYING THEIR ACTIVITIES IN DIFFERENT SYSTEMS, AND IN PARTICULAR UNDERSTANDING HOW THEY INTERACT WILL ENHANCE OUR COMPREHENSION OF THE AGING PROCESS, AND COULD YIELD INSIGHTS INTO THE PERMISSIVE ROLE THAT SENESCENCE PLAYS IN THE EMERGENCE OF ACUTE AND CHRONIC DISEASES OF THE ELDERLY. 2010 8 5945 14 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 9 4663 12 NEW HORIZONS: NOVEL APPROACHES TO ENHANCE HEALTHSPAN THROUGH TARGETING CELLULAR SENESCENCE AND RELATED AGING MECHANISMS. THE ELDERLY POPULATION IS INCREASING FASTER THAN OTHER SEGMENTS OF THE POPULATION THROUGHOUT THE WORLD. AGE IS THE LEADING PREDICTOR FOR MOST CHRONIC DISEASES AND DISORDERS, MULTIMORBIDITY, GERIATRIC SYNDROMES, AND IMPAIRED ABILITY TO RECOVER FROM ACCIDENTS OR ILLNESSES. ENHANCING THE DURATION OF HEALTH AND INDEPENDENCE, TERMED HEALTHSPAN, WOULD BE MORE DESIRABLE THAN EXTENDING LIFESPAN MERELY BY PROLONGING THE PERIOD OF MORBIDITY TOWARD THE END OF LIFE. THE GEROSCIENCE HYPOTHESIS POSITS THAT HEALTHSPAN CAN BE EXTENDED BY TARGETING FUNDAMENTAL AGING MECHANISMS, RATHER THAN ATTEMPTING TO ADDRESS EACH AGE-RELATED DISEASE ONE AT A TIME, ONLY SO THE AFFLICTED INDIVIDUAL SURVIVES DISABLED AND DIES SHORTLY AFTERWARD OF ANOTHER AGE-RELATED DISEASE. THESE FUNDAMENTAL AGING MECHANISMS INCLUDE, AMONG OTHERS, CHRONIC INFLAMMATION, FIBROSIS, STEM CELL/ PROGENITOR DYSFUNCTION, DNA DAMAGE, EPIGENETIC CHANGES, METABOLIC SHIFTS, DESTRUCTIVE METABOLITE GENERATION, MITOCHONDRIAL DYSFUNCTION, MISFOLDED OR AGGREGATED PROTEIN ACCUMULATION, AND CELLULAR SENESCENCE. THESE PROCESSES APPEAR TO BE TIGHTLY INTERLINKED, AS TARGETING ANY ONE APPEARS TO AFFECT MANY OF THE REST, UNDERLYING OUR UNITARY THEORY OF FUNDAMENTAL AGING MECHANISMS. INTERVENTIONS TARGETING MANY FUNDAMENTAL AGING PROCESSES ARE BEING DEVELOPED, INCLUDING DIETARY MANIPULATIONS, METFORMIN, MTOR (MECHANISTIC TARGET OF RAPAMYCIN) INHIBITORS, AND SENOLYTICS, WHICH ARE IN EARLY HUMAN TRIALS. THESE INTERVENTIONS COULD LEAD TO GREATER HEALTHSPAN BENEFITS THAN TREATING AGE-RELATED DISEASES ONE AT A TIME. TO ILLUSTRATE THESE POINTS, WE FOCUS ON CELLULAR SENESCENCE AND THERAPIES IN DEVELOPMENT TO TARGET SENESCENT CELLS. COMBINING INTERVENTIONS TARGETING AGING MECHANISMS WITH DISEASE-SPECIFIC DRUGS COULD RESULT IN MORE THAN ADDITIVE BENEFITS FOR CURRENTLY DIFFICULT-TO-TREAT OR INTRACTABLE DISEASES. MORE RESEARCH ATTENTION NEEDS TO BE DEVOTED TO TARGETING FUNDAMENTAL AGING PROCESSES. 