1 6188 110 THE IMPACT OF INSOMNIA ON FRAILTY AND THE HALLMARKS OF AGING. THROUGHOUT THE COURSE OF LIFE, THERE ARE AGE-RELATED CHANGES IN SLEEP. DESPITE THESE NORMAL CHANGES, THERE IS A HIGH PERCENTAGE OF OLDER ADULTS THAT REPORT SLEEP DISSATISFACTION WITH A HIGH PERVASIVENESS OF CHRONIC INSOMNIA, THE MOST COMMON SLEEP DISORDER WORLDWIDE, WITH ITS PREVALENCE BEING EXPECTED TO CONTINUOUSLY INCREASE DUE TO THE GROWING RATES OF AGING AND OBESITY. THIS CAN HAVE DIFFERENT ADVERSE HEALTH OUTCOMES, ESPECIALLY BY PROMOTING BOTH PHYSICAL AND COGNITIVE DECLINE, WHICH ULTIMATELY MAY AGGRAVATE FRAILTY IN OLDER ADULTS. MOREOVER, AGE-RELATED FRAILTY AND SLEEP DYSFUNCTION MAY HAVE A COMMON MECHANISM RELATED TO THE HALLMARKS OF CELLULAR AGING. CELLULAR AGING WAS CATEGORIZED INTO NINE HALLMARKS, SUCH AS DNA DAMAGE, TELOMERE ATTRITION AND EPIGENETIC CHANGES. IN THE CONTEXT OF GERIATRIC AND CHRONIC INSOMNIA RESEARCH, THIS REVIEW AIMS AT DISCUSSING THE CURRENT EVIDENCE FROM BOTH ANIMAL MODELS AND HUMAN COHORTS ADDRESSING THE LINK BETWEEN CHRONIC INSOMNIA, THE HALLMARKS OF AGING AND THEIR IMPACT ON FRAILTY. MOREOVER, THE MOST RECENT RESEARCH ABOUT THE PUTATIVE EFFECT OF INSOMNIA THERAPEUTIC APPROACHES ON HALLMARKS OF AGING WILL BE ALSO HIGHLIGHTED. 2023 2 929 30 CHRONIC INFLAMMATION: ACCELERATOR OF BIOLOGICAL AGING. BIOLOGICAL AGING IS CHARACTERIZED BY A CHRONIC LOW-GRADE INFLAMMATION LEVEL. THIS CHRONIC PHENOMENON HAS BEEN NAMED "INFLAMM-AGING" AND IS A HIGHLY SIGNIFICANT RISK FACTOR FOR MORBIDITY AND MORTALITY IN THE OLDER PERSONS. THE MOST COMMON THEORIES OF INFLAMM-AGING INCLUDE REDOX STRESS, MITOCHONDRIAL DYSFUNCTION, GLYCATION, DEREGULATION OF THE IMMUNE SYSTEM, HORMONAL CHANGES, EPIGENETIC MODIFICATIONS, AND DYSFUNCTION TELOMERE ATTRITION. INFLAMM-AGING PLAYS A ROLE IN THE INITIATION AND PROGRESSION OF AGE-RELATED DISEASES SUCH AS TYPE II DIABETES, ALZHEIMER'S DISEASE, CARDIOVASCULAR DISEASE, FRAILTY, SARCOPENIA, OSTEOPOROSIS, AND CANCER. THIS REVIEW WILL COVER THE IDENTIFICATION OF PATHWAYS THAT CONTROL AGE-RELATED INFLAMMATION ACROSS MULTIPLE SYSTEMS AND ITS POTENTIAL CAUSAL ROLE IN CONTRIBUTING TO ADVERSE HEALTH OUTCOMES. 2017 3 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 4 293 35 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 5 627 42 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 6 5948 22 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 7 6893 24 [SLEEP AND DEMENTIA]. AGING IS ASSOCIATED WITH CHANGES IN SLEEP STRUCTURE AND CEREBRAL DEPOSITION OF AMYLOID BETA AND TAU PROTEINS. SLEEP DISTURBANCES PRECEDE THE ONSET OF DEMENTIA BY YEARS. COMORBID SLEEP DISORDERS, SUCH