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1.
Adv Exp Med Biol ; 1178: 175-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31493228

RESUMO

A global DNA hypomethylation and local changes in the methylation levels of specific DNA loci occur during aging in mammals. Global hypomethylation mainly affects highly methylated repeat sequences, such as transposable elements; it is an essentially stochastic process usually referred to as "epigenetic drift." Specific changes in DNA methylation affect various genome sequences and could be either hypomethylation or hypermethylation, but the prevailing tendencies are hypermethylation of promoter sequences associated with CpG islands and hypomethylation of CpG poor genes. Methylation levels of multiple CpG sites display a strong correlation to age common between individuals of the same species. Collectively, methylation of such CpG sites could be used as "epigenetic clocks" to predict biological age. Furthermore, the discrepancy between epigenetic and chronological ages could be predictive of all-cause mortality and multiple age-associated diseases. Random changes in DNA methylation (epigenetic drift) could also affect the aging phenotype, causing accidental changes in gene expression and increasing the transcriptional noise between cells of the same tissue. Both effects could become detrimental to tissue functioning and cause a gradual decline in organ function during aging. Strong evidence shows that epigenetic systems contribute to lifespan control in various organisms. Similar to other cell systems, the epigenome is prone to gradual degradation due to the genome damage, stressful agents and other aging factors. However, unlike mutations and many other hallmarks of aging, age-related epigenetic changes could be fully or partially reversed to a "young" state.


Assuntos
Envelhecimento , Epigênese Genética , Marcadores Genéticos , Envelhecimento/genética , Animais , Ilhas de CpG/genética , Metilação de DNA , Epigenômica , Marcadores Genéticos/genética , Longevidade
2.
High Blood Press Cardiovasc Prev ; 26(4): 321-329, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31325087

RESUMO

Cardiovascular disease (CVD) remains the leading cause of morbility and mortality worldwide. The identification of common cardiovascular risk factors has led to the development of effective treatments that enabled a significant reduction of the global cardiovascular disease burden. However, a significant proportion of cardiovascular risk remains unexplained by these risk factors leaving many individuals at risk of cardiovascular events despite good control of the risk factors. Recent randomized clinical trials and Mendelian randomization studies have suggested that inflammation explains a significant proportion of the residual cardiovascular risk in subjects with good control of risk factors. An accelerated process of vascular ageing is increasingly recognized as a potential mechanism by which inflammation might increase the risk of CVD. In turn, cellular ageing represents an important source of inflammation within the vascular wall, potentially creating a vicious cycle that might promote progression of atherosclerosis, independently from the individual cardiovascular risk factor burden. In this review, we summarise current evidence suggesting a role for biological ageing in CVD and how inflammation might act as a key mediator of this association.


Assuntos
Envelhecimento/metabolismo , Doenças Cardiovasculares/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Telômero/metabolismo , Fatores Etários , Envelhecimento/genética , Envelhecimento/patologia , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Senescência Celular , Humanos , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Medição de Risco , Fatores de Risco , Transdução de Sinais , Telômero/genética , Telômero/patologia , Homeostase do Telômero , Encurtamento do Telômero , Fatores de Tempo
3.
Nature ; 571(7766): 489-499, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31341302

RESUMO

Epigenetic research has accelerated rapidly in the twenty-first century, generating justified excitement and hope, but also a degree of hype. Here we review how the field has evolved over the last few decades and reflect on some of the recent advances that are changing our understanding of biology. We discuss the interplay between epigenetics and DNA sequence variation as well as the implications of epigenetics for cellular memory and plasticity. We consider the effects of the environment and both intergenerational and transgenerational epigenetic inheritance on biology, disease and evolution. Finally, we present some new frontiers in epigenetics with implications for human health.


Assuntos
Doença/genética , Epigênese Genética/genética , Epigenômica/tendências , Interação Gene-Ambiente , Envelhecimento/genética , Animais , Cromatina/genética , Cromatina/metabolismo , Metilação de DNA/genética , Variação Genética/genética , Humanos , Neoplasias/genética
4.
Nature ; 571(7764): 183-192, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31292558

RESUMO

For several decades, understanding ageing and the processes that limit lifespan have challenged biologists. Thirty years ago, the biology of ageing gained unprecedented scientific credibility through the identification of gene variants that extend the lifespan of multicellular model organisms. Here we summarize the milestones that mark this scientific triumph, discuss different ageing pathways and processes, and suggest that ageing research is entering a new era that has unique medical, commercial and societal implications. We argue that this era marks an inflection point, not only in ageing research but also for all biological research that affects the human healthspan.