2021 10 6189 18 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 11 6412 20 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 12 4985 19 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 13 3922 17 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 14 293 15 AGING HALLMARKS AND THE ROLE OF OXIDATIVE STRESS. AGING IS A COMPLEX BIOLOGICAL PROCESS ACCOMPANIED BY A PROGRESSIVE DECLINE IN THE PHYSICAL FUNCTION OF THE ORGANISM AND AN INCREASED RISK OF AGE-RELATED CHRONIC DISEASES SUCH AS CARDIOVASCULAR DISEASES, CANCER, AND NEURODEGENERATIVE DISEASES. STUDIES HAVE ESTABLISHED THAT THERE EXIST NINE HALLMARKS OF THE AGING PROCESS, INCLUDING (I) TELOMERE SHORTENING, (II) GENOMIC INSTABILITY, (III) EPIGENETIC MODIFICATIONS, (IV) MITOCHONDRIAL DYSFUNCTION, (V) LOSS OF PROTEOSTASIS, (VI) DYSREGULATED NUTRIENT SENSING, (VII) STEM CELL EXHAUSTION, (VIII) CELLULAR SENESCENCE, AND (IX) ALTERED CELLULAR COMMUNICATION. ALL THESE ALTERATIONS HAVE BEEN LINKED TO SUSTAINED SYSTEMIC INFLAMMATION, AND THESE MECHANISMS CONTRIBUTE TO THE AGING PROCESS IN TIMING NOT CLEARLY DETERMINED YET. NEVERTHELESS, MITOCHONDRIAL DYSFUNCTION IS ONE OF THE MOST IMPORTANT MECHANISMS CONTRIBUTING TO THE AGING PROCESS. MITOCHONDRIA IS THE PRIMARY ENDOGENOUS SOURCE OF REACTIVE OXYGEN SPECIES (ROS). DURING THE AGING PROCESS, THERE IS A DECLINE IN ATP PRODUCTION AND ELEVATED ROS PRODUCTION TOGETHER WITH A DECLINE IN THE ANTIOXIDANT DEFENSE. ELEVATED ROS LEVELS CAN CAUSE OXIDATIVE STRESS AND SEVERE DAMAGE TO THE CELL, ORGANELLE MEMBRANES, DNA, LIPIDS, AND PROTEINS. THIS DAMAGE CONTRIBUTES TO THE AGING PHENOTYPE. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES IN THE MECHANISMS OF AGING WITH AN EMPHASIS ON MITOCHONDRIAL DYSFUNCTION AND ROS PRODUCTION. 2023 15 4387 17 MITOTIC DYSFUNCTION ASSOCIATED WITH AGING HALLMARKS. AGING IS A BIOLOGICAL PROCESS CHARACTERIZED BY THE PROGRESSIVE DETERIORATION OF PHYSIOLOGICAL FUNCTIONS KNOWN TO BE THE MAIN RISK FACTOR FOR CHRONIC DISEASES AND DECLINING HEALTH. THERE HAS BEEN AN EMERGING CONNECTION BETWEEN AGING AND ANEUPLOIDY, AN ABERRANT NUMBER OF CHROMOSOMES, EVEN THOUGH THE MOLECULAR MECHANISMS BEHIND AGE-ASSOCIATED ANEUPLOIDY REMAIN LARGELY UNKNOWN. IN RECENT YEARS, SEVERAL GENETIC PATHWAYS AND BIOCHEMICAL PROCESSES CONTROLLING THE RATE OF AGING HAVE BEEN IDENTIFIED AND PROPOSED AS AGING HALLMARKS. PRIMARY HALLMARKS THAT CAUSE THE ACCUMULATION OF CELLULAR DAMAGE INCLUDE GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS AND LOSS OF PROTEOSTASIS (LOPEZ-OTIN ET AL., CELL 153:1194-1217, 2013). HERE WE REVIEW THE PROVOCATIVE LINK BETWEEN THESE AGING HALLMARKS AND THE