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Centenarians (CENs) are excellent subjects to study the mechanisms of human longevity and healthy aging. Here, we analyzed the transcriptomes of 76 centenarians, 54 centenarian-children, and 41 spouses of centenarian-children by RNA sequencing and found that, among the significantly differentially expressed genes (SDEGs) exhibited by CENs, the autophagy-lysosomal pathway is significantly up-regulated. Overexpression of several genes from this pathway, CTSB, ATP6V0C, ATG4D, and WIPI1, could promote autophagy and delay senescence in cultured IMR-90 cells, while overexpression of the Drosophila homolog of WIPI1, Atg18a, extended the life span in transgenic flies. Interestingly, the enhanced autophagy-lysosomal activity could be partially passed on to their offspring, as manifested by their higher levels of both autophagy-encoding genes and serum beclin 1 (BECN1). In light of the normal age-related decline of autophagy-lysosomal functions, these findings provide a compelling explanation for achieving longevity in, at least, female CENs, given the gender bias in our collected samples, and suggest that the enhanced waste-cleaning activity via autophagy may serve as a conserved mechanism to prolong the life span from Drosophila to humans.
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Autofagia/genética , Longevidad/genética , Transcriptoma , Anciano , Anciano de 80 o más Años , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Beclina-1/genética , Beclina-1/metabolismo , Catepsina B/genética , Catepsina B/metabolismo , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismo , Femenino , Humanos , Lisosomas/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , ATPasas de Translocación de Protón Vacuolares/genética , ATPasas de Translocación de Protón Vacuolares/metabolismoRESUMEN
The purpose of this study was to investigate the association between refined grains intake and obesity in China. Refined grain intake was considered in relation to energy intake and at varied levels of macronutrient distribution. A cross-sectional study of 6913 participants was conducted using internet-based dietary questionnaire for Chinese (IDQC). The associations and dose-response relationships between refined grains intake and obesity were investigated using multivariable logistic regression analyses and restricted cubic spline (RCS) models. There was a positive association between refined grains intake and abdominal obesity for all participants (forth quartile OR, 1.313; 95% CI, 1.103-1.760; p < .05) and this association persisted in low energy, low carbohydrate, high fat and high protein level subgroups. A range of favourable refined grains intake was 88-116 g/d (3-4 servings/d), which might decrease the likelihood of obesity for Chinese residents. Further prospective studies are needed to confirm these findings.
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Dieta Alta en Grasa/efectos adversos , Dieta Rica en Proteínas/efectos adversos , Carbohidratos de la Dieta/efectos adversos , Grano Comestible , Ingestión de Energía , Obesidad Abdominal/tratamiento farmacológico , Adolescente , Adulto , Anciano , Pueblo Asiatico , China/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nutrientes , Adulto JovenRESUMEN
Adipocyte differentiation and adipogenesis are closely related to obesity and obesity-induced metabolic disorders. The calcium-sensing receptor (CaSR) has been reported to play an antilipolytic role in human adipocyte and regulate cell differentiation in many tissues. However, the effects of CaSR on adipocyte differentiation and adipogenesis have not been clarified. In the study, we observed that activation of CaSR significantly promoted adipocyte differentiation and adipogenesis in human SW872 adipocytes. Gene expression analysis revealed that the CaSR activation increased the transcription factor proliferator-activated receptor γ (PPARγ) and its downstream genes including CCAAT element binding protein α (C/EBPα), adipose fatty acid-binding protein (aP2), and lipoprotein lipase. The activity of glycerol-3-phosphate dehydrogenase was also increased after the stimulation of CaSR. In addition, levels of cyclic AMP and calcium which have been shown to regulate PPARγ gene expression were significantly affected by the activation of CaSR. These effects could be suppressed by CaSR small interfering RNA (CaSR-siRNA). In conclusion, our findings suggest that activation of CaSR promotes differentiation and adipogenesis in adipocytes, which might be achieved by upregulating PPARγ and its downstream gene expressions. Therefore, CaSR in adipocytes may be involved in the pathogenesis of obesity by promoting adipocyte differentiation and adipogenesis.
