Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 11.135
Filtrar
1.
BMC Med Genet ; 21(1): 54, 2020 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-32183743

RESUMEN

BACKGROUND: The ABCG2 rs2231142 single nucleotide polymorphism (SNP) is one of the most significant genetic variants associated with hyperuricemia (HUA) in Asian populations. However, the risk of ABCG2 rs2231142 variants for HUA could interact with other important HUA risk variants and cardiovascular factors. This study investigated the effects of the combined association among ABCG2 rs2231142 and multiple HUA genetic variants or cardiovascular risk factors on HUA risk and serum uric acid (sUA) levels in an elderly Chinese population. METHODS: A total of 1206 participants over 65 years old were enrolled in this study. Physical and laboratory examinations were performed for all participants. The ABCG2 rs2231142, SLC2A9 rs3733591, and SLC22A12 rs893006 SNPs were assayed using a standardized protocol. Logistic regression analysis and liner regression were adjusted respectively to account for the association between ABCG2 rs2231142 and other genetic variants, as well as between cardiovascular risk factors and HUA risk and sUA levels. RESULTS: The prevalence of HUA was 14.71% in the elderly community-dwelling population. The ABCG2 rs2231142 risk T allele was associated with HUA risk (odds ratio (OR) = 1.63, 95% confidence interval (CI): 1.27-2.11; p = 1.65 × 10- 4) and with increased sUA levels (Beta = 0.16, p = 6.75 × 10- 9) in the whole study population. Linear regression analysis showed that the mean sUA level increased linearly with the number of risk alleles of the three candidate genetic variants (Beta = 0.18, p = 1.94 × 10- 12) The joint effect of the ABCG2 rs2231142 T allele and cardiovascular risk factors (obesity, hypertension and dyslipidemia) was also associated with increased HUA risk and sUA levels. Each copy of the risk T allele was significantly associated with enhanced HUA risk in patients with hypertriglyceridemia (OR = 2.52, 95% CI: 1.33-4.60; p = 0.003) compared to controls. CONCLUSION: Our findings reinforce the importance of the ABCG2 rs2231143 variant as a crucial genetic locus for HUA in Chinese populations and demonstrated the combined effects of multiple genetic risk variants and cardiovascular risk exposures on HUA risk and increased sUA level.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Enfermedades Cardiovasculares/etiología , Genes Modificadores , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Hiperuricemia/genética , Proteínas de Neoplasias/genética , Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Envejecimiento/fisiología , Enfermedades Cardiovasculares/epidemiología , China/epidemiología , Estudios de Cohortes , Modificador del Efecto Epidemiológico , Epistasis Genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Hiperuricemia/sangre , Hiperuricemia/epidemiología , Vida Independiente/estadística & datos numéricos , Masculino , Factores de Riesgo , Ácido Úrico/sangre
3.
Life Sci ; 248: 117452, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32088214

RESUMEN

AIMS: The aim of this study was to elucidate the signaling pathway involved in the anti-aging effect of tropisetron and to clarify whether it affects mitochondrial oxidative stress, apoptosis and inflammation in the aging mouse brain by upregulating Sirtuin 1 or silent information regulator 1 (SIRT1). MATERIALS AND METHODS: Aging was induced by d-galactose (DG) at the dose of 200 mg/kg body weight/day subcutaneously injected to male mice for six weeks. Tropisetron was simultaneously administered intraperitoneally once a day at three various doses (1, 3 and 5 mg/kg body weight). Oxidative stress and mitochondrial dysfunction markers were evaluated. Nitric oxide (NO) and pro-inflammatory cytokines levels including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were studied. Besides, the expressions of apoptosis-associated genes (Bax and Bcl-2) and the aging-related gene (SIRT1) were determined by the real time polymerase chain reaction (RT-PCR). In addition, histopathological alterations were assessed. KEY FINDINGS: Tropisetron reversed the induction of oxidative damage, mitochondrial dysfunction and overproduction of inflammatory mediators induced by DG in the brain tissue. In addition, tropisetron suppressed DG-induced apoptosis and found to significantly elevate SIRT1 gene expression. Besides, tropisetron could markedly alleviate DG-induced abnormal changes in the brain morphology. SIGNIFICANCE: Tropisetron exhibited anti-aging effects in the context of DG-induced senescence in mouse brain through various pathways. Our results suggest that tropisetron may attenuate DG-induced brain aging via SIRT1 signaling activation.