AS INSOMNIA AND SLEEP-DISORDERED BREATHING, A FAMILY HISTORY OF DEMENTIA AND EPIGENETIC FACTORS CAN CONTRIBUTE TO THE DEVELOPMENT OF DEMENTIA. THIS ARTICLE EXPLORES THE QUESTION OF THE INTERACTION BETWEEN SLEEP AND DEMENTIA BASED ON THE EXISTING LITERATURE. ALTERATIONS CAUSED BY SLOW WAVE SLEEP LEAD TO CHANGES IN THE GLYMPHATIC CLEARANCE OF AMYLOID BETA, TAU PROTEINS AND OTHER PROTEINS. TRANSIENT AND CHRONIC SLEEP DISORDERS CAUSE DISTURBANCES IN THE BRAIN AREAS RESPONSIBLE FOR COGNITION AND BEHAVIOR. SLEEP-REGULATING BRAIN AREAS ARE THE FIRST TO BE AFFECTED IN THE NEURODEGENERATIVE PROCESS AND ACCELERATE THE RISK OF DEMENTIA. CIRCADIAN AGE-RELATED CHANGES IN AMYLOID BETA AND TAU PROTEINS AFFECT THE AMOUNT AND DEPTH OF SLEEP AND VICE VERSA. AMYLOID BETA IN CEREBROSPINAL FLUID SHOWS AN INVERSE CORRELATION WITH SLEEP. OREXINS MODULATE AMYLOID BETA AND SLEEP. 2023 8 4379 30 MITOCHONDRIAL DYSFUNCTION AND AGING: INSIGHTS FROM THE ANALYSIS OF EXTRACELLULAR VESICLES. THE PROGRESSIVE DECLINE OF CELL FUNCTION AND INTEGRITY, MANIFESTING CLINICALLY AS INCREASED VULNERABILITY TO ADVERSE OUTCOMES AND DEATH, IS CORE TO BIOLOGICAL AGING. MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, ALTERED INTERCELLULAR COMMUNICATION (INCLUDING CHRONIC LOW-GRADE INFLAMMATION), GENOMIC INSTABILITY, TELOMERE ATTRITION, LOSS OF PROTEOSTASIS, ALTERED NUTRIENT SENSING, EPIGENETIC ALTERATIONS, AND STEM CELL EXHAUSTION HAVE BEEN PROPOSED AS HALLMARKS OF AGING. THESE "AGING PILLARS" ARE NOT MUTUALLY EXCLUSIVE, MAKING THE MATTER INTRICATE AND LEAVING NUMEROUS UNANSWERED QUESTIONS. THE CHARACTERIZATION OF CIRCULATING EXTRACELLULAR VESICLES (EVS) HAS RECENTLY ALLOWED SPECIFIC SECRETORY PHENOTYPES ASSOCIATED WITH AGING TO BE IDENTIFIED. AS SUCH, EVS MAY SERVE AS NOVEL BIOMARKERS FOR CAPTURING THE COMPLEXITY OF AGING. BESIDES THE MITOCHONDRIAL(-)LYSOSOMAL AXIS, EV TRAFFICKING HAS BEEN PROPOSED AS AN ADDITIONAL LAYER IN MITOCHONDRIAL QUALITY CONTROL. INDEED, DISRUPTION OF THE MITOCHONDRIAL(-)LYSOSOMAL AXIS COUPLED WITH ABNORMAL EV SECRETION MAY PLAY A ROLE IN THE PATHOGENESIS OF AGING AND SEVERAL DISEASE CONDITIONS. HERE, WE DISCUSS (1) THE MECHANISMS OF EV GENERATION; (2) THE RELATIONSHIP BETWEEN THE MITOCHONDRIAL(-)LYSOSOMAL AXIS AND EV TRAFFICKING IN THE SETTING OF MITOCHONDRIAL QUALITY CONTROL; AND (3) THE PROSPECT OF USING EVS AS AGING BIOMARKERS AND AS DELIVERY SYSTEMS FOR THERAPEUTICS AGAINST AGE-RELATED CONDITIONS. 