1 5919 136 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 2 3181 36 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 5322 33 PULMONARY DISEASES AND AGEING. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND IDIOPATHIC PULMONARY FIBROSIS ARE REGARDED AS A DISEASES OF ACCELERATED LUNG AGEING AND SHOW ALL OF THE HALLMARKS OF AGEING, 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 DUE TO SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). MANY OF THESE AGEING MECHANISMS ARE DRIVEN BY EXOGENOUS AND ENDOGENOUS OXIDATIVE STRESS. THERE IS ALSO A REDUCTION IN ANTI-AGEING MOLECULES, SUCH AS SIRTUINS AND KLOTHO, WHICH FURTHER ACCELERATE THE AGEING PROCESS. UNDERSTANDING THESE MOLECULAR MECHANISMS HAS IDENTIFIED SEVERAL NOVEL THERAPEUTIC TARGETS AND SEVERAL DRUGS AND DIETARY INTERVENTIONS ARE NOW IN DEVELOPMENT TO TREAT CHRONIC LUNG DISEASE. 2019 4 5632 44 SENESCENT CELLS: SASPECTED DRIVERS OF AGE-RELATED PATHOLOGIES. THE PROGRESSION OF PHYSIOLOGICAL AGEING IS DRIVEN BY INTRACELLULAR ABERRATIONS INCLUDING TELOMERE ATTRITION, GENOMIC INSTABILITY, EPIGENETIC ALTERATIONS AND LOSS OF PROTEOSTASIS. THESE IN TURN DAMAGE CELLS AND COMPROMISE THEIR FUNCTIONALITY. CELLULAR SENESCENCE, A STABLE IRREVERSIBLE CELL-CYCLE ARREST, IS ELICITED IN DAMAGED CELLS AND PREVENTS THEIR PROPAGATION IN THE ORGANISM. UNDER NORMAL CONDITIONS, SENESCENT CELLS RECRUIT THE IMMUNE SYSTEM WHICH FACILITATES THEIR REMOVAL FROM TISSUES. NEVERTHELESS, DURING AGEING, TISSUE-RESIDING SENESCENT CELLS TEND TO ACCUMULATE, AND MIGHT NEGATIVELY IMPACT THEIR MICROENVIRONMENT VIA PROFOUND SECRETORY PHENOTYPE WITH PRO-INFLAMMATORY CHARACTERISTICS, TERMED SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). INDEED, SENESCENT CELLS ARE MOSTLY ABUNDANT AT SITES OF AGE-RELATED PATHOLOGIES, INCLUDING DEGENERATIVE DISORDERS AND MALIGNANCIES. INTERESTINGLY, STUDIES ON PROGEROID MICE INDICATE THAT SELECTIVE ELIMINATION OF SENESCENT CELLS CAN DELAY AGE-RELATED DETERIORATION. THIS SUGGESTS THAT CHRONIC INFLAMMATION INDUCED BY SENESCENT CELLS MIGHT BE A MAIN DRIVER OF THESE PATHOLOGIES. IMPORTANTLY, SENESCENT CELLS ACCUMULATE AS A RESULT OF DEFICIENT IMMUNE SURVEILLANCE, AND THEIR REMOVAL IS INCREASED UPON THE USE OF IMMUNE STIMULATORY AGENTS. INSIGHTS INTO MECHANISMS OF SENESCENCE SURVEILLANCE COULD BE COMBINED WITH CURRENT APPROACHES FOR CANCER IMMUNOTHERAPY TO PROPOSE NEW PREVENTIVE AND THERAPEUTIC STRATEGIES FOR AGE-RELATED DISEASES. 2014 5 798 34 CELLULAR SENESCENCE, SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE, AND CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS INCREASINGLY BEING ACCEPTED AS A TYPE OF RENAL AGEING. THE KIDNEY UNDERGOES AGE-RELATED ALTERATIONS IN BOTH STRUCTURE AND FUNCTION. TO DATE, A COMPREHENSIVE ANALYSIS OF CELLULAR SENESCENCE AND SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) IN CKD IS LACKING. HENCE, THIS REVIEW MAINLY DISCUSSES THE RELATIONSHIP BETWEEN THE TWO PHENOMENA TO SHOW THE STRIKING SIMILARITIES BETWEEN SASP AND CKD-ASSOCIATED SECRETORY