RESUMEN
Transcription factors can reprogram gene expression to promote longevity. Here, we investigate the role of Drosophila Xbp1. Xbp1 is activated by splicing of its primary transcript, Xbp1u, to generate Xbp1s, a key activator of the endoplasmic reticulum unfolded protein response (UPRER). We show that Xbp1s induces the conical UPRER in the gut, promoting longevity from the resident stem cells. In contrast, in the fat body, Xbp1s does not appear to trigger UPRER but alters metabolic gene expression and is still able to extend lifespan. In the fat body, Xbp1s and dFOXO impinge on the same target genes, including the PGC-1α orthologue Srl, and dfoxo requires Xbp1 to extend lifespan. Interestingly, unspliceable version of the Xbp1 mRNA, Xbp1u can also extend lifespan, hinting at roles in longevity for the poorly characterized Xbp1u transcription factor. These findings reveal the diverse functions of Xbp1 in longevity in the fruit fly.
RESUMEN
Organismal growth and lifespan are inextricably linked. Target of Rapamycin (TOR) signalling regulates protein production for growth and development, but if reduced, extends lifespan across species. Reduction in the enzyme RNA polymerase III, which transcribes tRNAs and 5S rRNA, also extends longevity. Here, we identify a temporal genetic relationship between TOR and Pol III in Caenorhabditis elegans, showing that they collaborate to regulate progeny production and lifespan. Interestingly, the lifespan interaction between Pol III and TOR is only revealed when TOR signaling is reduced, specifically in adulthood, demonstrating the importance of timing to control TOR regulated developmental versus adult programs. In addition, we show that Pol III acts in C. elegans muscle to promote both longevity and healthspan and that reducing Pol III even in late adulthood is sufficient to extend lifespan. This demonstrates the importance of Pol III for lifespan and age-related health in adult C. elegans.
Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Longevidad , Diana Mecanicista del Complejo 1 de la Rapamicina , ARN Polimerasa III , Transducción de Señal , Animales , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Longevidad/genética , ARN Polimerasa III/metabolismo , ARN Polimerasa III/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Serina-Treonina Quinasas TOR/metabolismo , Envejecimiento/metabolismo , Envejecimiento/genética , Envejecimiento/fisiologíaRESUMEN
The genetic pathways that modulate ageing in multicellular organisms are typically highly conserved across wide evolutionary distances. Recently RNA polymerase III (Pol III) was shown to promote ageing in yeast, C. elegans and D. melanogaster. In this study we investigated the role of Pol III in mammalian ageing using C57BL/6N mice heterozygous for Pol III (Polr3b+/-). We identified sexually dimorphic, organ-specific beneficial as well as detrimental effects of the Polr3b+/- mutation on health. Female Polr3b+/- mice displayed improved bone health during ageing, but their ability to maintain an effective gut barrier function was compromised and they were susceptible to idiopathic dermatitis (ID). In contrast, male Polr3b+/- mice were lighter than wild-type (WT) males and had a significantly improved gut barrier function in old age. Several metabolic parameters were affected by both age and sex, but no genotype differences were detected. Neither male nor female Polr3b+/- mice were long-lived compared to WT controls. Overall, we find no evidence that a reduced Pol III activity extends mouse lifespan but we do find some potential organ- and sex-specific benefits for old-age health.