Assuntos
Envelhecimento/fisiologia , Pesquisa Biomédica , Envelhecimento Saudável/fisiologia , Rejuvenescimento/fisiologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Relógios Circadianos , Ensaios Clínicos como Assunto , Envelhecimento Saudável/efeitos dos fármacos , Envelhecimento Saudável/genética , Humanos , Inflamação , Longevidade/efeitos dos fármacos , Longevidade/genética , Longevidade/fisiologia , Mitocôndrias/metabolismo , Estado Nutricional , Estresse Oxidativo , Transdução de Sinais
5.
DNA Cell Biol ; 38(9): 955-961, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31361513

RESUMO

The chromatin-remodeling complex ATRX/DAXX is one of the major epigenetic factors that controls heterochromatin maintenance due to its role in histone deposition. ATRX is involved in nucleosome configuration and maintenance of higher order chromatin structure, and DAXX is a specific histone chaperone for H3.3 deposition. Dysfunctions in this complex have been associated with telomere shortening, which influences cell senescence. However, data about this complex in brain tissue related to aging are still scarce. Therefore, in the present study, we analyzed ATRX and DAXX expressions in autopsied human brain specimens and the telomere length. A significant decrease in gene and protein expressions was observed in the brain tissues from the elderly compared with those from the young, which were related to short telomeres. These findings may motivate further functional analysis to confirm the ATRX-DAXX complex involvement in telomere maintenance and brain aging.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Envelhecimento/genética , Encéfalo/metabolismo , Proteínas Nucleares/genética , Proteína Nuclear Ligada ao X/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/crescimento & desenvolvimento , Humanos , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Homeostase do Telômero , Proteína Nuclear Ligada ao X/metabolismo
6.
Environ Pollut ; 246: 904-913, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31159140

RESUMO

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) has been frequently detected in environmental media and biological samples. However, knowledge of its adverse health consequences is limited. In the current study, Caenorhabditis elegans (C. elegans, L1 larvae) were exposed to TDCPP at environmentally relevant concentrations (control, 0.1, 1, 100 and 1000 µg L-1) for 72 h to explore any association between TDCPP and the aging process. Some of the degenerative age-related indicators were observed, including locomotion behaviors and lifespan. As crucial biomarkers of aging, the accumulation of lipofuscin, and lipid peroxidation (LPO) products exemplified by 4-hydroxynon-2-enal (4-HNE) were detected. This product forms as a result of oxidative stress, as confirmed by an N-acetyl-L-cysteine (NAC) pharmacological assay. Moreover, a significant increase in reactive oxide species (ROS) production in a dose-dependent manner using a fluorescent probe was observed. For the underlying molecular mechanism of the above aging phenotypes, significantly upregulated transcription of genes related to antioxidant systems, especially a subset of glutathione S-transferase (gst-5, gst-6, gst-9, gst-10, gst-19, gst-24, gst-26, gst-29, gst-33, and gst-38), was found by RNA-Seq and further confirmed by RT-qPCR. The elevated glutathione S-transferase (GST) was attributed to the significant increase in 4-HNE because mutations in gst-5 and gst-24 inhibited the conjugation of GSTs with 4-HNE. Therefore, GST play an indispensable role in the detoxification process of TDCPP exposure and further confirmed LPO accumulation at the molecular mechanism level. In conclusion, TDCPP accelerated the aging process induced by the LPO products, 4-HNE, response to reactive oxidative species in C. elegans.