PHENOTYPE (CASP). IT HAS BEEN REPORTED THAT REPLICATIVE SENESCENCE, STRESS-INDUCED PREMATURE AGEING, AND EPIGENETIC ABNORMALITIES PARTICIPATE IN THE OCCURRENCE AND DEVELOPMENT OF CKD. GENOMIC DAMAGE AND EXTERNAL ENVIRONMENTAL STIMULI CAUSE INCREASED LEVELS OF OXIDATIVE STRESS AND A CHRONIC INFLAMMATORY STATE AS A RESULT OF IRREVERSIBLE CELL CYCLE ARREST AND LOW DOSES OF SASP. SIMILAR TO SASP, CASP FACTORS ACTIVATE TISSUE REPAIR BY MULTIPLE MECHANISMS. ONCE TISSUE REPAIR FAILS, THE ACCUMULATED SASP OR CASP SPECIES AGGRAVATE DNA DAMAGE RESPONSE (DDR) AND CAUSE THE SENESCENT CELLS TO SECRETE MORE SASP FACTORS, ACCELERATING THE PROCESS OF CELLULAR AGEING AND EVENTUALLY LEADING TO VARIOUS AGEING-RELATED CHANGES. IT IS CONCLUDED THAT CELLULAR SENESCENCE AND SASP PARTICIPATE IN THE PATHOLOGICAL PROCESS OF CKD, AND CORRESPONDINGLY CKD ACCELERATED THE PROGRESSION OF CELL SENESCENCE AND THE SECRETION OF SASP. THESE RESULTS WILL FACILITATE THE INTEGRATION OF THESE MECHANISMS INTO THE CARE AND MANAGEMENT OF CKD AND OTHER AGE-RELATED DISEASES. 2017 6 182 37 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 7 5140 30 POTENTIAL REGULATORS OF THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE DURING SENESCENCE AND AGING. SENESCENT CELLS EXPRESS AND SECRETE A VARIETY OF EXTRACELLULAR MODULATORS THAT INCLUDE CYTOKINES, CHEMOKINES, PROTEASES, GROWTH FACTORS, AND SOME ENZYMES ASSOCIATED WITH EXTRACELLULAR MATRIX REMODELING, DEFINED AS THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). SASP REINFORCES SENESCENT CELL CYCLE ARREST, STIMULATES AND RECRUITS IMMUNE CELLS FOR IMMUNE-MEDIATED CLEARANCE OF POTENTIALLY TUMORIGENIC CELLS, LIMITS OR INDUCES FIBROSIS, AND PROMOTES WOUND HEALING AND TISSUE REGENERATION. ON THE OTHER HAND, SASP MEDIATES CHRONIC INFLAMMATION LEADING TO THE DESTRUCTION OF TISSUE STRUCTURE AND FUNCTION AND STIMULATING THE GROWTH AND SURVIVAL OF TUMOR CELLS. SASP IS HIGHLY HETEROGENEOUS AND THE ROLE OF SASP DEPENDS ON THE CONTEXT. THE REGULATION OF SASP OCCURS AT MULTIPLE LEVELS INCLUDING CHROMATIN REMODELING, TRANSCRIPTION, MRNA TRANSLATION, INTRACELLULAR TRAFFICKING, AND SECRETION. SEVERAL SASP MODULATORS HAVE ALREADY BEEN IDENTIFIED SETTING THE STAGE FOR FUTURE RESEARCH ON THEIR CLINICAL APPLICATIONS. IN THIS REVIEW, WE SUMMARIZE IN DETAIL THE POTENTIAL SIGNALING PATHWAYS THAT TRIGGER AND REGULATE SASP PRODUCTION DURING AGING AND SENESCENCE. 2022 8 5629 33 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 9 5432 27 REJUVENATION OF MESENCHYMAL STEM CELLS TO AMELIORATE SKELETAL AGING. ADVANCED AGE IS A SHARED RISK FACTOR FOR MANY CHRONIC AND DEBILITATING SKELETAL DISEASES INCLUDING OSTEOPOROSIS AND PERIODONTITIS. MESENCHYMAL STEM CELLS DEVELOP VARIOUS AGING PHENOTYPES INCLUDING THE ONSET OF SENESCENCE, INTRINSIC LOSS OF REGENERATIVE POTENTIAL AND EXACERBATION OF INFLAMMATORY MICROENVIRONMENT VIA SECRETORY FACTORS. THIS REVIEW ELABORATES ON THE EMERGING CONCEPTS ON THE MOLECULAR AND EPIGENETIC MECHANISMS OF MSC SENESCENCE, SUCH AS THE ACCUMULATION OF OXIDATIVE STRESS, DNA DAMAGE AND MITOCHONDRIAL DYSFUNCTION. SENESCENT MSCS AGGRAVATE LOCAL INFLAMMATION, DISRUPT BONE REMODELING AND BONE-FAT BALANCE, THEREBY CONTRIBUTING TO THE PROGRESSION OF AGE-RELATED BONE DISEASES. VARIOUS REJUVENATION STRATEGIES TO TARGET SENESCENT MSCS COULD PRESENT A PROMISING PARADIGM TO RESTORE SKELETAL AGING. 