1 5634 167 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 2 1894 48 ENDOTHELIAL CELL SENESCENCE AND INFLAMMAGING: MICRORNAS AS BIOMARKERS AND INNOVATIVE THERAPEUTIC TOOLS. AGING IS ACCOMPANIED BY A PROGRESSIVE DECLINE OF ENDOTHELIAL FUNCTION AND A PROGRESSIVE DRIFT TOWARD A SYSTEMIC PRO-INFLAMMATORY STATUS THAT HAS BEEN DESIGNATED "INFLAMMAGING". BOTH PHENOMENA ARE ACCELERATED AND EXACERBATED IN PATIENTS WITH THE MOST COMMON AGE-RELATED DISEASES (ARDS), INCLUDING CANCER. THE FINDING THAT CHRONIC CELL STRESS ACTIVATES A PRO-INFLAMMATORY PROGRAM LEADING TO ACQUISITION OF THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) AND TO THE PROPAGATION OF SENESCENCE TO SURROUNDING CELLS THROUGH THE SECRETOME, SUGGESTS THAT CELL SENESCENCE MAY HAVE A ROLE IN BOTH PROCESSES. HERE WE: I) DESCRIBE THE ROLE OF CELL SENESCENCE IN ENDOTHELIAL DYSFUNCTION, II) EMPHASIZE THE CONTRIBUTION OF THE ENDOTHELIAL CELL SASP TO INFLAMMAGING, AND III) SUGGEST THAT SELECTIVE REMOVAL OF SENESCENT ENDOTHELIAL CELLS MAY NOT ONLY HINDER SUCH HARMFUL PROCESSES, BUT ALSO REDUCE THE RISK OF DEVELOPING ARDS AND THEIR COMPLICATIONS. ALTHOUGH IN VIVO DETECTION AND TARGETING OF SENESCENT ENDOTHELIAL CELLS ARE STILL BEING INVESTIGATED, IT IS LIKELY THAT THERAPEUTIC STRATEGIES BASED ON ANTIOXIDANT AND ANTI-INFLAMMATORY COMPOUNDS WOULD INVOLVE GENERALIZED ANTI-AGING EFFECTS ALSO BENEFITING ENDOTHELIAL CELLS. MICRORNA (MIRNAS) - SINGLE-STRANDED, NON-CODING RNAS EXPRESSED BY ALL LIVING CELLS AND INVOLVED IN THE EPIGENETIC MODULATION OF ALL TRANSCRIPTIONAL PROGRAMS - MAY CONSTITUTE AN INNOVATIVE, VALUABLE TOOL TO DETECT AND TARGET SENESCENT ENDOTHELIAL CELLS AND TO DEVISE TREATMENTS THAT CAN SLOW DOWN THE PRO-INFLAMMATORY PROGRAM ACTIVATED IN SENESCENT ENDOTHELIAL CELLS. 2016 3 5632 45 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 4 4122 44 MECHANISMS OF DEVELOPMENT OF MULTIMORBIDITY IN THE ELDERLY. IN AGEING POPULATIONS MANY PATIENTS HAVE MULTIPLE DISEASES CHARACTERISED BY ACCELERATION OF THE NORMAL AGEING PROCESS. BETTER UNDERSTANDING OF THE SIGNALLING PATHWAYS AND CELLULAR EVENTS INVOLVED IN AGEING SHOWS THAT THESE ARE CHARACTERISTIC OF MANY CHRONIC DEGENERATIVE DISEASES, SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), CHRONIC CARDIOVASCULAR AND METABOLIC DISEASES, AND NEURODEGENERATION. COMMON MECHANISMS HAVE NOW BEEN IDENTIFIED IN THESE DISEASES, WHICH SHOW EVIDENCE OF CELLULAR SENESCENCE WITH TELOMERE SHORTENING, ACTIVATION OF PI3K-AKT-MTOR SIGNALLING, IMPAIRED AUTOPHAGY, MITOCHONDRIAL DYSFUNCTION, STEM CELL EXHAUSTION, EPIGENETIC CHANGES, ABNORMAL MICRORNA PROFILES, IMMUNOSENESCENCE AND LOW GRADE CHRONIC INFLAMMATION ("INFLAMMAGING"). MANY OF THESE PATHWAYS ARE DRIVEN BY CHRONIC OXIDATIVE STRESS. THERE IS ALSO A REDUCTION IN ANTI-AGEING MOLECULES, SUCH AS SIRTUINS AND KLOTHO, WHICH FURTHER ACCELERATES THE AGEING