2019 9 182 27 ACCELERATED LUNG AGING AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE PREVALENCE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) INCREASES EXPONENTIALLY WITH AGING. ITS PATHOGENESIS, HOWEVER, IS NOT WELL KNOWN AND ASIDE FROM SMOKING CESSATION, THERE ARE NO DISEASE-MODIFYING TREATMENTS FOR THIS DISEASE. AREAS COVERED: COPD IS ASSOCIATED WITH ACCELERATING AGING AND AGING-RELATED DISEASES. IN THIS REVIEW, WE WILL DISCUSS THE HALLMARKS OF AGING INCLUDING GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATION, LOSS OF PROTEOSTASIS, MITOCHONDRIAL DYSFUNCTION, DEREGULATED NUTRIENT SENSING, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION, WHICH MAY BE INVOLVED IN COPD PATHOGENESIS. EXPERT COMMENTARY: COPD AND THE AGING PROCESS SHARE SIMILAR MOLECULAR AND CELLULAR CHANGES. AGING-RELATED MOLECULAR PATHWAYS MAY REPRESENT NOVEL THERAPEUTIC TARGETS AND BIOMARKERS FOR COPD. 2019 10 5945 32 TARGETING THE "HALLMARKS OF AGING" TO SLOW AGING AND TREAT AGE-RELATED DISEASE: FACT OR FICTION? AGING IS A MAJOR RISK FACTOR FOR A NUMBER OF CHRONIC DISEASES, INCLUDING NEURODEGENERATIVE AND CEREBROVASCULAR DISORDERS. AGING PROCESSES HAVE THEREFORE BEEN DISCUSSED AS POTENTIAL TARGETS FOR THE DEVELOPMENT OF NOVEL AND BROADLY EFFECTIVE PREVENTATIVES OR THERAPEUTICS FOR AGE-RELATED DISEASES, INCLUDING THOSE AFFECTING THE BRAIN. MECHANISMS THOUGHT TO CONTRIBUTE TO AGING HAVE BEEN SUMMARIZED UNDER THE TERM THE "HALLMARKS OF AGING" AND INCLUDE A LOSS OF PROTEOSTASIS, MITOCHONDRIAL DYSFUNCTION, ALTERED NUTRIENT SENSING, TELOMERE ATTRITION, GENOMIC INSTABILITY, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, EPIGENETIC ALTERATIONS AND ALTERED INTERCELLULAR COMMUNICATION. WE HERE EXAMINE KEY CLAIMS ABOUT THE "HALLMARKS OF AGING". OUR ANALYSIS REVEALS IMPORTANT WEAKNESSES THAT PRECLUDE STRONG AND DEFINITIVE CONCLUSIONS CONCERNING A POSSIBLE ROLE OF THESE PROCESSES IN SHAPING ORGANISMAL AGING RATE. SIGNIFICANT AMBIGUITY ARISES FROM THE OVERRELIANCE ON LIFESPAN AS A PROXY MARKER FOR AGING, THE USE OF MODELS WITH UNCLEAR RELEVANCE FOR ORGANISMAL AGING, AND THE USE OF STUDY DESIGNS THAT DO NOT ALLOW TO PROPERLY ESTIMATE INTERVENTION EFFECTS ON AGING RATE. WE ALSO DISCUSS FUTURE RESEARCH DIRECTIONS THAT SHOULD BE TAKEN TO CLARIFY IF AND TO WHAT EXTENT PUTATIVE AGING REGULATORS DO IN FACT INTERACT WITH AGING. THESE INCLUDE MULTIDIMENSIONAL ANALYTICAL FRAMEWORKS AS WELL AS DESIGNS THAT FACILITATE THE PROPER ASSESSMENT OF INTERVENTION EFFECTS ON AGING RATE. 2023 11 285 28 AGING AND AGING-RELATED DISEASES: FROM MOLECULAR MECHANISMS TO INTERVENTIONS AND TREATMENTS. AGING IS A GRADUAL AND IRREVERSIBLE PATHOPHYSIOLOGICAL PROCESS. IT PRESENTS WITH DECLINES IN TISSUE AND CELL FUNCTIONS AND SIGNIFICANT INCREASES IN THE RISKS OF VARIOUS AGING-RELATED DISEASES, INCLUDING