Asunto(s)
Envejecimiento/efectos de los fármacos , Antioxidantes/farmacología , Encéfalo/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT3/farmacología , Sirtuina 1/genética , Tropisetrón/farmacología , Envejecimiento/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Encéfalo/metabolismo , Encéfalo/patología , Esquema de Medicación , Galactosa/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Sirtuina 1/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo
4.
Clin Chim Acta ; 505: 108-118, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32097628

RESUMEN

Under normal physiological conditions, free radical generation and antioxidant defences are balanced, and reactive oxygen species (ROS) usually act as secondary messengers in a plethora of biological processes. However, when this balance is impaired, oxidative stress develops due to imbalanced redox homeostasis resulting in cellular damage. Oxidative stress is now recognized as a trigger of cellular senescence, which is associated with multiple chronic 'burden of lifestyle' diseases, including atherosclerosis, type-2 diabetes, chronic kidney disease and vascular calcification; all of which possess signs of early vascular ageing. Nuclear factor erythroid 2-related factor 2 (Nrf2), termed the master regulator of antioxidant responses, is a transcription factor found to be frequently dysregulated in conditions characterized by oxidative stress and inflammation. Recent evidence suggests that activation of Nrf2 may be beneficial in protecting against vascular senescence and calcification. Both natural and synthetic Nrf2 agonists have been introduced as promising drug classes in different phases of clinical trials. However, overexpression of the Nrf2 pathway has also been linked to tumorigenesis, which highlights the requirement for further understanding of pathways involving Nrf2 activity, especially in the context of cellular senescence and vascular calcification. Therefore, comprehensive translational pre-clinical and clinical studies addressing the targeting capabilities of Nrf2 agonists are urgently required. The present review discusses the impact of Nrf2 in senescence and calcification in early vascular ageing, with focus on the potential clinical implications of Nrf2 agonists and non-pharmacological Nrf2 therapeutics.


Asunto(s)
Envejecimiento/genética , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/terapia , Sistema Cardiovascular/crecimiento & desarrollo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Calcificación Vascular/genética , Calcificación Vascular/terapia , Animales , Enfermedades Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Senescencia Celular , Humanos , Transducción de Señal/genética
5.
Nat Rev Mol Cell Biol ; 21(3): 137-150, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32020082

RESUMEN

Ageing is characterized by the functional decline of tissues and organs and the increased risk of ageing-associated disorders. Several 'rejuvenating' interventions have been proposed to delay ageing and the onset of age-associated decline and disease to extend healthspan and lifespan. These interventions include metabolic manipulation, partial reprogramming, heterochronic parabiosis, pharmaceutical administration and senescent cell ablation. As the ageing process is associated with altered epigenetic mechanisms of gene regulation, such as DNA methylation, histone modification and chromatin remodelling, and non-coding RNAs, the manipulation of these mechanisms is central to the effectiveness of age-delaying interventions. This Review discusses the epigenetic changes that occur during ageing and the rapidly increasing knowledge of how these epigenetic mechanisms have an effect on healthspan and lifespan extension, and outlines questions to guide future research on interventions to rejuvenate the epigenome and delay ageing processes.


Asunto(s)
Envejecimiento/genética , Epigénesis Genética/genética , Rejuvenecimiento/fisiología , Animales , Ensamble y Desensamble de Cromatina/genética , Metilación de ADN/genética , Epigenoma/genética , Epigenómica/métodos , Regulación de la Expresión Génica/genética , Código de Histonas/genética , Humanos , Longevidad/genética
6.
Nat Commun ; 11(1): 751, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-32029736

RESUMEN

Differences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22-93 years of age using ATAC-seq, RNA-seq, and flow cytometry. These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte and cytotoxic cell functions. These changes are greater in magnitude in men and accompanied by a male-specific decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. Impact of age and sex on immune phenotypes can be visualized at https://immune-aging.jax.org to provide insights into future studies.


