1 3807 149 INTRACELLULAR PROTONS ACCELERATE AGING AND SWITCH ON AGING HALLMARKS IN MICE. DIET-INDUCED METABOLIC ACIDOSIS IS ASSOCIATED WITH THE IMPAIRMENT OF BONE METABOLISM AND AN INCREASED RISK OF A NUMBER OF CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS TYPE 2 DIABETES MELLITUS AND HYPERTENSION. THE SERUM BICARBONATE LEVEL IS AN INDEPENDENT PREDICTOR OF CHRONIC KIDNEY DISEASE PROGRESSION. WE INVESTIGATED WHETHER PROTON ACCELERATES AGING BY ANALYZING BOTH COUPLING FACTOR 6-OVEREXPRESSING TRANSGENIC (TG) AND HIGH SALT-FED MICE WHICH DISPLAY SUSTAINED INTRACELLULAR ACIDOSIS, DUE TO ENHANCED PROTON IMPORT THROUGH ECTO-F(1) F(O) COMPLEX AND/OR REDUCED PROTON EXPORT THROUGH NA(+) -K(+) ATPASE INHIBITION. BOTH TYPES OF MICE DISPLAYED SHORTENED LIFESPAN AND EARLY SENESCENCE-ASSOCIATED PHENOTYPES SUCH AS SIGNS OF HAIR GREYING AND ALOPECIA, WEIGHT LOSS, AND/OR REDUCED ORGAN MASS. IN CHRONIC INTRACELLULAR ACIDOSIS MICE, AUTOPHAGY WAS IMPAIRED BY REGRESSION OF ATG7, AN INCREASE IN NUCLEAR ACETYLATED LC3 II, AND ACETYLATION OF ATG7. THE INCREASE IN HISTONE 3 TRIMETHYLATION AT LYSINE 4 (H3K4ME3) AND H4K20ME3 AND THE DECREASE IN H3K9ME3 AND H3K27ME3 WERE OBSERVED IN THE HEART AND KIDNEY OBTAINED FROM BOTH TG AND HIGH SALT-FED MICE. THE DECREASE IN LAMIN A/C, EMERIN, AND HETEROCHROMATIN PROTEIN 1ALPHA WITHOUT CHANGES IN BARRIER-TO-AUTOINTEGRATION FACTOR AND HIGH-MOBILITY GROUP BOX 1 WAS CONFIRMED IN TG AND HIGH SALT-FED MICE. SUPPRESSION OF NUCLEAR HISTONE DEACETYLASE 3-EMERIN SYSTEM IS ATTRIBUTABLE TO EPIGENETIC REGRESSION OF ATG7 AND H4K5 ACETYLATION. THESE FINDINGS WILL SHED LIGHT ON NOVEL AGING AND IMPAIRED AUTOPHAGY MECHANISM, AND PROVIDE IMPLICATIONS IN A TARGET FOR ANTIAGING THERAPY. 2018 2 4211 27 METFORMIN FOR CARDIOVASCULAR PROTECTION, INFLAMMATORY BOWEL DISEASE, OSTEOPOROSIS, PERIODONTITIS, POLYCYSTIC OVARIAN SYNDROME, NEURODEGENERATION, CANCER, INFLAMMATION AND SENESCENCE: WHAT IS NEXT? DIABETES IS ACCOMPANIED BY SEVERAL COMPLICATIONS. HIGHER PREVALENCE OF CANCERS, CARDIOVASCULAR DISEASES, CHRONIC KIDNEY DISEASE (CKD), OBESITY, OSTEOPOROSIS, AND NEURODEGENERATIVE DISEASES HAS BEEN REPORTED AMONG PATIENTS WITH DIABETES. METFORMIN IS THE OLDEST ORAL ANTIDIABETIC DRUG AND CAN IMPROVE COEXISTING COMPLICATIONS OF DIABETES. CLINICAL TRIALS AND OBSERVATIONAL STUDIES UNCOVERED THAT METFORMIN CAN REMARKABLY PREVENT OR ALLEVIATE CARDIOVASCULAR DISEASES, OBESITY, POLYCYSTIC OVARIAN SYNDROME (PCOS), OSTEOPOROSIS, CANCER, PERIODONTITIS, NEURONAL DAMAGE AND NEURODEGENERATIVE DISEASES, INFLAMMATION, INFLAMMATORY