NEURODEGENERATIVE DISEASES, CARDIOVASCULAR DISEASES, METABOLIC DISEASES, MUSCULOSKELETAL DISEASES, AND IMMUNE SYSTEM DISEASES. ALTHOUGH THE DEVELOPMENT OF MODERN MEDICINE HAS PROMOTED HUMAN HEALTH AND GREATLY EXTENDED LIFE EXPECTANCY, WITH THE AGING OF SOCIETY, A VARIETY OF CHRONIC DISEASES HAVE GRADUALLY BECOME THE MOST IMPORTANT CAUSES OF DISABILITY AND DEATH IN ELDERLY INDIVIDUALS. CURRENT RESEARCH ON AGING FOCUSES ON ELUCIDATING HOW VARIOUS ENDOGENOUS AND EXOGENOUS STRESSES (SUCH AS GENOMIC INSTABILITY, TELOMERE DYSFUNCTION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, COMPROMISE OF AUTOPHAGY, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, ALTERED INTERCELLULAR COMMUNICATION, DEREGULATED NUTRIENT SENSING) PARTICIPATE IN THE REGULATION OF AGING. FURTHERMORE, THOROUGH RESEARCH ON THE PATHOGENESIS OF AGING TO IDENTIFY INTERVENTIONS THAT PROMOTE HEALTH AND LONGEVITY (SUCH AS CALORIC RESTRICTION, MICROBIOTA TRANSPLANTATION, AND NUTRITIONAL INTERVENTION) AND CLINICAL TREATMENT METHODS FOR AGING-RELATED DISEASES (DEPLETION OF SENESCENT CELLS, STEM CELL THERAPY, ANTIOXIDATIVE AND ANTI-INFLAMMATORY TREATMENTS, AND HORMONE REPLACEMENT THERAPY) COULD DECREASE THE INCIDENCE AND DEVELOPMENT OF AGING-RELATED DISEASES AND IN TURN PROMOTE HEALTHY AGING AND LONGEVITY. 2022 12 3102 46 GENOMIC INSTABILITIES, CELLULAR SENESCENCE, AND AGING: IN VITRO, IN VIVO AND AGING-LIKE HUMAN SYNDROMES. AS AVERAGE LIFE SPAN AND ELDERLY PEOPLE PREVALENCE IN THE WESTERN WORLD POPULATION IS GRADUALLY INCREASING, THE INCIDENCE OF AGE-RELATED DISEASES SUCH AS CANCER, HEART DISEASES, DIABETES, AND DEMENTIA IS INCREASING, BEARING SOCIAL AND ECONOMIC CONSEQUENCES WORLDWIDE. UNDERSTANDING THE MOLECULAR BASIS OF AGING-RELATED PROCESSES CAN HELP EXTEND THE ORGANISM'S HEALTH SPAN, I.E., THE LIFE PERIOD IN WHICH THE ORGANISM IS FREE OF CHRONIC DISEASES OR DECREASE IN BASIC BODY FUNCTIONS. DURING THE LAST FEW DECADES, IMMENSE PROGRESS WAS MADE IN THE UNDERSTANDING OF MAJOR COMPONENTS OF AGING AND HEALTHY AGING BIOLOGY, INCLUDING GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC CHANGES, PROTEOSTASIS, NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND INTRACELLULAR COMMUNICATIONS. THIS PROGRESS HAS BEEN MADE BY THREE SPEAR-HEADED STRATEGIES: IN VITRO (CELL AND TISSUE CULTURE FROM VARIOUS SOURCES), IN VIVO (INCLUDES DIVERSE MODEL AND NON-MODEL ORGANISMS), BOTH CAN BE MANIPULATED AND TRANSLATED TO HUMAN BIOLOGY, AND THE STUDY OF AGING-LIKE HUMAN SYNDROMES AND HUMAN POPULATIONS. HEREIN, WE WILL FOCUS ON CURRENT REPOSITORY OF GENOMIC "SENESCENCE" STAGE OF AGING, WHICH INCLUDES HEALTH DECLINE, STRUCTURAL