Asunto(s)
Envejecimiento , Heterocigoto , Longevidad , ARN Polimerasa III , Animales , Femenino , Masculino , Ratones , Envejecimiento/genética , Longevidad/genética , Ratones Endogámicos C57BL , ARN Polimerasa III/genética , ARN Polimerasa III/metabolismoRESUMEN
Pharmacological therapies are promising interventions to slow down aging and reduce multimorbidity in the elderly. Studies in animal models are the first step toward translation of candidate molecules into human therapies, as they aim to elucidate the molecular pathways, cellular mechanisms, and tissue pathologies involved in the anti-aging effects. Trametinib, an allosteric inhibitor of MEK within the Ras/MAPK (Ras/Mitogen-Activated Protein Kinase) pathway and currently used as an anti-cancer treatment, emerged as a geroprotector candidate because it extended lifespan in the fruit fly Drosophila melanogaster. Here, we confirm that trametinib consistently and robustly extends female lifespan, and reduces intestinal stem cell (ISC) proliferation, tumor formation, tissue dysplasia, and barrier disruption in guts in aged flies. In contrast, pro-longevity effects of trametinib are weak and inconsistent in males, and it does not influence gut homeostasis. Inhibition of the Ras/MAPK pathway specifically in ISCs is sufficient to partially recapitulate the effects of trametinib. Moreover, in ISCs, trametinib decreases the activity of the RNA polymerase III (Pol III), a conserved enzyme synthesizing transfer RNAs and other short, non-coding RNAs, and whose inhibition also extends lifespan and reduces gut pathology. Finally, we show that the pro-longevity effect of trametinib in ISCs is partially mediated by Maf1, a repressor of Pol III, suggesting a life-limiting Ras/MAPK-Maf1-Pol III axis in these cells. The mechanism of action described in this work paves the way for further studies on the anti-aging effects of trametinib in mammals and shows its potential for clinical application in humans.
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Drosophila melanogaster , Drosophila , Piridonas , Pirimidinonas , Animales , Masculino , Humanos , Femenino , Anciano , Drosophila melanogaster/genética , Envejecimiento/fisiología , Células Madre/metabolismo , MamíferosRESUMEN
Reduced provision of protein translation machinery promotes healthy aging in a number of animal models. In humans, however, inborn impairments in translation machinery are a known cause of several developmental disorders, collectively termed ribosomopathies. Here, we use casual inference approaches in genetic epidemiology to investigate whether adult, tissue-specific biogenesis of translation machinery drives human aging. We assess naturally occurring variation in the expression of genes encoding subunits specific to the two RNA polymerases (Pols) that transcribe ribosomal and transfer RNAs, namely Pol I and III, and the variation in expression of ribosomal protein (RP) genes, using Mendelian randomization. We find each causally associated with human longevity (ß = -0.15 ± 0.047, P = 9.6 × 10-4, q = 0.015; ß = -0.13 ± 0.040, P = 1.4 × 10-3, q = 0.023; ß = -0.048 ± 0.016, P = 3.5 × 10-3, q = 0.056, respectively), and this does not appear to be mediated by altered susceptibility to a single disease. We find that reduced expression of Pol III, RPs, or Pol I promotes longevity from different organs, namely visceral adipose, liver, and skeletal muscle, echoing the tissue specificity of ribosomopathies. Our study shows the utility of leveraging genetic variation in expression to elucidate how essential cellular processes impact human aging. The findings extend the evolutionary conservation of protein synthesis as a critical process that drives animal aging to include humans.
Asunto(s)
Envejecimiento , Biosíntesis de Proteínas , ARN Polimerasa I , Envejecimiento/genética , Animales , ARN Polimerasas Dirigidas por ADN , Humanos , Análisis de la Aleatorización Mendeliana , ARN Polimerasa I/metabolismo , Proteínas Ribosómicas/genética , Ribosomas/genética , Ribosomas/metabolismoRESUMEN
A transient, homeostatic transcriptional response can result in transcriptional memory, programming subsequent transcriptional outputs. Transcriptional memory has great but unappreciated potential to alter animal aging as animals encounter a multitude of diverse stimuli throughout their lifespan. Here we show that activating an evolutionarily conserved, longevity-promoting transcription factor, dFOXO, solely in early adulthood of female fruit flies is sufficient to improve their subsequent health and survival in midlife and late life. This youth-restricted dFOXO activation causes persistent changes to chromatin landscape in the fat body and requires chromatin remodelers such as the SWI/SNF and ISWI complexes to program health and longevity. Chromatin remodeling is accompanied by a long-lasting transcriptional program that is distinct from that observed during acute dFOXO activation and includes induction of Xbp1. We show that this later-life induction of Xbp1 is sufficient to curtail later-life mortality. Our study demonstrates that transcriptional memory can profoundly alter how animals age.
Asunto(s)
Ensamble y Desensamble de Cromatina , Proteínas de Drosophila , Animales , Femenino , Ensamble y Desensamble de Cromatina/genética , Factores de Transcripción/genética , Regulación de la Expresión Génica , Drosophila/metabolismo , Cromatina/genética , Proteínas de Unión al ADN/genéticaRESUMEN
[This corrects the article DOI: 10.3389/fgene.2021.705122.].