LOSS OF CHROMOSOME SEGREGATION FIDELITY DURING CELL DIVISION, WHICH COULD SUPPORT THE CORRELATION BETWEEN AGING AND ANEUPLOIDY SEEN OVER THE PAST DECADES. SECONDLY, WE REVIEW THE SYSTEMIC IMPACTS OF ANEUPLOIDY IN CELL PHYSIOLOGY AND EMPHASIZE HOW THESE INCLUDE SOME OF THE PRIMARY HALLMARKS OF AGING. BASED ON THE EVIDENCE, WE PROPOSE A MUTUAL CAUSALITY BETWEEN AGING AND ANEUPLOIDY, AND SUGGEST MODULATION OF MITOTIC FIDELITY AS A POTENTIAL MEANS TO AMELIORATE HEALTHY LIFESPAN. 2017 16 3818 12 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 17 303 15 AIR POLLUTION STRESS AND THE AGING PHENOTYPE: THE TELOMERE CONNECTION. AGING IS A COMPLEX PHYSIOLOGICAL PHENOMENON. THE QUESTION WHY SOME SUBJECTS GROW OLD WHILE REMAINING FREE FROM DISEASE WHEREAS OTHERS PREMATURELY DIE REMAINS LARGELY UNANSWERED. WE FOCUS HERE ON THE ROLE OF AIR POLLUTION IN BIOLOGICAL AGING. HALLMARKS OF AGING CAN BE GROUPED INTO THREE MAIN CATEGORIES: GENOMIC INSTABILITY, TELOMERE ATTRITION, AND EPIGENETIC ALTERATIONS LEADING TO ALTERED MITOCHONDRIAL FUNCTION AND CELLULAR SENESCENCE. AT BIRTH, THE INITIAL TELOMERE LENGTH OF A PERSON IS LARGELY DETERMINED BY ENVIRONMENTAL FACTORS. TELOMERE LENGTH SHORTENS WITH EACH CELL DIVISION AND EXPOSURE TO AIR POLLUTION AS WELL AS LOW RESIDENTIAL GREENS SPACE EXPOSURE IS ASSOCIATED WITH SHORTER TELOMERE LENGTH. RECENT STUDIES SHOW THAT THE ESTIMATED EFFECTS OF PARTICULATE AIR POLLUTION EXPOSURE ON THE TELOMERE MITOCHONDRIAL AXIS OF AGING MAY PLAY AN IMPORTANT ROLE IN CHRONIC HEALTH EFFECTS OF AIR POLLUTION. THE EXPOSOME ENCOMPASSES ALL EXPOSURES OVER AN ENTIRE LIFE. AS TELOMERES CAN BE CONSIDERED AS THE CELLULAR MEMORIES OF EXPOSURE TO OXIDATIVE STRESS AND INFLAMMATION, TELOMERE MAINTENANCE MAY BE A PROXY FOR ASSESSING THE "EXPOSOME". IF TELOMERES ARE CAUSALLY RELATED TO THE AGING PHENOTYPE AND ENVIRONMENTAL AIR POLLUTION IS AN IMPORTANT DETERMINANT OF TELOMERE LENGTH, THIS MIGHT PROVIDE NEW AVENUES FOR FUTURE PREVENTIVE STRATEGIES. 2016 18 5919 14 TARGETING CELLULAR SENESCENCE FOR AGE-RELATED DISEASES: PATH TO CLINICAL TRANSLATION. BEYOND THE PALLIATIVE REACH OF TODAY'S MEDICINES, MEDICAL THERAPIES OF TOMORROW AIM TO TREAT THE ROOT CAUSE OF AGE-RELATED DISEASES BY TARGETING FUNDAMENTAL AGING MECHANISMS. PILLARS OF AGING INCLUDE, AMONG OTHERS, GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DYSREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION. THE UNITARY THEORY OF FUNDAMENTAL AGING PROCESSES POSITS THAT BY TARGETING ONE FUNDAMENTAL AGING PROCESS, IT MAY BE