1 2998 115 GENETIC VARIANTS IN TELOMERASE REVERSE TRANSCRIPTASE CONTRIBUTE TO SOLAR LENTIGINES. SOLAR LENTIGINES (SLS) ARE A HALLMARK OF HUMAN SKIN AGING. THEY RESULT FROM CHRONIC EXPOSURE TO SUNLIGHT AND OTHER ENVIRONMENTAL STRESSORS. RECENT STUDIES ALSO IMPLY GENETIC FACTORS, BUT FINDINGS ARE PARTIALLY CONFLICTING AND LACK OF REPLICATION. THROUGH A MULTI-TRAIT BASED ANALYSIS STRATEGY, WE DISCOVERED THAT GENETIC VARIANTS IN TELOMERASE REVERSE TRANSCRIPTASE WERE SIGNIFICANTLY ASSOCIATED WITH NON-FACIAL SL IN TWO EAST ASIAN (TAIZHOU LONGITUDINAL COHORT, N = 2,964 AND NATIONAL SURVEY OF PHYSICAL TRAITS, N = 2,954) AND ONE CAUCASIAN POPULATION (SALIA, N = 462), TOP SNP RS2853672 (P-VALUE FOR TAIZHOU LONGITUDINAL COHORT = 1.32 X 10(?28) AND P-VALUE FOR NATIONAL SURVEY OF PHYSICAL TRAITS = 3.66 X 10(?17) AND P-VALUE FOR SALIA = 0.0007 AND P(META) = 4.93 X 10(?44)). THE SAME VARIANTS WERE NOMINALLY ASSOCIATED WITH FACIAL SL BUT NOT WITH OTHER SKIN AGING OR SKIN PIGMENTATION TRAITS. THE SL-ENHANCED ALLELE/HAPLOTYPE UPREGULATED THE TRANSCRIPTION OF THE TELOMERASE REVERSE TRANSCRIPTASE GENE. OF NOTE, WELL-KNOWN TELOMERASE REVERSE TRANSCRIPTASE?RELATED AGING MARKERS SUCH AS LEUKOCYTE TELOMERE LENGTH AND INTRINSIC EPIGENETIC AGE ACCELERATION WERE NOT ASSOCIATED WITH SL. OUR RESULTS INDICATE A PREVIOUSLY UNRECOGNIZED ROLE OF TELOMERASE REVERSE TRANSCRIPTASE IN SKIN AGING?RELATED LENTIGINES FORMATION. 2023 2 3596 27 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 3 3181 15 HALLMARKS OF AGING: AN EXPANDING UNIVERSE. AGING IS DRIVEN BY HALLMARKS FULFILLING THE FOLLOWING THREE PREMISES: (1) THEIR AGE-ASSOCIATED MANIFESTATION, (2) THE ACCELERATION OF AGING BY EXPERIMENTALLY ACCENTUATING THEM, AND (3) THE OPPORTUNITY TO DECELERATE, STOP, OR REVERSE AGING BY THERAPEUTIC INTERVENTIONS ON THEM. WE PROPOSE THE FOLLOWING TWELVE HALLMARKS OF AGING: GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DISABLED MACROAUTOPHAGY, DEREGULATED NUTRIENT-SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, ALTERED INTERCELLULAR COMMUNICATION, CHRONIC INFLAMMATION, AND DYSBIOSIS. THESE HALLMARKS ARE INTERCONNECTED AMONG EACH OTHER, AS WELL AS TO THE RECENTLY PROPOSED HALLMARKS OF HEALTH, WHICH INCLUDE ORGANIZATIONAL FEATURES OF SPATIAL COMPARTMENTALIZATION, MAINTENANCE OF HOMEOSTASIS, AND ADEQUATE RESPONSES TO STRESS. 2023 4 4387 19 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 5 4183 19 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 6 5919 19 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 1083 24 CNL AND ACML SHOULD BE CONSIDERED AS A SINGLE ENTITY BASED ON MOLECULAR PROFILES AND OUTCOMES. CHRONIC NEUTROPHILIC LEUKEMIA (CNL) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) ARE RARE MYELOID DISORDERS THAT ARE CHALLENGING WITH REGARD TO DIAGNOSIS AND CLINICAL MANAGEMENT. TO STUDY THE SIMILARITIES AND DIFFERENCES BETWEEN THESE DISORDERS, WE UNDERTOOK A MULTICENTER INTERNATIONAL STUDY OF ONE OF THE LARGEST CASE SERIES (CNL, N = 24; ACML, N = 37 CASES, RESPECTIVELY), FOCUSING ON THE CLINICAL AND MUTATIONAL PROFILES (N = 53 WITH