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1.
PLoS One ; 15(2): e0228576, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049962

RESUMO

Anopheles arabiensis is an opportunistic malaria vector that rests and feeds outdoors, circumventing current vector control methods. Furthermore, this vector will readily feed on animal as well as human hosts. Targeting the vector, while feeding on animals, can provide an additional intervention for the current vector control activities. Agricultural animals are regularly vaccinated with recombinant proteins for the control of multiple endo- and ecto-parasitic infestations. The use of a Subolesin-vaccine showed a mark reduction in tick reproductive fitness. The orthologous gene of Subolesin, called Akirin in insects, might provide a valuable species-specific intervention against outdoor biting An. arabiensis. However, the biological function of this nuclear protein has not yet been investigated in this mosquito. The effects on An. arabiensis lifetable parameters were evaluated after Akirin was knocked down using commercial small-interfering RNA (siRNA) and in vitro transcribed double-stranded RNA (dsRNA). The siRNA mediated interference of Akirin significantly reduced fecundity by 17%, fertility by 23% and longevity by 32% when compared to the controls in the female mosquitoes tested. Similarly, dsRNA treatment had a 25% decrease in fecundity, 29% decrease in fertility, and 48% decrease in longevity, when compared to the control treatments. Mosquitoes treated with Akirin dsRNA had a mean survival time of 15-days post-inoculation, which would impact on their ability to transmit malaria parasites. These results strongly suggest that Akirin has a pleiotropic function in An. arabiensis longevity and reproductive fitness.


Assuntos
Anopheles/genética , Fertilidade/genética , Proteínas de Insetos/genética , Longevidade/genética , Animais , Anopheles/fisiologia , Feminino , Masculino , Interferência de RNA
2.
Nat Rev Mol Cell Biol ; 21(3): 137-150, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32020082

RESUMO

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.


Assuntos
Envelhecimento/genética , Epigênese Genética/genética , Rejuvenescimento/fisiologia , Animais , Montagem e Desmontagem da Cromatina/genética , Metilação de DNA/genética , Epigenoma/genética , Epigenômica/métodos , Regulação da Expressão Gênica/genética , Código das Histonas/genética , Humanos , Longevidade/genética
3.
Nat Commun ; 11(1): 987, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080190

RESUMO

Longevity is influenced by genetic and environmental factors, but the underlying mechanisms remain elusive. Here, we functionally characterise a Drosophila small nucleolar RNA (snoRNA), named jouvence whose loss of function reduces lifespan. The genomic region of jouvence rescues the longevity in mutant, while its overexpression in wild-type increases lifespan. Jouvence is required in enterocytes. In mutant, the epithelium of the gut presents more hyperplasia, while the overexpression of jouvence prevents it. Molecularly, the mutant lack pseudouridylation on 18S and 28S-rRNA, a function rescued by targeted expression of jouvence in the gut. A transcriptomic analysis performed from the gut reveals that several genes are either up- or down-regulated, while restoring the mRNA level of two genes (ninaD or CG6296) rescue the longevity. Since snoRNAs are structurally and functionally well conserved throughout evolution, we identified putative jouvence orthologue in mammals including humans, suggesting that its function in longevity could be conserved.


Assuntos
Drosophila melanogaster/genética , Longevidade/genética , RNA Nucleolar Pequeno/genética , Animais , Animais Geneticamente Modificados , Sequência Conservada , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Enterócitos/metabolismo , Evolução Molecular , Feminino , Deleção de Genes , Perfilação da Expressão Gênica , Genoma de Inseto , Humanos , Mucosa Intestinal/metabolismo , Mutação com Perda de Função , Masculino , Camundongos , Conformação de Ácido Nucleico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Nucleolar Pequeno/química , RNA Nucleolar Pequeno/metabolismo , Receptores Imunológicos/genética
4.
Nature ; 579(7797): 118-122, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32103178

RESUMO

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.


Assuntos
Caenorhabditis elegans/genética , Epigênese Genética , Envelhecimento Saudável/genética , Envelhecimento/genética , Animais , Cognição , Disfunção Cognitiva , Histona-Lisina N-Metiltransferase/genética , Histonas/química , Histonas/metabolismo , Humanos , Longevidade/genética , Lisina/metabolismo , Masculino , Memória , Metilação , Camundongos , Mitocôndrias/metabolismo , Neurônios/metabolismo , Proteínas/genética , Interferência de RNA , Aprendizagem Espacial
6.
Hum Genet ; 139(3): 381-399, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31997134

RESUMO

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.


Assuntos
Envelhecimento/genética , DNA Mitocondrial/genética , Animais , Núcleo Celular/genética , Genoma Mitocondrial/genética , Genômica/métodos , Humanos , Longevidade/genética , Mitocôndrias/genética
7.
Parasit Vectors ; 13(1): 18, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931885

RESUMO

BACKGROUND: The recent reference genome assembly and annotation of the Asian malaria vector Anopheles stephensi detected only one gene encoding the leucine-rich repeat immune factor APL1, while in the Anopheles gambiae and sibling Anopheles coluzzii, APL1 factors are encoded by a family of three paralogs. The phylogeny and biological function of the unique APL1 gene in An. stephensi have not yet been specifically examined. METHODS: The APL1 locus was manually annotated to confirm the computationally predicted single APL1 gene in An. stephensi. APL1 evolution within Anopheles was explored by phylogenomic analysis. The single or paralogous APL1 genes were silenced in An. stephensi and An. coluzzii, respectively, followed by mosquito survival analysis, experimental infection with Plasmodium and expression analysis. RESULTS: APL1 is present as a single ancestral gene in most Anopheles including An. stephensi but has expanded to three paralogs in an African lineage that includes only the Anopheles gambiae species complex and Anopheles christyi. Silencing of the unique APL1 copy in An. stephensi results in significant mosquito mortality. Elevated mortality of APL1-depleted An. stephensi is rescued by antibiotic treatment, suggesting that pathology due to bacteria is the cause of mortality, and indicating that the unique APL1 gene is essential for host survival. Successful Plasmodium development in An. stephensi depends upon APL1 activity for protection from high host mortality due to bacteria. In contrast, silencing of all three APL1 paralogs in An. coluzzii does not result in elevated mortality, either with or without Plasmodium infection. Expression of the single An. stephensi APL1 gene is regulated by both the Imd and Toll immune pathways, while the two signaling pathways regulate different APL1 paralogs in the expanded APL1 locus. CONCLUSIONS: APL1 underwent loss and gain of functions concomitant with expansion from a single ancestral gene to three paralogs in one lineage of African Anopheles. We infer that activity of the unique APL1 gene promotes longevity in An. stephensi by conferring protection from or tolerance to an effect of bacterial pathology. The evolution of an expanded APL1 gene family could be a factor contributing to the exceptional levels of malaria transmission mediated by human-feeding members of the An. gambiae species complex in Africa.


Assuntos
Anopheles/genética , Chaperonina 60/genética , Fatores Imunológicos/genética , Fragmentos de Peptídeos/genética , Animais , Anopheles/imunologia , Evolução Molecular , Dosagem de Genes , Proteínas de Insetos/genética , Insetos Vetores/genética , Longevidade/genética , Malária/imunologia , Malária/transmissão , Filogenia
8.
Nat Commun ; 11(1): 138, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919361

RESUMO

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.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica/genética , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Fatores de Elongação da Transcrição/metabolismo , Envelhecimento/genética , Animais , Caenorhabditis elegans/genética , Proteínas Cromossômicas não Histona/genética , Longevidade/genética , Complexos Multiproteicos/metabolismo , Interferência de RNA , RNA Polimerase II/metabolismo , Estresse Fisiológico/genética , Transcrição Genética/genética , Fatores de Elongação da Transcrição/genética
9.
Nat Commun ; 11(1): 307, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949142

RESUMO

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.


Assuntos
Envelhecimento/fisiologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Longevidade/fisiologia , Neoplasias , Envelhecimento/genética , Animais , Autofagia/genética , Proteína 5 Relacionada à Autofagia/genética , Transplante de Medula Óssea , Modelos Animais de Doenças , Feminino , Inflamação , Longevidade/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculos , Fenótipo , Proteína Sequestossoma-1/metabolismo , Pele/patologia
10.
Arch Insect Biochem Physiol ; 103(2): e21635, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31625210

RESUMO

Among insects, lifespans vary over a broad range, from the short-lived mayflies to the 17-year periodical cicadas. Generally, lifespans are determined by a phase in life, the reproductive lifespan, which varies among species. Numerous pathways, such as the insulin/insulin-like growth factor signaling pathway, the target of rapamycin pathway and the mitogen-activated protein kinase/extracellular signal-regulated kinases pathways, influence aging and lifespan. Components of these pathways were identified as lifespan-related genes, including genes mediating growth, metabolism, development, resistance, and other processes. Many age-related genes have been discovered in fruit flies, honeybees, and ants among other insect species. Studies of insect aging and longevity can help understand insect biology and develop new pest management technologies. In this paper, we interrogated the new Pteromalus puparum genome, from which we predicted 133 putative lifespan-related genes based on their homology with known lifespan-related genes of Drosophila melanogaster. These genes function in five signaling pathways and three physiological processes. The conserved domain structures of these genes were predicted and their expression patterns were analyzed. Amino acid sequence alignments and domain structure analysis indicate that most components remain conserved across at least six insect orders. The data in this paper will facilitate future work on parasitoid lifespans, which may have economic value in biocontrol programs.


Assuntos
Genoma de Inseto , Longevidade/genética , Transdução de Sinais , Transcriptoma , Vespas/fisiologia , Animais , Vespas/genética
11.
Hum Genet ; 139(3): 291-308, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31297598

RESUMO

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.


Assuntos
Envelhecimento/genética , Longevidade/genética , MicroRNAs/genética , Animais , Humanos , Transdução de Sinais/genética
12.
Hum Genet ; 139(3): 357-369, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31834493

RESUMO

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.


Assuntos
Envelhecimento/genética , Processamento Alternativo/genética , Longevidade/genética , Animais , Humanos , Fenótipo , Fatores de Processamento de RNA/genética
13.
J Dairy Sci ; 103(1): 583-596, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31677834

RESUMO

The aim of this study was to infer phenotypic and genetic effects of health disorders on longevity traits, considering Holstein dairy cow records from large-scale co-operator herds. In this regard, we focused on 13 different disease traits and on 2 longevity definitions: length of productive life (LPL) and stayability (STAY). The LPL was defined as the interval in days from first calving to culling. For LPL, we considered 90,215 cows with known culling dates. For binary STAY, we defined 3 survival stages in the first 3 lactations: from calving to DIM 59, from DIM 60 to DIM 299, and from DIM 300 to the next calving date. Due to the earlier trait recording possibilities, 129,386 cows were considered for the STAY analysis. Accordingly, the presence or absence of diseases in lactation stages were defined as binary traits. A further data set for the 90,215 cows with a culling date included the subjective culling reasons defined by farmers. Comparison of culling reasons, as defined by farmers, with diagnoses from the disease data set indicated some disagreements. For example, only 18.71% of the cows with the farmer culling reason "metabolic diseases" were diagnosed with a metabolic disorder. Better agreements were identified for mastitis (84.09%). Phenotypically, in most cases, occurrence of diseases at different lactation stages had negative influence on LPL and STAY. In this regard, we identified strong detrimental effects of clinical mastitis and of metabolic disorders from early lactation stages on longevity traits. For example, the presence of clinical mastitis in the first stage of first lactation was associated with LPL decrease of 95.35 d. Using generalized linear mixed models for binary health disorders, heritabilities ranged from <0.01 (±0.079 standard error) for ruminal acidosis early in first, second, and third lactation to 0.24 (±0.039) for interdigital hyperplasia from the last stage in third lactation. Heritabilities from single-trait and bivariate animal models ranged from 0.03 (±0.003) to 0.10 (±0.007) for LPL, and from 0.01 (±0.002) to 0.06 (±0.007) for STAY. Genetic correlations between longevity traits and health disorders were mostly negative (i.e., favorable in a breeding sense). For improvements to longevity genetic evaluations for young bulls with a limited number of daughter culling dates, we suggest consideration of health traits from a well-organized co-operator herd monitoring system as early longevity predictors, especially for censored data. Genetic correlations between mastitis from different lactation stages with LPL and STAY ranged from -0.28 (±0.07) to -0.69 (±0.05), and from -0.26 (±0.08) to -0.77 (±0.08), respectively. Interestingly, only diagnoses for dermatitis digitalis showed opposite results phenotypically and genetically. Strong genetic associations between ruminal acidosis and STAY were observed (genetic correlations: -0.48 ± 0.18 to -0.98 ± 0.31), supporting the inferred phenotypic associations. Genetic correlations between longevity traits LPL and STAY were quite large, between 0.77 (±0.11) and 0.94 (±0.02) for the different lactation stages, suggesting utility of early STAY information when attempting genetic improvements for longevity.


Assuntos
Doenças dos Bovinos/fisiopatologia , Longevidade , Animais , Cruzamento , Bovinos , Indústria de Laticínios , Fazendeiros , Feminino , Lactação , Longevidade/genética , Fenótipo
15.
Nat Med ; 25(12): 1843-1850, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31806903

RESUMO

Aging is a predominant risk factor for several chronic diseases that limit healthspan1. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues2-10, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases.


Assuntos
Envelhecimento/sangue , Proteínas Sanguíneas/genética , Longevidade/genética , Proteoma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Animais , Doença Crônica , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
16.
Nat Med ; 25(12): 1822-1832, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31806905

RESUMO

Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.


Assuntos
Doença Crônica/epidemiologia , Inflamação/fisiopatologia , Longevidade/genética , Doenças Autoimunes/etiologia , Doenças Autoimunes/fisiopatologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus/etiologia , Diabetes Mellitus/fisiopatologia , Humanos , Inflamação/complicações , Inflamação/epidemiologia , Estilo de Vida , Longevidade/fisiologia , Neoplasias/etiologia , Neoplasias/fisiopatologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco
17.
Nat Commun ; 10(1): 5725, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844058

RESUMO

Many traits vary among isogenic individuals in homogeneous environments. In microbes, plants and animals, variation in the protein chaperone system affects many such traits. In the animal model C. elegans, the expression level of hsp-16.2 chaperone biomarkers correlates with or predicts the penetrance of mutations and lifespan after heat shock. But the physiological mechanisms causing cells to express different amounts of the biomarker were unknown. Here, we used an in vivo microscopy approach to dissect different contributions to cell-to-cell variation in hsp-16.2 expression in the intestines of young adult animals, which generate the most lifespan predicting signal. While we detected both cell autonomous intrinsic noise and signaling noise, we found both contributions were relatively unimportant. The major contributor to cell-to-cell variation in biomarker expression was general differences in protein dosage. The hsp-16.2 biomarker reveals states of high or low effective dosage for many genes.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Dosagem de Genes , Proteínas de Choque Térmico/genética , Longevidade/genética , Penetrância , Animais , Animais Geneticamente Modificados , Biomarcadores/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Genes Reporter/genética , Proteínas de Choque Térmico/metabolismo , Microscopia Intravital/métodos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Microscopia de Fluorescência/métodos , Modelos Animais , Imagem Molecular , Transdução de Sinais/genética
18.
PLoS Biol ; 17(11): e3000528, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31751331

RESUMO

The immune system comprises a complex network of specialized cells that protects against infection, eliminates cancerous cells, and regulates tissue repair, thus serving a critical role in homeostasis, health span, and life span. The subterranean-dwelling naked mole-rat (NM-R; Heterocephalus glaber) exhibits prolonged life span relative to its body size, is unusually cancer resistant, and manifests few physiological or molecular changes with advancing age. We therefore hypothesized that the immune system of NM-Rs evolved unique features that confer enhanced cancer immunosurveillance and prevent the age-associated decline in homeostasis. Using single-cell RNA-sequencing (scRNA-seq) we mapped the immune system of the NM-R and compared it to that of the short-lived, cancer-prone mouse. In contrast to the mouse, we find that the NM-R immune system is characterized by a high myeloid-to-lymphoid cell ratio that includes a novel, lipopolysaccharide (LPS)-responsive, granulocyte cell subset. Surprisingly, we also find that NM-Rs lack canonical natural killer (NK) cells. Our comparative genomics analyses support this finding, showing that the NM-R genome lacks an expanded gene family that controls NK cell function in several other species. Furthermore, we reconstructed the evolutionary history that likely led to this genomic state. The NM-R thus challenges our current understanding of mammalian immunity, favoring an atypical, myeloid-biased mode of innate immunosurveillance, which may contribute to its remarkable health span.


Assuntos
Ratos-Toupeira/genética , Ratos-Toupeira/imunologia , Animais , Evolução Biológica , Biologia Computacional/métodos , Genoma , Genômica/métodos , Longevidade/genética , Mamíferos/imunologia , Camundongos/imunologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Transcriptoma/genética
19.
PLoS Genet ; 15(11): e1008104, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31738745

RESUMO

'Epigenetic age acceleration' is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-wide association studies of Horvath-EAA and Hannum-EAA in 13,493 unrelated individuals of European ancestry, to elucidate genetic determinants of differential epigenetic ageing. We identified ten independent SNPs associated with Horvath-EAA, five of which are novel. We also report 21 Horvath-EAA-associated genes including several involved in metabolism (NHLRC, TPMT) and immune system pathways (TRIM59, EDARADD). GWAS of Hannum-EAA identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (UBE2D3, MANBA, TRIM46), with metabolic functions (UBE2D3, MANBA), or linked to lifespan regulation (CISD2). Both measures had nominal inverse genetic correlations with father's age at death, a rough proxy for lifespan. Nominally significant genetic correlations between Hannum-EAA and lifestyle factors including smoking behaviours and education support the hypothesis that Hannum-based epigenetic ageing is sensitive to variations in environment, whereas Horvath-EAA is a more stable cellular ageing process. We identified novel SNPs and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of Horvath-based and Hannum-based epigenetic ageing measures. Understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.


Assuntos
Envelhecimento/genética , Epigênese Genética , Predisposição Genética para Doença , Longevidade/genética , Envelhecimento/patologia , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética
20.
PLoS Biol ; 17(10): e3000452, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31589601

RESUMO

Neurons have a lifespan that parallels that of the organism and are largely irreplaceable. Their unusually long lifespan predisposes neurons to neurodegenerative disease. We sought to identify physiological mechanisms that delay neuron aging in Caenorhabditis elegans by asking how neuron morphological aging is arrested in the long-lived, alternate organismal state, the dauer diapause. We find that a hormone signaling pathway, the abnormal DAuer Formation (DAF) 12 nuclear hormone receptor (NHR) pathway, functions cell-intrinsically in the dauer diapause to arrest neuron morphological aging, and that same pathway can be cell-autonomously manipulated during normal organismal aging to delay neuron morphological aging. This delayed aging is mediated by suppressing constitutive endocytosis, which alters the subcellular localization of the actin regulator T cell lymphoma Invasion And Metastasis 1 (TIAM-1), thereby decreasing age-dependent neurite growth. Intriguingly, we show that suppressed endocytosis appears to be a general feature of cells in diapause, suggestive that this may be a mechanism to halt the growth and other age-related programs supported by most endosome recycling.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Diapausa/genética , Longevidade/genética , Neurônios/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/genética , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Senescência Celular/genética , Endocitose/genética , Endossomos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genótipo , Neurônios/citologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/metabolismo
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