Asunto(s)
Envejecimiento/inmunología , Caracteres Sexuales , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Linfocitos B/inmunología , Secuenciación de Inmunoprecipitación de Cromatina , Epigénesis Genética , Femenino , Citometría de Flujo , Humanos , Leucocitos Mononucleares/clasificación , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Modelos Inmunológicos , Monocitos/inmunología , RNA-Seq , Transcriptoma , Adulto Joven
7.
Nature ; 579(7797): 118-122, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32103178

RESUMEN

It has long been assumed that lifespan and healthspan correlate strongly, yet the two can be clearly dissociated1-6. Although there has been a global increase in human life expectancy, increasing longevity is rarely accompanied by an extended healthspan4,7. Thus, understanding the origin of healthy behaviours in old people remains an important and challenging task. Here we report a conserved epigenetic mechanism underlying healthy ageing. Through genome-wide RNA-interference-based screening of genes that regulate behavioural deterioration in ageing Caenorhabditis elegans, we identify 59 genes as potential modulators of the rate of age-related behavioural deterioration. Among these modulators, we found that a neuronal epigenetic reader, BAZ-2, and a neuronal histone 3 lysine 9 methyltransferase, SET-6, accelerate behavioural deterioration in C. elegans by reducing mitochondrial function, repressing the expression of nuclear-encoded mitochondrial proteins. This mechanism is conserved in cultured mouse neurons and human cells. Examination of human databases8,9 shows that expression of the human orthologues of these C. elegans regulators, BAZ2B and EHMT1, in the frontal cortex increases with age and correlates positively with the progression of Alzheimer's disease. Furthermore, ablation of Baz2b, the mouse orthologue of BAZ-2, attenuates age-dependent body-weight gain and prevents cognitive decline in ageing mice. Thus our genome-wide RNA-interference screen in C. elegans has unravelled conserved epigenetic negative regulators of ageing, suggesting possible ways to achieve healthy ageing.


Asunto(s)
Caenorhabditis elegans/genética , Epigénesis Genética , Envejecimiento Saludable/genética , Envejecimiento/genética , Animales , Cognición , Disfunción Cognitiva , N-Metiltransferasa de Histona-Lisina/genética , Histonas/química , Histonas/metabolismo , Humanos , Longevidad/genética , Lisina/metabolismo , Masculino , Memoria , Metilación , Ratones , Mitocondrias/metabolismo , Neuronas/metabolismo , Proteínas/genética , Interferencia de ARN , Aprendizaje Espacial
8.
PLoS Biol ; 18(1): e3000604, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31935214

RESUMEN

Schizophrenia is a severe mental disorder with an unclear pathophysiology. Increased expression of the immune gene C4 has been linked to a greater risk of developing schizophrenia; however, it is not known whether C4 plays a causative role in this brain disorder. Using confocal imaging and whole-cell electrophysiology, we demonstrate that overexpression of C4 in mouse prefrontal cortex neurons leads to perturbations in dendritic spine development and hypoconnectivity, which mirror neuropathologies found in schizophrenia patients. We find evidence that microglia-mediated synaptic engulfment is enhanced with increased expression of C4. We also show that C4-dependent circuit dysfunction in the frontal cortex leads to decreased social interactions in juvenile and adult mice. These results demonstrate that increased expression of the schizophrenia-associated gene C4 causes aberrant circuit wiring in the developing prefrontal cortex and leads to deficits in juvenile and adult social behavior, suggesting that altered C4 expression contributes directly to schizophrenia pathogenesis.


Asunto(s)
Complemento C4/genética , Neuronas/fisiología , Corteza Prefrontal/citología , Esquizofrenia/genética , Conducta Social , Envejecimiento/genética , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Animales Recién Nacidos , Comunicación Celular/genética , Células Cultivadas , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Vías Nerviosas/metabolismo , Corteza Prefrontal/patología , Esquizofrenia/patología , Regulación hacia Arriba/genética
9.
PLoS One ; 15(1): e0225392, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31917799

