RESUMEN
Household air pollution (HAP) from indoor combustion of solid fuel is a global health burden that has been linked to multiple diseases including lung cancer. In Xuanwei, China, lung cancer rate for non-smoking women is among the highest in the world and largely attributed to high levels of polycyclic aromatic hydrocarbons (PAHs) that are produced from combustion of smoky (bituminous) coal. Alu retroelements, repetitive mobile DNA sequences that can somatically multiply and promote genomic instability have been associated with risk of lung cancer and diesel engine exhaust exposure. We conducted analyses for 160 non-smoking women in an exposure assessment study in Xuanwei, China with a repeat sample from 49 subjects. Quantitative PCR was used to measure Alu repeat copy number relative to albumin gene copy number (Alu/ALB ratio). Associations between clusters derived from predicted levels of 43 HAP constituents, 5-methylchrysene (5-MC), a PAH previously associated with lung cancer in Xuanwei and was selected a priori for analysis, and Alu repeats were analyzed using generalized estimating equations. A cluster of 31 PAHs reflecting current exposure was associated with increased Alu copy number (ß:0.03 per standard deviation change; 95% confidence interval (CI):0.01,0.04; P-valueâ =â 2E-04). One compound within this cluster, 5-MC, was also associated with increased Alu copy number (P-valueâ =â 0.02). Our findings suggest that exposure to PAHs due to indoor smoky coal combustion may contribute to genomic instability. Additionally, our study provides further support for 5-MC as a prominent carcinogenic component of smoky coal emissions. Further studies are needed to replicate our findings.
Asunto(s)
Contaminación del Aire Interior , Neoplasias Pulmonares , Hidrocarburos Policíclicos Aromáticos , Humanos , Femenino , Retroelementos/genética , Carbón Mineral/efectos adversos , Carbón Mineral/análisis , Variaciones en el Número de Copia de ADN/genética , China/epidemiología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/epidemiología , Hidrocarburos Policíclicos Aromáticos/toxicidad , Leucocitos , Contaminación del Aire Interior/análisisRESUMEN
BACKGROUND: Millions of workers worldwide are exposed to diesel engine exhaust (DEE), a known genotoxic carcinogen. Alu retroelements are repetitive DNA sequences that can multiply and compromise genomic stability. There is some evidence linking altered Alu repeats to cancer and elevated mortality risks. However, whether Alu repeats are influenced by environmental pollutants is unexplored. In an occupational setting with high DEE exposure levels, we investigated associations with Alu repeat copy number. METHODS: A cross-sectional study of 54 male DEE-exposed workers from an engine testing facility and a comparison group of 55 male unexposed controls was conducted in China. Personal air samples were assessed for elemental carbon, a DEE surrogate, using NIOSH Method 5040. Quantitative PCR (qPCR) was used to measure Alu repeat copy number relative to albumin (Alb) single-gene copy number in leucocyte DNA. The unitless Alu/Alb ratio reflects the average quantity of Alu repeats per cell. Linear regression models adjusted for age and smoking status were used to estimate relations between DEE-exposed workers versus unexposed controls, DEE tertiles (6.1-39.0, 39.1-54.5 and 54.6-107.7 µg/m3) and Alu/Alb ratio. RESULTS: DEE-exposed workers had a higher average Alu/Alb ratio than the unexposed controls (p=0.03). Further, we found a positive exposure-response relationship (p=0.02). The Alu/Alb ratio was highest among workers exposed to the top tertile of DEE versus the unexposed controls (1.12±0.08 SD vs 1.06±0.07 SD, p=0.01). CONCLUSION: Our findings suggest that DEE exposure may contribute to genomic instability. Further investigations of environmental pollutants, Alu copy number and carcinogenesis are warranted.