RESUMEN
Transcription in eukaryotic cells is performed by three RNA polymerases. RNA polymerase I synthesises most rRNAs, whilst RNA polymerase II transcribes all mRNAs and many non-coding RNAs. The largest of the three polymerases is RNA polymerase III (Pol III) which transcribes a variety of short non-coding RNAs including tRNAs and the 5S rRNA, in addition to other small RNAs such as snRNAs, snoRNAs, SINEs, 7SL RNA, Y RNA, and U6 spilceosomal RNA. Pol III-mediated transcription is highly dynamic and regulated in response to changes in cell growth, cell proliferation and stress. Pol III-generated transcripts are involved in a wide variety of cellular processes, including translation, genome and transcriptome regulation and RNA processing, with Pol III dys-regulation implicated in diseases including leukodystrophy, Alzheimer's, Fragile X-syndrome and various cancers. More recently, Pol III was identified as an evolutionarily conserved determinant of organismal lifespan acting downstream of mTORC1. Pol III inhibition extends lifespan in yeast, worms and flies, and in worms and flies acts from the intestine and intestinal stem cells respectively to achieve this. Intriguingly, Pol III activation achieved through impairment of its master repressor, Maf1, has also been shown to promote longevity in model organisms, including mice. In this review we introduce the Pol III transcription apparatus and review the current understanding of RNA Pol III's role in ageing and lifespan in different model organisms. We then discuss the potential of Pol III as a therapeutic target to improve age-related health in humans.
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The increasing number of older people is resulting in an increased prevalence of age-related diseases. Research has shown that the ageing process itself is a potential point of intervention. Indeed, gene expression can be optimised for health in older ages through manipulation of transcription factor (TF) activity. This review is focused on the ever-growing number of TFs whose effects on ageing are evolutionarily conserved. These regulate a plethora of functions, including stress resistance, metabolism, and growth. They are engaged in complex interactions within and between different cell types, impacting the physiology of the entire organism. Since ageing is not programmed, the conservation of their effects on lifespan is most likely a reflection of the conservation of their functions in youth.
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Secuencia Conservada/genética , Evolución Molecular , Longevidad/genética , Factores de Transcripción/genética , Envejecimiento/genética , Regulación de la Expresión Génica/genética , HumanosRESUMEN
Inhibition of signalling through several receptor tyrosine kinases (RTKs), including the insulin-like growth factor receptor and its orthologues, extends healthy lifespan in organisms from diverse evolutionary taxa. This raises the possibility that other RTKs, including those already well studied for their roles in cancer and developmental biology, could be promising targets for extending healthy lifespan. Here, we focus on anaplastic lymphoma kinase (Alk), an RTK with established roles in nervous system development and in multiple cancers, but whose effects on aging remain unclear. We find that several means of reducing Alk signalling, including mutation of its ligand jelly belly (jeb), RNAi knock-down of Alk, or expression of dominant-negative Alk in adult neurons, can extend healthy lifespan in female, but not male, Drosophila. Moreover, reduced Alk signalling preserves neuromuscular function with age, promotes resistance to starvation and xenobiotic stress, and improves night sleep consolidation. We find further that inhibition of Alk signalling in adult neurons modulates the expression of several insulin-like peptides, providing a potential mechanistic link between neuronal Alk signalling and organism-wide insulin-like signalling. Finally, we show that TAE-684, a small molecule inhibitor of Alk, can extend healthy lifespan in Drosophila, suggesting that the repurposing of Alk inhibitors may be a promising direction for strategies to promote healthy aging.
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Quinasa de Linfoma Anaplásico/metabolismo , Longevidad , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Animales , Senescencia Celular/efectos de los fármacos , Drosophila , Femenino , Longevidad/efectos de los fármacos , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
The Insulin/IGF-1 signalling (IIS) pathway plays an essential role in the regulation of glucose and lipid homeostasis. At the same time, a reduction in the IIS pathway activity can extend lifespan and healthspan in various model organisms. Amongst a number of body organs that sense and respond to insulin/IGF-1, the adipose tissue has a central role in both the metabolic and lifespan effects of IIS at the organismal level. Genetic inactivation of IIS components specifically in the adipose tissue has been shown before to improve metabolic profile and extend lifespan in various model organisms. We sought to identify conserved molecular mechanisms that may underlie the beneficial effects of IIS inhibition in the adipose tissue, specifically at the level of phosphoinositide 3-kinase (PI3K), a key IIS effector molecule. To this end, we inactivated PI3K by genetic means in the fly fat body and by pharmacological inhibition in mammalian adipocytes. Gene expression studies revealed changes to metabolism and upregulation of mitochondrial activity in mouse adipocytes and fly fat bodies with downregulated PI3K, which were confirmed by biochemical assays in mammalian adipocytes. These data suggest that PI3K inactivation has a conserved effect of upregulating mitochondrial metabolism in both fly and mammalian adipose tissue, which likely contributes to the health- and life-span extending effect of IIS pathway downregulation.
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Tejido Adiposo/metabolismo , Proteínas de Drosophila/metabolismo , Insulina/metabolismo , Metabolismo de los Lípidos , Mitocondrias/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Células 3T3-L1 , Animales , Proteínas de Drosophila/genética , Drosophila melanogaster , Insulina/genética , Ratones , Mitocondrias/genética , Fosfatidilinositol 3-Quinasas/genéticaRESUMEN
Health and survival in old age can be improved by changes in gene expression. RNA polymerase (Pol) I is the essential, conserved enzyme whose task is to generate the pre-ribosomal RNA (rRNA). We find that reducing the levels of Pol I activity is sufficient to extend lifespan in the fruit fly. This effect can be recapitulated by partial, adult-restricted inhibition, with both enterocytes and stem cells of the adult midgut emerging as important cell types. In stem cells, Pol I appears to act in the same longevity pathway as Pol III, implicating rRNA synthesis in these cells as the key lifespan determinant. Importantly, reduction in Pol I activity delays broad, age-related impairment and pathology, improving the function of diverse organ systems. Hence, our study shows that Pol I activity in the adult drives systemic, age-related decline in animal health and anticipates mortality.
Asunto(s)
Proteínas de Drosophila/genética , Drosophila melanogaster/genética , ARN Polimerasa I/antagonistas & inhibidores , Animales , LongevidadRESUMEN
Ageing populations pose one of the main public health crises of our time. Reprogramming gene expression by altering the activities of sequence-specific transcription factors (TFs) can ameliorate deleterious effects of age. Here we explore how a circuit of TFs coordinates pro-longevity transcriptional outcomes, which reveals a multi-tissue and multi-species role for an entire protein family: the E-twenty-six (ETS) TFs. In Drosophila, reduced insulin/IGF signalling (IIS) extends lifespan by coordinating activation of Aop, an ETS transcriptional repressor, and Foxo, a Forkhead transcriptional activator. Aop and Foxo bind the same genomic loci, and we show that, individually, they effect similar transcriptional programmes in vivo. In combination, Aop can both moderate or synergise with Foxo, dependent on promoter context. Moreover, Foxo and Aop oppose the gene-regulatory activity of Pnt, an ETS transcriptional activator. Directly knocking down Pnt recapitulates aspects of the Aop/Foxo transcriptional programme and is sufficient to extend lifespan. The lifespan-limiting role of Pnt appears to be balanced by a requirement for metabolic regulation in young flies, in which the Aop-Pnt-Foxo circuit determines expression of metabolic genes, and Pnt regulates lipolysis and responses to nutrient stress. Molecular functions are often conserved amongst ETS TFs, prompting us to examine whether other Drosophila ETS-coding genes may also affect ageing. We show that five out of eight Drosophila ETS TFs play a role in fly ageing, acting from a range of organs and cells including the intestine, adipose and neurons. We expand the repertoire of lifespan-limiting ETS TFs in C. elegans, confirming their conserved function in ageing and revealing that the roles of ETS TFs in physiology and lifespan are conserved throughout the family, both within and between species.