Assuntos
Envelhecimento/efeitos dos fármacos , Aldeídos/metabolismo , Poluentes Ambientais/toxicidade , Compostos Organofosforados/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Caenorhabditis elegans/fisiologia , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Peroxidação de Lipídeos , Estresse Oxidativo
7.
Gene ; 710: 218-232, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31158448

RESUMO

Alterations in the global gene expression profile are considered to contribute to the various physiological and pathological changes during the course of ageing. Genes that code for the molecular components of the innate system are alter markedly as ageing occurs; and this may define the susceptibility of very young and very old individuals to reproductive tract infections. The expression pattern of genes that code for beta-defensins (effectors of innate immune response) in male reproductive tract tissues of different stages of ageing is not yet reported. Further, the induction of beta-defensins during endotoxin challenge and whether epigenetic modulators can influence the expression of these genes in different stages of ageing are not reported. We analyzed the basal mRNA levels of beta-defensins and defensin-like proteins (Sperm Associated Antigen 11 (SPAG11) family members), their induction during endotoxin challenge and modulation by epigenetic modifiers (Trichostatin A and Azacytidine) in the caput, cauda, testis, prostate and seminal vesicle of rats that represent early stage to late stages of life (20 day to 730 day old). We observed differential basal gene expression pattern in the male reproductive tract tissues and the induction by LPS was not consistent neither among the age groups not the tissues analyzed. Trichostatin A and Azacytidine also influenced antimicrobial gene expression and the pattern was not consistent in different tissues obtained from different age groups. Results of this study demonstrate that antimicrobial gene expression varies to a great extent during ageing and is strongly influenced by endotoxins and epigenetic modulators.


Assuntos
Envelhecimento/genética , Genitália Masculina/química , Glicopeptídeos/genética , beta-Defensinas/genética , Animais , Azacitidina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Genitália Masculina/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Ratos , Ratos Wistar
8.
J Agric Food Chem ; 67(28): 7832-7843, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31242723

RESUMO

Oxidative-stress-induced senescence constitutes a great risk factor for chronic diseases. Therefore, ameliorating oxidative-stress-induced senescence is expected to prevent chronic diseases. The beneficial effects of bilberry anthocyanin (BA) on healthy aging were evaluated using 12 month old, aging female SD rats in this study. The experimental results suggested that consumption of a middle-dose of BA (MBA) appreciably increased the relative liver mass by 7.34% when compared with that of the AC group. Furthermore, BA significantly increased the total antioxidant capacity, total superoxide dismutase activity, and catalase activities; decreased malondialdehyde, serum low-density lipoprotein cholesterol (LDL-C), serum total cholesterol (TC), serum triglyceride (TG), and glycated serum protein (GSP) levels; and reduced TC/high-density lipoprotein cholesterol (HDL-C) and LDL-C/HDL-C ratios. In addition, MBA decreased the activity of fecal bacterial enzymes and increased the content of fecal short-chain fatty acids. The Western blot results showed that MBA significantly upregulated the expression of OCLN, ZO-1, and autophagy-related proteins (ATP6 V0C, ATG4D, and CTSB) in aging rats. Moreover, it also showed that MBA induced the phosphorylation of AMPK and FOXO3a and inhibited the phosphorylation of mTOR, which indicated that bilberry anthocyanin induced autophagy via the AMPK-mTOR signaling pathways. This induction of autophagy further promoted oxidative stress resistance effects and intestinal epithelial barrier function of bilberry anthocyanin in aging female rats.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento/fisiologia , Antocianinas/administração & dosagem , Autofagia/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Vaccinium myrtillus/química , Proteínas Quinases Ativadas por AMP/genética , Envelhecimento/sangue , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Suplementos Nutricionais/análise , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Humanos , Lipoproteínas LDL/sangue , Malondialdeído/sangue , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Triglicerídeos/sangue
9.
Anticancer Res ; 39(5): 2447-2451, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092438

RESUMO

BACKGROUND/AIM: The insulin-like growth factor 1 (IGF1) signaling pathway as an aging mechanism related to p53 in human melanogenesis remains unclear. The aim of this study was to investigate the relationship between p53 and IGF1 signaling pathway in young, senescent and H2O2-treated cells. MATERIALS AND METHODS: The protein and gene expression in young, senescent and H2O2-treated cells were analyzed using western blot and reverse transcription polymerase chain reaction (RT-PCR) assays, respectively. RESULTS: The expression levels of (phosphoinositide 3-kinases) PI3K, v-akt murine thymoma viral oncogene homolog 1 (AKT1), mammalian target of rapamycin, ß-catenin (CTNNB1), acetylated p53 (ac-p53), p53 and p-p21 proteins, related to IGF1 and p53 signaling pathways, were higher in senescent and H2O2-treated cells than those of young cells. Furthermore, AKT reduced melanogenesis through microphthalmia-associated transcription factor (MITF) inactivation by the inhibition of CTNNB1. The gene expression levels of PI3K, TP53 and catalase (CAT) in senescent and H2O2-treated cells were increased compared to young cells. CONCLUSION: p53 protein plays a key role in the aging of melanocytes via IGF1 signaling pathways.