RESUMEN

Late onset Alzheimer's disease (LOAD) is a progressive neurodegenerative disease with four well-established risk factors: age, APOE4 genotype, female chromosomal sex, and maternal history of AD. Each risk factor impacts multiple systems, making LOAD a complex systems biology challenge. To investigate interactions between LOAD risk factors, we performed multiple scale analyses, including metabolomics, transcriptomics, brain magnetic resonance imaging (MRI), and beta-amyloid assessment, in 16 months old male and female mice with humanized human APOE3 (hAPOE3) or APOE4 (hAPOE4) genes. Metabolomic analyses indicated a sex difference in plasma profile whereas APOE genotype determined brain metabolic profile. Consistent with the brain metabolome, gene and pathway-based RNA-Seq analyses of the hippocampus indicated increased expression of fatty acid/lipid metabolism related genes and pathways in both hAPOE4 males and females. Further, female transcription of fatty acid and amino acids pathways were significantly different from males. MRI based imaging analyses indicated that in multiple white matter tracts, hAPOE4 males and females exhibited lower fractional anisotropy than their hAPOE3 counterparts, suggesting a lower level of white matter integrity in hAPOE4 mice. Consistent with the brain metabolomic and transcriptomic profile of hAPOE4 carriers, beta-amyloid generation was detectable in 16-month-old male and female brains. These data provide therapeutic targets based on chromosomal sex and APOE genotype. Collectively, these data provide a framework for developing precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest.


Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Encéfalo/metabolismo , Edad de Inicio , Envejecimiento/genética , Envejecimiento/metabolismo , Envejecimiento/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Modelos Animales de Enfermedad , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Metaboloma/genética , Ratones , Ratones Transgénicos , Caracteres Sexuales , Cromosomas Sexuales/genética , Cromosomas Sexuales/metabolismo
10.
Nat Commun ; 11(1): 307, 2020 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-31949142

RESUMEN

Autophagy is an important cellular degradation pathway with a central role in metabolism as well as basic quality control, two processes inextricably linked to ageing. A decrease in autophagy is associated with increasing age, yet it is unknown if this is causal in the ageing process, and whether autophagy restoration can counteract these ageing effects. Here we demonstrate that systemic autophagy inhibition induces the premature acquisition of age-associated phenotypes and pathologies in mammals. Remarkably, autophagy restoration provides a near complete recovery of morbidity and a significant extension of lifespan; however, at the molecular level this rescue appears incomplete. Importantly autophagy-restored mice still succumb earlier due to an increase in spontaneous tumour formation. Thus, our data suggest that chronic autophagy inhibition confers an irreversible increase in cancer risk and uncovers a biphasic role of autophagy in cancer development being both tumour suppressive and oncogenic, sequentially.


Asunto(s)
Envejecimiento/fisiología , Autofagia/efectos de los fármacos , Autofagia/fisiología , Longevidad/fisiología , Neoplasias , Envejecimiento/genética , Animales , Autofagia/genética , Proteína 5 Relacionada con la Autofagia/genética , Trasplante de Médula Ósea , Modelos Animales de Enfermedad , Femenino , Inflamación , Longevidad/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculos , Fenotipo , Proteína Sequestosoma-1/metabolismo , Piel/patología
11.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 1-8, 2020 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-31897470

RESUMEN

Dementia, a devastating neurological disorder commonly found in the elderly, is characterized by severe cognitive and memory impairment. Ample clinical and epidemiological evidence has depicted a close association between dementia and heart failure. While cerebral blood under perfusion and neurohormonal activation due to the dampened cardiac pump function contribute to the loss of nutrient supply and neuronal injury, Alzheimer's disease (AD), the most common type of dementia, also provokes cardiovascular function impairment, in particular impairment of diastolic function. Aggregation of amyloid-ß proteins and mutations of Presenilin (PSEN) genes are believed to participate in the pathological changes in the heart although it is still debatable with regards to the pathological cue of cardiac anomalies in AD process. In consequence, reduced cerebral blood flow triggered by cardiac dysfunction further deteriorates vascular dementia and AD pathology. Patients with atrial fibrillation, heart failure, and other cardiac anomalies are at a higher risk for cognitive decline and dementia. Conclusion: Due to the increased incidence of dementia and cardiovascular diseases, the coexistence of the two will cause more threat to public health, warranting much more attention. Here, we will update recent reports on dementia, AD, and cardiovascular diseases and discuss the causal relationship between dementia and heart dysfunction.