Asunto(s)
Contaminantes Ocupacionales del Aire/análisis , Elementos Alu , Exposición Profesional/efectos adversos , Emisiones de Vehículos/análisis , Adulto , Carbono/análisis , Estudios Transversales , Humanos , Masculino , Persona de Mediana Edad , Exposición Profesional/análisis , Retroelementos , FumarRESUMEN
Age-related vascular dysfunction in large elastic and resistance arteries is associated with reductions in microvascular perfusion and elevations in blood pressure. Recent evidence indicates that telomere uncapping-induced senescence in vascular cells may be an important source of oxidative stress and vascular dysfunction in aging, but the causal relationship between these processes has yet to be elucidated. To test this important unexplored hypothesis, we measured arterial senescence signaling and oxidative stress, carotid and mesenteric artery endothelium-dependent vasodilatory capacity, markers of mesenteric microvascular perfusion and endothelial glycocalyx deterioration, and blood pressure in a novel mouse model of Cre-inducible whole body Trf2 deletion and telomere uncapping. Trf2 deletion led to a 320% increase in arterial senescence signaling (Pâ¯<â¯.05). There was a concurrent 29% and 22% reduction in peak endothelium-dependent vasodilation in carotid and mesenteric arteries, respectively, as well as a 63% reduction in mesenteric microvascular endothelial glycocalyx thickness (all Pâ¯≤â¯.01). Mesenteric microvascular perfusion was reduced by 8% and systolic blood pressure was increased by 9% following Trf2 deletion (both Pâ¯<â¯.05). Trf2 deletion also led to a pro-oxidative arterial phenotype characterized by increased in NADPH oxidase gene expression; a 210% increase in superoxide levels that was partly dependent on NADPH oxidase activity; and an oxidative stress mediated reduction in carotid artery vasodilation (all Pâ¯≤â¯.05). Collectively, our findings demonstrate that induced Trf2 deletion leads to telomere uncapping, increased senescence signaling, and oxidative stress mediated functional impairments in the vasculature similar to those seen in human aging.
Asunto(s)
Envejecimiento/metabolismo , Arterias/metabolismo , Senescencia Celular , Eliminación de Gen , Estrés Oxidativo , Transducción de Señal , Telómero/metabolismo , Proteína 2 de Unión a Repeticiones Teloméricas/deficiencia , Tejido Adiposo/metabolismo , Animales , Presión Sanguínea , Peso Corporal , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Glicocálix/metabolismo , Ratones , Microvasos/metabolismo , Perfusión , Fenotipo , Homeostasis del Telómero , Proteína 2 de Unión a Repeticiones Teloméricas/metabolismo , VasodilataciónRESUMEN
Disruption of ribosomal DNA (rDNA) has been linked to a variety of diseases in humans, including carcinogenesis. To evaluate the associations between rDNA copy number (CN) and risk of lung cancer, we measured 5.8S and 18S rDNA CN in the peripheral blood of 229 incident lung cancer cases and 1:1 matched controls from a nested case-control study within a prospective cohort of male smokers. There was a dose-response relationship between quartiles of both 18S and 5.8S rDNA CN and risk of lung cancer (odds ratio [OR], 95% confidence interval [CI]: 18S: 1.0 [ref]; 1.2 [0.6-2.1]; 1.8 [1.0-3.4]; 2.3 [1.3-4.1; Ptrend = 0.0002; 5.8S: 1.0 [ref]; 1.6 [0.8-2.9]; 2.2 [1.1-4.2]; 2.6 [1.3-5.1]; Ptrend = 0.0001). The associations between rDNA CN and lung cancer risk were similar when excluding cases diagnosed within 5 years of follow-up, and when stratifying by heavy (>20 cigarettes per day) and light smokers (≤20 cigarettes per day). We are the first to report that rDNA CN may be associated with future risk of lung cancer. To further elucidate the relationship between rDNA and lung cancer, replication studies are needed in additional populations, particularly those that include non-smokers.
Asunto(s)
Carcinogénesis/genética , Variaciones en el Número de Copia de ADN/genética , ADN Ribosómico/genética , Neoplasias Pulmonares/genética , Anciano , Carcinogénesis/patología , Estudios de Casos y Controles , Estudios de Cohortes , ADN Ribosómico/sangre , Suplementos Dietéticos , Finlandia/epidemiología , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/dietoterapia , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Fumar/efectos adversos , Fumar/sangre , alfa-Tocoferol/administración & dosificación , beta Caroteno/administración & dosificaciónRESUMEN
BACKGROUND: Leukocyte telomere length (LTL) is a potential biomarker of cancer prognosis; however, evidence for renal cell carcinoma (RCC) is inconsistent. METHODS: We investigated LTL and RCC-specific survival among 684 cases from the US kidney cancer study (USKC) and 241 cases from the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO). Leukocyte telomere length was measured by quantitative polymerase chain reaction, and hazard ratios (HRs) and 95% confidence intervals (CIs) computed using multivariable Cox models. RESULTS: Short LTL was associated with poorer disease-specific survival in both USKC (lowest vs highest quartile: HR: 2.3, 95% CI: 1.2-4.4; P for trend=0.02) and PLCO (HR: 2.4, 95% CI: 1.0-5.4; P=0.04). Among USKC cases, the association was strongest for stage-I RCC (HR: 5.5, 95% CI: 1.6-19.0; P=0.006). CONCLUSIONS: Our findings suggest that shorter LTL is an independent marker of poor RCC prognosis, particularly for stage-I disease.