CHANGES OF THE GENOME, FAULTY DNA DAMAGE RESPONSE AND DNA DAMAGE, TELOMERE SHORTENING, AND EPIGENETIC ALTERATIONS. ALTHOUGH AGING IS A COMPLEX PROCESS, MANY OF THE "HALLMARKS" OF AGING ARE DIRECTLY RELATED TO DNA STRUCTURE AND FUNCTION. THIS REVIEW WILL ILLUSTRATE THE VARIETY OF THESE STUDIES, DONE IN IN VITRO, IN VIVO AND HUMAN LEVELS, AND HIGHLIGHT THE UNIQUE POTENTIAL AND CONTRIBUTION OF EACH RESEARCH LEVEL AND EVENTUALLY THE LINK BETWEEN THEM. 2018 13 6189 37 THE IMPACT OF LIFE STRESS ON HALLMARKS OF AGING AND ACCELERATED SENESCENCE: CONNECTIONS IN SICKNESS AND IN HEALTH. CHRONIC STRESS IS A RISK FACTOR FOR NUMEROUS AGING-RELATED DISEASES AND HAS BEEN SHOWN TO SHORTEN LIFESPAN IN HUMANS AND OTHER SOCIAL MAMMALS. YET HOW LIFE STRESS CAUSES SUCH A VAST RANGE OF DISEASES IS STILL LARGELY UNCLEAR. IN RECENT YEARS, THE IMPACT OF STRESS ON HEALTH AND AGING HAS BEEN INCREASINGLY ASSOCIATED WITH THE DYSREGULATION OF THE SO-CALLED HALLMARKS OF AGING. THESE ARE BASIC BIOLOGICAL MECHANISMS THAT INFLUENCE INTRINSIC CELLULAR FUNCTIONS AND WHOSE ALTERATION CAN LEAD TO ACCELERATED AGING. HERE, WE REVIEW CORRELATIONAL AND EXPERIMENTAL LITERATURE (PRIMARILY FOCUSING ON EVIDENCE FROM HUMANS AND MURINE MODELS) ON THE CONTRIBUTION OF LIFE STRESS - PARTICULARLY STRESS DERIVED FROM ADVERSE SOCIAL ENVIRONMENTS - TO TRIGGER HALLMARKS OF AGING, INCLUDING CELLULAR SENESCENCE, STERILE INFLAMMATION, TELOMERE SHORTENING, PRODUCTION OF REACTIVE OXYGEN SPECIES, DNA DAMAGE, AND EPIGENETIC CHANGES. WE ALSO EVALUATE THE VALIDITY OF STRESS-INDUCED SENESCENCE AND ACCELERATED AGING AS AN ETIOPATHOLOGICAL PROPOSITION. FINALLY, WE HIGHLIGHT CURRENT GAPS OF KNOWLEDGE AND FUTURE DIRECTIONS FOR THE FIELD, AND DISCUSS PERSPECTIVES FOR TRANSLATIONAL GEROSCIENCE. 2023 14 303 32 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 15 788 25 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 16 4799 32 OBESITY AND AGEING: TWO SIDES OF THE SAME COIN. CONDITIONS AND COMORBIDITIES OF OBESITY MIRROR THOSE OF AGEING AND AGE-RELATED DISEASES. OBESITY AND AGEING SHARE A SIMILAR SPECTRUM OF PHENOTYPES SUCH AS COMPROMISED GENOMIC INTEGRITY, IMPAIRED MITOCHONDRIAL FUNCTION, ACCUMULATION OF INTRACELLULAR MACROMOLECULES, WEAKENED IMMUNITY, SHIFTS IN TISSUE AND BODY COMPOSITION, AND ENHANCED SYSTEMIC INFLAMMATION. MOREOVER, IT HAS BEEN SHOWN THAT OBESITY REDUCES LIFE EXPECTANCY BY 5.8 YEARS IN MEN AND 7.1 YEARS IN WOMEN AFTER THE AGE OF 40. SHORTER LIFE EXPECTANCY COULD BE BECAUSE OBESITY HOLISTICALLY ACCELERATES AGEING AT MULTIPLE LEVELS. BESIDES JEOPARDIZING NUCLEAR DNA AND MITOCHONDRIAL DNA INTEGRITY, OBESITY MODIFIES