Assuntos
Envelhecimento/genética , Proliferação de Células/genética , Fator de Crescimento Insulin-Like I/genética , Proteína Supressora de Tumor p53/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Catalase/genética , Proliferação de Células/efeitos dos fármacos , Senescência Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/toxicidade , Melanócitos/metabolismo , Melanócitos/patologia , Camundongos , Fator de Transcrição Associado à Microftalmia/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , beta Catenina/genética
10.
Biosci Biotechnol Biochem ; 83(8): 1490-1497, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31119979

RESUMO

To examine metabolic effects of sake cake ingestion, plasma and tissues were analyzed in senescence-accelerated mice prone 8 (SAMP8) fed a sake cake diet. As a result, branched-chain amino acids (BCAA) were found to be significantly higher in the plasma, gastrocnemius muscles and brains of the sake cake group than in the control group. Mice in the sake cake group showed stronger grip strength than the control group. High levels of circulating BCAA have been reported to be associated with pathological states, such as metabolic diseases, but the parameters of glucose and lipid metabolism were not affected between the two groups. Otherwise, pyridoxal was significantly higher and nicotinamide as well as 1-methylnicotinamide showed a tendency to be higher in the plasma of the sake cake group than in the control group. These findings indicate that intake of sake cake increases the levels of BCAA, vitamin B6, and vitamin B3. Abbreviation: CE-TOFMS: capillary electrophoresis time-of-flight mass spectrometry.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Encéfalo/metabolismo , Alimento Funcional , Músculo Esquelético/metabolismo , Oryza , Envelhecimento/genética , Aminoácidos de Cadeia Ramificada/sangue , Animais , Glicemia/metabolismo , Dieta , Eletroforese Capilar , Metabolismo dos Lipídeos , Espectrometria de Massas , Camundongos , Niacinamida/sangue , Niacinamida/metabolismo , Vitamina B 6/sangue , Vitamina B 6/metabolismo
11.
Biomed Res Int ; 2019: 3842312, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31058188

RESUMO

There are about 1-2 million follicles presented in the ovary at birth, while only around 1000 primordial follicles are left at menopause. The ovarian function also decreases in parallel with aging. Folliculogenesis is vital for ovarian function, no matter the synthesis of female hormones or ovulation, yet the mechanisms for its changing with increasing age are not fully understood. Early follicle growth up to the large preantral stage is independent of gonadotropins in rodents and relies on intraovarian factors. To further understand the age-related molecular changes in the process of folliculogenesis, we performed microarray gene expression profile analysis using total RNA extracted from young (9 weeks old) and old (32 weeks old) mouse ovarian secondary follicles. The results of our current microarray study revealed that there were 371 (≥2-fold, q-value ≤0.05) genes differentially expressed in which 174 genes were upregulated and 197 genes were downregulated in old mouse ovarian secondary follicles compared to young mouse ovarian secondary follicles. The gene ontology and KEGG pathway analysis of differentially expressed genes uncovered critical biological functions such as immune system process, aging, transcription, DNA replication, DNA repair, protein stabilization, and apoptotic process were affected in the process of aging. The considerable changes in gene expression profile may have an adverse influence on follicle quality and folliculogenesis. Our study provided information on the processes that may contribute to age-related decline in ovarian function.