Asunto(s)
Carcinoma de Células Renales/ultraestructura , Neoplasias Colorrectales/ultraestructura , Neoplasias Renales/ultraestructura , Leucocitos/ultraestructura , Neoplasias Pulmonares/ultraestructura , Neoplasias Ováricas/ultraestructura , Neoplasias de la Próstata/ultraestructura , Acortamiento del Telómero , Telómero/ultraestructura , Anciano , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/mortalidad , Estudios de Casos y Controles , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Femenino , Humanos , Neoplasias Renales/sangre , Neoplasias Renales/genética , Neoplasias Renales/mortalidad , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Neoplasias Ováricas/sangre , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Pronóstico , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/mortalidad , Tasa de SupervivenciaRESUMEN
Telomeres are repeating DNA at chromosome ends. Telomere length (TL) declines with age in most human tissues, and shorter TL is thought to accelerate senescence. In contrast, older men have sperm with longer TL; correspondingly, older paternal age at conception (PAC) predicts longer TL in offspring. This PAC-effect could be a unique form of transgenerational genetic plasticity that modifies somatic maintenance in response to cues of recent ancestral experience. The PAC-effect has not been examined in any non-human mammals. OBJECTIVES: Here, we examine the PAC-effect in chimpanzees (Pan troglodytes). The PAC-effect on TL is thought to be driven by continual production of sperm-the same process that drives increased de novo mutations with PAC. As chimpanzees have both greater sperm production and greater sperm mutation rates with PAC than humans, we predict that the PAC-effect on TL will be more pronounced in chimpanzees. Additionally we examine whether PAC predicts TL of grandchildren. MATERIALS AND METHODS: TL were measured using qPCR from DNA from blood samples from 40 captive chimpanzees and 144 humans. RESULTS: Analyses showed increasing TL with PAC in chimpanzees (p = .009) with a slope six times that in humans (p = .026). No associations between TL and grandpaternal ages were found in humans or chimpanzees-although statistical power was low. DISCUSSION: These results suggest that sperm production rates across species may be a determinant of the PAC-effect on offspring TL. This raises the possibility that sperm production rates within species may influence the TL passed on to offspring.
Asunto(s)
Pan troglodytes/genética , Edad Paterna , Telómero/química , Telómero/genética , Adulto , Animales , Antropología Física , Evolución Biológica , Epigenómica , Humanos , Modelos Lineales , Masculino , Adulto JovenRESUMEN
Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleótido Simple , Telómero/genética , Adulto , Anciano , Pueblo Asiatico/genética , China , Femenino , Predisposición Genética a la Enfermedad/etnología , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Hong Kong , Humanos , Japón , Neoplasias Pulmonares/etnología , Persona de Mediana Edad , Oportunidad Relativa , Estudios Prospectivos , República de Corea , Factores de Riesgo , Singapur , Fumar , Taiwán , Homeostasis del Telómero/genéticaRESUMEN
BACKGROUND: The mitochondria are essential organelles and are the location of cellular respiration, which is responsible for the majority of ATP production. Each cell contains multiple mitochondria, and each mitochondrion contains multiple copies of its own circular genome. The ratio of mitochondrial genomes to nuclear genomes is referred to as mitochondrial copy number. Decreases in mitochondrial copy number are known to occur in many tissues as people age, and in certain diseases. The regulation of mitochondrial copy number by nuclear genes has been studied extensively. While mitochondrial variation has been associated with longevity and some of the diseases known to have reduced mitochondrial copy number, the role that the mitochondrial genome itself has in regulating mitochondrial copy number remains poorly understood. RESULTS: We analyzed the complete mitochondrial genomes from 1007 individuals randomly selected from the Cache County Study on Memory Health and Aging utilizing the inferred evolutionary history of the mitochondrial haplotypes present in our dataset to identify sequence variation and mitochondrial haplotypes associated with changes in mitochondrial copy number. Three variants belonging to mitochondrial haplogroups U5A1 and T2 were significantly associated with higher mitochondrial copy number in our dataset. CONCLUSIONS: We identified three variants associated with higher mitochondrial copy number and suggest several hypotheses for how these variants influence mitochondrial copy number by interacting with known regulators of mitochondrial copy number. Our results are the first to report sequence variation in the mitochondrial genome that causes changes in mitochondrial copy number. The identification of these variants that increase mtDNA copy number has important implications in understanding the pathological processes that underlie these phenotypes.