PROCESS. UNDERSTANDING THESE MOLECULAR MECHANISMS HAS IDENTIFIED SEVERAL NOVEL THERAPEUTIC TARGETS AND SEVERAL DRUGS HAVE ALREADY BEEN DEVELOPED THAT MAY SLOW THE AGEING PROCESS, AS WELL AS LIFESTYLE INTERVENTIONS, SUCH AS DIET AND PHYSICAL ACTIVITY. THIS INDICATES THAT IN THE FUTURE NEW TREATMENT APPROACHES MAY TARGET THE COMMON PATHWAYS INVOLVED IN MULTIMORBIDITY AND THIS AREA OF RESEARCH SHOULD BE GIVEN HIGH PRIORITY. THUS, COPD SHOULD BE CONSIDERED AS A COMPONENT OF MULTIMORBIDITY AND COMMON DISEASE PATHWAYS, PARTICULARLY ACCELERATED AGEING, SHOULD BE TARGETED. 2015 5 5322 40 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 6 5919 48 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 7 5140 41 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 5801 36 STIFFNESS AND AGING IN CARDIOVASCULAR DISEASES: THE DANGEROUS RELATIONSHIP BETWEEN FORCE AND SENESCENCE. BIOLOGICAL AGING IS A PROCESS ASSOCIATED WITH A GRADUAL DECLINE IN TISSUES' HOMEOSTASIS BASED ON THE PROGRESSIVE INABILITY OF THE CELLS TO SELF-RENEW. CELLULAR SENESCENCE IS ONE OF THE HALLMARKS OF THE AGING PROCESS, CHARACTERIZED BY AN IRREVERSIBLE CELL CYCLE ARREST DUE TO REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, TELOMERES SHORTENING, CHRONIC INFLAMMATORY ACTIVATION, AND CHROMATIN MODIFICATIONS. IN THIS REVIEW, WE WILL DESCRIBE THE EFFECTS OF SENESCENCE ON TISSUE STRUCTURE, EXTRACELLULAR MATRIX (ECM) ORGANIZATION, AND NUCLEUS ARCHITECTURE, AND SEE HOW THESE CHANGES AFFECT (ARE AFFECTED BY) MECHANO-TRANSDUCTION. IN OUR VIEW, THIS IS ESSENTIAL FOR A DEEPER UNDERSTANDING OF THE PROGRESSIVE PATHOLOGICAL EVOLUTION OF THE CARDIOVASCULAR SYSTEM AND ITS RELATIONSHIP WITH THE DETRIMENTAL EFFECTS OF RISK FACTORS, KNOWN TO ACT AT AN EPIGENETIC LEVEL. 2021 9 6880 35 [RESEARCH PROGRESS OF LUNG AGING IN CHRONIC RESPIRATORY DISEASES]. CELL AGING IS AN EXTREMELY COMPLEX PROCESS, WHICH IS CHARACTERIZED BY MITOCHONDRIAL STRUCTURAL DYSFUNCTION, TELOMERE SHORTENING, INFLAMMATORY MICROENVIRONMENT, PROTEIN HOMEOSTASIS IMBALANCE, EPIGENETIC CHANGES, ABNORMAL DNA DAMAGE AND REPAIR, ETC. AGING IS USUALLY ACCOMPANIED BY STRUCTURAL AND FUNCTIONAL DAMAGE OF TISSUES AND ORGANS WHICH FURTHER INDUCES THE OCCURRENCE AND DEVELOPMENT OF AGING-RELATED DISEASES. AGING INCLUDES PHYSIOLOGICAL AGING CAUSED BY INCREASED AGE AND PATHOLOGICAL AGING INDUCED BY A VARIETY OF FACTORS. NOTEWORTHY, AS A TARGET ORGAN DIRECTLY CONTACTING WITH THE OUTSIDE AIR, LUNG IS MORE PRONE TO VARIOUS STIMULI, CAUSING PATHOLOGICAL PREMATURE AGING WHICH IS LUNG AGING. STUDIES HAVE FOUND THAT THERE IS A CERTAIN PROPORTION OF SENESCENT CELLS IN THE LUNGS OF MOST CHRONIC RESPIRATORY DISEASES. HOWEVER, THE UNDERLYING MECHANISM BY WHICH THESE SENESCENT CELLS INDUCE LUNG SENESCENCE AND THEIR ROLE IN CHRONIC RESPIRATORY DISEASES IS STILL OBSCURE. THIS PAPER FOCUSES ON THE CAUSES AND CLASSIFICATION OF LUNG AGING, THE INTERNAL MECHANISM OF LUNG AGING INVOLVED IN CHRONIC RESPIRATORY DISEASES, AND THE APPLICATION OF ANTI-AGING TREATMENTS IN CHRONIC RESPIRATORY DISEASES. WE HOPE TO PROVIDE NEW RESEARCH IDEAS AND THEORETICAL BASIS FOR THE CLINICAL PREVENTION AND TREATMENT IN CHRONIC RESPIRATORY DISEASES. 