1 5948 75 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 2 3181 12 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 3 182 20 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 4 929 17 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 6188 22 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 6 560 17 BACK TO THE FUTURE: EPIGENETIC CLOCK PLASTICITY TOWARDS HEALTHY AGING. AGING IS THE MOST IMPORTANT RISK FACTOR FOR MAJOR HUMAN LIFESTYLE DISEASES, INCLUDING CANCER, NEUROLOGICAL AND CARDIOMETABOLIC DISORDERS. DUE TO THE COMPLEX INTERPLAY BETWEEN GENETICS, LIFESTYLE AND ENVIRONMENTAL FACTORS, SOME INDIVIDUALS SEEM TO AGE FASTER THAN OTHERS, WHEREAS CENTENARIANS SEEM TO HAVE A SLOWER AGING PROCESS. THEREFORE, A BIOCHEMICAL BIOMARKER REFLECTING THE RELATIVE BIOLOGICAL AGE WOULD BE HELPFUL TO PREDICT AN INDIVIDUAL'S HEALTH STATUS AND AGING DISEASE RISK. ALTHOUGH IT IS ALREADY KNOWN FOR YEARS THAT CUMULATIVE EPIGENETIC CHANGES OCCUR UPON AGING, DNA METHYLATION PATTERNS WERE ONLY RECENTLY USED TO CONSTRUCT AN EPIGENETIC CLOCK PREDICTOR FOR BIOLOGICAL AGE, WHICH IS A MEASURE OF HOW WELL YOUR BODY FUNCTIONS COMPARED TO YOUR CHRONOLOGICAL AGE. MOREOVER, THE EPIGENETIC DNA METHYLATION CLOCK SIGNATURE IS INCREASINGLY APPLIED AS A BIOMARKER TO ESTIMATE AGING DISEASE SUSCEPTIBILITY AND MORTALITY RISK. FINALLY, THE EPIGENETIC CLOCK SIGNATURE COULD BE USED AS A LIFESTYLE MANAGEMENT TOOL TO MONITOR HEALTHY AGING, TO EVALUATE PREVENTIVE INTERVENTIONS AGAINST CHRONIC AGING DISORDERS AND TO EXTEND HEALTHY LIFESPAN. DISSECTING THE MECHANISM OF THE EPIGENETIC AGING CLOCK WILL YIELD VALUABLE INSIGHTS INTO THE AGING PROCESS AND HOW IT CAN BE MANIPULATED TO IMPROVE HEALTH SPAN. 2018 7 5945 22 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 8 285 18 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 9 739 18 CANCER TREATMENT-INDUCED ACCELERATED AGING IN CANCER SURVIVORS: BIOLOGY AND ASSESSMENT. RAPID IMPROVEMENTS IN CANCER SURVIVAL LED TO THE REALIZATION THAT MANY MODALITIES USED TO TREAT OR CONTROL CANCER MAY CAUSE ACCELERATED AGING IN CANCER SURVIVORS. CLINICALLY, "ACCELERATED AGING" PHENOTYPES IN CANCER SURVIVORS INCLUDE SECONDARY CANCERS, FRAILTY, CHRONIC ORGAN DYSFUNCTION, AND COGNITIVE IMPAIRMENT, ALL OF WHICH CAN IMPACT LONG-TERM HEALTH AND QUALITY OF LIFE IN CANCER SURVIVORS. THE TREATMENT-INDUCED ACCELERATED AGING IN CANCER SURVIVORS COULD BE EXPLAINED BY TELOMERE ATTRITION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, DNA