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Adipocitos/fisiología , Adipogénesis , PPAR gamma/metabolismo , Receptores Sensibles al Calcio/metabolismo , Adipocitos/metabolismo , Proteína alfa Potenciadora de Unión a CCAAT/genética , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Señalización del Calcio , Diferenciación Celular , Línea Celular , AMP Cíclico/metabolismo , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Gadolinio/farmacología , Expresión Génica , Humanos , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/metabolismo , PPAR gamma/genética , Receptores Sensibles al Calcio/agonistas , Receptores Sensibles al Calcio/genética , Triglicéridos/metabolismoRESUMEN
Deep RNA sequencing of 164 blood samples collected from long-lived families was performed to investigate the expression patterns of circular RNAs (circRNAs). Unlike that observed in previous studies, circRNA expression in long-lived elderly individuals (98.3 ± 3.4 year) did not exhibit an age-accumulating pattern. Based on weighted circRNA co-expression network analysis, we found that longevous elders specifically gained eight but lost seven conserved circRNA-circRNA co-expression modules (c-CCMs) compared with normal elder controls (spouses of offspring of long-lived individuals, age = 59.3 ± 5.8 year). Further analysis showed that these modules were associated with healthy aging-related pathways. These results together suggest an important role of circRNAs in regulating human lifespan extension.
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MicroARNs , ARN Circular , Anciano , Secuencia de Bases , Humanos , Longevidad/genética , MicroARNs/genética , Persona de Mediana Edad , ARN Circular/genética , Análisis de Secuencia de ARNRESUMEN
Low-calcium intake is associated with increased risk of obesity, but the mechanism underlying this is not clear. We previously reported that the calcium-sensing receptor (CaSR) plays an important role in modulating the expression of rate-limiting lipolysis enzymes in human adipocytes. In the present study, rats were fed diets containing normal [0.50% (NC)], low [0.30% (LC)], or very low [0.15% (VLC)] calcium for 15 wk. Ten rats of each group were killed at wk 5, 10, and 15 of the intervention. The LC-fed rats had greater visceral fat mass, lower serum FFA and glycerol concentrations, and greater CaSR expression in white adipose tissue than did those fed the NC diet at wk 10 and 15. Hormone-sensitive lipase (HSL) and adipose TG lipase (ATGL) protein levels were lower, whereas fatty acid synthase mRNA in white adipose tissue was greater in the LC-fed rats compared with the NC-fed rats. These differences from the NC group were greater in the VLC group than in the LC group at wk 15. In vitro experiments showed that 1,25-dihydroxycholecalciferol stimulated the expression of CaSR through the nuclear vitamin D receptor (nVDR). This resulted in an antilipolytic effect by increasing intracellular calcium, decreasing the intracellular cAMP level, and downregulating HSL and ATGL protein expression in adipocytes. These effects were suppressed by either nVDR or CaSR small-interfering RNA. These results suggest that CaSR affects fat accumulation by mediating antilipolytic pathways in adipose tissue of rats fed low-calcium diets.
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Calcio de la Dieta/administración & dosificación , Grasa Intraabdominal/fisiología , Lipólisis/fisiología , Receptores Sensibles al Calcio/fisiología , Animales , Secuencia de Bases , Western Blotting , Densidad Ósea , Calcitriol/sangre , Calcio/sangre , AMP Cíclico/metabolismo , Conducta Alimentaria , Grasa Intraabdominal/metabolismo , Lipoproteína Lipasa/sangre , Masculino , Hormona Paratiroidea/sangre , ARN Interferente Pequeño , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Esteroide Hidroxilasas/metabolismo , Aumento de PesoRESUMEN
DNA replication is precisely regulated in cells and its dysregulation can trigger tumorigenesis. Here we identified that the TOPBP1 interacting checkpoint and replication regulator (TICRR) mRNA level was universally and highly expressed in 15 solid cancer types. Depletion of TICRR significantly inhibited tumor cell growth, colony formation and migration in vitro, and strikingly inhibited tumor growth in the xenograft model. We reveal that knockdown of TICRR inhibited not only the initiation but also the fork progression of DNA replication. Suppression of DNA synthesis by TICRR silencing caused DNA damage accumulation, subsequently activated the ATM/CHK2 dependent p53 signaling, and finally induced cell cycle arrest and apoptosis at least in p53-wild cancer cells. Further, we show that a higher TICRR level was associated with poorer overall survival (OS) and disease free survival (DFS) in multiple cancer types. In conclusion, our study shows that TICRR is involved in tumorigenesis by regulating DNA replication, acting as a common biomarker for cancer prognosis and could be a promising target for drug-development and cancer treatment.