Asunto(s)
Envejecimiento , Variaciones en el Número de Copia de ADN , ADN Mitocondrial/genética , Genoma Mitocondrial , Anciano , Secuencia de Aminoácidos , Animales , Complejo IV de Transporte de Electrones/química , Complejo IV de Transporte de Electrones/genética , Femenino , Variación Genética , Haplotipos , Humanos , Longevidad , Masculino , Mitocondrias/genética , Datos de Secuencia Molecular , Alineación de SecuenciaRESUMEN
Telomeres play an essential role in maintaining chromosomal integrity in the face of physiological stressors. Although the age-related shortening of TL (telomere length) in highly proliferative tissue is predominantly due to the replication process, the mechanism for telomere shortening in skeletal muscle, which is minimally proliferative, is unclear. By studying TL in both the upper and lower limbs of the young, old-mobile and old-immobile subjects and by virtue of the bipedal nature of human locomotion, which declines with age, it may be possible to elucidate the mechanism(s) responsible for cellular aging of skeletal muscle. With this approach, we revealed that TL (~15 kb) in arm skeletal muscle is unaffected by age. In contrast TL fell progressively in the legs across the young (~15 kb), the old mobile (~13 kb) and old immobile (~11 kb) subjects. Interestingly, there was a reciprocal increase in leg muscle free radicals across these groups that was correlated with TL (r=0.7), with no such relationship in the arm (r=0.09). Our results document that chronological age does not affect the cellular aging of skeletal muscle, but reveals that physical inactivity, probably mediated by free radicals, has a profound effect upon this process.
Asunto(s)
Músculo Esquelético/metabolismo , Telómero/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento , Senescencia Celular/genética , Femenino , Radicales Libres/metabolismo , Humanos , Masculino , Telomerasa/metabolismo , Adulto JovenRESUMEN
OBJECTIVES: Slower rates of aging distinguish humans from our nearest living cousins. Chimpanzees rarely survive their forties while large fractions of women are postmenopausal even in high-mortality hunter-gatherer populations. Cellular and molecular mechanisms for these somatic aging differences remain to be identified, though telomeres might play a role. To find out, we compared telomere lengths across age-matched samples of female chimpanzees and women. METHODS: We used a monochrome multiplex quantitative polymerase chain reaction to assay canonical telomere repeats in blood cells from captive female chimpanzees (65 individuals; age: 6.2-56.7 years) and compared them to the same measure in human females (43 individuals; age: 7.4-57.3 years). RESULTS: Our samples showed little difference in attrition rates between the species (~0.022 T/S per year for chimpanzees and ~0.012 T/S per year for humans with overlapping 95% confidence intervals), but telomeres were twice as long in chimpanzees as in humans (T/S ratios = 2.70 and 1.26, respectively). CONCLUSIONS: Based on the longevity differences, we initially hypothesized that telomere shortening rates would be faster in chimpanzees than in humans. Instead, it is shorter telomere length that appears to be the derived state in humans. This comparison indicates that better characterization of physiological aging in our closest living relatives will be indispensable for understanding the evolution of distinctive human longevity.
Asunto(s)
Leucocitos/citología , Pan troglodytes/genética , Acortamiento del Telómero , Telómero/genética , Adolescente , Adulto , Animales , Niño , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex , Adulto JovenRESUMEN
Telomeres are involved in maintaining genomic stability. Previous studies have linked both telomere length (TL) and telomere-related genes with cancer. We evaluated associations between telomere-related genes, TL, and breast cancer risk in an admixed population of US non-Hispanic white (1,481 cases, 1,586 controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based on their genetic ancestry. TL-related genes assessed were MEN1, MRE11A, RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2. Longer TL was associated with increased breast cancer risk [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women with high Indigenous American ancestry. Several TL-related single nucleotide polymorphisms had modest association with breast cancer risk overall, including TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95); TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24); TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93); TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24); TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several differences in association were detected by hormone receptor status of tumors. Most notable were associations with TERT rs2736118 (ORadj 6.18, 95% CI 2.90, 13.19) with estrogen receptor negative/progesterone receptor positive (ER-/PR+) tumors and TERT rs2735940 (ORadj 0.73, 95% CI 0.59, 0.91) with ER-/PR- tumors. These data provide support for an association between TL and TL-related genes and risk of breast cancer. The association may be modified by hormone receptor status and genetic ancestry.
Asunto(s)
Neoplasias de la Mama/genética , Estudios de Asociación Genética , Telomerasa/genética , Homeostasis del Telómero/genética , Telómero/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Femenino , Inestabilidad Genómica , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptores de Estrógenos/genética , Receptores de Progesterona/genética , Factores de RiesgoRESUMEN
Smoking and diabetes, consistent risk factors for pancreatic cancer, are also factors that influence telomere length maintenance. To test whether telomere length is associated with pancreatic cancer risk, we conducted a nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50-69 years at baseline. Between 1992 and 2004, 193 incident cases of pancreatic adenocarcinoma occurred (mean follow-up from blood draw: 6.3 years) among participants with whole blood samples available for telomere length assays. For these cases and 660 controls, we calculated odds ratios (OR) and 95% confidence intervals using unconditional logistic regression, adjusting for age, number of years smoked regularly, and history of diabetes mellitus. Telomere length was categorized into quartiles (shortest to longest) and analyzed as both a categorical and a continuous normal variable (reported per 0.2 unit increase in telomere length). All statistical tests were two-sided. Longer telomere length was significantly associated with increased pancreatic cancer risk (continuous OR = 1.26 95% CI = 1.09-1.46; highest quartile compared to lowest, OR = 1.57, 95% CI = 1.01-2.43, p-trend = 0.007). This association remained for subjects diagnosed within the first five years of blood draw (continuous OR = 1.46, 95% CI = 1.19-1.79 highest quartile OR = 2.92, 95% CI = 1.47-5.77, p-trend = 0.002), but not those diagnosed greater than five years after blood draw (continuous OR = 1.03, 95% CI = 0.85-1.22; highest quartile OR = 1.04, 95% CI = 0.60-1.79). This is the first prospective study to suggest an association between longer blood leukocyte telomere length and increased pancreatic cancer risk.
Asunto(s)
Neoplasias Pancreáticas/patología , Homeostasis del Telómero/genética , alfa-Tocoferol/administración & dosificación , beta Caroteno/administración & dosificación , Anciano , Estudios de Casos y Controles , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/genética , Estudios Prospectivos , Factores de Riesgo , Fumar/efectos adversos , Homeostasis del Telómero/efectos de los fármacosRESUMEN
Arterial telomere dysfunction may contribute to chronic arterial inflammation by inducing cellular senescence and subsequent senescence-associated inflammation. Although telomere shortening has been associated with arterial aging in humans, age-related telomere uncapping has not been described in non-cultured human tissues and may have substantial prognostic value. In skeletal muscle feed arteries from 104 younger, middle-aged, and older adults, we assessed the potential role of age-related telomere uncapping in arterial inflammation. Telomere uncapping, measured by p-histone γ-H2A.X (ser139) localized to telomeres (chromatin immunoprecipitation; ChIP), and telomeric repeat binding factor 2 bound to telomeres (ChIP) was greater in arteries from older adults compared with those from younger adults. There was greater tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence, measured by P53 bound to P21 gene promoter (ChIP), and greater expression of P21, interleukin 8, and monocyte chemotactic protein 1 mRNA (RT-PCR) in arteries from older adults compared with younger adults. Telomere uncapping was a highly influential covariate for the age-group difference in P53/P21-induced senescence. Despite progressive age-related telomere shortening in human arteries, mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence. Collectively, these findings demonstrate that advancing age is associated with greater telomere uncapping in arteries, which is linked to P53/P21-induced senescence independent of telomere shortening.