Assuntos
Envelhecimento/genética , Folículo Ovariano/crescimento & desenvolvimento , Ovário/crescimento & desenvolvimento , RNA/genética , Animais , Reparo do DNA/genética , Replicação do DNA/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Menopausa/genética , Camundongos , Oócitos/crescimento & desenvolvimento , Oócitos/metabolismo , Folículo Ovariano/metabolismo , Ovário/metabolismo , Ovulação/genética , RNA/biossíntese , Transcriptoma/genética
12.
BMC Genomics ; 20(1): 305, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31014230

RESUMO

BACKGROUND: Evolutionary theory indicates that the dynamics of aging in the soma and reproductive tissues may be distinct. This difference arises from the fact that only the germline lineage establishes future generations. In the soma, changes in the landscape of heterochromatin have been proposed to have an important role in aging. This is because redistribution of heterochromatin during aging has been linked to the derepression of transposable elements and an overall loss of somatic gene regulation. A role for changes in the chromatin landscape in the aging of reproductive tissues is less well established. Whether or not epigenetic factors, such as heterochromatin marks, are perturbed in aging reproductive tissues is of interest because, in special cases, epigenetic variation may be heritable. Using mRNA sequencing data from late-stage egg chambers in Drosophila melanogaster, we characterized the landscape of altered gene and transposable element expression in aged reproductive tissues. This allowed us to test the hypothesis that reproductive tissues may differ from somatic tissues in their response to aging. RESULTS: We show that age-related expression changes in late-stage egg chambers tend to occur in genes residing in heterochromatin, particularly on the largely heterochromatic 4th chromosome. However, these expression differences are seen as both decreases and increases during aging, inconsistent with a general loss of heterochromatic silencing. We also identify an increase in expression of the piRNA machinery, suggesting an age-related increased investment in the maintenance of genome stability. We further identify a strong age-related reduction in the expression of mitochondrial transcripts. However, we find no evidence for global TE derepression in reproductive tissues. Rather, the observed effects of aging on TEs are primarily strain and family specific. CONCLUSIONS: These results identify unique responses in somatic versus reproductive tissue with regards to aging. As in somatic tissues, female reproductive tissues show reduced expression of mitochondrial genes. In contrast, the piRNA machinery shows increased expression during aging. Overall, these results also indicate that global loss of TE control observed in other studies may be unique to the soma and sensitive to genetic background and TE family.


Assuntos
Envelhecimento/genética , Elementos de DNA Transponíveis/genética , Drosophila melanogaster/fisiologia , Perfilação da Expressão Gênica , Mitocôndrias/genética , Ovário/fisiologia , RNA Interferente Pequeno/genética , Animais , Drosophila melanogaster/genética , Feminino , Genoma Mitocondrial/genética , Heterocromatina/genética , Óvulo/metabolismo , RNA Mensageiro/genética
13.
Int J Mol Sci ; 20(8)2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31003407

RESUMO

A growing body of evidence suggests that meal timing is an important factor for metabolic regulation and that the circadian clock tightly interacts with metabolic functions. The proper functioning of the circadian clock is critical for maintaining metabolic health. Therefore, chrononutrition, a novel discipline which investigates the relation between circadian rhythms, nutrition, and metabolism, has attracted increasing attention in recent years. Circadian rhythms are strongly affected by obesity, type 2 diabetes, and other dietary-induced metabolic diseases. With increasing age, the circadian system also undergoes significant changes which contribute to the dysregulation of metabolic rhythms. Metabolic diseases are a major health concern, particularly in light of a growing aging population, and effective approaches for their prevention and treatment are urgently needed. Recently, animal studies have impressively shown beneficial effects of several dietary patterns (e.g., caloric restriction or time-restricted feeding) on circadian rhythms and metabolic outcomes upon nutritional challenges. Whether these dietary patterns show the same beneficial effects in humans is, however, less well studied. As indicated by recent studies, dietary approaches might represent a promising, attractive, and easy-to-adapt strategy for the prevention and therapy of circadian and metabolic disturbances in humans of different age.


Assuntos
Envelhecimento/genética , Restrição Calórica , Relógios Circadianos/genética , Doenças Metabólicas/dietoterapia , Envelhecimento/fisiologia , Animais , Humanos , Doenças Metabólicas/genética , Doenças Metabólicas/fisiopatologia , Avaliação Nutricional
14.
Int J Mol Sci ; 20(8)2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-31013989