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BACKGROUND: Accelerated age-associated DNA methylation changes in males may explain the earlier onset of age-related diseases (e.g., cardiovascular disease (CVD)) and thus contribute to sexually dimorphic morbidity and lifespan. However, the details regarding the emergence of this sex-biased methylation pattern remain unclear. RESULTS: To address these issues, we collected publicly available peripheral blood methylation datasets detected by Illumina HumanMethylation450 BeadChip platform from four studies that contain age and gender information of samples. We analyzed peripheral blood methylation data screened from 708 subjects of European ancestry. Results revealed a significant methylation change acceleration in middle-aged males (40-50 years old), which was further supported by another cohort containing 2711 subjects with Indian ancestry. Additional analyses suggested that these sexually dimorphic methylation changes were significantly overrepresented in genes associated with CVD, which may impact the potential activation of disease expression. Furthermore, we showed that higher prevalence of drinking and smoking in the males has some contribution to the sex-based methylation patterns during aging. CONCLUSION: Our results indicated that the sex-biased methylation changes occurred in middle-aged men in an acceleration manner and likely contribute to the sexual dimorphism observed in human lifespan by promoting the occurrence of CVD. As drinking and smoking were also found to be associated with this accelerated methylation change in men, it is possible that male lifespan may be prolonged by improving unhealthy lifestyles at or before middle age.
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Metilación de ADN , Estudio de Asociación del Genoma Completo/métodos , Longevidad/genética , Fumar/genética , Factores de Edad , Estudios de Cohortes , Islas de CpG , Ingestión de Líquidos , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Caracteres Sexuales , Fumar/epidemiologíaRESUMEN
Cellular senescence is a fundamental cell fate playing a significant role throughout the natural aging process. However, the molecular determinants distinguishing senescence from other cell-cycle arrest states such as quiescence and post-mitotic state, and the specified mechanisms underlying cell-fate decisions towards senescence versus cell death in response to cellular stress stimuli remain less understood. Employing multi-omics approaches, we revealed that switching off the specific mitochondrial processing machinery involving the peptidase IMMP2L serves as the foundation of the senescence program, which was also observed during the mammalian aging process. Mechanistically, we demonstrate that IMMP2L processes and thus activates at least two substrates, mitochondrial metabolic enzyme glycerol-3-phosphate dehydrogenase (GPD2) and cell death regulator apoptosis-inducing factor (AIF). For cells destined to senesce, concerted shutdown of the IMMP2L-GPD2 and IMMP2L-AIF signaling axes collaboratively drives the senescent process by reprogramming mitochondria-associated redox status, phospholipid metabolism and signaling network, and simultaneously blocking cell death under oxidative stress conditions.
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Factor Inductor de la Apoptosis/metabolismo , Senescencia Celular , Endopeptidasas/metabolismo , Glicerolfosfato Deshidrogenasa/metabolismo , Transducción de Señal , Envejecimiento , Animales , Muerte Celular , Línea Celular , Células HEK293 , Células HeLa , Humanos , Ratones Endogámicos C57BL , Estrés OxidativoRESUMEN
Tumorigenesis is linked to the role of DNA methylation in gene expression regulation. Yet, cancer is a highly heterogeneous disease in which the global pattern of DNA methylation and gene expression, especially across diverse cancers, is not well understood. We investigated DNA methylation status and its association with gene expressions across 12 solid cancer types obtained from The Cancer Genome Atlas. Results showed that global hypermethylation was an important characteristic across all 12 cancer types. Moreover, there were more epigenetically silenced than epigenetically activated genes across the cancers. Further analysis identified epigenetically silenced genes shared in the calcium-signaling pathway across the different cancer types. Reversing the aberrant DNA methylation of genes involved in the calcium-signaling pathway could be an effective strategy for suppressing cancers and developing anti-cancer drugs.