DAMAGE, AND EPIGENETIC ALTERATIONS. SEVERAL AGING CLOCKS AND BIOMARKERS OF AGING HAVE BEEN PROPOSED TO BE POTENTIALLY USEFUL IN ESTIMATING BIOLOGICAL AGE, WHICH CAN PROVIDE SPECIFIC INFORMATION ABOUT HOW OLD AN INDIVIDUAL IS BIOLOGICALLY INDEPENDENT OF CHRONOLOGICAL AGE. MEASURING BIOLOGICAL AGE IN CANCER SURVIVORS MAY BE IMPORTANT FOR TWO REASONS. FIRST, IT CAN BETTER PREDICT THE RISK OF CANCER TREATMENT-RELATED COMORBIDITIES THAN CHRONOLOGICAL AGE. SECOND, BIOLOGICAL AGE MAY PROVIDE ADDITIONAL VALUE IN EVALUATING THE EFFECTS OF TREATMENTS AND PERSONALIZING CANCER THERAPIES TO MAXIMIZE EFFICACY OF TREATMENT. A DEEPER UNDERSTANDING OF TREATMENT-INDUCED ACCELERATED AGING IN INDIVIDUALS WITH CANCER MAY LEAD TO NOVEL STRATEGIES THAT REDUCE THE ACCELERATED AGING AND IMPROVE THE QUALITY OF LIFE IN CANCER SURVIVORS. 2021 10 303 19 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 11 1558 21 DNA METHYLATION MODULATES AGING PROCESS IN ADIPOCYTES. AGING HAS BEEN RECOGNIZED TO BE A HIGHLY COMPLEX BIOLOGICAL HEALTH PROBLEM WITH A HIGH RISK OF CHRONIC DISEASES, INCLUDING TYPE 2 DIABETES, ATHEROSCLEROSIS, CHRONIC BRONCHITIS OR EMPHYSEMA, CANCER AND ALZHEIMER'S DISEASE. PARTICULARLY, AGE-RELATED TURNOVER IN ADIPOSE TISSUE IS A MAJOR CONTRIBUTOR TO METABOLIC SYNDROMES AND SHORTENED LIFESPAN. ADIPOCYTES UNDERGO SENESCENCE IN EARLY STAGE, WHICH RESULTS IN ADIPOSE TISSUE METABOLIC DYSFUNCTION, REDISTRIBUTION, AND INFLAMMATION. THE WELL-ESTABLISHED ASSOCIATION BETWEEN DNA METHYLATION (DNAM) AND AGING HAS BEEN OBSERVED IN THE PAST FEW DECADES. INDEED, AGE-RELATED ALTERATION IN DNAM IS HIGHLY TISSUE-SPECIFIC. THIS REVIEW INTENDS TO SUMMARIZE THE ADVANCEMENTS HOW DNAM CHANGES COUPLED WITH AGING PROCESS IN ADIPOSE TISSUE, BY WHICH DNAM REGULATES CELLULAR SENESCENCE, METABOLIC FUNCTION, ADIPOKINE SECRETION AND BEIGING PROCESS IN ADIPOCYTES. ELUCIDATION OF THE EFFECT OF DNAM ON ADIPOSE AGING WOULD HAVE GREAT POTENTIAL TO THE DEVELOPMENT OF EPIGENETIC THERAPEUTIC STRATEGIES AGAINST AGING-RELATED DISEASES IN CLINICAL SETTINGS. 2022 12 4387 26 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 13 5919 18 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 14 1780 20 EDUCATION AND LIFESTYLE FACTORS ARE ASSOCIATED WITH DNA METHYLATION CLOCKS IN OLDER AFRICAN AMERICANS. DNA METHYLATION (DNAM) CLOCKS ARE IMPORTANT BIOMARKERS OF CELLULAR AGING AND ARE ASSOCIATED WITH A VARIETY OF AGE-RELATED CHRONIC DISEASES AND ALL-CAUSE