RESUMO

The incidence of aging-related disorders may be decreased through strategies influencing the expression of longevity genes. Although numerous approaches have been suggested, no effective, safe, and easily applicable approach is yet available. Efficacy of low-dose fluvastatin and valsartan, separately or in combination, on the expression of the longevity genes in middle-aged males, was assessed. Stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin-valsartan combination (10 and 20 mg, respectively), and placebo (control) were analyzed. They were taken before and after 30 days of treatment and, additionally, five months after treatment discontinuation. The expression of the following longevity genes was assessed: SIRT1, PRKAA, KLOTHO, NFE2L2, mTOR, and NF-κB. Treatment with fluvastatin and valsartan in combination significantly increased the expression of SIRT1 (1.8-fold; p < 0.0001), PRKAA (1.5-fold; p = 0.262) and KLOTHO (1.7-fold; p < 0.0001), but not NFE2L2, mTOR and NF-κB. Both fluvastatin and valsartan alone significantly, but to a lesser extent, increased the expression of SIRT1, and did not influence the expression of other genes. Five months after treatment discontinuation, genes expression decreased to the basal levels. In addition, analysis with previously obtained results revealed significant correlation between SIRT1 and both increased telomerase activity and improved arterial wall characteristics. We showed that low-dose fluvastatin and valsartan, separately and in combination, substantially increase expression of SIRT1, PRKAA, and KLOTHO genes, which may be attributed to their so far unreported pleiotropic beneficial effects. This approach could be used for prevention of ageing (and longevity genes)-related disorders.


Assuntos
Fluvastatina/farmacologia , Expressão Gênica/efeitos dos fármacos , Longevidade/genética , Doenças Neurodegenerativas/prevenção & controle , Valsartana/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Adulto , Envelhecimento/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Fluvastatina/uso terapêutico , Glucuronidase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Sirtuína 1/genética , Telomerase/metabolismo , Valsartana/uso terapêutico
15.
Bull Exp Biol Med ; 166(6): 797-801, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31028589

RESUMO

We studied the intensity of age-specific changes in the dermis (number and proliferative activity of fibroblasts) in mice with normal and experimentally changed level of thyroid hormones. Receptors of thyroid hormones, TR-α and TR-ß, in mouse dermal fibroblasts were identified by immunohistochemical methods. The relative expression of Thra, Thrb, and Dio2 genes was assessed by real-time PCR analysis. From the second to fifth month of life, the number of fibroblasts in the connective tissue layer of mouse skin decreased by 42.3%. The number of fibroblasts in the dermis of 5-month-old mice treated with Thyrozol significantly decreases by 25.9% (p<0.05), and vice versa, in mice receiving thyroxin this parameter increased by 4.7% in comparison with the control (p>0.05). TR-α and TR-ß were identified in dermal fibroblasts in all groups of mice. No differences in the content TR-α and Thra gene expression in 2- and 5-month-old mice of the control and experimental were revealed. TR-ß content in dermal fibroblasts of 2-month-old animals was maximum and exceeded this value in 5-month-old control mice by 25%. The number of these receptors decreased by 33.3% in mice treated with Thyrozol and increased by 25% in animals receiving thyroxin injection in comparison with the control. Relative expression of Thrb gene significantly increased only in mice treated with thyroxin. Comparative analysis of the relative expression of Dio2 gene revealed no differences between the experimental and control groups. Changes in the level of thyroid hormones, content of TR-ß, and relative Thrb gene expression contribute to agerelated shifts in the number and proliferative activity of mouse dermal fibroblasts.


Assuntos
Envelhecimento/genética , Fibroblastos/metabolismo , Iodeto Peroxidase/genética , Glândula Tireoide/metabolismo , Receptores alfa dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/genética , Envelhecimento/metabolismo , Animais , Antitireóideos/farmacologia , Proliferação de Células , Derme/citologia , Derme/efeitos dos fármacos , Derme/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Expressão Gênica , Iodeto Peroxidase/metabolismo , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Metimazol/farmacologia , Camundongos , Camundongos Endogâmicos , Glândula Tireoide/citologia , Glândula Tireoide/efeitos dos fármacos , Receptores alfa dos Hormônios Tireóideos/metabolismo , Receptores beta dos Hormônios Tireóideos/metabolismo , Tiroxina/farmacologia
16.
Biomed Pharmacother ; 114: 108833, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30978525