2023 10 1175 27 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 11 5634 48 SENOLYTICS AND SENOMORPHICS: NATURAL AND SYNTHETIC THERAPEUTICS IN THE TREATMENT OF AGING AND CHRONIC DISEASES. CELLULAR SENESCENCE IS A HETEROGENEOUS PROCESS GUIDED BY GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS, CHARACTERIZING MANY TYPES OF SOMATIC CELLS. IT HAS BEEN SUGGESTED AS AN AGING HALLMARK THAT IS BELIEVED TO CONTRIBUTE TO AGING AND CHRONIC DISEASES. SENESCENT CELLS (SC) EXHIBIT A SPECIFIC SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP), MAINLY CHARACTERIZED BY THE PRODUCTION OF PROINFLAMMATORY AND MATRIX-DEGRADING MOLECULES. WHEN SC ACCUMULATE, A CHRONIC, SYSTEMIC, LOW-GRADE INFLAMMATION, KNOWN AS INFLAMMAGING, IS INDUCED. IN TURN, THIS CHRONIC IMMUNE SYSTEM ACTIVATION RESULTS IN REDUCED SC CLEARANCE THUS ESTABLISHING A VICIOUS CIRCLE THAT FUELS INFLAMMAGING. SC ACCUMULATION REPRESENTS A CAUSAL FACTOR FOR VARIOUS AGE-RELATED PATHOLOGIES. TARGETING OF SEVERAL AGING HALLMARKS HAS BEEN SUGGESTED AS A STRATEGY TO AMELIORATE HEALTHSPAN AND POSSIBLY LIFESPAN. CONSEQUENTLY, SC AND SASP ARE VIEWED AS POTENTIAL THERAPEUTIC TARGETS EITHER THROUGH THE SELECTIVE KILLING OF SC OR THE SELECTIVE SASP BLOCKAGE, THROUGH NATURAL OR SYNTHETIC COMPOUNDS. THESE COMPOUNDS ARE MEMBERS OF A FAMILY OF AGENTS CALLED SENOTHERAPEUTICS DIVIDED INTO SENOLYTICS AND SENOMORPHICS. FEW OF THEM ARE ALREADY IN CLINICAL TRIALS, POSSIBLY REPRESENTING A FUTURE TREATMENT OF AGE-RELATED PATHOLOGIES INCLUDING DISEASES SUCH AS ATHEROSCLEROSIS, OSTEOARTHRITIS, OSTEOPOROSIS, CANCER, DIABETES, NEURODEGENERATIVE DISEASES SUCH AS ALZHEIMER'S DISEASE, CARDIOVASCULAR DISEASES, HEPATIC STEATOSIS, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, IDIOPATHIC PULMONARY FIBROSIS AND AGE-RELATED MACULAR DEGENERATION. IN THIS REVIEW, WE PRESENT THE ALREADY IDENTIFIED SENOLYTICS AND SENOMORPHICS FOCUSING ON THEIR REDOX-SENSITIVE PROPERTIES. WE DESCRIBE THE STUDIES THAT REVEALED THEIR EFFECTS ON CELLULAR SENESCENCE AND ENABLED THEIR NOMINATION AS NOVEL ANTI-AGING AGENTS. WE REFER TO THE SENOLYTICS THAT ARE ALREADY IN CLINICAL TRIALS AND WE PRESENT VARIOUS ADVERSE EFFECTS EXHIBITED BY SENOTHERAPEUTICS SO FAR. FINALLY, WE DISCUSS ASPECTS OF THE SENOTHERAPEUTICS THAT NEED IMPROVEMENT AND WE SUGGEST THE DESIGN OF FUTURE SENOTHERAPEUTICS TO TARGET SPECIFIC REDOX-REGULATED SIGNALING PATHWAYS IMPLICATED EITHER IN THE REGULATION OF SASP OR IN THE ELIMINATION OF SC. 2021 12 3596 45 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 13 293 42 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 14 285 40 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 15 4183 35 