Asunto(s)
Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/metabolismo , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Envejecimiento/metabolismo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Animales , Enfermedades Cardiovasculares/genética , Comorbilidad , Modelos Animales de Enfermedad , Humanos , Ratones , Persona de Mediana Edad , Mutación , Presenilinas/genética , Factores de Riesgo
12.
Hum Genet ; 139(3): 381-399, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31997134

RESUMEN

Our cells operate based on two distinct genomes that are enclosed in the nucleus and mitochondria. The mitochondrial genome presumably originates from endosymbiotic bacteria. With time, a large portion of the original genes in the bacterial genome is considered to have been lost or transferred to the nuclear genome, leaving a reduced 16.5 Kb circular mitochondrial DNA (mtDNA). Traditionally only 37 genes, including 13 proteins, were thought to be encoded within mtDNA, its genetic repertoire is expanding with the identification of mitochondrial-derived peptides (MDPs). The biology of aging has been largely unveiled to be regulated by genes that are encoded in the nuclear genome, whereas the mitochondrial genome remained more cryptic. However, recent studies position mitochondria and mtDNA as an important counterpart to the nuclear genome, whereby the two organelles constantly regulate each other. Thus, the genomic network that regulates lifespan and/or healthspan is likely constituted by two unique, yet co-evolved, genomes. Here, we will discuss aspects of mitochondrial biology, especially mitochondrial communication that may add substantial momentum to aging research by accounting for both mitonuclear genomes to more comprehensively and inclusively map the genetic and molecular networks that govern aging and age-related diseases.


Asunto(s)
Envejecimiento/genética , ADN Mitocondrial/genética , Animales , Núcleo Celular/genética , Genoma Mitocondrial/genética , Genómica/métodos , Humanos , Longevidad/genética , Mitocondrias/genética
13.
Nat Commun ; 11(1): 138, 2020 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-31919361

RESUMEN

In C. elegans, the conserved transcription factor DAF-16/FOXO is a powerful aging regulator, relaying dire conditions into expression of stress resistance and longevity promoting genes. For some of these functions, including low insulin/IGF signaling (IIS), DAF-16 depends on the protein SMK-1/SMEK, but how SMK-1 exerts this role has remained unknown. We show that SMK-1 functions as part of a specific Protein Phosphatase 4 complex (PP4SMK-1). Loss of PP4SMK-1 hinders transcriptional initiation at several DAF-16-activated genes, predominantly by impairing RNA polymerase II recruitment to their promoters. Search for the relevant substrate of PP4SMK-1 by phosphoproteomics identified the conserved transcriptional regulator SPT-5/SUPT5H, whose knockdown phenocopies the loss of PP4SMK-1. Phosphoregulation of SPT-5 is known to control transcriptional events such as elongation and termination. Here we also show that transcription initiating events are influenced by the phosphorylation status of SPT-5, particularly at DAF-16 target genes where transcriptional initiation appears rate limiting, rendering PP4SMK-1 crucial for many of DAF-16's physiological roles.


Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica/genética , Fosfoproteínas Fosfatasas/genética , Fosfoproteínas Fosfatasas/metabolismo , Factores de Elongación Transcripcional/metabolismo , Envejecimiento/genética , Animales , Caenorhabditis elegans/genética , Proteínas Cromosómicas no Histona/genética , Longevidad/genética , Complejos Multiproteicos/metabolismo , Interferencia de ARN , ARN Polimerasa II/metabolismo , Estrés Fisiológico/genética , Transcripción Genética/genética , Factores de Elongación Transcripcional/genética
14.
Adv Exp Med Biol ; 1217: 225-239, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31898231

RESUMEN

DNA damage occurs in a human cell at an average frequency of 10,000 incidences per day by means of external and internal culprits, damage that triggers sequential cellular responses and stalls the cell cycle while activating specific DNA repair pathways. Failure to remove DNA lesions would compromise genomic integrity, leading to human diseases such as cancer and premature aging. If DNA damage is extensive and cannot be repaired, cells undergo apoptosis. DNA damage response (DDR) often entails posttranslational modifications of key DNA repair and DNA damage checkpoint proteins, including phosphorylation and ubiquitination. Cullin-RING ligase 4 (CRL4) enzyme has been found to target multiple DDR proteins for ubiquitination. In this chapter, we will discuss key repair and checkpoint proteins that are subject to ubiquitin-dependent regulation by members of the CRL4 family during ultraviolet light (UV)-induced DNA damage.