RESUMO

Age-related changes such as increased oxidative stress and DNA damage are important risk factors for Alzheimer's disease (AD). This study aimed to clarify the role of POLD1, the catalytic subunit of DNA polymerase δ, in neurodegeneration symptoms of AD. POLD1 expression levels were evaluated in patients with different neurodegenerative diseases by ELISA, RT-PCR and Western blot analysis. The impairment of cognitive ability in AD patients and senescence-accelerated mouse prone 8 (SAMP8) mice were evaluated by MMSE/MoCA score and Morris water maze (MWM) test. We found that serum concentration and expression levels of POLD1 in lymphocytes were reduced in AD patients. The cognitive impairment in AD patients and SAMP8 mice was associated with reduced POLD1 expression. In addition, POLD1 knockdown led to premature senescence and increased DNA damage in primary neuronal cells of SAMP8 mice. In conclusion, this is the first study suggesting that the deficiency of POLD1 may aggravate AD progression, and POLD1 is a potential diagnostic marker and therapeutic target for AD.


Assuntos
Doença de Alzheimer/genética , Transtornos Cognitivos/genética , Cognição/fisiologia , Disfunção Cognitiva/genética , DNA Polimerase III/deficiência , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Animais , Modelos Animais de Doenças , Feminino , Humanos , Linfócitos/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Pessoa de Meia-Idade , Estresse Oxidativo/genética
17.
Twin Res Hum Genet ; 22(1): 4-13, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30944055

RESUMO

Large multigenerational cohort studies offer powerful ways to study the hereditary effects on various health outcomes. However, accounting for complex kinship relations in big data structures can be methodologically challenging. The traditional kinship model is computationally infeasible when considering thousands of individuals. In this article, we propose a computationally efficient alternative that employs fractional relatedness of family members through a series of founding members. The primary goal of this study is to investigate whether the effect of determinants on health outcome variables differs with and without accounting for family structure. We compare a fixed-effects model without familial effects with several variance components models that account for heritability and shared environment structure. Our secondary goal is to apply the fractional relatedness model in a realistic setting. Lifelines is a three-generation cohort study investigating the biological, behavioral, and environmental determinants of healthy aging. We analyzed a sample of 89,353 participants from 32,452 reconstructed families. Our primary conclusion is that the effect of determinants on health outcome variables does not differ with and without accounting for family structure. However, accounting for family structure through fractional relatedness allows for estimating heritability in a computationally efficient way, showing some interesting differences between physical and mental quality of life heritability. We have shown through simulations that the proposed fractional relatedness model performs better than the standard kinship model, not only in terms of computational time and convenience of fitting using standard functions in R, but also in terms of bias of heritability estimates and coverage.


Assuntos
Envelhecimento/genética , Big Data , Bases de Dados Genéticas , Família , Interação Gene-Ambiente , Modelos Genéticos , Feminino , Humanos , Masculino
18.
Nat Commun ; 10(1): 1318, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30899013

RESUMO

Macroautophagy is an evolutionarily conserved cellular maintenance program, meant to protect the brain from premature aging and neurodegeneration. How neuronal autophagy, usually loosing efficacy with age, intersects with neuronal processes mediating brain maintenance remains to be explored. Here, we show that impairing autophagy in the Drosophila learning center (mushroom body, MB) but not in other brain regions triggered changes normally restricted to aged brains: impaired associative olfactory memory as well as a brain-wide ultrastructural increase of presynaptic active zones (metaplasticity), a state non-compatible with memory formation. Mechanistically, decreasing autophagy within the MBs reduced expression of an NPY-family neuropeptide, and interfering with autocrine NPY signaling of the MBs provoked similar brain-wide metaplastic changes. Our results in an exemplary fashion show that autophagy-regulated signaling emanating from a higher brain integration center can execute high-level control over other brain regions to steer life-strategy decisions such as whether or not to form memories.