BOWEL DISEASE (IBD), TUBERCULOSIS, AND COVID-19. IN ADDITION, METFORMIN HAS BEEN PROPOSED AS AN ANTIAGING AGENT. NUMEROUS MECHANISMS WERE SHOWN TO BE INVOLVED IN THE PROTECTIVE EFFECTS OF METFORMIN. METFORMIN ACTIVATES THE LKB1/AMPK PATHWAY TO INTERACT WITH SEVERAL INTRACELLULAR SIGNALING PATHWAYS AND MOLECULAR MECHANISMS. THE DRUG MODIFIES THE BIOLOGIC FUNCTION OF NF-KAPPAB, PI3K/AKT/MTOR, SIRT1/PGC-1ALPHA, NLRP3, ERK, P38 MAPK, WNT/BETA-CATENIN, NRF2, JNK, AND OTHER MAJOR MOLECULES IN THE INTRACELLULAR SIGNALING NETWORK. IT ALSO REGULATES THE EXPRESSION OF NONCODING RNAS. THEREBY, METFORMIN CAN REGULATE METABOLISM, GROWTH, PROLIFERATION, INFLAMMATION, TUMORIGENESIS, AND SENESCENCE. ADDITIONALLY, METFORMIN MODULATES IMMUNE RESPONSE, AUTOPHAGY, MITOPHAGY, ENDOPLASMIC RETICULUM (ER) STRESS, AND APOPTOSIS AND EXERTS EPIGENETIC EFFECTS. FURTHERMORE, METFORMIN PROTECTS AGAINST OXIDATIVE STRESS AND GENOMIC INSTABILITY, PRESERVES TELOMERE LENGTH, AND PREVENTS STEM CELL EXHAUSTION. IN THIS REVIEW, THE PROTECTIVE EFFECTS OF METFORMIN ON EACH DISEASE WILL BE DISCUSSED USING THE RESULTS OF RECENT META-ANALYSES, CLINICAL TRIALS, AND OBSERVATIONAL STUDIES. THEREAFTER, IT WILL BE METICULOUSLY EXPLAINED HOW METFORMIN REPROGRAMS INTRACELLULAR SIGNALING PATHWAYS AND ALTERS MOLECULAR AND CELLULAR INTERACTIONS TO MODIFY THE CLINICAL PRESENTATIONS OF SEVERAL DISEASES. 2021 3 4731 103 NOVEL ANTI-AGING GENE NM_026333 CONTRIBUTES TO PROTON-INDUCED AGING VIA NCX1-PATHWAY. DIET-INDUCED METABOLIC ACIDOSIS IS ASSOCIATED WITH THE IMPAIRMENT OF BONE METABOLISM AND AN INCREASED RISK OF A NUMBER OF CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS TYPE 2 DIABETES MELLITUS AND HYPERTENSION. LOW SERUM BICARBONATE IS ASSOCIATED WITH HIGH MORTALITY IN HEALTHY OLDER INDIVIDUALS. RECENTLY, WE DEMONSTRATED THAT BOTH COUPLING FACTOR 6 (CF6)-OVEREXPRESSING TRANSGENIC (TG) AND HIGH SALT-FED MICE WHICH HAD SUSTAINED INTRACELLULAR ACIDOSIS, DUE TO ENHANCED PROTON IMPORT THROUGH ECTO-F(1)F(O) COMPLEX AND/OR REDUCED PROTON EXPORT THROUGH NA(+)-K(+) ATPASE INHIBITION, DISPLAYED SHORTENED LIFESPAN AND EARLY SENESCENCE-ASSOCIATED PHENOTYPES SUCH AS SIGNS OF HAIR GREYING AND ALOPECIA, WEIGHT LOSS, AND/OR REDUCED ORGAN MASS. IN THIS STUDY, WE SEARCHED CAUSATIVE GENES OF PROTON-INDUCED AGING IN CF6-OVEREXPRESSING TG AND HIGH SALT-FED MICE. WE DISCOVERED NM_026333 AS A NOVEL ANTI-AGING GENE WHICH WAS DOWNREGULATED IN THE HEART AND KIDNEY IN BOTH TYPES OF MICE. NM_026333 PROTEIN CONSISTS OF 269 AMINO ACIDS WITH