Asunto(s)
Daño del ADN , Reparación del ADN , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina/metabolismo , Ubiquitinación , Envejecimiento/genética , Envejecimiento/patología , Animales , Apoptosis , Humanos , Neoplasias/genética , Neoplasias/patología
15.
PLoS One ; 15(1): e0227258, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31978074

RESUMEN

BACKGROUND: The molecular changes involved in Alzheimer's disease (AD) progression remain unclear since we cannot easily access antemortem human brains. Some non-mammalian vertebrates such as the zebrafish preserve AD-relevant transcript isoforms of the PRESENILIN genes lost from mice and rats. One example is PS2V, the alternative transcript isoform of the PSEN2 gene. PS2V is induced by hypoxia/oxidative stress and shows increased expression in late onset, sporadic AD brains. A unique, early onset familial AD mutation of PSEN2, K115fs, mimics the PS2V coding sequence suggesting that forced, early expression of PS2V-like isoforms may contribute to AD pathogenesis. Here we use zebrafish to model the K115fs mutation to investigate the effects of forced PS2V-like expression on the transcriptomes of young adult and aged adult brains. METHODS: We edited the zebrafish genome to model the K115fs mutation. To explore its effects at the molecular level, we analysed the brain transcriptome and proteome of young (6-month-old) and aged (24-month-old) wild type and heterozygous mutant female sibling zebrafish. Finally, we used gene co-expression network analysis (WGCNA) to compare molecular changes in the brains of these fish to human AD. RESULTS: Young heterozygous mutant fish show transcriptional changes suggesting accelerated brain aging and increased glucocorticoid signalling. These early changes precede a transcriptional 'inversion' that leads to glucocorticoid resistance and other likely pathological changes in aged heterozygous mutant fish. Notably, microglia-associated immune responses regulated by the ETS transcription factor family are altered in both our zebrafish mutant model and in human AD. The molecular changes we observe in aged heterozygous mutant fish occur without obvious histopathology and possibly in the absence of Aß. CONCLUSIONS: Our results suggest that forced expression of a PS2V-like isoform contributes to immune and stress responses favouring AD pathogenesis. This highlights the value of our zebrafish genetic model for exploring molecular mechanisms involved in AD pathogenesis.


Asunto(s)
Envejecimiento/genética , Enfermedad de Alzheimer/genética , Encéfalo/patología , Redes Reguladoras de Genes , Presenilina-1/genética , Proteínas de Pez Cebra/genética , Envejecimiento/patología , Empalme Alternativo , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Animales , Animales Modificados Genéticamente , Encéfalo/citología , Encéfalo/inmunología , Conjuntos de Datos como Asunto , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Mutación del Sistema de Lectura , Edición Génica , Heterocigoto , Humanos , Microglía/inmunología , Microglía/patología , Presenilina-1/metabolismo , Presenilina-2/genética , Presenilina-2/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteómica , RNA-Seq , Regulación hacia Arriba , Pez Cebra , Proteínas de Pez Cebra/metabolismo
16.
Hum Genet ; 139(3): 291-308, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31297598

RESUMEN

MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress translation or induce mRNA degradation of target transcripts through sequence-specific binding. miRNAs target hundreds of transcripts to regulate diverse biological pathways and processes, including aging. Many microRNAs are differentially expressed during aging, generating interest in their use as aging biomarkers and roles as regulators of the aging process. In the invertebrates Caenorhabditis elegans and Drosophila, a number of miRNAs have been found to both positive and negatively modulate longevity through canonical aging pathways. Recent studies have also shown that miRNAs regulate age-associated processes and pathologies in a diverse array of mammalian tissues, including brain, heart, bone, and muscle. The review will present an overview of these studies, highlighting the role of individual miRNAs as biomarkers of aging and regulators of longevity and tissue-specific aging processes.