Asunto(s)
Envejecimiento/genética , Arteritis/genética , Senescencia Celular , Músculo Esquelético/irrigación sanguínea , Acortamiento del Telómero , Telómero/metabolismo , Adulto , Factores de Edad , Anciano , Envejecimiento/inmunología , Envejecimiento/metabolismo , Envejecimiento/patología , Análisis de Varianza , Arterias/inmunología , Arterias/metabolismo , Arterias/patología , Arteritis/inmunología , Arteritis/metabolismo , Arteritis/patología , Sitios de Unión , Quimiocina CCL2/genética , Distribución de Chi-Cuadrado , Inmunoprecipitación de Cromatina , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Femenino , Histonas/metabolismo , Humanos , Interleucina-8/genética , Masculino , Persona de Mediana Edad , Fosforilación , Reacción en Cadena de la Polimerasa , Medicamentos bajo Prescripción/uso terapéutico , Regiones Promotoras Genéticas , ARN Mensajero/metabolismo , Factores de Riesgo , Proteína 2 de Unión a Repeticiones Teloméricas/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Morbidity and mortality are greater among socially disadvantaged racial/ethnic groups and those of lower socioeconomic status (SES). Greater chronic stress exposure in disadvantaged groups may contribute to this by accelerating cellular aging, indexed by shorter age-adjusted telomere length. While studies consistently relate shorter leukocyte telomere length (LTL) to stress, the few studies, mostly from the UK, examining associations of LTL with SES have been mixed. The current study examined associations between educational attainment and LTL among 2599 high-functioning black and white adults age 70-79 from the Health, Aging and Body Composition Study. Multiple regression analyses tested associations of race/ethnicity, educational attainment and income with LTL, adjusting for potential confounders. Those with only a high school education had significantly shorter mean LTL (4806 basepairs) than those with post-high school education (4926 basepairs; B=125, SE=47.6, p=.009). A significant interaction of race and education (B=207.8, SE=98.7, p=.035) revealed more beneficial effects of post-high school education for blacks than for whites. Smokers had shorter LTL than non-smokers, but the association of education and LTL remained significant when smoking was covaried (B=119.7, SE=47.6, p=.012). While higher income was associated with longer LTL, the effect was not significant (p>.10). This study provides the first demonstration of an association between educational attainment and LTL in a US population where higher education appears to have a protective effect against telomere shortening, particularly in blacks.
Asunto(s)
Disparidades en el Estado de Salud , Clase Social , Acortamiento del Telómero , HumanosRESUMEN
OBJECTIVE: We tested the hypothesis that short telomere length is associated with increased risk of myocardial infarction, ischemic heart disease, and early death. METHODS AND RESULTS: We measured leukocyte telomere length in 2 prospective studies of 19 838 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 19 years for incident myocardial infarction (n=929), ischemic heart disease (n=2038), and death (n=4342). Follow-up was 100% complete. Telomere length decreased linearly with increasing age in women and men in both studies (P=7×10(-74) to P=3×10(-125)). Multifactorially adjusted hazard ratios were 1.10 (95% CI 1.01-1.19) for myocardial infarction, 1.06 (1.00-1.11) for ischemic heart disease, and 1.09 (1.05-1.13) for early death per 1000-base pair decrease in telomere length. The multifactorially adjusted hazard ratios for the shortest versus the longest decile of telomere length were 1.49 (1.07-2.07) for myocardial infarction, 1.24 (1.01-1.53) for ischemic heart disease, and 1.25 (1.07-1.46) for early death. CONCLUSION: Short telomere length is associated with only modestly increased risk of myocardial infarction, ischemic heart disease, and early death.
Asunto(s)
Infarto del Miocardio/genética , Infarto del Miocardio/mortalidad , Isquemia Miocárdica/genética , Isquemia Miocárdica/mortalidad , Acortamiento del Telómero , Adulto , Factores de Edad , Anciano , Envejecimiento/genética , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Reacción en Cadena en Tiempo Real de la Polimerasa , Medición de Riesgo , Factores de Riesgo , Factores de TiempoRESUMEN
Telomere length in humans is emerging as a biomarker of aging because its shortening is associated with aging-related diseases and early mortality. However, genetic mechanisms responsible for these associations are not known. Here, in a cohort of Ashkenazi Jewish centenarians, their offspring, and offspring-matched controls, we studied the inheritance and maintenance of telomere length and variations in two major genes associated with telomerase enzyme activity, hTERT and hTERC. We demonstrated that centenarians and their offspring maintain longer telomeres compared with controls with advancing age and that longer telomeres are associated with protection from age-related diseases, better cognitive function, and lipid profiles of healthy aging. Sequence analysis of hTERT and hTERC showed overrepresentation of synonymous and intronic mutations among centenarians relative to controls. Moreover, we identified a common hTERT haplotype that is associated with both exceptional longevity and longer telomere length. Thus, variations in human telomerase gene that are associated with better maintenance of telomere length may confer healthy aging and exceptional longevity in humans.
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Variación Genética , Longevidad/genética , ARN/genética , Telomerasa/genética , Telómero , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Haplotipos , Humanos , Lípidos/sangre , Masculino , Persona de Mediana EdadRESUMEN
(1) Background: Colorectal cancer risk and survival have previously been associated with telomere length in peripheral blood leukocytes and tumor tissue. A systematic review and meta-analysis of the literature was conducted. The PubMed, Embase, and Web of Science databases were searched through March 2022. (2) Methods: Relevant studies were identified through database searching following PRISMA guidelines. Risk estimates were extracted from identified studies; meta-analyses were conducted using random effects models. (3) Results: Fourteen studies were identified (eight on risk; six on survival) through systematic review. While no association was observed between circulating leukocyte telomere length and the risk of colorectal cancer [overall OR (95% CI) = 1.01 (0.82-1.24)], a worse survival for those with shorter telomeres in leukocytes and longer telomeres in tumor tissues was observed [Quartile1/Quartile2-4 overall HR (95% CI) = 1.41 (0.26-7.59) and 0.82 (0.69-0.98), respectively]. (4) Conclusions: Although there was no association with colorectal cancer risk, a poorer survival was observed among those with shorter leukocyte telomere length. Future larger studies evaluating a potentially non-linear relationship between telomeres and colorectal cancer are needed.
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BACKGROUND: The complex relationship between measured leukocyte telomere length (LTL), genetically predicted LTL (gTL), and carcinogenesis is exemplified by lung cancer. We previously reported associations between longer pre-diagnostic LTL, gTL, and increased lung cancer risk among European and East Asian populations. However, we had limited statistical power to examine the associations among never smokers by gender and histology. METHODS: To investigate further, we conducted nested case-control analyses on an expanded sample of never smokers from the prospective Shanghai Women's Health Studies (798 cases and 792 controls) and Shanghai Men's Health Studies (161 cases and 162 controls). We broke the case-control matching and used multivariable unconditional logistic regression models to estimate the ORs and 95% confidence intervals (CI) of incident lung cancer and adenocarcinoma (LUAD), in relation to LTL measured using quantitative PCR and gTL determined using a polygenic score. In addition, we conducted Mendelian randomization (MR) using MR-PRESSO. RESULTS: We found striking dose-response relationships between longer LTL and gTL, and increased lung cancer risk among never-smoking women (P trendLTL = 4×10-6; P trendgTL = 3×10-4). Similarly, among never-smoking men, longer measured LTL was associated with over triple the risk compared with those with the shortest (OR, 3.48; 95% CI, 1.85-6.57). The overall results were similar for LUAD among women and men. MR analyses supported causal associations with LUAD among women (OR1 SD gTL, 1.19; 95% CI, 1.03-1.37; P = 0.03). CONCLUSIONS: Longer pre-diagnostic LTL is associated with increased lung cancer risk among never smokers. IMPACT: Our findings firmly support the role of longer telomeres in lung carcinogenesis.
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Neoplasias Pulmonares , Masculino , Humanos , Femenino , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/genética , Estudios Prospectivos , China/epidemiología , Fumadores , Homeostasis del Telómero/genética , Leucocitos , Pulmón , Telómero/genética , CarcinogénesisRESUMEN
Importance: Research suggests that increased mitochondrial DNA copy number (mtDNAcn) is associated with increased risk of non-Hodgkin lymphoma (NHL); however, no studies to date have evaluated whether the mitochondrial DNA fraction with breaks (mtDNAfb) is associated with risk of NHL. Objective: To evaluate the association of mtDNAfb with NHL risk. Design, Setting, and Participants: This nested case-control study, which used prospectively collected samples as part of baseline enrollment (from 1985 through 1988) of 29â¯133 men who smoked for the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study conducted in southwest Finland, included 107 incident NHL cases and 107 controls (matched on date of birth ±5 years). Analyses were conducted from January to September 2022. Exposure: High-throughput real-time polymerase chain reaction assays quantifying mtDNAfb. Main Outcomes and Measures: Incident NHL cases were identified in the ATBC Study through April 30, 2002, using the Finnish Cancer Registry and the Register of Causes of Death. The mtDNAfb was quantified and categorized based on the median, tertile, and quartile distributions among controls. Odds ratios (ORs) and 95% CIs were estimated using conditional logistic regression models to assess the associations between categorized mtDNAfb and future risk of NHL, controlling for age, body mass index, number of cigarettes smoked per day, number of pack-years, and mtDNAcn. Results: A total of 29â¯133 men (median [IQR] age, 57.2 [52.6-62.5] years) participated in ATBC Study. Higher mtDNAfb was associated with an increased risk of NHL (median OR, 2.89; 95% CI, 1.40-5.93) in a dose-dependent manner (quartile 2 vs 1 OR, 1.24; 95% CI, 0.43-3.40; quartile 3 vs 1 OR, 3.58; 95% CI, 1.39-9.24; quartile 4 vs 1 OR, 3.42; 95% CI, 1.30- 8.99; P = .004 for trend). Conclusions and Relevance: This study's findings suggest that increased mtDNAfb is associated with an increased future risk of NHL. Additional studies are needed to confirm these findings, particularly among women and nonsmokers.
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ADN Mitocondrial , Linfoma no Hodgkin , Masculino , Humanos , Femenino , Persona de Mediana Edad , ADN Mitocondrial/genética , Factores de Riesgo , Estudios de Casos y Controles , Fragmentación del ADN , Linfoma no Hodgkin/epidemiología , Linfoma no Hodgkin/genéticaRESUMEN
BACKGROUND: Household air pollution (HAP) from indoor combustion of solid fuel is a global health burden linked to lung cancer. In Xuanwei, China, lung cancer rate for nonsmoking women is among the highest in the world and largely attributed to high levels of polycyclic aromatic hydrocarbons (PAHs) that are produced from combustion of smoky (bituminous) coal used for cooking and heating. Epigenetic age acceleration (EAA), a DNA methylation-based biomarker of aging, has been shown to be highly correlated with biological processes underlying the susceptibility of age-related diseases. We aim to assess the association between HAP exposure and EAA. METHODS: We analyzed data from 106 never-smoking women from Xuanwei, China. Information on fuel type was collected using a questionnaire, and validated exposure models were used to predict levels of 43 HAP constituents. Exposure clusters were identified using hierarchical clustering. EAA was derived for five epigenetic clocks defined as the residuals resulting from regressing each clock on chronological age. We used generalized estimating equations to test associations between exposure clusters derived from predicted levels of HAP exposure, ambient 5-methylchrysene (5-MC), a PAH previously found to be associated with risk of lung cancer, and EAA, while accounting for repeated-measurements and confounders. RESULTS: We observed an increase in GrimAge EAA for clusters with 31 and 33 PAHs reflecting current (ß = 0.77 y per standard deviation (SD) increase, 95 % CI:0.36,1.19) and childhood (ß = 0.92 y per SD, 95 % CI:0.40,1.45) exposure, respectively. 5-MC (ng/m3-year) was found to be associated with GrimAge EAA for current (ß = 0.15 y, 95 % CI:0.05,0.25) and childhood (ß = 0.30 y, 95 % CI:0.13,0.47) exposure. CONCLUSIONS: Our findings suggest that exposure to PAHs from indoor smoky coal combustion, particularly 5-MC, is associated with GrimAge EAA, a biomarker of mortality.