MOLECULAR DATA) OF THESE DISEASES. WE FOUND NO DIFFERENCES IN CLINICAL PRESENTATIONS OR OUTCOMES OF BOTH ENTITIES. AS PREVIOUSLY DESCRIBED, BOTH CNL AND ACML SHARE A COMPLEX MUTATIONAL PROFILE WITH MUTATIONS IN GENES INVOLVED IN EPIGENETIC REGULATION, SPLICING, AND SIGNALING PATHWAYS. APART FROM CSF3R, ONLY EZH2 AND TET2 WERE DIFFERENTIALLY MUTATED BETWEEN THEM. THE MOLECULAR PROFILES SUPPORT THE NOTION OF CNL AND ACML BEING A CONTINUUM OF THE SAME DISEASE THAT MAY FIT BEST WITHIN THE MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS. WE IDENTIFIED 4 HIGH-RISK MUTATED GENES, SPECIFICALLY CEBPA (BETA = 2.26, HAZARD RATIO [HR] = 9.54, P = .003), EZH2 (BETA = 1.12, HR = 3.062, P = .009), NRAS (BETA = 1.29, HR = 3.63, P = .048), AND U2AF1 (BETA = 1.75, HR = 5.74, P = .013) USING MULTIVARIATE ANALYSIS. OUR FINDINGS UNDERSCORE THE RELEVANCE OF MOLECULAR-RISK CLASSIFICATION IN CNL/ACML AS WELL AS THE IMPORTANCE OF CSF3R MUTATIONS IN THESE DISEASES. 2023 8 182 17 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 9 1277 19 DATA ON RNA-SEQ ANALYSIS OF DROSOPHILA MELANOGASTER DURING AGEING. AGEING IS DEFINED AS GRADUAL DECLINE OF PHYSIOLOGICAL, CELLULAR AND MOLECULAR STATE OF AN ORGANISM WITH TIME. THE AGE-ASSOCIATED CELL DYSFUNCTIONS USUALLY CAUSE CHRONIC DISEASES SUCH AS DIABETES, CANCERS AND OTHER AGE-RELATED DISEASES. MANY OF THE GENES AND PATHWAYS INVOLVED IN AGEING ARE CONSERVED IN DIFFERENT SPECIES. THESE GENES AND PATHWAYS HAVE BEEN CATEGORISED INTO NINE CELLULAR AND MOLECULAR HALLMARKS, NAMELY, GENOMIC INSTABILITY, TELOMERE ATTRITION, LOSS OF PROTEOSTASIS, MITOCHONDRIAL DYSFUNCTION, EPIGENETIC ALTERATIONS, DEREGULATED NUTRIENT SENSING, STEM CELL EXHAUSTION, CELLULAR SENESCENCE AND ALTERED INTERCELLULAR COMMUNICATION. DESPITE COUNTLESS STUDIES ON AGEING, THE MOLECULAR MECHANISM OF AGEING IS POORLY UNDERSTOOD. HERE, WE PERFORMED GENOME WIDE TRANSCRIPTOME MAPPING OF AGEING PROCESS IN D. MELANOGASTER. IN WHICH, TRANSCRIPTOMIC ANALYSIS CONDUCTED ON THE 1 DAY AND 60 DAYS FLIES. ILLUMINA HISEQ PLATFORM WERE USED TO GENERATE RAW DATA. AFTERWARDS, FURTHER ANALYSIS INCLUDING DIFFERENTIAL EXPRESSION ANALYSIS, GO CLASSIFICATION AND KEGG PATHWAY ENRICHMENT ANALYSIS WERE PERFORMED. THE RAW DATA WERE UPLOADED TO SRA DATABASE AND THE BIOPROJECT ID IS PRJNA718442. THESE DATA PROVIDE THE BASIS FOR FUTURE RESEARCH IN ORDER TO DISCOVER THE GENES AND PATHWAYS INVOLVED IN AGEING. 2021 10 5588 25 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 11 175 26 ACCELERATED AGING WITH HIV BEGINS AT THE TIME OF INITIAL HIV INFECTION. LIVING WITH HIV INFECTION IS ASSOCIATED WITH EARLY ONSET OF AGING-RELATED CHRONIC CONDITIONS, SOMETIMES DESCRIBED AS ACCELERATED AGING. EPIGENETIC DNA METHYLATION PATTERNS CAN EVALUATE ACCELERATION OF BIOLOGICAL AGE RELATIVE TO CHRONOLOGICAL AGE. THE IMPACT OF INITIAL HIV INFECTION ON FIVE EPIGENETIC MEASURES OF AGING WAS EXAMINED BEFORE AND APPROXIMATELY 3 YEARS AFTER HIV INFECTION IN THE SAME INDIVIDUALS (N=102). SIGNIFICANT EPIGENETIC AGE ACCELERATION (MEDIAN 1.9-4.8 YEARS) AND ESTIMATED TELOMERE LENGTH SHORTENING (ALL P