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Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/fisiología , Proteínas del Ojo/metabolismo , Factores de Transcripción Forkhead/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Tejido Adiposo/metabolismo , Animales , Proteínas de Unión al ADN/genética , Drosophila/genética , Proteínas de Drosophila/genética , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Mucosa Intestinal/metabolismo , Lipólisis , Longevidad , Redes y Vías Metabólicas , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genéticaRESUMEN
Lifespan and health in older age are strongly influenced by diet. Feeding Drosophila melanogaster diets high in sugar has increasingly been used as an experimental model to understand the physiological effects of unhealthy, contemporary human diets. Several metabolic parameters and physiological responses to nutrition are known to be dependent on the sex of the animal. However, sexual dimorphism in the responses to high-sugar diets in fruit flies has not been examined. Here we show that a high-sugar diet in Drosophila melanogaster elicits sexually dimorphic effects on feeding behaviour, starvation resistance and lifespan. Females feed less on such diets, while males feed more, and these feeding responses may have secondary consequences. Females, more than males, gain the ability to resist periods of starvation from high-sugar diets, indicating that the female response to excess sugar may be geared towards surviving food shortages in early life. At the same time, female lifespan is more susceptible to the detrimental effects of high sugar diets. Our study reveals differences between Drosophila sexes in their responses to sugar-rich diets, indicating the fruit fly could be used as a model to understand the sexually dimorphic features of human metabolic health.
Asunto(s)
Azúcares de la Dieta/efectos adversos , Conducta Alimentaria/fisiología , Longevidad/fisiología , Caracteres Sexuales , Animales , Drosophila melanogaster , Femenino , MasculinoRESUMEN
Three distinct RNA polymerases transcribe different classes of genes in the eukaryotic nucleus. RNA polymerase (Pol) III is the essential, evolutionarily conserved enzyme that generates short, non-coding RNAs, including tRNAs and 5S rRNA. The historical focus on transcription of protein-coding genes has left the roles of Pol III in organismal physiology relatively unexplored. Target of rapamycin kinase complex 1 (TORC1) regulates Pol III activity, and is also an important determinant of longevity. This raises the possibility that Pol III is involved in ageing. Here we show that Pol III limits lifespan downstream of TORC1. We find that a reduction in Pol III extends chronological lifespan in yeast and organismal lifespan in worms and flies. Inhibiting the activity of Pol III in the gut of adult worms or flies is sufficient to extend lifespan; in flies, longevity can be achieved by Pol III inhibition specifically in intestinal stem cells. The longevity phenotype is associated with amelioration of age-related gut pathology and functional decline, dampened protein synthesis and increased tolerance of proteostatic stress. Pol III acts on lifespan downstream of TORC1, and limiting Pol III activity in the adult gut achieves the full longevity benefit of systemic TORC1 inhibition. Hence, Pol III is a pivotal mediator of this key nutrient-signalling network for longevity; the growth-promoting anabolic activity of Pol III mediates the acceleration of ageing by TORC1. The evolutionary conservation of Pol III affirms its potential as a therapeutic target.
Asunto(s)
Longevidad/fisiología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , ARN Polimerasa III/metabolismo , Envejecimiento/efectos de los fármacos , Envejecimiento/fisiología , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/enzimología , Caenorhabditis elegans/fisiología , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/enzimología , Drosophila melanogaster/fisiología , Evolución Molecular , Femenino , Alimentos , Intestinos/citología , Intestinos/enzimología , Longevidad/efectos de los fármacos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Biosíntesis de Proteínas , ARN Polimerasa III/antagonistas & inhibidores , ARN Polimerasa III/deficiencia , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/fisiología , Células Madre/citología , Células Madre/enzimologíaRESUMEN
Reduced activity of nutrient-sensing signaling networks can extend organismal lifespan, yet the underlying biology remains unclear. We show that the anti-aging effects of rapamycin and reduced intestinal insulin/insulin growth factor (IGF) signaling (IIS) require the Drosophila FoxA transcription factor homolog Fork Head (FKH). Intestinal FKH induction extends lifespan, highlighting a role for the gut. FKH binds to and is phosphorylated by AKT and Target of Rapamycin. Gut-specific FKH upregulation improves gut barrier function in aged flies. Additionally, it increases the expression of nutrient transporters, as does lowered IIS. Evolutionary conservation of this effect of lowered IIS is suggested by the upregulation of related nutrient transporters in insulin receptor substrate 1 knockout mouse intestine. Our study highlights a critical role played by FKH in the gut in mediating anti-aging effects of reduced IIS. Malnutrition caused by poor intestinal absorption is a major problem in the elderly, and a better understanding of the mechanisms involved will have important therapeutic implications for human aging.