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Señalización del Calcio/genética , Calcio/metabolismo , Metilación de ADN , Neoplasias/genética , Neoplasias/metabolismo , Línea Celular Tumoral , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , HumanosRESUMEN
By analyzing 4987 cancer transcriptomes from The Cancer Genome Atlas (TCGA), we identified that excision repair cross-complementation group 6 like (ERCC6L), a newly discovered DNA helicase, is highly expressed in 12 solid cancers. However, its role and mechanism in tumorigenesis are largely unknown. In this study, we found that ERCC6L silencing by small interring RNA (siRNA) or short hairpin RNA (shRNA) significantly inhibited the proliferation of breast (MCF-7, MDA-MB-231) and kidney cancer cells (786-0). Furthermore, ERCC6L silencing induced cell cycle arrest at G0/G1 phase without affecting apoptosis. We then performed RNA sequencing (RNA-seq) analysis after ERCC6L silencing and identified that RAB31 was markedly downregulated at both the transcriptional and translational levels. Its downstream protein, phosphorylated MAPK and CDK2 were also inhibited by ERCC6L silencing. The xenograft experiment showed that silencing of ERCC6L strikingly inhibited tumor growth from the 7th day after xenograft in nude mice. In addition, higher ERCC6L expression was found to be significantly associated with worse clinical survival in breast and kidney cancers. In conclusion, our results suggest that ERCC6L may stimulates cancer cell proliferation by promoting cell cycle through a way of RAB31-MAPK-CDK2, and it could be a potential biomarker for cancer prognosis and target for cancer treatment.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , ADN Helicasas/genética , Neoplasias Renales/genética , Neoplasias Renales/mortalidad , Animales , Apoptosis/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Xenoinjertos , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Ratones , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Pronóstico , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismoRESUMEN
Heterogeneity in transcriptional data hampers the identification of differentially expressed genes (DEGs) and understanding of cancer, essentially because current methods rely on cross-sample normalization and/or distribution assumption-both sensitive to heterogeneous values. Here, we developed a new method, Cross-Value Association Analysis (CVAA), which overcomes the limitation and is more robust to heterogeneous data than the other methods. Applying CVAA to a more complex pan-cancer dataset containing 5,540 transcriptomes discovered numerous new DEGs and many previously rarely explored pathways/processes; some of them were validated, both in vitro and in vivo, to be crucial in tumorigenesis, e.g., alcohol metabolism (ADH1B), chromosome remodeling (NCAPH) and complement system (Adipsin). Together, we present a sharper tool to navigate large-scale expression data and gain new mechanistic insights into tumorigenesis.
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Biología Computacional/métodos , Perfilación de la Expresión Génica/métodos , Genes Relacionados con las Neoplasias , Neoplasias/patología , HumanosRESUMEN
Aging is a major risk factor for individuals' health problems. Moreover, environmental signals have a widespread influence on the aging process. Epigenetic modification, e.g. DNA methylation, represents a link between genetic and environmental signals via the regulation of gene transcription. An abundance of literature indicates that aberrant epigenetic change occurs throughout the aging process at both the cellular and the organismal level. In particular, DNA methylation presents globally decreasing and site-specific increasing in aging. In this review, we focus on the crucial roles of DNA methylation in aging and age-related disease and highlight the great potential of DNA methylation as a therapeutic target in preventing age-related diseases and promoting healthy longevity.
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Envejecimiento/genética , Metilación de ADN , Epigénesis Genética , Regulación de la Expresión Génica , Longevidad/genética , Animales , HumanosRESUMEN
BACKGROUND: Long noncoding RNAs (lncRNAs) are a class of ubiquitous noncoding RNAs and have been found to act as tumor suppressors or oncogenes, which dramatically altered our understanding of cancer. Naked mole rat (NMR, Heterocephalus glaber) is an exceptionally long-lived and cancer-resistant rodent; however, whether lncRNAs play roles in cancer resistance in this seductive species remains unknown. RESULTS: In this study, we developed a pipeline and identified a total of 4422 lncRNAs across the NMR genome based on 12 published transcriptomes. Systematic analysis revealed that NMR lncRNAs share many common characteristics with other vertebrate species, such as tissue specificity and low expression. BLASTN against with 1057 human cancer-related lncRNAs showed that only 5 NMR lncRNAs displayed homology, demonstrating the low sequence conservation between NMR lncRNAs and human cancer-related lncRNAs. Further correlation analysis of lncRNAs and protein-coding genes indicated that a total of 1295 lncRNAs were intensively coexpressed (r ≥ 0.9 or r ≤ -0.9, cP value ≤ 0.01) with potential tumor-suppressor genes in NMR, and 194 lncRNAs exhibited strong correlation (r ≥ 0.8 or r ≤ -0.8, cP value ≤ 0.01) with four high-molecular-mass hyaluronan related genes that were previously identified to play key roles in cancer resistance of NMR. CONCLUSION: In this study, we provide the first comprehensive genome-wide analysis of NMR lncRNAs and their possible associations with cancer resistance. Our results suggest that lncRNAs may have important effects on anticancer mechanism in NMR.
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Resistencia a la Enfermedad/genética , Ratas Topo/genética , Neoplasias/genética , ARN Largo no Codificante/metabolismo , Animales , Bases de Datos Genéticas , Genoma , Humanos , Ratones , Neoplasias/metabolismo , Neoplasias/patología , ARN Largo no Codificante/genética , Ratas , TranscriptomaRESUMEN
The mitochondrion is a double membrane-bound organelle which plays important functional roles in aging and many other complex phenotypes. Transmission of the mitochondrial genome in the matrilineal line causes the evolutionary selection sieve only in females. Theoretically, beneficial or neutral variations are more likely to accumulate and be retained in the female mitochondrial genome during evolution, which may be an initial trigger of gender dimorphism in aging. The asymmetry of evolutionary processes between gender could lead to males and females aging in different ways. If so, gender specific variation loads could be an evolutionary result of maternal heritage of mitochondrial genomes, especially in centenarians who live to an extreme age and are considered as good models for healthy aging. Here, we tested whether the mitochondrial variation loads were associated with altered aging patterns by investigating the mtDNA haplogroup distribution and genetic diversity between female and male centenarians. We found no evidence of differences in aging patterns between genders in centenarians. Our results indicate that the evolutionary consequence of gender dimorphism in mitochondrial genomes is not a factor in the altered aging patterns in human, and that mitochondrial DNA contributes equally to longevity in males and females.
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ADN Mitocondrial/genética , Longevidad/genética , Mitocondrias/genética , Factores Sexuales , Adulto , Anciano , Anciano de 80 o más Años , China , Femenino , Variación Genética , Genoma Mitocondrial , Haplotipos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Centenarians are a good healthy aging model. Interestingly, centenarians' offspring are prone to achieve longevity. Here we recruited 60 longevity families and investigated the blood biochemical indexes of family members to seek candidate factors associated with familial longevity. First, associations of blood indexes with age were tested. Second, associations of blood parameters in centenarians (CEN) with their first generation of offspring (F1) and F1 spouses (F1SP) were analyzed. Third, genes involved in regulating target factors were investigated. We found that total cholesterol (TC) and triglyceride (TG) increased with age (20-80 years), but decreased in CEN. Similarly, blood urea nitrogen (BUN) and blood creatinine (BCr) increased with age (20-80 years), but were maintained on a plateau in CEN. Importantly, we first revealed dual changes in blood pressure, i.e., decreased diastolic blood pressure but increased systolic blood pressure in CEN, which associated with altered CST3 expression. Genetic analysis revealed a significant association of blood uric acid (BUA) and BCr in CEN with F1 but not with F1SP, suggesting they may be heritable traits. Taken together, our results suggest serum lipids, kidney function and especially diastolic pressure rather than systolic pressure were improved in CEN or their offspring, suggesting these factors may play an important role in familial longevity.