MORTALITY. EXAMINING THE RELATIONSHIP BETWEEN EDUCATION AND LIFESTYLE RISK FACTORS FOR AGE-RELATED DISEASES AND MULTIPLE DNAM CLOCKS CAN INCREASE THE UNDERSTANDING OF HOW RISK FACTORS CONTRIBUTE TO AGING AT THE CELLULAR LEVEL. THIS STUDY EXPLORED THE ASSOCIATION BETWEEN EDUCATION OR LIFESTYLE RISK FACTORS FOR AGE-RELATED DISEASES AND THE ACCELERATION OF FOUR DNAM CLOCKS, INCLUDING INTRINSIC (IEAA) AND EXTRINSIC EPIGENETIC AGE ACCELERATION (EEAA), PHENOAGE ACCELERATION (PHENOAA), AND GRIMAGE ACCELERATION (GRIMAA) IN THE AFRICAN AMERICAN PARTICIPANTS OF THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY. WE PERFORMED BOTH CROSS-SECTIONAL AND LONGITUDINAL ANALYSES. IN CROSS-SECTIONAL ANALYSES, GENDER, EDUCATION, BMI, SMOKING, AND ALCOHOL CONSUMPTION WERE ALL INDEPENDENTLY ASSOCIATED WITH GRIMAA, WHEREAS ONLY SOME OF THEM WERE ASSOCIATED WITH OTHER CLOCKS. THE EFFECT OF SMOKING AND EDUCATION ON GRIMAA VARIED BY GENDER. LONGITUDINAL ANALYSES SUGGEST THAT AGE AND BMI CONTINUED TO INCREASE GRIMAA, AND THAT AGE AND CURRENT SMOKING CONTINUED TO INCREASE PHENOAA AFTER CONTROLLING DNAM CLOCKS AT BASELINE. IN CONCLUSION, EDUCATION AND COMMON LIFESTYLE RISK FACTORS WERE ASSOCIATED WITH MULTIPLE DNAM CLOCKS. HOWEVER, THE ASSOCIATION WITH EACH RISK FACTOR VARIED BY CLOCK, WHICH SUGGESTS THAT DIFFERENT CLOCKS MAY CAPTURE ADVERSE EFFECTS FROM DIFFERENT ENVIRONMENTAL STIMULI. 2019 15 2485 20 EPIGENETIC-BASED AGE ACCELERATION IN A REPRESENTATIVE SAMPLE OF OLDER AMERICANS: ASSOCIATIONS WITH AGING-RELATED MORBIDITY AND MORTALITY. BIOMARKERS DEVELOPED FROM DNA METHYLATION (DNAM) DATA ARE OF GROWING INTEREST AS PREDICTORS OF HEALTH OUTCOMES AND MORTALITY IN OLDER POPULATIONS. HOWEVER, IT IS UNKNOWN HOW EPIGENETIC AGING FITS WITHIN THE CONTEXT OF KNOWN SOCIOECONOMIC AND BEHAVIORAL ASSOCIATIONS WITH AGING-RELATED HEALTH OUTCOMES IN A LARGE, POPULATION-BASED, AND DIVERSE SAMPLE. THIS STUDY USES DATA FROM A REPRESENTATIVE, PANEL STUDY OF US OLDER ADULTS TO EXAMINE THE RELATIONSHIP BETWEEN DNAM-BASED AGE ACCELERATION MEASURES IN THE PREDICTION OF CROSS-SECTIONAL AND LONGITUDINAL HEALTH OUTCOMES AND MORTALITY. WE EXAMINE WHETHER RECENT IMPROVEMENTS TO THESE SCORES, USING PRINCIPAL COMPONENT (PC)-BASED MEASURES DESIGNED TO REMOVE SOME OF THE TECHNICAL NOISE AND UNRELIABILITY IN MEASUREMENT, IMPROVE THE PREDICTIVE CAPABILITY OF THESE MEASURES. WE ALSO EXAMINE HOW WELL DNAM-BASED MEASURES PERFORM AGAINST WELL-KNOWN PREDICTORS OF HEALTH OUTCOMES SUCH AS