Assuntos
Envelhecimento/metabolismo , Autofagia/genética , Drosophila melanogaster/metabolismo , Memória/fisiologia , Corpos Pedunculados/metabolismo , Neuropeptídeo Y/genética , Envelhecimento/genética , Animais , Comunicação Autócrina/genética , Proteínas Relacionadas à Autofagia/antagonistas & inibidores , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Regulação da Expressão Gênica , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Corpos Pedunculados/citologia , Neurônios/citologia , Neurônios/metabolismo , Neuropeptídeo Y/deficiência , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Sinapses/metabolismo , Transmissão Sináptica
19.
Curr Med Sci ; 39(1): 67-74, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30868493

RESUMO

Demyelination of axons plays an important role in the pathology of many spinal cord diseases and injuries. Remyelination in demyelinated lesions is primarily performed by oligodendrocyte progenitor cells (OPCs), which generate oligodendrocytes in the developing and mature central nervous system. The efficiency of remyelination decreases with age. Many reports suggest that this decline in remyelination results from impaired OPC recruitment and differentiation during aging. Of the various molecular mechanisms involved in aging, changes in epigenetic modifications have received particular attention. Global DNA methylation is a major epigenetic modification that plays important roles in cellular senescence and organismal aging. Thus, we aimed to evaluate the dynamic changes in the global DNA methylation profiles of OPCs derived from rat spinal cords during the aging process. We separated and cultured OPCs from the spinal cords of neonatal, 4-month-old, and 16-month-old rats and investigated the age-related alterations of genomic DNA methylation levels by using quantitative colorimetric analysis. To determine the potential cause of dynamic changes in global DNA methylation, we further analyzed the activity of DNA methyltransferases (DNMTs) and the expression of DNMT1, DNMT3a, DNMT3b, TET1, TET2, TET3, MBD2, and MeCP2 in the OPCs from each group. Our results showed the genomic DNA methylation level and the activity of DNMTs from OPCs derived from rat spinal cords decreased gradually during aging, and OPCs from 16-month-old rats were characterized by global hypomethylation. During OPC aging, the mRNA and protein expression levels of DNMT3a, DNMT3b, and MeCP2 were significantly elevated; those of DNMT1 were significantly down-regulated; and no significant changes were observed in those for TET1, TET2, TET3, or MBD2. Our results indicated that global DNA hypomethylation in aged OPCs is correlated with DNMT1 downregulation. Together, these data provide important evidence for partly elucidating the mechanism of age-related impaired OPC recruitment and differentiation and assist in the development of new treatments for promoting efficient remyelination.


Assuntos
Envelhecimento/genética , Metilação de DNA , DNA-Citosina Metilases/metabolismo , Células Precursoras de Oligodendrócitos/citologia , Medula Espinal/citologia , Envelhecimento/metabolismo , Animais , Animais Recém-Nascidos , Diferenciação Celular , Células Cultivadas , DNA-Citosina Metilases/genética , Epigênese Genética , Regulação da Expressão Gênica , Células Precursoras de Oligodendrócitos/química , Ratos , Medula Espinal/química
20.
Med Sci Monit ; 25: 1994-2001, 2019 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-30879019

RESUMO

BACKGROUND Studies on the effects of sociodemographic factors on health in aging now include the use of statistical models and machine learning. The aim of this study was to evaluate the determinants of health in aging using machine learning methods and to compare the accuracy with traditional methods. MATERIAL AND METHODS The health status of 6,209 adults, age <65 years (n=1,585), 65-79 years (n=3,267), and >80 years (n=1,357) were measured using an established health metric (0-100) that incorporated physical function and activities of daily living (ADL). Data from the English Longitudinal Study of Ageing (ELSA) included socio-economic and sociodemographic characteristics and history of falls. Health-trend and personal-fitted variables were generated as predictors of health metrics using three machine learning methods, random forest (RF), deep learning (DL) and the linear model (LM), with calculation of the percentage increase in mean square error (%IncMSE) as a measure of the importance of a given predictive variable, when the variable was removed from the model. RESULTS Health-trend, physical activity, and personal-fitted variables were the main predictors of health, with the%incMSE of 85.76%, 63.40%, and 46.71%, respectively. Age, employment status, alcohol consumption, and household income had the%incMSE of 20.40%, 20.10%, 16.94%, and 13.61%, respectively. Performance of the RF method was similar to the traditional LM (p=0.7), but RF significantly outperformed DL (p=0.006). CONCLUSIONS Machine learning methods can be used to evaluate multidimensional longitudinal health data and may provide accurate results with fewer requirements when compared with traditional statistical modeling.


Assuntos
Envelhecimento/fisiologia , Envelhecimento/psicologia , Previsões/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Feminino , Nível de Saúde , Humanos , Estudos Longitudinais , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Fatores Socioeconômicos
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