TRANSMEMBRANE REGION (90-193AA). INDUCTION OF NM_026333 OR RECOMBINANT PROTEIN RESCUED TG CELLS AND CF6-TREATED HUMAN CELLS FROM AGING HALLMARKS OF IMPAIRED AUTOPHAGY, GENOMIC INSTABILITY, AND EPIGENETIC ALTERATION. NM_026333 PROTEIN DIRECTLY BOUND PLASMA MEMBRANE NA(+)-CA(2+) EXCHANGER 1 (NCX1) TO SUPPRESS ITS REVERSE MODE, AND CANCELLED PROTON-INDUCED EPIGENETIC REGRESSION OF ATG7 THAT WAS CAUSED BY H3K4 AND H4K20 TRI-METHYLATION VIA SUPPRESSION OF DEMETHYLASE AND H4K5 ACETYLATION VIA SUPPRESSION OF NUCLEAR HDAC3-HDAC4-EMERIN SYSTEM. NM_026333 ALSO ATTENUATED PROTON-INDUCED IMPAIRED FORMATION OF AUTOLYSOSOME, AN INCREASE IN NUCLEAR ACETYLATED LC3 II, AND ACETYLATION OF ATG7. THESE EFFECTS REAPPEARED BY NCX1 INHIBITOR. FURTHERMORE, NCX1 INHIBITOR EXTENDED LIFESPAN COMPARED WITH VEHICLE-TREATMENT IN TG MICE. THIS STUDY WILL SHED LIGHT ON NOVEL AGING MECHANISM AND PROVIDE IMPLICATIONS IN A TARGET FOR ANTI-AGING THERAPY. 2018 4 5629 30 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 5 5322 27 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 1207 31 COVID-19 AND CROSSTALK WITH THE HALLMARKS OF AGING. WITHIN THE PAST SEVERAL DECADES, THE EMERGENCE OF NEW VIRAL DISEASES WITH SEVERE HEALTH COMPLICATIONS AND MORTALITY IS EVIDENCE OF AN AGE-DEPENDENT, COMPROMISED BODILY RESPONSE TO ABRUPT STRESS WITH CONCOMITANTLY REDUCED IMMUNITY. THE NEW SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2, SARS-COV-2, CAUSES CORONAVIRUS DISEASE 2019 (COVID-19). IT HAS INCREASED MORBIDITY AND MORTALITY IN PERSONS WITH UNDERLYING CHRONIC DISEASES AND THOSE WITH A COMPROMISED IMMUNE SYSTEM REGARDLESS OF AGE AND IN OLDER ADULTS WHO ARE MORE LIKELY TO HAVE THESE CONDITIONS. WHILE SARS-COV-2 IS HIGHLY VIRULENT, THERE IS VARIABILITY IN THE SEVERITY OF THE DISEASE AND ITS COMPLICATIONS IN HUMANS. SEVERE PNEUMONIA, ACUTE RESPIRATORY DISTRESS SYNDROME, LUNG FIBROSIS, CARDIOVASCULAR EVENTS, ACUTE KIDNEY INJURY, STROKE, HOSPITALIZATION, AND MORTALITY HAVE BEEN REPORTED THAT RESULT FROM PATHOGEN-HOST INTERACTIONS. HALLMARKS OF AGING, INTERACTING WITH ONE ANOTHER, HAVE BEEN PROPOSED TO INFLUENCE HEALTH SPAN IN OLDER ADULTS, POSSIBLY VIA MECHANISMS REGULATING THE IMMUNE SYSTEM. HERE, WE REVIEW THE POTENTIAL ROLES OF THE HALLMARKS OF AGING, COUPLED WITH HOST-CORONAVIRUS INTERACTIONS. OF THESE HALLMARKS, WE FOCUSED ON THOSE THAT DIRECTLY OR INDIRECTLY INTERACT WITH VIRAL INFECTIONS, INCLUDING IMMUNOSENESCENCE, INFLAMMATION AND INFLAMMASOMES, ADAPTIVE IMMUNOSENESCENCE, GENOMIC INSTABILITY, MITOCHONDRIAL DYSFUNCTION, EPIGENETIC