2022 10 797 40 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 11 5765 43 SOURCE OF CHRONIC INFLAMMATION IN AGING. AGING IS A COMPLEX PROCESS THAT RESULTS FROM A COMBINATION OF ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS. A CHRONIC PRO-INFLAMMATORY STATUS IS A PERVASIVE FEATURE OF AGING. THIS CHRONIC LOW-GRADE INFLAMMATION OCCURRING IN THE ABSENCE OF OVERT INFECTION HAS BEEN DEFINED AS "INFLAMMAGING" AND REPRESENTS A SIGNIFICANT RISK FACTOR FOR MORBIDITY AND MORTALITY IN THE ELDERLY. THE LOW-GRADE INFLAMMATION PERSISTS EVEN AFTER REVERSING PRO-INFLAMMATORY STIMULI SUCH AS LDL CHOLESTEROL AND THE RENIN-ANGIOTENSIN SYSTEM (RAS). RECENTLY, SEVERAL POSSIBLE SOURCES OF CHRONIC LOW-GRADE INFLAMMATION OBSERVED DURING AGING AND AGE-RELATED DISEASES HAVE BEEN PROPOSED. CELL SENESCENCE AND DYSREGULATION OF INNATE IMMUNITY IS ONE SUCH MECHANISM BY WHICH PERSISTENT PROLONGED INFLAMMATION OCCURS EVEN AFTER THE INITIAL STIMULUS HAS BEEN REMOVED. ADDITIONALLY, THE COAGULATION FACTOR THAT ACTIVATES INFLAMMATORY SIGNALING BEYOND ITS ROLE IN THE COAGULATION SYSTEM HAS BEEN IDENTIFIED. THIS SIGNAL COULD BE A NEW SOURCE OF CHRONIC INFLAMMATION AND CELL SENESCENCE. HERE, WE SUMMARIZED THE FACTORS AND CELLULAR PATHWAYS/PROCESSES THAT ARE KNOWN TO REGULATE LOW-GRADE PERSISTENT INFLAMMATION IN AGING AND AGE-RELATED DISEASE. 2018 12 5629 40 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 13 285 34 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 14 290 40 AGING AND PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS IS A CHRONIC, PROGRESSIVE, AND USUALLY FATAL LUNG DISORDER OF UNKNOWN ETIOLOGY. THE DISEASE LIKELY RESULTS FROM THE INTERACTION OF GENETIC SUSCEPTIBILITY ARCHITECTURE, ENVIRONMENTAL FACTORS SUCH AS SMOKING, AND AN ABNORMAL EPIGENETIC REPROGRAMMING THAT LEADS TO A COMPLEX PATHOGENESIS. IDIOPATHIC PULMONARY FIBROSIS OCCURS IN MIDDLE-AGED AND MAINLY ELDERLY ADULTS, AND IN THIS CONTEXT AGE HAS EMERGED AS ITS STRONGEST RISK FACTOR. HOWEVER, THE MECHANISMS LINKING IT TO AGING ARE UNCERTAIN. RECENTLY, NINE MOLECULAR AND CELLULAR HALLMARKS OF AGING HAVE BEEN PROPOSED: GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DEREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THESE MOLECULAR MECHANISMS AND THEIR INVOLVEMENT IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS, WHILE EMPHASIZING THAT THE STUDIES ON THIS DISEASE ARE FEW AND THE FINDINGS ARE NOT DEFINITIVE. 