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 16 4376 29 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 17 4145 40 MECHANISMS OF VASCULAR AGING. AGING OF THE VASCULATURE PLAYS A CENTRAL ROLE IN MORBIDITY AND MORTALITY OF OLDER PEOPLE. TO DEVELOP NOVEL TREATMENTS FOR AMELIORATION OF UNSUCCESSFUL VASCULAR AGING AND PREVENTION OF AGE-RELATED VASCULAR PATHOLOGIES, IT IS ESSENTIAL TO UNDERSTAND THE CELLULAR AND FUNCTIONAL CHANGES THAT OCCUR IN THE VASCULATURE DURING AGING. IN THIS REVIEW, THE PATHOPHYSIOLOGICAL ROLES OF FUNDAMENTAL CELLULAR AND MOLECULAR MECHANISMS OF AGING, INCLUDING OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, IMPAIRED RESISTANCE TO MOLECULAR STRESSORS, CHRONIC LOW-GRADE INFLAMMATION, GENOMIC INSTABILITY, CELLULAR SENESCENCE, EPIGENETIC ALTERATIONS, LOSS OF PROTEIN HOMEOSTASIS, DEREGULATED NUTRIENT SENSING, AND STEM CELL DYSFUNCTION IN THE VASCULAR SYSTEM ARE CONSIDERED IN TERMS OF THEIR CONTRIBUTION TO THE PATHOGENESIS OF BOTH MICROVASCULAR AND MACROVASCULAR DISEASES ASSOCIATED WITH OLD AGE. THE IMPORTANCE OF PROGERONIC AND ANTIGERONIC CIRCULATING FACTORS IN RELATION TO DEVELOPMENT OF VASCULAR AGING PHENOTYPES ARE DISCUSSED. FINALLY, FUTURE DIRECTIONS AND OPPORTUNITIES TO DEVELOP NOVEL INTERVENTIONS TO PREVENT/DELAY AGE-RELATED VASCULAR PATHOLOGIES BY TARGETING FUNDAMENTAL CELLULAR AND MOLECULAR AGING PROCESSES ARE PRESENTED. 2018 18 929 26 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 19 797 33 CELLULAR SENESCENCE IN OSTEOARTHRITIS PATHOLOGY. CELLULAR SENESCENCE IS A STATE OF STABLE PROLIFERATION ARREST OF CELLS. THE SENESCENCE PATHWAY HAS MANY BENEFICIAL EFFECTS AND IS SEEN TO BE ACTIVATED IN DAMAGED/STRESSED CELLS, AS WELL AS DURING EMBRYONIC DEVELOPMENT AND WOUND HEALING. HOWEVER, THE PERSISTENCE AND ACCUMULATION OF SENESCENT CELLS IN VARIOUS TISSUES CAN ALSO IMPAIR FUNCTION AND HAVE BEEN IMPLICATED IN THE PATHOGENESIS OF MANY AGE-RELATED DISEASES. OSTEOARTHRITIS (OA), A SEVERELY DEBILITATING CHRONIC CONDITION CHARACTERIZED BY PROGRESSIVE TISSUE REMODELING AND LOSS OF JOINT FUNCTION, IS THE MOST PREVALENT DISEASE OF THE SYNOVIAL JOINTS, AND INCREASING AGE IS THE PRIMARY OA RISK FACTOR. THE PROFILE OF INFLAMMATORY AND CATABOLIC MEDIATORS PRESENT DURING THE PATHOGENESIS OF OA IS STRIKINGLY SIMILAR TO THE SECRETORY PROFILE OBSERVED IN 'CLASSICAL' SENESCENT CELLS. DURING OA, CHONDROCYTES (THE SOLE CELL TYPE PRESENT WITHIN ARTICULAR CARTILAGE) EXHIBIT INCREASED LEVELS OF VARIOUS SENESCENCE MARKERS, SUCH AS SENESCENCE-ASSOCIATED BETA-GALACTOSIDASE (SABETAGAL) ACTIVITY, TELOMERE ATTRITION, AND ACCUMULATION OF P16INK4A. THIS SUGGESTS THE HYPOTHESIS THAT SENESCENCE OF CELLS WITHIN JOINT TISSUES MAY PLAY A PATHOLOGICAL ROLE IN THE CAUSATION OF OA. IN THIS REVIEW, WE DISCUSS THE MECHANISMS BY WHICH SENESCENT CELLS MAY PREDISPOSE SYNOVIAL JOINTS TO THE DEVELOPMENT AND/OR PROGRESSION OF OA, AS WELL AS TOUCHING UPON VARIOUS EPIGENETIC ALTERATIONS ASSOCIATED WITH BOTH OA AND SENESCENCE. 2017 20 3183 27 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