FEASIBLE TO IMPACT SEVERAL OR ALL OTHERS GIVEN ITS INTERDEPENDENCE. INDEED, PATHOLOGIC ACCUMULATION OF SENESCENT CELLS IS IMPLICATED IN CHRONIC DISEASES AND AGE-ASSOCIATED MORBIDITIES, SUGGESTING THAT SENESCENT CELLS ARE A GOOD TARGET FOR WHOLE-BODY AGING INTERVENTION. PRECLINICAL STUDIES USING SENOLYTICS, AGENTS THAT SELECTIVELY ELIMINATE SENESCENT CELLS, AND SENOMORPHICS, AGENTS THAT INHIBIT PRODUCTION OR RELEASE OF SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE FACTORS, SHOW PROMISE IN SEVERAL AGING AND DISEASE PRECLINICAL MODELS. EARLY CLINICAL TRIALS USING A SENOLYTIC COMBINATION (DASATINIB AND QUERCETIN), AND OTHER SENOLYTICS INCLUDING FLAVONOID, FISETIN, AND BCL-XL INHIBITORS, ILLUSTRATE THE POTENTIAL OF SENOLYTICS TO ALLEVIATE AGE-RELATED DYSFUNCTION AND DISEASES INCLUDING WOUND HEALING. TRANSLATION INTO CLINICAL APPLICATIONS REQUIRES PARALLEL CLINICAL TRIALS ACROSS INSTITUTIONS TO VALIDATE SENOTHERAPEUTICS AS A VANGUARD FOR DELAYING, PREVENTING, OR TREATING AGE-RELATED DISORDERS AND AESTHETIC AGING. 2022 19 5766 19 SPECIAL ISSUE: ALZHEIMER'S DISEASE. MORE THAN 45 MILLION PEOPLE WORLDWIDE HAVE ALZHEIMER'S DISEASE (AD), A DETERIORATION OF MEMORY AND OTHER COGNITIVE DOMAINS THAT LEADS TO DEATH WITHIN 3 TO 9 YEARS AFTER DIAGNOSIS. THE PRINCIPAL RISK FACTOR FOR AD IS AGE. AS THE AGING POPULATION INCREASES, THE PREVALENCE WILL APPROACH 131 MILLION CASES WORLDWIDE IN 2050. AD IS THEREFORE A GLOBAL PROBLEM CREATING A RAPIDLY GROWING EPIDEMIC AND BECOMING A MAJOR THREAT TO HEALTHCARE IN OUR SOCIETIES. IT HAS BEEN MORE THAN 20 YEARS SINCE IT WAS FIRST PROPOSED THAT THE NEURODEGENERATION IN AD MAY BE CAUSED BY DEPOSITION OF AMYLOID-BETA (ABETA) PEPTIDES IN PLAQUES IN BRAIN TISSUE. ACCORDING TO THE AMYLOID HYPOTHESIS, ACCUMULATION OF ABETA PEPTIDES, RESULTING FROM A CHRONIC IMBALANCE BETWEEN ABETA PRODUCTION AND ABETA CLEARANCE IN THE BRAIN, IS THE PRIMARY INFLUENCE DRIVING AD PATHOGENESIS. CURRENT AVAILABLE MEDICATIONS APPEAR TO BE ABLE TO PRODUCE MODERATE SYMPTOMATIC BENEFITS BUT NOT TO STOP DISEASE PROGRESSION. THE SEARCH FOR BIOMARKERS AS WELL AS NOVEL THERAPEUTIC APPROACHES FOR AD HAS BEEN A MAJOR FOCUS OF RESEARCH. RECENT FINDINGS, HOWEVER, SHOW THAT NEURONAL-INJURY BIOMARKERS ARE INDEPENDENT OF ABETA SUGGESTING EPIGENETIC MODIFICATIONS, GENE-GENE AND/OR GENE-ENVIRONMENT INTERACTIONS IN THE DISEASE ETIOLOGY, AND CALLING FOR RECONSIDERATION OF THE PATHOLOGICAL CASCADE AND ASSESSMENT OF ALTERNATIVE THERAPEUTIC STRATEGIES. IN ADDITION, RECENT RESEARCH RESULTS REGARDING THE