ALTERATIONS, TELOMERE ATTRITION, AND IMPAIRED AUTOPHAGY. THESE HALLMARKS LIKELY CONTRIBUTE TO THE INCREASED PATHOPHYSIOLOGICAL RESPONSES TO SARS-COV-2 AMONG OLDER ADULTS AND MAY PLAY ROLES AS AN ADDITIVE RISK OF ACCELERATED BIOLOGICAL AGING EVEN AFTER RECOVERY. WE ALSO BRIEFLY DISCUSS THE ROLE OF ANTIAGING DRUG CANDIDATES THAT REQUIRE PARAMOUNT ATTENTION IN COVID-19 RESEARCH. 2020 7 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 8 6087 22 THE EFFECTS OF AEROBIC AND ANAEROBIC EXERCISES ON CIRCULATING SOLUBLE-KLOTHO AND IGF-I IN YOUNG AND ELDERLY ADULTS AND IN CAD PATIENTS. DIFFERENT STUDIES SUPPORT THE NOTION THAT CHRONIC AEROBIC EXERCISES TRAINING CAN INFLUENCE THE CIRCULATING LEVELS OF SOLUBLE-KLOTHO (S-KLOTHO) AND INSULIN-LIKE GROWTH FACTOR 1 (IGF-I). THE EFFECTS OF S-KLOTHO INCLUDE IMPROVING THE QUALITY OF LIFE, ALLEVIATING THE NEGATIVE IMPACT OF AGE ON THE BODY'S WORK CAPACITY, AND POSSIBLY INCREASING LONGEVITY. THIS REVIEW PROVIDES AN OVERVIEW OF THE LATEST FINDINGS IN THIS FIELD OF RESEARCH IN HUMANS. THE DIFFERENT MODES OF DYNAMIC EXERCISE AND THEIR IMPACT ON CIRCULATING LEVELS OF S-KLOTHO AND IGF-I IN YOUNG ADULT ATHLETES, UNTRAINED YOUNG ADULTS, TRAINED HEALTHY OLDER ADULTS, UNTRAINED HEALTHY OLDER ADULTS, AND CORONARY ARTERY DISEASE (CAD) PATIENTS ARE REVIEWED AND DISCUSSED. TOGETHER THESE FINDINGS SUGGEST THAT LONG-LASTING (CHRONIC) AEROBIC EXERCISE TRAINING IS PROBABLY ONE OF THE ANTIAGING FACTORS THAT COUNTERACT THE AGING AND CAD PROCESS BY INCREASING THE CIRCULATING S-KLOTHO AND LOWERING THE IGF-I LEVELS. HOWEVER, FOLLOWING ANAEROBIC EXERCISE TRAINING THE OPPOSITE OCCURS. THE EXACT METABOLIC AND PHYSIOLOGICAL PATHWAYS INVOLVED IN THE ACTIVITY OF THESE WELL-TRAINED YOUNG AND MASTER SPORTSMEN SHOULD BE FURTHER STUDIED AND ELUCIDATED. THE PURPOSE OF THIS REVIEW WAS TO PROVIDE A CLARIFICATION REGARDING THE ROLES OF S-KLOTHO AND INTENSITIES AND DURATIONS OF DIFFERENT EXERCISE ON HUMAN HEALTH. 2017 9 182 24 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 5050 28 PHARMACOLOGICAL MIMICKING OF CALORIC RESTRICTION ELICITS EPIGENETIC REPROGRAMMING OF DIFFERENTIATED CELLS TO STEM-LIKE SELF-RENEWAL STATES. NETWORKS OF ONCOGENES AND TUMOR SUPPRESSOR GENES THAT CONTROL CANCER CELL PROLIFERATION ALSO REGULATE STEM CELL RENEWAL AND POSSIBLY STEM CELL AGING. BECAUSE (DE)DIFFERENTIATION PROCESSES MIGHT DICTATE TUMOR CELLS TO RETROGRESS TO A MORE STEM-LIKE STATE IN RESPONSE TO AGING-RELEVANT EPIGENETIC AND/OR ENVIRONMENTAL PLAYERS, WE RECENTLY ENVISIONED THAT CULTURED HUMAN CANCER