Asunto(s)
Envejecimiento/genética , Longevidad/genética , MicroARNs/genética , Animales , Humanos , Transducción de Señal/genética
17.
Hum Genet ; 139(3): 401-407, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31134332

RESUMEN

The extent of aneuploidy of the sex chromosomes increases with age in human leukocytes. Here, we re-explore the dynamics of normal loss of the Y chromosome (LOY) with age based on microarray data using two exponential models and two different ways to estimate the fraction of LOY. This analysis shows the existence of a significant correlation between the fraction of LOY estimated from molecular cytogenetics and genotyping microarray data. Although the specific estimates of the parameters for the two exponential models are different from those derived from cytogenetics data, the present analysis in an independent dataset of normal individuals confirms that X0 cells have a selective advantage over XY cells. Moreover, patients with age-related macular degeneration display higher fraction of LOY values and seem to have a predisposition to lose their Y chromosome even at young ages compared to control individuals. As there are no data available for the same individuals at different time points, the parameters reported here are average values drawn from population analyses.


Asunto(s)
Envejecimiento/genética , Cromosomas Humanos Y/genética , Degeneración Macular/genética , Aneuploidia , Deleción Cromosómica , Genotipo , Humanos , Leucocitos/fisiología , Masculino
18.
Hum Genet ; 139(3): 409-420, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31713020

RESUMEN

Mutation accumulation has been proposed as a cause of senescence. During this process, age-related genetic and epigenetic mutations steadily accumulate. Cascading deleterious effects of mutations might initiate a steady "accumulation of deficits" in cells, despite the existence of repair mechanisms, leading to cellular senescence and functional decline of tissues and organs, which ultimately manifest as frailty and disease. Here, we investigate several of these aspects in differentiating cell populations through modeling and simulation using the Moran birth-death (demographic) process, under several scenarios of mutation accumulation. Deleterious mutations seem to rapidly accumulate particularly early in the course of life, during which the rate of cell division is high, thereby exerting a greater effect on subsequent cellular senescence. Our results are compatible with the principle of the Muller's ratchet taking place in asexually reproducing organisms. The ratchet speed in a given tissue depends on the size of the cell population, mutation rate and the impact of such mutations on cell phenotypes. It varies substantially among cells in different tissues and organs due to heterogeneity in relation to cell and organ-specific demographic features. Ratchet accelerates particularly after middle age, resulting in a synergistic fitness decay at the level of cell populations. We extend Fisher's average excess concept and rank order scale to interpret differential phenotypic effects of the increase of the mutation load among cell populations within a given tissue. We postulate that classical evolutionary genetic models can explain, at least in part, the origins of frailty, subclinical conditions, morbidity and the health consequences of senescence.


Asunto(s)
Envejecimiento/genética , Epigénesis Genética/genética , Fragilidad/genética , Diferenciación Celular/genética , División Celular/genética , Senescencia Celular/genética , Simulación por Computador , Evolución Molecular , Genética de Población/métodos , Humanos , Modelos Genéticos , Morbilidad , Mutación/genética , Tasa de Mutación
19.
Hum Genet ; 139(3): 357-369, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31834493

RESUMEN

Alternative pre-mRNA splicing increases the complexity of the proteome that can be generated from the available genomic coding sequences. Dysregulation of the splicing process has been implicated in a vast repertoire of diseases. However, splicing has recently been linked to both the aging process itself and pro-longevity interventions. This review focuses on recent research towards defining RNA splicing as a new hallmark of aging. We highlight dysfunctional alternative splicing events that contribute to the aging phenotype across multiple species, along with recent efforts toward deciphering mechanistic roles for RNA splicing in the regulation of aging and longevity. Further, we discuss recent research demonstrating a direct requirement for specific splicing factors in pro-longevity interventions, and specifically how nutrient signaling pathways interface to splicing factor regulation and downstream splicing targets. Finally, we review the emerging potential of using splicing profiles as a predictor of biological age and life expectancy. Understanding the role of RNA splicing components and downstream targets altered in aging may provide opportunities to develop therapeutics and ultimately extend healthy lifespan in humans.


Asunto(s)
Envejecimiento/genética , Empalme Alternativo/genética , Longevidad/genética , Animales , Humanos , Fenotipo , Factores de Empalme de ARN/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA