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1.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804275

RESUMO

Fumarylacetoacetate hydrolase (FAH) proteins form a superfamily found in Archaea, Bacteria, and Eukaryota. However, few fumarylacetoacetate hydrolase domain (FAHD)-containing proteins have been studied in Metazoa and their role in plants remains elusive. Sequence alignments revealed high homology between two Arabidopsis thaliana FAHD-containing proteins and human FAHD1 (hFAHD1) implicated in mitochondrial dysfunction-associated senescence. Transcripts of the closest hFAHD1 orthologue in Arabidopsis (AtFAHD1a) peak during seed maturation drying, which influences seed longevity and dormancy. Here, a homology study was conducted to assess if AtFAHD1a contributes to seed longevity and vigour. We found that an A. thaliana T-DNA insertional line (Atfahd1a-1) had extended seed longevity and shallower thermo-dormancy. Compared to the wild type, metabolite profiling of dry Atfahd1a-1 seeds showed that the concentrations of several amino acids, some reducing monosaccharides, and δ-tocopherol dropped, whereas the concentrations of dehydroascorbate, its catabolic intermediate threonic acid, and ascorbate accumulated. Furthermore, the redox state of the glutathione disulphide/glutathione couple shifted towards a more reducing state in dry mature Atfahd1a-1 seeds, suggesting that AtFAHD1a affects antioxidant redox poise during seed development. In summary, AtFAHD1a appears to be involved in seed redox regulation and to affect seed quality traits such as seed thermo-dormancy and longevity.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Hidrolases/genética , Dormência de Plantas/genética , Arabidopsis/crescimento & desenvolvimento , Regulação da Expressão Gênica de Plantas/genética , Germinação/genética , Humanos , Longevidade/genética , Oxirredução , Sementes/genética , Sementes/crescimento & desenvolvimento
2.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806348

RESUMO

There is substantial genetic variation for common traits associated with reproductive lifespan and for common diseases influencing female fertility. Progress in high-throughput sequencing and genome-wide association studies (GWAS) have transformed our understanding of common genetic risk factors for complex traits and diseases influencing reproductive lifespan and fertility. The data emerging from GWAS demonstrate the utility of genetics to explain epidemiological observations, revealing shared biological pathways linking puberty timing, fertility, reproductive ageing and health outcomes. The observations also identify unique genetic risk factors specific to different reproductive diseases impacting on female fertility. Sequencing in patients with primary ovarian insufficiency (POI) have identified mutations in a large number of genes while GWAS have revealed shared genetic risk factors for POI and ovarian ageing. Studies on age at menopause implicate DNA damage/repair genes with implications for follicle health and ageing. In addition to the discovery of individual genes and pathways, the increasingly powerful studies on common genetic risk factors help interpret the underlying relationships and direction of causation in the regulation of reproductive lifespan, fertility and related traits.


Assuntos
Fertilidade/genética , Reprodução/genética , Envelhecimento/genética , Envelhecimento/fisiologia , Feminino , Fertilidade/fisiologia , Hormônio Foliculoestimulante Humano/genética , Hormônio Foliculoestimulante Humano/fisiologia , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Longevidade/genética , Longevidade/fisiologia , Hormônio Luteinizante/genética , Hormônio Luteinizante/fisiologia , Menopausa/genética , Menopausa/fisiologia , Polimorfismo de Nucleotídeo Único , Reprodução/fisiologia , Fatores de Risco
3.
Nat Commun ; 12(1): 1981, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790287

RESUMO

Histone acetylations are important epigenetic markers for transcriptional activation in response to metabolic changes and various stresses. Using the high-throughput SEquencing-Based Yeast replicative Lifespan screen method and the yeast knockout collection, we demonstrate that the HDA complex, a class-II histone deacetylase (HDAC), regulates aging through its target of acetylated H3K18 at storage carbohydrate genes. We find that, in addition to longer lifespan, disruption of HDA results in resistance to DNA damage and osmotic stresses. We show that these effects are due to increased promoter H3K18 acetylation and transcriptional activation in the trehalose metabolic pathway in the absence of HDA. Furthermore, we determine that the longevity effect of HDA is independent of the Cyc8-Tup1 repressor complex known to interact with HDA and coordinate transcriptional repression. Silencing the HDA homologs in C. elegans and Drosophila increases their lifespan and delays aging-associated physical declines in adult flies. Hence, we demonstrate that this HDAC controls an evolutionarily conserved longevity pathway.


Assuntos
Envelhecimento/genética , Histona Desacetilases/genética , Longevidade/genética , Trealose/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Ativação Enzimática/genética , Histona Desacetilases/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
4.
Molecules ; 26(7)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33805024

RESUMO

Depression and anxiety disorders are widespread diseases, and they belong to the leading causes of disability and greatest burdens on healthcare systems worldwide. It is expected that the numbers will dramatically rise during the COVID-19 pandemic. Established medications are not sufficient to adequately treat depression and are not available for everyone. Plants from traditional medicine may be promising alternatives to treat depressive symptoms. The model organism Chaenorhabditis elegans was used to assess the stress reducing effects of methanol/dichlormethane extracts from plants used in traditional medicine. After initial screening for antioxidant activity, nine extracts were selected for in vivo testing in oxidative stress, heat stress, and osmotic stress assays. Additionally, anti-aging properties were evaluated in lifespan assay. The extracts from Acanthopanax senticosus, Campsis grandiflora, Centella asiatica, Corydalis yanhusuo, Dan Zhi, Houttuynia cordata, Psoralea corylifolia, Valeriana officinalis, and Withaniasomnifera showed antioxidant activity of more than 15 Trolox equivalents per mg extract. The extracts significantly lowered ROS in mutants, increased resistance to heat stress and osmotic stress, and the extended lifespan of the nematodes. The plant extracts tested showed promising results in increasing stress resistance in the nematode model. Further analyses are needed, in order to unravel underlying mechanisms and transfer results to humans.


Assuntos
Antidepressivos/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Animais , Antioxidantes/farmacologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Técnicas de Inativação de Genes , Resposta ao Choque Térmico/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Longevidade/genética , Longevidade/fisiologia , Mutação , Pressão Osmótica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Espécies Reativas de Oxigênio/metabolismo
5.
Nat Commun ; 12(1): 1615, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712580

RESUMO

Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression.


Assuntos
Quirópteros/genética , Metilação de DNA , Longevidade/genética , Envelhecimento/genética , Animais , Carcinogênese/genética , Cromatina , Epigênese Genética , Técnicas Genéticas , Histonas , Imunidade Inata/genética , Filogenia
6.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669501

RESUMO

People are living longer, not, as was previously the case, due to reduced child mortality, but because we are postponing the ill-health of old age [...].


Assuntos
Longevidade/fisiologia , Modelos Biológicos , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Dieta , Epigênese Genética , Saúde , Humanos , Longevidade/genética , Probióticos/farmacologia
7.
Nat Commun ; 12(1): 1789, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741976

RESUMO

Sensory perception and metabolic homeostasis are known to deteriorate with ageing, impairing the health of aged animals, while mechanisms underlying their deterioration remain poorly understood. The potential interplay between the declining sensory perception and the impaired metabolism during ageing is also barely explored. Here, we report that the intraflagellar transport (IFT) in the cilia of sensory neurons is impaired in the aged nematode Caenorhabditis elegans due to a daf-19/RFX-modulated decrease of IFT components. We find that the reduced IFT in sensory cilia thus impairs sensory perception with ageing. Moreover, we demonstrate that whereas the IFT-dependent decrease of sensory perception in aged worms has a mild impact on the insulin/IGF-1 signalling, it remarkably suppresses AMP-activated protein kinase (AMPK) signalling across tissues. We show that upregulating daf-19/RFX effectively enhances IFT, sensory perception, AMPK activity and autophagy, promoting metabolic homeostasis and longevity. Our study determines an ageing pathway causing IFT decay and sensory perception deterioration, which in turn disrupts metabolism and healthy ageing.


Assuntos
Envelhecimento , Caenorhabditis elegans/metabolismo , Cílios/metabolismo , Flagelos/metabolismo , Células Receptoras Sensoriais/fisiologia , Transdução de Sinais/fisiologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Animais Geneticamente Modificados , Transporte Biológico , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Longevidade/genética , Percepção/fisiologia , Interferência de RNA , Fator Regulador X1/genética , Fator Regulador X1/metabolismo , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
8.
Int J Mol Sci ; 22(5)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673647

RESUMO

Small RNAs are essential to coordinate many cellular processes, including the regulation of gene expression patterns, the prevention of genomic instability, and the suppression of the mutagenic transposon activity. These processes determine the aging, longevity, and sensitivity of cells and an organism to stress factors (particularly, ionizing radiation). The biogenesis and activity of small RNAs are provided by proteins of the Argonaute family. These proteins participate in the processing of small RNA precursors and the formation of an RNA-induced silencing complex. However, the role of Argonaute proteins in regulating lifespan and radioresistance remains poorly explored. We studied the effect of knockdown of Argonaute genes (AGO1, AGO2, AGO3, piwi) in various tissues on the Drosophila melanogaster lifespan and survival after the γ-irradiation at a dose of 700 Gy. In most cases, these parameters are reduced or did not change significantly in flies with tissue-specific RNA interference. Surprisingly, piwi knockdown in both the fat body and the nervous system causes a lifespan increase. But changes in radioresistance depend on the tissue in which the gene was knocked out. In addition, analysis of changes in retrotransposon levels and expression of stress response genes allow us to determine associated molecular mechanisms.


Assuntos
Proteínas Argonauta/antagonistas & inibidores , Proteínas de Drosophila/antagonistas & inibidores , Drosophila melanogaster/crescimento & desenvolvimento , Longevidade/genética , RNA Interferente Pequeno/genética , Tolerância a Radiação/genética , Animais , Proteínas Argonauta/genética , Proteínas Argonauta/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/efeitos da radiação , Feminino , Raios gama , Masculino , Especificidade de Órgãos , Interferência de RNA
10.
Nat Commun ; 12(1): 513, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479240

RESUMO

Missense mutations in Valosin-Containing Protein (VCP) are linked to diverse degenerative diseases including IBMPFD, amyotrophic lateral sclerosis (ALS), muscular dystrophy and Parkinson's disease. Here, we characterize a VCP-binding co-factor (SVIP) that specifically recruits VCP to lysosomes. SVIP is essential for lysosomal dynamic stability and autophagosomal-lysosomal fusion. SVIP mutations cause muscle wasting and neuromuscular degeneration while muscle-specific SVIP over-expression increases lysosomal abundance and is sufficient to extend lifespan in a context, stress-dependent manner. We also establish multiple links between SVIP and VCP-dependent disease in our Drosophila model system. A biochemical screen identifies a disease-causing VCP mutation that prevents SVIP binding. Conversely, over-expression of an SVIP mutation that prevents VCP binding is deleterious. Finally, we identify a human SVIP mutation and confirm the pathogenicity of this mutation in our Drosophila model. We propose a model for VCP disease based on the differential, co-factor-dependent recruitment of VCP to intracellular organelles.


Assuntos
Longevidade/genética , Lisossomos/metabolismo , Proteínas de Membrana/genética , Mutação , Doenças Neurodegenerativas/genética , Proteínas de Ligação a Fosfato/genética , Proteína com Valosina/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/metabolismo , Doenças Neurodegenerativas/metabolismo , Osteíte Deformante/genética , Osteíte Deformante/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Ligação Proteica , Proteína com Valosina/metabolismo
11.
PLoS Genet ; 17(1): e1008951, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33428620

RESUMO

70 kDa heat shock proteins (Hsp70) are essential chaperones of the protein quality control network; vital for cellular fitness and longevity. The four cytosolic Hsp70's in yeast, Ssa1-4, are thought to be functionally redundant but the absence of Ssa1 and Ssa2 causes a severe reduction in cellular reproduction and accelerates replicative aging. In our efforts to identify which Hsp70 activities are most important for longevity assurance, we systematically investigated the capacity of Ssa4 to carry out the different activities performed by Ssa1/2 by overproducing Ssa4 in cells lacking these Hsp70 chaperones. We found that Ssa4, when overproduced in cells lacking Ssa1/2, rescued growth, mitigated aggregate formation, restored spatial deposition of aggregates into protein inclusions, and promoted protein degradation. In contrast, Ssa4 overproduction in the Hsp70 deficient cells failed to restore the recruitment of the disaggregase Hsp104 to misfolded/aggregated proteins, to fully restore clearance of protein aggregates, and to bring back the formation of the nucleolus-associated aggregation compartment. Exchanging the nucleotide-binding domain of Ssa4 with that of Ssa1 suppressed this 'defect' of Ssa4. Interestingly, Ssa4 overproduction extended the short lifespan of ssa1Δ ssa2Δ mutant cells to a lifespan comparable to, or even longer than, wild type cells, demonstrating that Hsp104-dependent aggregate clearance is not a prerequisite for longevity assurance in yeast.


Assuntos
Adenosina Trifosfatases/genética , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico/genética , Longevidade/genética , Proteínas de Saccharomyces cerevisiae/genética , Citosol/metabolismo , Chaperonas Moleculares/genética , Proteínas Mutantes/genética , Mutação/genética , Dobramento de Proteína , Saccharomyces cerevisiae/genética
12.
Int J Biol Macromol ; 172: 223-230, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33453252

RESUMO

Microsporidia are obligate single-celled eukaryote parasites. Microsporidian infection can cause large economic losses to beneficial insects such as silkworms and honey bees. Identification of resistance biomacromolecules and breeding of transgenic lines resistant to the microsporidian Nosema bombycis are important for disease management. We previously used transcriptome analysis to identify a guanylate binding protein family BmAtlastin-n gene that was significantly upregulated after Nosema bombycis infection, and we determined that the molecule was highly expressed in resistance-related tissues such as the midgut, fat body and the epidermis. The transgenic silkworm line overexpressing BmAtlastin-n biomolecules had economic characters similar to those of non-transgenic lines. The transgenic OE-BmAtlastin-n lines had significantly improved survival after microspore infection. We used RT-PCR and H&E staining to show that the number of spores in the transgenic lines was significantly lower than in the control lines. In this study, we identified a BmAtlastin-n macromolecule with resistance to N. bombycis and developed a transgenic line. The results improved understanding of the GBP protein family and provided biomacromolecule material for the treatment and prevention of microsporidia.


Assuntos
Bombyx/genética , Resistência à Doença/genética , Proteínas de Ligação ao GTP/genética , Interações Hospedeiro-Patógeno/genética , Proteínas de Insetos/genética , Nosema/patogenicidade , Animais , Animais Geneticamente Modificados , Bombyx/imunologia , Bombyx/microbiologia , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/imunologia , Proteínas de Ligação ao GTP/imunologia , Regulação da Expressão Gênica , Engenharia Genética/métodos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/imunologia , Interações Hospedeiro-Patógeno/imunologia , Proteínas de Insetos/imunologia , Longevidade/genética , Longevidade/imunologia , Nosema/crescimento & desenvolvimento , Plasmídeos/química , Plasmídeos/metabolismo , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/imunologia , Esporos Fúngicos/crescimento & desenvolvimento , Esporos Fúngicos/patogenicidade , Transcrição Genética
13.
Int J Biol Macromol ; 172: 263-269, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33453254

RESUMO

In insects, the cytochrome P450 CYP6B family plays key roles in the detoxification of toxic plant substances. However, the function of CYP6 family genes in degrading plant toxicants in Tribolium castaneum, an extremely destructive global storage pest, have yet to be elucidated. In this study, a T. castaneum CYP gene, TcCYP6BQ7, was characterized. TcCYP6BQ7 expression was significantly induced after exposure to essential oil of the plant Artemisia vulgaris (EOAV). Spatiotemporal expression profiling revealed that TcCYP6BQ7 expression was higher in larval and adult stages of T. castaneum than in other developmental stages, and that TcCYP6BQ7 was predominantly expressed in the brain and hemolymph from the late larval stage. TcCYP6BQ7 silencing by RNA interference increased larvae mortality in response to EOAV from 49.67% to 71.67%, suggesting that this gene is associated with plant toxicant detoxification. Combined results from this study indicate that the CYP6 family gene TcCYP6BQ7 likely plays a pivotal role in influencing the susceptibility of T. castaneum to plant toxicants. These findings may have implications for the development of novel therapeutics to control this agriculturally important pest.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Óleos Voláteis/farmacologia , Proteínas de Plantas/genética , Pupa/efeitos dos fármacos , Tribolium/efeitos dos fármacos , Animais , Artemisia/química , Artemisia/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Regulação da Expressão Gênica , Hemolinfa/efeitos dos fármacos , Hemolinfa/metabolismo , Inseticidas/isolamento & purificação , Inseticidas/metabolismo , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Longevidade/efeitos dos fármacos , Longevidade/genética , Masculino , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/metabolismo , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/metabolismo , Pupa/genética , Pupa/crescimento & desenvolvimento , Pupa/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Tribolium/genética , Tribolium/crescimento & desenvolvimento , Tribolium/metabolismo
14.
J Anim Sci ; 99(1)2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33340044

RESUMO

The objective of this study was to evaluate wool (Dorset and Rambouillet) and hair (Dorper, Katahdin, and White Dorper) breeds for their ability to complement Romanov germplasm in an annual fall lambing system by estimating direct maternal grandsire and sire breed effects on economically important lamb and ewe traits. After 3 yr of evaluation under spring lambing, ewes of the five F1 types were transitioned to spring mating, exposed to composite terminal sires, and evaluated under a barn lambing system at 4, 5, and 6 yr of age. A total of 527 first generation crossbred (F1) ewes produced 1,151 litters and 2,248 lambs from 1,378 May exposures. After accounting for differences in dam age, birth type, and sex, lamb survival to weaning was unaffected by maternal grandsire breed (P = 0.30). However, lambs born to 50% Dorset (16.8 ± 0.21 kg) or 50% White Dorper ewes (16.8 ± 0.28 kg) were heavier at weaning than those born to 50% Katahdin dams (13.8 ± 0.32 kg; P < 0.001). Additionally, lambs born to 50% Dorset ewes were heavier than those born to 50% Rambouillet (16.0 ± 0.22 kg) and 50% Dorper ewes (15.7 ± 0.33; P ≤ 0.03), but no other pairwise maternal grandsire breed differences were observed (P ≥ 0.06). Ewe body weight (n = 3,629) was recorded prior to each of six possible mating seasons and, across ages, was greatest for Dorset- and Rambouillet-sired ewes (56.7 ± 0.44 and 56.5 ± 0.45 kg, respectively), intermediate for Dorper- and White Dorper-sired ewes (54.7 ± 0.78 and 54.1 ± 0.64 kg, respectively), and least for Katahdin-sired ewes (51.5 ± 0.45 kg). Fertility after spring mating (0.80 ± 0.03 to 0.87 ± 0.02), litter size at birth (1.46 ± 0.09 to 1.71 ± 0.07), and litter size at weaning (1.25 ± 0.06 to 1.46 ± 0.06) were not impacted by sire breed (P ≥ 0.16). Ewe longevity, assessed as the probability of being present after 6 production years, was also not affected by sire breed (0.39 ± 0.03 to 0.47 ± 0.03; P = 0.44). Rambouillet-sired ewes weaned more total weight of lamb (21.5 ± 0.94 kg) than Katahdin-sired ewes (17.8 ± 0.94 kg; P = 0.05), but no other sire breed differences were detected (P ≥ 0.07). Results demonstrated that incorporating the Romanov into a crossbreeding system is a practical means of improving out-of-season ewe productivity.


Assuntos
Longevidade , , Animais , Peso Corporal/genética , Feminino , Longevidade/genética , Gravidez , Estações do Ano , Ovinos/genética , Carneiro Doméstico , Desmame
15.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33374973

RESUMO

There is increasing recognition that environmental nano-biological interactions in model species, and the resulting effects on progeny, are of paramount importance for nanomaterial (NM) risk assessment. In this work, Daphnia magna F0 mothers were exposed to a range of silver and titanium dioxide NMs. The key biological life history traits (survival, growth and reproduction) of the F1 intergenerations, at the first (F1B1), third (F1B3) and fifth (F1B5) broods, were investigated. Furthermore, the F1 germlines of each of the three broods were investigated over 3 more generations (up to 25 days each) in continuous or removed-from NM exposure, to identify how the length of maternal exposure affects the resulting clonal broods. Our results show how daphnids respond to NM-induced stress, and how the maternal effects show trade-offs between growth, reproduction and survivorship. The F1B1 (and following germline) had the shortest F0 maternal exposure times to the NMs, and thus were the most sensitive showing reduced size and reproductive output. The F1B3 generation had a sub-chronic maternal exposure, whereas the F1B5 generation suffered chronic maternal exposure where (in most cases) the most compensatory adaptive effects were displayed in response to the prolonged NM exposure, including enhanced neonate output and reduced gene expression. Transgenerational responses of multiple germlines showed a direct link with maternal exposure time to 'sub-lethal' effect concentrations of NMs (identified from standard OECDs acute toxicity tests which chronically presented as lethal) including increased survival and production of males in the F1B3 and G1B5 germlines. This information may help to fine-tune environmental risk assessments of NMs and prediction of their impacts on environmental ecology.


Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Daphnia/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Exposição Materna , Nanoestruturas/toxicidade , Animais , Daphnia/genética , Daphnia/fisiologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Longevidade/genética , Nanoestruturas/química , Reprodução/efeitos dos fármacos , Reprodução/genética , Fatores de Tempo , Titânio/química , Titânio/toxicidade
16.
PLoS One ; 15(12): e0229812, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33315870

RESUMO

Insulin and insulin-like growth factors are longevity determinants that negatively regulate Forkhead box class O (FoxO) transcription factors. In C. elegans mutations that constitutively activate DAF-16, the ortholog of mammalian FoxO3a, extend lifespan by two-fold. While environmental insults induce DAF-16 activity in younger animals, it also becomes activated in an age-dependent manner in the absence of stress, modulating gene expression well into late adulthood. The mechanism by which DAF-16 activity is regulated during aging has not been defined. Since phosphorylation of DAF-16 generally leads to its inhibition, we asked whether phosphatases might be necessary for its increased transcriptional activity in adult C. elegans. We focused on the PP2A/4/6 subfamily of phosphoprotein phosphatases, members of which had been implicated to regulate DAF-16 under low insulin signaling conditions but had not been investigated during aging in wildtype animals. Using reverse genetics, we functionally characterized all C. elegans orthologs of human catalytic, regulatory, and scaffolding subunits of PP2A/4/6 holoenzymes in postreproductive adults. We found that PP2A complex constituents PAA-1 and PPTR-1 regulate DAF-16 transcriptional activity during aging and that they cooperate with the catalytic subunit LET-92 to protect adult animals from ultraviolet radiation. PP4 complex members PPH-4.1/4.2, and SMK-1 also appear to regulate DAF-16 in an age-dependent manner, and together with PPFR-2 they contribute to innate immunity. Interestingly, SUR-6 but no other subunit of the PP2A complex was necessary for the survival of pathogen-infected animals. Finally, we found that PP6 complex constituents PPH-6 and SAPS-1 contribute to host defense during aging, apparently without affecting DAF-16 transcriptional activity. Our studies indicate that a set of PP2A/4/6 complexes protect adult C. elegans from environmental stress, thus preserving healthspan. Therefore, along with their functions in cell division and development, the PP2A/4/6 phosphatases also appear to play critical roles later in life.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Proteína Fosfatase 2/metabolismo , Estresse Fisiológico/fisiologia , Envelhecimento/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/fisiologia , Fatores de Transcrição Forkhead/fisiologia , Longevidade/genética , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Proteína Fosfatase 2/fisiologia , Transdução de Sinais
17.
PLoS Genet ; 16(8): e1008982, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32841230

RESUMO

High glucose diets are unhealthy, although the mechanisms by which elevated glucose is harmful to whole animal physiology are not well understood. In Caenorhabditis elegans, high glucose shortens lifespan, while chemically inflicted glucose restriction promotes longevity. We investigated the impact of glucose metabolism on aging quality (maintained locomotory capacity and median lifespan) and found that, in addition to shortening lifespan, excess glucose negatively impacts locomotory healthspan. Conversely, disrupting glucose utilization by knockdown of glycolysis-specific genes results in large mid-age physical improvements via a mechanism that requires the FOXO transcription factor DAF-16. Adult locomotory capacity is extended by glycolysis disruption, but maximum lifespan is not, indicating that limiting glycolysis can increase the proportion of life spent in mobility health. We also considered the largely ignored role of glucose biosynthesis (gluconeogenesis) in adult health. Directed perturbations of gluconeogenic genes that specify single direction enzymatic reactions for glucose synthesis decrease locomotory healthspan, suggesting that gluconeogenesis is needed for healthy aging. Consistent with this idea, overexpression of the central gluconeogenic gene pck-2 (encoding PEPCK) increases health measures via a mechanism that requires DAF-16 to promote pck-2 expression in specific intestinal cells. Dietary restriction also features DAF-16-dependent pck-2 expression in the intestine, and the healthspan benefits conferred by dietary restriction require pck-2. Together, our results describe a new paradigm in which nutritional signals engage gluconeogenesis to influence aging quality via DAF-16. These data underscore the idea that promotion of gluconeogenesis might be an unappreciated goal for healthy aging and could constitute a novel target for pharmacological interventions that counter high glucose consequences, including diabetes.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead/genética , Gluconeogênese/genética , Envelhecimento Saudável/genética , Animais , Restrição Calórica , Regulação da Expressão Gênica no Desenvolvimento/genética , Glucose/metabolismo , Humanos , Expectativa de Vida , Longevidade/genética , Fosfoenolpiruvato Carboxiquinase (ATP)/genética , Transdução de Sinais/genética
18.
Proc Natl Acad Sci U S A ; 117(34): 20662-20671, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32753383

RESUMO

The endangered whale shark (Rhincodon typus) is the largest fish on Earth and a long-lived member of the ancient Elasmobranchii clade. To characterize the relationship between genome features and biological traits, we sequenced and assembled the genome of the whale shark and compared its genomic and physiological features to those of 83 animals and yeast. We examined the scaling relationships between body size, temperature, metabolic rates, and genomic features and found both general correlations across the animal kingdom and features specific to the whale shark genome. Among animals, increased lifespan is positively correlated to body size and metabolic rate. Several genomic traits also significantly correlated with body size, including intron and gene length. Our large-scale comparative genomic analysis uncovered general features of metazoan genome architecture: Guanine and cytosine (GC) content and codon adaptation index are negatively correlated, and neural connectivity genes are longer than average genes in most genomes. Focusing on the whale shark genome, we identified multiple features that significantly correlate with lifespan. Among these were very long gene length, due to introns being highly enriched in repetitive elements such as CR1-like long interspersed nuclear elements, and considerably longer neural genes of several types, including connectivity, activity, and neurodegeneration genes. The whale shark genome also has the second slowest evolutionary rate observed in vertebrates to date. Our comparative genomics approach uncovered multiple genetic features associated with body size, metabolic rate, and lifespan and showed that the whale shark is a promising model for studies of neural architecture and lifespan.


Assuntos
Adaptação Fisiológica/genética , Tamanho Corporal/fisiologia , Tubarões/genética , Animais , Sequência de Bases/genética , Tamanho Corporal/genética , Genoma/genética , Genômica/métodos , Longevidade/genética , Tubarões/metabolismo , Temperatura
19.
PLoS One ; 15(7): e0236888, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735637

RESUMO

Maximum lifespan for most animal species is difficult to define. This is challenging for wildlife management as it is critical for estimating important aspects of population biology such as mortality rate, population viability, and period of reproductive potential. Recently, it has been shown cytosine-phosphate-guanine (CpG) density is predictive of maximum lifespan in vertebrates. This has made it possible to predict lifespan in long-lived species, which are generally the most intractable. In this study, we use gene promoter CpG density to predict the lifespan of five marine turtle species. Marine turtles are a particularly difficult group for lifespan estimation because of their migratory behaviour, longevity and high juvenile mortality rates, which all restrict individual tracking over their lifespan. Sanger sequencing was used to determine the CpG density in selected promoters. We predicted the lifespans for marine turtle species ranged from 50.4 years (flatback turtle, Natator depressus) to 90.4 years (leatherback turtle, Dermochelys coriacea). These lifespan predictions have broad applications in marine turtle research such as better understanding life cycles and determining population viability.


Assuntos
Longevidade/genética , Regiões Promotoras Genéticas , Tartarugas , Animais , Genômica , Vertebrados/genética
20.
PLoS Genet ; 16(7): e1008835, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32644988

RESUMO

In most organisms, dietary restriction (DR) increases lifespan. However, several studies have found that genotypes within the same species vary widely in how they respond to DR. To explore the mechanisms underlying this variation, we exposed 178 inbred Drosophila melanogaster lines to a DR or ad libitum (AL) diet, and measured a panel of 105 metabolites under both diets. Twenty four out of 105 metabolites were associated with the magnitude of the lifespan response. These included proteinogenic amino acids and metabolites involved in α-ketoglutarate (α-KG)/glutamine metabolism. We confirm the role of α-KG/glutamine synthesis pathways in the DR response through genetic manipulations. We used covariance network analysis to investigate diet-dependent interactions between metabolites, identifying the essential amino acids threonine and arginine as "hub" metabolites in the DR response. Finally, we employ a novel metabolic and genetic bipartite network analysis to reveal multiple genes that influence DR lifespan response, some of which have not previously been implicated in DR regulation. One of these is CCHa2R, a gene that encodes a neuropeptide receptor that influences satiety response and insulin signaling. Across the lines, variation in an intronic single nucleotide variant of CCHa2R correlated with variation in levels of five metabolites, all of which in turn were correlated with DR lifespan response. Inhibition of adult CCHa2R expression extended DR lifespan of flies, confirming the role of CCHa2R in lifespan response. These results provide support for the power of combined genomic and metabolomic analysis to identify key pathways underlying variation in this complex quantitative trait.


Assuntos
Envelhecimento/genética , Proteínas de Drosophila/genética , Longevidade/genética , Metaboloma/genética , Receptores Acoplados a Proteínas-G/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Restrição Calórica , Dieta , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/genética , Insulina/genética , Metabolômica , Mutação/genética , Transdução de Sinais/genética
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