2016 15 4377 35 MITOCHONDRIAL AGING: FOCUS ON MITOCHONDRIAL DNA DAMAGE IN ATHEROSCLEROSIS - A MINI-REVIEW. ATHEROSCLEROSIS IS A COMPLEX DISEASE WHICH CAN BE DESCRIBED AS AN EXCESSIVE FIBROFATTY, PROLIFERATIVE, INFLAMMATORY RESPONSE TO DAMAGE TO THE ARTERY WALL INVOLVING SEVERAL CELL TYPES SUCH AS SMOOTH MUSCLE CELLS, MONOCYTE-DERIVED MACROPHAGES, LYMPHOCYTES, DENDRITIC CELLS AND PLATELETS. ON THE OTHER HAND, ATHEROSCLEROSIS IS A TYPICAL AGE-RELATED DEGENERATIVE PATHOLOGY, WHICH IS CHARACTERIZED BY SIGNS OF CELL SENESCENCE IN THE ARTERIAL WALL INCLUDING REDUCED CELL PROLIFERATION, IRREVERSIBLE GROWTH ARREST AND APOPTOSIS, INCREASED DNA DAMAGE, THE PRESENCE OF EPIGENETIC MODIFICATIONS, SHORTENING OF TELOMERE LENGTH AND MITOCHONDRIAL DYSFUNCTION. THE MOST PROMINENT CHARACTERISTICS OF MITOCHONDRIAL AGING ARE THEIR STRUCTURAL ALTERATIONS AND MITOCHONDRIAL DNA DAMAGE. THE MECHANISMS OF MITOCHONDRIAL GENOME DAMAGE IN THE DEVELOPMENT OF CHRONIC AGE-RELATED DISEASES SUCH AS ATHEROSCLEROSIS ARE NOT YET WELL UNDERSTOOD. THIS REVIEW FOCUSES ON THE LATEST FINDINGS FROM STUDIES OF THOSE MUTATIONS OF THE MITOCHONDRIAL GENOME WHICH MAY PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF ATHEROSCLEROSIS AND WHICH ARE, AT THE SAME TIME, ALSO MARKERS OF MITOCHONDRIAL AGING AND CELL SENESCENCE. 2015 16 6412 52 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 17 3551 39 IMMUNOSENESCENCE: MOLECULAR MECHANISMS AND DISEASES. INFECTION SUSCEPTIBILITY, POOR VACCINATION EFFICACY, AGE-RELATED DISEASE ONSET, AND NEOPLASMS ARE LINKED TO INNATE AND ADAPTIVE IMMUNE DYSFUNCTION THAT ACCOMPANIES AGING (KNOWN AS IMMUNOSENESCENCE). DURING AGING, ORGANISMS TEND TO DEVELOP A CHARACTERISTIC INFLAMMATORY STATE THAT EXPRESSES HIGH LEVELS OF PRO-INFLAMMATORY MARKERS, TERMED INFLAMMAGING. THIS CHRONIC INFLAMMATION IS A TYPICAL PHENOMENON LINKED TO IMMUNOSENESCENCE AND IT IS CONSIDERED THE MAJOR RISK FACTOR FOR AGE-RELATED DISEASES. THYMIC INVOLUTION, NAIVE/MEMORY CELL RATIO IMBALANCE, DYSREGULATED METABOLISM, AND EPIGENETIC ALTERATIONS ARE STRIKING FEATURES OF IMMUNOSENESCENCE. DISTURBED T-CELL POOLS AND CHRONIC ANTIGEN STIMULATION MEDIATE PREMATURE SENESCENCE OF IMMUNE CELLS, AND SENESCENT IMMUNE CELLS DEVELOP A PROINFLAMMATORY SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE THAT EXACERBATES INFLAMMAGING. ALTHOUGH THE UNDERLYING MOLECULAR MECHANISMS REMAIN TO BE ADDRESSED, IT IS WELL DOCUMENTED THAT SENESCENT T CELLS AND INFLAMMAGING MIGHT BE MAJOR DRIVING FORCES IN IMMUNOSENESCENCE. POTENTIAL COUNTERACTIVE MEASURES WILL BE DISCUSSED, INCLUDING INTERVENTION OF CELLULAR SENESCENCE AND METABOLIC-EPIGENETIC AXES TO MITIGATE IMMUNOSENESCENCE. IN RECENT YEARS, IMMUNOSENESCENCE HAS ATTRACTED INCREASING ATTENTION FOR ITS ROLE IN TUMOR DEVELOPMENT. AS A RESULT OF THE LIMITED PARTICIPATION OF ELDERLY PATIENTS, THE IMPACT OF IMMUNOSENESCENCE ON CANCER IMMUNOTHERAPY IS UNCLEAR. DESPITE SOME SURPRISING RESULTS FROM CLINICAL TRIALS AND DRUGS, IT IS NECESSARY TO INVESTIGATE THE ROLE OF IMMUNOSENESCENCE IN CANCER AND OTHER AGE-RELATED DISEASES. 