CELLS MIGHT BE USED AS RELIABLE MODELS TO TEST THE ABILITY OF ANTIAGING INTERVENTIONS FOR PROMOTING THE INITIATION AND MAINTENANCE OF SELF-RENEWING DIVISIONS. CANCER CELL LINES NATURALLY BEARING UNDETECTABLE AMOUNTS OF STEM/PROGENITOR-LIKE CELL POPULATIONS WERE CONTINUOUSLY CULTURED IN THE PRESENCE OF THE CALORIC RESTRICTION MIMETIC METFORMIN FOR SEVERAL MONTHS. MICROARRAY TECHNOLOGY WAS EMPLOYED TO PROFILE EXPRESSION OF GENES RELATED TO THE IDENTIFICATION, GROWTH, AND DIFFERENTIATION OF STEM CELLS. DETECTION OF FUNCTIONALLY RELATED GENE GROUPS USING A PATHWAY ANALYSIS PACKAGE PROVIDED ANNOTATED GENETIC SIGNATURES OVER- AND UNDEREXPRESSED IN RESPONSE TO PHARMACOLOGICAL MIMICKING OF CALORIC RESTRICTION. BY FOLLOWING THIS METHODOLOGICAL APPROACH, WE RECENTLY OBTAINED DATA FITTING A MODEL IN WHICH, IN RESPONSE TO CHRONIC IMPAIRMENT OF CELLULAR BIOENERGETICS IMPOSED BY METFORMIN-INDUCED MITOCHONDRIAL UNCOUPLING AS ASSESSED BY THE PHOSPHORYLATION STATE OF CAMP-RESPONSE ELEMENT BINDING PROTEIN (CREB), TUMOR CELLS CAN RETROGRESS FROM A DIFFERENTIATED STATE TO A MORE CD44(+) STEM-LIKE PRIMITIVE STATE EPIGENETICALLY GOVERNED BY THE POLYCOMB-GROUP SUPPRESSOR BMI1-A CRUCIAL "STEMNESS" GENE INVOLVED IN THE EPIGENETIC MAINTENANCE OF ADULT STEM CELLS. THESE FINDINGS MIGHT PROVIDE A NOVEL MOLECULAR AVENUE TO INVESTIGATE IF ANTIAGING BENEFITS FROM CALORIC RESTRICTION MIMETICS MIGHT RELATE TO THEIR ABILITY TO EPIGENETICALLY REPROGRAM STEMNESS WHILE PROLONGING THE CAPACITY OF STEM-LIKE CELL STATES TO PROLIFERATE, DIFFERENTIATE, AND REPLACE MATURE CELLS IN ADULT AGING TISSUES. 2010 11 5986 27 TFEB IS A CENTRAL REGULATOR OF THE AGING PROCESS AND AGE-RELATED DISEASES. OLD AGE IS ASSOCIATED WITH A GREATER BURDEN OF DISEASE, INCLUDING NEURODEGENERATIVE DISORDERS SUCH AS ALZHEIMER'S DISEASE AND PARKINSON'S DISEASE, AS WELL AS OTHER CHRONIC DISEASES. COINCIDENTALLY, POPULAR LIFESTYLE INTERVENTIONS, SUCH AS CALORIC RESTRICTION, INTERMITTENT FASTING, AND REGULAR EXERCISE, IN ADDITION TO PHARMACOLOGICAL INTERVENTIONS INTENDED TO PROTECT AGAINST AGE-RELATED DISEASES, INDUCE TRANSCRIPTION FACTOR EB (TFEB) AND AUTOPHAGY. IN THIS REVIEW, WE SUMMARIZE EMERGING DISCOVERIES THAT POINT TO TFEB ACTIVITY AFFECTING THE HALLMARKS OF AGING, INCLUDING INHIBITING DNA DAMAGE AND EPIGENETIC MODIFICATIONS, INDUCING AUTOPHAGY AND CELL CLEARANCE TO PROMOTE PROTEOSTASIS, REGULATING MITOCHONDRIAL QUALITY CONTROL, LINKING NUTRIENT-SENSING TO ENERGY METABOLISM, REGULATING PRO- AND ANTI-INFLAMMATORY PATHWAYS, INHIBITING SENESCENCE AND