DEMOGRAPHICS, SES, AND HEALTH BEHAVIORS. IN OUR SAMPLE, AGE ACCELERATION CALCULATED USING "SECOND AND THIRD GENERATION CLOCKS," PHENOAGE, GRIMAGE, AND DUNEDINPACE, IS CONSISTENTLY A SIGNIFICANT PREDICTOR OF HEALTH OUTCOMES INCLUDING CROSS-SECTIONAL COGNITIVE DYSFUNCTION, FUNCTIONAL LIMITATIONS AND CHRONIC CONDITIONS ASSESSED 2 Y AFTER DNAM MEASUREMENT, AND 4-Y MORTALITY. PC-BASED EPIGENETIC AGE ACCELERATION MEASURES DO NOT SIGNIFICANTLY CHANGE THE RELATIONSHIP OF DNAM-BASED AGE ACCELERATION MEASURES TO HEALTH OUTCOMES OR MORTALITY COMPARED TO EARLIER VERSIONS OF THESE MEASURES. WHILE THE USEFULNESS OF DNAM-BASED AGE ACCELERATION AS A PREDICTOR OF LATER LIFE HEALTH OUTCOMES IS QUITE CLEAR, OTHER FACTORS SUCH AS DEMOGRAPHICS, SES, MENTAL HEALTH, AND HEALTH BEHAVIORS REMAIN EQUALLY, IF NOT MORE ROBUST, PREDICTORS OF LATER LIFE OUTCOMES. 2023 16 6189 24 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 17 4183 16 META-HALLMARKS OF AGING AND CANCER. BOTH AGING AND CANCER ARE CHARACTERIZED BY A SERIES OF PARTIALLY OVERLAPPING "HALLMARKS" THAT WE SUBJECT HERE TO A META-ANALYSIS. SEVERAL HALLMARKS OF AGING (I.E., GENOMIC INSTABILITY, EPIGENETIC ALTERATIONS, CHRONIC INFLAMMATION, AND DYSBIOSIS) ARE VERY SIMILAR TO SPECIFIC CANCER HALLMARKS AND HENCE CONSTITUTE COMMON "META-HALLMARKS," WHILE OTHER FEATURES OF AGING (I.E., TELOMERE ATTRITION AND STEM CELL EXHAUSTION) ACT LIKELY TO SUPPRESS ONCOGENESIS AND HENCE CAN BE VIEWED AS PREPONDERANTLY "ANTAGONISTIC HALLMARKS." DISABLED MACROAUTOPHAGY AND CELLULAR SENESCENCE ARE TWO HALLMARKS OF AGING THAT EXERT CONTEXT-DEPENDENT ONCOSUPPRESSIVE AND PRO-TUMORIGENIC EFFECTS. SIMILARLY, THE EQUIVALENCE OR ANTAGONISM BETWEEN AGING-ASSOCIATED DEREGULATED NUTRIENT-SENSING AND CANCER-RELEVANT ALTERATIONS OF CELLULAR METABOLISM IS COMPLEX. THE AGONISTIC AND ANTAGONISTIC RELATIONSHIP BETWEEN THE PROCESSES THAT DRIVE AGING AND CANCER HAS BEARINGS FOR THE AGE-RELATED INCREASE AND OLDEST AGE-RELATED DECREASE OF CANCER MORBIDITY AND MORTALITY, AS WELL AS FOR THE THERAPEUTIC MANAGEMENT OF MALIGNANT DISEASE IN THE ELDERLY. 2023 18 5959 23 TELOMERE LENGTH AS A MARKER OF BIOLOGICAL AGE: STATE-OF-THE-ART, OPEN ISSUES, AND FUTURE PERSPECTIVES. TELOMERE SHORTENING IS A WELL-KNOWN HALLMARK OF BOTH CELLULAR SENESCENCE AND ORGANISMAL AGING. AN ACCELERATED RATE OF TELOMERE ATTRITION IS ALSO A COMMON FEATURE OF AGE-RELATED DISEASES. THEREFORE, TELOMERE LENGTH (TL) HAS BEEN RECOGNIZED FOR A LONG TIME AS ONE OF THE BEST BIOMARKERS OF AGING. RECENT RESEARCH FINDINGS, HOWEVER, INDICATE THAT TL PER SE CAN ONLY ALLOW A ROUGH ESTIMATE OF AGING RATE AND CAN HARDLY BE REGARDED AS A CLINICALLY IMPORTANT RISK MARKER FOR AGE-RELATED PATHOLOGIES AND MORTALITY. EVIDENCE IS OBTAINED THAT OTHER INDICATORS SUCH AS CERTAIN IMMUNE PARAMETERS, INDICES OF EPIGENETIC AGE, ETC., COULD BE STRONGER PREDICTORS OF THE HEALTH STATUS AND THE RISK OF CHRONIC DISEASE. HOWEVER, DESPITE THESE ISSUES AND LIMITATIONS, TL REMAINS TO BE VERY INFORMATIVE MARKER IN ACCESSING THE BIOLOGICAL AGE WHEN USED ALONG WITH OTHER MARKERS SUCH AS INDICES OF HOMEOSTATIC DYSREGULATION, FRAILTY INDEX, EPIGENETIC CLOCK, ETC. THIS REVIEW ARTICLE IS AIMED AT DESCRIBING THE CURRENT STATE OF THE ART IN THE FIELD AND AT DISCUSSING RECENT RESEARCH FINDINGS AND DIVERGENT VIEWPOINTS REGARDING THE USEFULNESS OF LEUKOCYTE TL FOR ESTIMATING THE HUMAN BIOLOGICAL AGE. 2020 19 5588 16 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 20 3596 24 IMPLICATIONS OF SPHINGOLIPIDS ON AGING AND AGE-RELATED DISEASES. AGING IS A PROCESS LEADING TO A PROGRESSIVE LOSS OF PHYSIOLOGICAL INTEGRITY AND HOMEOSTASIS, AND A PRIMARY RISK FACTOR FOR MANY LATE-ONSET CHRONIC DISEASES. THE MECHANISMS UNDERLYING AGING HAVE LONG PIQUED THE CURIOSITY OF SCIENTISTS. HOWEVER, THE IDEA THAT AGING IS A BIOLOGICAL PROCESS SUSCEPTIBLE TO GENETIC MANIPULATION WAS NOT WELL ESTABLISHED UNTIL THE DISCOVERY THAT THE INHIBITION OF INSULIN/IGF-1 SIGNALING EXTENDED THE LIFESPAN OF C. ELEGANS. ALTHOUGH AGING IS A COMPLEX MULTISYSTEM PROCESS, LOPEZ-OTIN ET AL. DESCRIBED AGING IN REFERENCE TO NINE HALLMARKS OF AGING. THESE NINE 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. DUE TO RECENT ADVANCES IN LIPIDOMIC, INVESTIGATION INTO THE ROLE OF LIPIDS IN BIOLOGICAL AGING HAS INTENSIFIED, PARTICULARLY THE ROLE OF SPHINGOLIPIDS (SL). SLS ARE A DIVERSE GROUP OF LIPIDS ORIGINATING FROM THE ENDOPLASMIC RETICULUM (ER) AND CAN BE MODIFIED TO CREATE A VASTLY DIVERSE GROUP OF BIOACTIVE METABOLITES THAT REGULATE ALMOST EVERY MAJOR CELLULAR PROCESS, INCLUDING CELL CYCLE REGULATION, SENESCENCE, PROLIFERATION, AND APOPTOSIS. ALTHOUGH SL BIOLOGY REACHES ALL NINE HALLMARKS OF AGING, ITS CONTRIBUTION TO EACH HALLMARK IS DISPROPORTIONATE. IN THIS REVIEW, WE WILL DISCUSS IN DETAIL THE MAJOR CONTRIBUTIONS OF SLS TO THE HALLMARKS OF AGING AND AGE-RELATED DISEASES WHILE ALSO SUMMARIZING THE IMPORTANCE OF THEIR OTHER MINOR BUT INTEGRAL CONTRIBUTIONS. 2021