EXPRESSION OF THE BETA-AMYLOID PRECURSOR PROTEIN (APP) GENE RESULTING IN THE PRESENCE OF VARIOUS APP-MRNA ISOFORMS AND THEIR QUANTIFICATION, ESPECIALLY FOR IDENTIFYING THE MOST ABUNDANT ONE THAT MAY DECISIVE FOR THE NORMAL STATUS OR DISEASE RISK, HAVE BEEN REPORTED. AS SUCH, A MORE COMPLETE UNDERSTANDING OF AD PATHOGENESIS WILL LIKELY REQUIRE GREATER INSIGHTS INTO THE PHYSIOLOGICAL FUNCTION OF THE BETA-AMYLOID PRECURSOR PROTEIN (APP). 2018 20 5381 17 RECONSIDERING THE ROLE OF MITOCHONDRIA IN AGING. BACKGROUND: MITOCHONDRIAL DYSFUNCTION HAS LONG BEEN CONSIDERED A MAJOR CONTRIBUTOR TO AGING AND AGE-RELATED DISEASES. HARMAN'S MITOCHONDRIAL FREE RADICAL THEORY OF AGING POSTULATED THAT SOMATIC MITOCHONDRIAL DNA MUTATIONS THAT ACCUMULATE OVER THE LIFE SPAN CAUSE EXCESSIVE PRODUCTION OF REACTIVE OXYGEN SPECIES THAT DAMAGE MACROMOLECULES AND IMPAIR CELL AND TISSUE FUNCTION. INDEED, STUDIES HAVE SHOWN THAT MAXIMAL OXIDATIVE CAPACITY DECLINES WITH AGE WHILE REACTIVE OXYGEN SPECIES PRODUCTION INCREASES. HARMAN'S HYPOTHESIS HAS BEEN SERIOUSLY CHALLENGED BY RECENT STUDIES SHOWING THAT REACTIVE OXYGEN SPECIES EVOKE METABOLIC HEALTH AND LONGEVITY, PERHAPS THROUGH HORMETIC MECHANISMS THAT INCLUDE AUTOPHAGY. THE PURPOSE OF THIS REVIEW IS TO SCAN THE EVER-GROWING LITERATURE ON MITOCHONDRIA FROM THE PERSPECTIVE OF AGING RESEARCH AND TRY TO IDENTIFY PRIORITY QUESTIONS THAT SHOULD BE ADDRESSED IN FUTURE RESEARCH. METHODS: A SYSTEMATIC SEARCH OF PEER-REVIEWED STUDIES WAS PERFORMED USING PUBMED. SEARCH TERMS INCLUDED (I) MITOCHONDRIA OR MITOCHONDRIAL; (II) AGING, AGEING, OLDER ADULTS OR ELDERLY; AND (III) REACTIVE OXYGEN SPECIES, MITOCHONDRIA DYNAMICS, MITOCHONDRIAL PROTEOSTASIS, CYTOSOL, MITOCHONDRIAL-ASSOCIATED MEMBRANES, REDOX HOMEOSTASIS, ELECTRON TRANSPORT CHAIN, ELECTRON TRANSPORT CHAIN EFFICIENCY, EPIGENETIC REGULATION, DNA HETEROPLASMY. RESULTS: THE IMPORTANCE OF MITOCHONDRIAL BIOLOGY AS A TRAIT D'UNION BETWEEN THE BASIC BIOLOGY OF AGING AND THE PATHOGENESIS OF AGE-RELATED DISEASES IS STRONGER THAN EVER, ALTHOUGH THE EMPHASIS HAS MOVED FROM REACTIVE OXYGEN SPECIES PRODUCTION TO OTHER ASPECTS OF MITOCHONDRIAL PHYSIOLOGY, INCLUDING MITOCHONDRIAL BIOGENESIS AND TURNOVER, ENERGY SENSING, APOPTOSIS, SENESCENCE, AND CALCIUM DYNAMICS. CONCLUSIONS: MITOCHONDRIA COULD PLAY A KEY ROLE IN THE PATHOPHYSIOLOGY OF AGING OR IN THE EARLIER STAGES OF SOME EVENTS THAT LEAD TO THE AGING PHENOTYPE. THEREFORE, MITOCHONDRIA WILL INCREASINGLY BE TARGETED TO PREVENT AND TREAT CHRONIC DISEASES AND TO PROMOTE HEALTHY AGING. 2015