2023 18 6258 47 THE MOLECULAR MECHANISM OF POLYPHENOLS IN THE REGULATION OF AGEING HALLMARKS. AGEING IS A COMPLEX PROCESS CHARACTERIZED MAINLY BY A DECLINE IN THE FUNCTION OF CELLS, TISSUES, AND ORGANS, RESULTING IN AN INCREASED RISK OF MORTALITY. THIS PROCESS INVOLVES SEVERAL CHANGES, DESCRIBED AS HALLMARKS OF AGEING, WHICH INCLUDE GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC CHANGES, LOSS OF PROTEOSTASIS, DYSREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL DEPLETION, AND ALTERED INTRACELLULAR COMMUNICATION. THE DETERMINING ROLE THAT ENVIRONMENTAL FACTORS SUCH AS DIET AND LIFESTYLE PLAY ON HEALTH, LIFE EXPECTANCY, AND SUSCEPTIBILITY TO DISEASES, INCLUDING CANCER AND NEURODEGENERATIVE DISEASES, IS WELLESTABLISHED. IN VIEW OF THE GROWING INTEREST IN THE BENEFICIAL EFFECTS OF PHYTOCHEMICALS IN THE PREVENTION OF CHRONIC DISEASES, SEVERAL STUDIES HAVE BEEN CONDUCTED, AND THEY STRONGLY SUGGEST THAT THE INTAKE OF DIETARY POLYPHENOLS MAY BRING NUMEROUS BENEFITS DUE TO THEIR ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES, AND THEIR INTAKE HAS BEEN ASSOCIATED WITH IMPAIRED AGEING IN HUMANS. POLYPHENOL INTAKE HAS BEEN SHOWN TO BE EFFECTIVE IN AMELIORATING SEVERAL AGE-RELATED PHENOTYPES, INCLUDING OXIDATIVE STRESS, INFLAMMATORY PROCESSES, IMPAIRED PROTEOSTASIS, AND CELLULAR SENESCENCE, AMONG OTHER FEATURES, WHICH CONTRIBUTE TO AN INCREASED RISK OF AGEING-ASSOCIATED DISEASES. THIS REVIEW AIMS TO ADDRESS, IN A GENERAL WAY, THE MAIN FINDINGS DESCRIBED IN THE LITERATURE ABOUT THE BENEFITS OF POLYPHENOLS IN EACH OF THE HALLMARKS OF AGEING, AS WELL AS THE MAIN REGULATORY MECHANISMS RESPONSIBLE FOR THE OBSERVED ANTIAGEING EFFECTS. 2023 19 4145 37 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 20 4037 29 MACROPHAGE IMMUNOMETABOLISM AND INFLAMMAGING: ROLES OF MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, CD38, AND NAD. AGING IS A COMPLEX PROCESS THAT INVOLVES DYSFUNCTION ON MULTIPLE LEVELS, ALL OF WHICH SEEM TO CONVERGE ON INFLAMMATION. MACROPHAGES ARE INTIMATELY INVOLVED IN INITIATING AND RESOLVING INFLAMMATION, AND THEIR DYSREGULATION WITH AGE IS A PRIMARY CONTRIBUTOR TO INFLAMMAGING-A STATE OF CHRONIC, LOW-GRADE INFLAMMATION THAT DEVELOPS DURING AGING. AMONG THE AGE-RELATED CHANGES THAT OCCUR TO MACROPHAGES ARE A HEIGHTENED STATE OF BASAL INFLAMMATION AND DIMINISHED OR HYPERACTIVE INFLAMMATORY RESPONSES, WHICH SEEM TO BE DRIVEN BY METABOLIC-DEPENDENT EPIGENETIC CHANGES. IN THIS REVIEW ARTICLE WE PROVIDE A BRIEF OVERVIEW OF MITOCHONDRIAL FUNCTIONS AND AGE-RELATED CHANGES THAT OCCUR TO MACROPHAGES, WITH AN EMPHASIS ON HOW THE INFLAMMAGING ENVIRONMENT, SENESCENCE, AND NAD DECLINE CAN AFFECT THEIR METABOLISM, PROMOTE DYSREGULATION, AND CONTRIBUTE TO INFLAMMAGING AND AGE-RELATED PATHOLOGIES. 2020