THE DNA METHYLATION PATTERN, WHICH IS ASSOCIATED WITH EPIGENETIC AGEING IN DIFFERENT TISSUES. ADDITIONALLY, OTHER SIGNS OF AGEING ARE SEEN IN INDIVIDUALS WITH OBESITY INCLUDING TELOMERE SHORTENING, SYSTEMIC INFLAMMATION, AND FUNCTIONAL DECLINES. THIS REVIEW AIMS TO SHOW HOW OBESITY AND AGEING ARE "TWO SIDES OF THE SAME COIN" THROUGH DISCUSSING HOW OBESITY PREDISPOSES AN INDIVIDUAL TO AGE-RELATED CONDITIONS, ILLNESS, AND DISEASE. WE WILL FURTHER DEMONSTRATE HOW THE MECHANISMS THAT PERPETUATE THE EARLY-ONSET OF CHRONIC DISEASES IN OBESITY PARALLEL THOSE OF AGEING. 2020 17 5588 31 ROLE OF SENESCENCE IN THE CHRONIC HEALTH CONSEQUENCES OF COVID-19. WHILE THE FULL IMPACT OF COVID-19 IS NOT YET CLEAR, EARLY STUDIES HAVE INDICATED THAT UPWARDS OF 10% OF PATIENTS EXPERIENCE COVID-19 SYMPTOMS LONGER THAN 3 WEEKS, KNOWN AS LONG-HAULER'S SYNDROME OR PACS (POSTACUTE SEQUELAE OF SARS-COV-2 INFECTION). THERE IS LITTLE KNOWN ABOUT RISK FACTORS OR PREDICTORS OF SUSCEPTIBILITY FOR LONG-HAULER'S SYNDROME, BUT OLDER ADULTS ARE AT GREATER RISK FOR SEVERE OUTCOMES AND MORTALITY FROM COVID-19. THE PILLARS OF AGING (INCLUDING CELLULAR SENESCENCE, TELOMERE DYSFUNCTION, IMPAIRED PROTEOSTASIS, MITOCHONDRIAL DYSFUNCTION, DEREGULATED NUTRIENT SENSING, GENOMIC INSTABILITY, PROGENITOR CELL EXHAUSTION, ALTERED INTERCELLULAR COMMUNICATION, AND EPIGENETIC ALTERATIONS) THAT CONTRIBUTE TO AGE-RELATED DYSFUNCTION AND CHRONIC DISEASES (THE "GEROSCIENCE HYPOTHESIS") MAY INTERFERE WITH DEFENSES AGAINST VIRAL INFECTION AND CONSEQUENCES OF THESE INFECTIONS. HEIGHTENING OF THE LOW-GRADE INFLAMMATION THAT IS ASSOCIATED WITH AGING MAY GENERATE AN EXAGGERATED RESPONSE TO AN ACUTE COVID-19 INFECTION. INNATE IMMUNE SYSTEM DYSFUNCTION THAT LEADS TO DECREASED SENESCENT CELL REMOVAL AND/OR INCREASED SENESCENT CELL FORMATION COULD CONTRIBUTE TO ACCUMULATION OF SENESCENT CELLS WITH BOTH AGING AND VIRAL INFECTIONS. THESE PROCESSES MAY CONTRIBUTE TO INCREASED RISK FOR LONG-TERM COVID-19 SEQUELAE IN OLDER OR CHRONICALLY ILL PATIENTS. HENCE, SENOLYTICS AND OTHER GEROSCIENCE INTERVENTIONS THAT MAY PROLONG HEALTHSPAN AND ALLEVIATE CHRONIC DISEASES AND MULTIMORBIDITY LINKED TO FUNDAMENTAL AGING PROCESSES MIGHT BE AN OPTION FOR DELAYING, PREVENTING, OR ALLEVIATING LONG-HAULER'S SYNDROME. 2022 18 4387 33 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 19 5629 29 SENESCENCE IN COPD AND ITS COMORBIDITIES. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS REGARDED AS A DISEASE OF ACCELERATED LUNG AGING. THIS AFFLICTION SHOWS ALL OF THE HALLMARKS OF AGING, INCLUDING TELOMERE SHORTENING, CELLULAR SENESCENCE, ACTIVATION OF PI3 KINASE-MTOR SIGNALING, IMPAIRED AUTOPHAGY, MITOCHONDRIAL DYSFUNCTION, STEM CELL EXHAUSTION, EPIGENETIC CHANGES, ABNORMAL MICRORNA PROFILES, IMMUNOSENESCENCE, AND A LOW-GRADE CHRONIC INFLAMMATION (INFLAMMAGING). MANY OF THESE PATHWAYS ARE DRIVEN BY CHRONIC EXOGENOUS AND ENDOGENOUS OXIDATIVE STRESS. THERE IS ALSO A REDUCTION IN ANTIAGING MOLECULES, SUCH AS SIRTUINS AND KLOTHO, WHICH FURTHER ACCELERATE THE AGING PROCESS. COPD IS ASSOCIATED WITH SEVERAL COMORBIDITIES (MULTIMORBIDITY), SUCH AS CARDIOVASCULAR AND METABOLIC DISEASES, THAT SHARE THE SAME PATHWAYS OF ACCELERATED AGING. UNDERSTANDING THESE MECHANISMS HAS HELPED IDENTIFY SEVERAL NOVEL THERAPEUTIC TARGETS, AND SEVERAL DRUGS AND DIETARY INTERVENTIONS ARE NOW IN DEVELOPMENT TO TREAT MULTIMORBIDITY. 2017 20 1175 28 CONTRIBUTIONS OF AGE-RELATED THYMIC INVOLUTION TO IMMUNOSENESCENCE AND INFLAMMAGING. IMMUNE SYSTEM AGING IS CHARACTERIZED BY THE PARADOX OF IMMUNOSENESCENCE (INSUFFICIENCY) AND INFLAMMAGING (OVER-REACTION), WHICH INCORPORATE TWO SIDES OF THE SAME COIN, RESULTING IN IMMUNE DISORDER. IMMUNOSENESCENCE REFERS TO DISRUPTION IN THE STRUCTURAL ARCHITECTURE OF IMMUNE ORGANS AND DYSFUNCTION IN IMMUNE RESPONSES, RESULTING FROM BOTH AGED INNATE AND ADAPTIVE IMMUNITY. INFLAMMAGING, DESCRIBED AS A CHRONIC, STERILE, SYSTEMIC INFLAMMATORY CONDITION ASSOCIATED WITH ADVANCED AGE, IS MAINLY ATTRIBUTED TO SOMATIC CELLULAR SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) AND AGE-RELATED AUTOIMMUNE PREDISPOSITION. HOWEVER, THE INABILITY TO REDUCE SENESCENT SOMATIC CELLS (SSCS), BECAUSE OF IMMUNOSENESCENCE, EXACERBATES INFLAMMAGING. AGE-RELATED ADAPTIVE IMMUNE SYSTEM DEVIATIONS, PARTICULARLY ALTERED T CELL FUNCTION, ARE DERIVED FROM AGE-RELATED THYMIC ATROPHY OR INVOLUTION, A HALLMARK OF THYMIC AGING. RECENTLY, THERE HAVE BEEN MAJOR DEVELOPMENTS IN UNDERSTANDING HOW AGE-RELATED THYMIC INVOLUTION CONTRIBUTES TO INFLAMMAGING AND IMMUNOSENESCENCE AT THE CELLULAR AND MOLECULAR LEVELS, INCLUDING GENETIC AND EPIGENETIC REGULATION, AS WELL AS DEVELOPMENTS OF MANY POTENTIAL REJUVENATION STRATEGIES. HEREIN, WE DISCUSS THE RESEARCH PROGRESS UNCOVERING HOW AGE-RELATED THYMIC INVOLUTION CONTRIBUTES TO IMMUNOSENESCENCE AND INFLAMMAGING, AS WELL AS THEIR INTERSECTION. WE ALSO DESCRIBE HOW T CELL ADAPTIVE IMMUNITY MEDIATES INFLAMMAGING AND PLAYS A CRUCIAL ROLE IN THE PROGRESSION OF AGE-RELATED NEUROLOGICAL AND CARDIOVASCULAR DISEASES, AS WELL AS CANCER. WE THEN BRIEFLY OUTLINE THE UNDERLYING CELLULAR AND MOLECULAR MECHANISMS OF AGE-RELATED THYMIC INVOLUTION, AND FINALLY SUMMARIZE POTENTIAL REJUVENATION STRATEGIES TO RESTORE AGED THYMIC FUNCTION. 2020