PROMOTING CELL REGENERATIVE CAPACITY. FURTHERMORE, THE THERAPEUTIC IMPACT OF TFEB ACTIVATION ON NORMAL AGING AND TISSUE-SPECIFIC DISEASE DEVELOPMENT IS ASSESSED IN THE CONTEXTS OF NEURODEGENERATION AND NEUROPLASTICITY, STEM CELL DIFFERENTIATION, IMMUNE RESPONSES, MUSCLE ENERGY ADAPTATION, ADIPOSE TISSUE BROWNING, HEPATIC FUNCTIONS, BONE REMODELING, AND CANCER. SAFE AND EFFECTIVE STRATEGIES OF ACTIVATING TFEB HOLD PROMISE AS A THERAPEUTIC STRATEGY FOR MULTIPLE AGE-ASSOCIATED DISEASES AND FOR EXTENDING LIFESPAN. 2023 12 3596 33 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 5919 23 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 14 285 26 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 15 929 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 16 5588 29 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 17 5632 28 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 18 3922 27 LIPIDS AND THE HALLMARKS OF AGEING: FROM PATHOLOGY TO INTERVENTIONS. LIPIDS ARE CRITICAL STRUCTURAL AND FUNCTIONAL ARCHITECTS OF CELLULAR HOMEOSTASIS. CHANGE IN SYSTEMIC LIPID PROFILE IS A CLINICAL INDICATOR OF UNDERLYING METABOLIC PATHOLOGIES, AND EMERGING EVIDENCE IS NOW DEFINING NOVEL ROLES OF LIPIDS IN MODULATING ORGANISMAL AGEING. CHARACTERISTIC ALTERATIONS IN LIPID METABOLISM CORRELATE WITH AGE, AND IMPAIRED SYSTEMIC LIPID PROFILE CAN ALSO ACCELERATE THE DEVELOPMENT OF AGEING PHENOTYPE. THE PRESENT WORK PROVIDES A COMPREHENSIVE REVIEW OF THE EXTENT OF LIPIDS AS REGULATORS OF THE MODERN HALLMARKS OF AGEING VIZ., CELLULAR SENESCENCE, CHRONIC INFLAMMATION, GUT DYSBIOSIS, TELOMERE ATTRITION, GENOME INSTABILITY, PROTEOSTASIS AND AUTOPHAGY, EPIGENETIC ALTERATIONS, AND STEM CELLS DYSFUNCTIONS. CURRENT EVIDENCE ON THE MODULATION OF EACH OF THESE HALLMARKS HAS BEEN DISCUSSED WITH EMPHASIS ON INHERENT AGE-DEPENDENT DEFICIENCIES IN LIPID METABOLISM AS WELL AS EXOGENOUS LIPID CHANGES. THERE APPEARS TO BE SUFFICIENT EVIDENCE TO CONSIDER IMPAIRED LIPID METABOLISM AS KEY DRIVER OF THE AGEING PROCESS ALTHOUGH MUCH OF KNOWLEDGE IS YET FRAGMENTED. CONSIDERING DIETARY LIPIDS, THE TYPE AND QUANTITY OF LIPIDS IN THE DIET IS A SIGNIFICANT, BUT OFTEN OVERLOOKED DETERMINANT THAT GOVERNS THE EFFECTS OF LIPIDS ON AGEING. FURTHER RESEARCH USING INTEGRATIVE APPROACHES AMIDST THE KNOWN AGING HALLMARKS IS HIGHLY DESIRABLE FOR UNDERSTANDING THE THERAPEUTICS OF LIPIDS ASSOCIATED WITH AGEING. 2023 19 4183 23 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 20 5432 23 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