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Presión Sanguínea/fisiología , Riñón/metabolismo , Lípidos/sangre , Longevidad , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento , Pueblo Asiatico , Nitrógeno de la Urea Sanguínea , China , Colesterol/sangre , Creatinina/sangre , Cistatina C/metabolismo , Humanos , Pruebas de Función Renal , Metabolismo de los Lípidos/genética , Masculino , Persona de Mediana Edad , Transcriptoma , Triglicéridos/sangre , Ácido Úrico/sangreRESUMEN
Reduced mitochondrial function is an important cause of aging and age-related diseases. We previously revealed a relatively higher level of mitochondrial DNA (mtDNA) content in centenarians. However, it is still unknown whether such an mtDNA content pattern of centenarians could be passed on to their offspring and how it was regulated. To address these issues, we recruited 60 longevity families consisting of 206 family members (cohort 1) and explored their mtDNA copy number. The results showed that the first generation of the offspring (F1 offspring) had a higher level of mtDNA copy number than their spouses (p < 0.05) independent of a gender effect. In addition, we found a positive association of mtDNA copy number in centenarians with that in F1 offspring (r = 0.54, p = 0.0008) but not with that in F1 spouses. These results were replicated in another independent cohort consisting of 153 subjects (cohort 2). RNA sequencing analysis suggests that the single-stranded DNA-binding protein 4 was significantly associated with mtDNA copy number and was highly expressed in centenarians as well as F1 offspring versus the F1 spouses, thus likely regulates the mtDNA copy number in the long-lived family members. In conclusion, our results suggest that the pattern of high mtDNA copy number is likely inheritable, which may act as a favorable factor to familial longevity through assuring adequate energy supply.
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Variaciones en el Número de Copia de ADN/genética , ADN Mitocondrial/genética , Estudios de Asociación Genética , Longevidad/genética , Anciano de 80 o más Años , Proteínas de Unión al ADN/genética , Metabolismo Energético/genética , Femenino , Humanos , MasculinoRESUMEN
It is recognized that genetic factors contribute to human longevity. Besides the hypothesis of existence of longevity genes, another suggests that a lower frequency of risk alleles decreases the incidence of age-related diseases in the long-lived people. However, the latter finds no support from recent genetic studies. Considering the crucial role of epigenetic modification in gene regulation, we then hypothesize that suppressing disease-related genes in longevity individuals is likely achieved by epigenetic modification, e.g. DNA methylation. To test this hypothesis, we investigated the genome-wide methylation profile in 4 Chinese female centenarians and 4 middle-aged controls using methyl-DNA immunoprecipitation sequencing. 626 differentially methylated regions (DMRs) were observed between both groups. Interestingly, genes with these DMRs were enriched in age-related diseases, including type-2 diabetes, cardiovascular disease, stroke and Alzheimer's disease. This pattern remains rather stable after including methylomes of two white individuals. Further analyses suggest that the observed DMRs likely have functional roles in regulating disease-associated gene expressions, with some genes [e.g. caspase 3 (CASP3)] being down-regulated whereas the others [i.e. interleukin 1 receptor, type 2 (IL1R2)] up-regulated. Therefore, our study suggests that suppressing the disease-related genes via epigenetic modification is an important contributor to human longevity.