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Drosophila melanogaster/metabolismo , Drosophila melanogaster/fisiología , Alimentos , Factores de Transcripción Forkhead/metabolismo , Absorción Intestinal , Mucosa Intestinal/metabolismo , Longevidad , Proteínas Nucleares/metabolismo , Animales , Restricción Calórica , Diferenciación Celular/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Enterocitos/efectos de los fármacos , Enterocitos/metabolismo , Femenino , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Absorción Intestinal/efectos de los fármacos , Intestinos/citología , Longevidad/efectos de los fármacos , Proteínas de Transporte de Membrana/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sirolimus/farmacología , Somatomedinas/metabolismo , Transcripción Genética/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Lowered activity of the insulin/IGF signalling (IIS) network can ameliorate the effects of ageing in laboratory animals and, possibly, humans. Although transcriptome remodelling in long-lived IIS mutants has been extensively documented, the causal mechanisms contributing to extended lifespan, particularly in specific tissues, remain unclear. We have characterized the proteomes of four key insulin-sensitive tissues in a long-lived Drosophila IIS mutant and control, and detected 44% of the predicted proteome (6,085 proteins). Expression of ribosome-associated proteins in the fat body was reduced in the mutant, with a corresponding, tissue-specific reduction in translation. Expression of mitochondrial electron transport chain proteins in fat body was increased, leading to increased respiration, which was necessary for IIS-mediated lifespan extension, and alone sufficient to mediate it. Proteasomal subunits showed altered expression in IIS mutant gut, and gut-specific over-expression of the RPN6 proteasomal subunit, was sufficient to increase proteasomal activity and extend lifespan, whilst inhibition of proteasome activity abolished IIS-mediated longevity. Our study thus uncovered strikingly tissue-specific responses of cellular processes to lowered IIS acting in concert to ameliorate ageing.
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Envejecimiento/metabolismo , Drosophila/metabolismo , Redes Reguladoras de Genes , Proteómica/métodos , Animales , Proteínas de Drosophila , Cuerpo Adiposo/metabolismo , Insulina/metabolismo , Mucosa Intestinal/metabolismo , Modelos Animales , Mutación , Especificidad de Órganos , Proteínas Ribosómicas/metabolismoRESUMEN
Consumption of unhealthy diets is exacerbating the burden of age-related ill health in aging populations. Such diets can program mammalian physiology to cause long-term, detrimental effects. Here, we show that, in Drosophila melanogaster, an unhealthy, high-sugar diet in early adulthood programs lifespan to curtail later-life survival despite subsequent dietary improvement. Excess dietary sugar promotes insulin-like signaling, inhibits dFOXO-the Drosophila homolog of forkhead box O (FOXO) transcription factors-and represses expression of dFOXO target genes encoding epigenetic regulators. Crucially, dfoxo is required both for transcriptional changes that mark the fly's dietary history and for nutritional programming of lifespan by excess dietary sugar, and this mechanism is conserved in Caenorhabditis elegans. Our study implicates FOXO factors, the evolutionarily conserved determinants of animal longevity, in the mechanisms of nutritional programming of animal lifespan.
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Fenómenos Fisiológicos Nutricionales de los Animales , Dieta , Carbohidratos de la Dieta/farmacología , Proteínas de Drosophila/antagonistas & inhibidores , Drosophila melanogaster/fisiología , Factores de Transcripción Forkhead/antagonistas & inhibidores , Longevidad , Animales , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Factores de Transcripción Forkhead/metabolismo , Análisis de Supervivencia , Transcripción Genética/efectos de los fármacosRESUMEN
Age-related cognitive decline is one of the most haunting aspects of human aging. In a recent publication, Coleen Murphy and colleagues (Kaletsky et al., 2016) describe the transcriptional program that maintains youthful function of aging neurons in the nematode worm.