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Metilación de ADN/fisiología , Longevidad/genética , Envejecimiento/genética , Caspasa 3/genética , Metilación de ADN/genética , Epigénesis Genética/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores Tipo II de Interleucina-1/genéticaRESUMEN
Hypertension is the most common and lethal risk factor for cardiovascular disease (CVD). Numerous variants have been associated with hypertension, however, most of which failed to get replication due to ethnic differences. In this study, we analyzed associations of 10 newly reported single nucleotide polymorphisms (SNPs) in Europeans with hypertension in Chinese. A total of 1766 samples consisting of 880 subjects with hypertension and 886 controls were collected and the SNPs were genotyped using multiple assays based on the SNaPshot mini-sequencing approach. Our results revealed a significant genotypic association of rs4746172 of VCL with hypertension with a lower frequency of minor allele in male subjects (OR = 0.70, 95% CI: 0.54-0.92, p = 0.011) but not in females. To validate the result, we genotyped the SNPs in another Chinese population with 546 individuals, and got a consistent association for the rs4746172 (OR = 0.56, 95% CI: 0.38-0.82, p = 2.4 × 10(-3)) in males. The VCL-encoding protein was involved in cardiomyopathy that associated with hypertension, therefore our results suggest the rs4746172 of VCL may be a novel target for clinical interventions to reduce CVD risk by regulating blood pressure in male Chinese.
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Cardiomiopatías/genética , Predisposición Genética a la Enfermedad , Hipertensión/genética , Vinculina/genética , Anciano , Pueblo Asiatico , Cardiomiopatías/complicaciones , Cardiomiopatías/patología , China , Femenino , Estudios de Asociación Genética , Genotipo , Haplotipos , Humanos , Hipertensión/complicaciones , Hipertensión/patología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Caracteres SexualesRESUMEN
Human lifespan is determined greatly by genetic factors and some investigations have identified putative genes implicated in human longevity. Although some genetic loci have been associated with longevity, most of them are difficult to replicate due to ethnic differences. In this study, we analyzed the association of 18 reported gene single nucleotide polymorphisms (SNPs) with longevity in 1075 samples consisting of 567 nonagenarians/centenarians and 508 younger controls using the GenomeLab SNPstream Genotyping System. Our results confirm the association of the forkhead box O3 (FOXO3) variant (rs13217795) and the ATM serine/threonine kinase (ATM) variant (rs189037) genotypes with longevity (p=0.0075 and p=0.026, using the codominant model and recessive model, respectively). Of note is that we first revealed the association of insulin-like growth factor binding protein 3 (IGFBP-3) gene polymorphism rs11977526 with longevity in Chinese nonagenarians/centenarians (p=0.033 using the dominant model and p=0.035 using the overdominant model). The FOXO3 and IGFBP-3 form important parts of the insulin/insulin-like growth factor-1 signaling pathway (IGF-1) implicated in human longevity, and the ATM gene is involved in sensing DNA damage and reducing oxidative stress, therefore our results highlight the important roles of insulin pathway and oxidative stress in the longevity in the Chinese population.
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Pueblo Asiatico/genética , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Longevidad/genética , Polimorfismo de Nucleótido Simple , Factores de Edad , Anciano de 80 o más Años , Proteínas de la Ataxia Telangiectasia Mutada/genética , Estudios de Casos y Controles , China/epidemiología , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/genética , Frecuencia de los Genes , Genotipo , Humanos , FenotipoRESUMEN
Mitochondrial DNA (mtDNA) content plays an important role in energy production and sustaining normal physiological function. A decline in the mtDNA content and subsequent dysfunction cause various senile diseases, with decreasing mtDNA content observed in the elderly individuals with age-related diseases. In contrast, the oldest old individuals, for example, centenarians, have a delayed or reduced prevalence of these diseases, suggesting centenarians may have a different pattern of the mtDNA content, enabling them to keep normal mitochondrial functions to help delay or escape senile diseases. To test this hypothesis, a total of 961 subjects, consisting of 424 longevity subjects and 537 younger control subjects from Hainan and Sichuan provinces of China, were recruited for this study. The mtDNA content was found to be inversely associated with age among the age of group 40-70 years. Surprisingly, no reduction of mtDNA content was observed in nonagenarians and centenarians; instead, these oldest old showed a significant increase than the elderly people aged between 50 and 70 years. The results suggest the higher mtDNA content may convey a beneficial effect to the longevity of people through assuring sufficient energy supply.