RESUMEN
The quest to slow aging has come far, and what used to be the domain of science fiction writers and snake oil salesmen may soon become science fact. Innovative new approaches, such as the use of the very short-lived African killifish (Harel et al.), are bridging the translational gap and bring the promise of healthy longevity to fruition.
Asunto(s)
Peces Killi/fisiología , Animales , Femenino , Humanos , MasculinoRESUMEN
The Dog Aging Project is a long-term longitudinal study of ageing in tens of thousands of companion dogs. The domestic dog is among the most variable mammal species in terms of morphology, behaviour, risk of age-related disease and life expectancy. Given that dogs share the human environment and have a sophisticated healthcare system but are much shorter-lived than people, they offer a unique opportunity to identify the genetic, environmental and lifestyle factors associated with healthy lifespan. To take advantage of this opportunity, the Dog Aging Project will collect extensive survey data, environmental information, electronic veterinary medical records, genome-wide sequence information, clinicopathology and molecular phenotypes derived from blood cells, plasma and faecal samples. Here, we describe the specific goals and design of the Dog Aging Project and discuss the potential for this open-data, community science study to greatly enhance understanding of ageing in a genetically variable, socially relevant species living in a complex environment.
Asunto(s)
Envejecimiento/fisiología , Perros/fisiología , Difusión de la Información , Mascotas/fisiología , Envejecimiento/efectos de los fármacos , Envejecimiento/genética , Animales , Biomarcadores , Entorno Construido , Ensayos Clínicos Veterinarios como Asunto , Estudios Transversales , Recolección de Datos , Perros/genética , Femenino , Fragilidad/veterinaria , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Objetivos , Envejecimiento Saludable/efectos de los fármacos , Humanos , Inflamación/veterinaria , Consentimiento Informado , Estilo de Vida , Longevidad/efectos de los fármacos , Longevidad/genética , Longevidad/fisiología , Estudios Longitudinales , Masculino , Modelos Animales , Multimorbilidad , Mascotas/genética , Privacidad , Sirolimus/farmacologíaRESUMEN
Organs and tissues age at different rates within a single individual. Such asynchrony in aging has been widely observed at multiple levels, from functional hallmarks, such as anatomical structures and physiological processes, to molecular endophenotypes, such as the transcriptome and metabolome. However, we lack a conceptual framework to understand why some components age faster than others. Just as demographic models explain why aging evolves, here we test the hypothesis that demographic differences among cell types, determined by cell-specific differences in turnover rate, can explain why the transcriptome shows signs of aging in some cell types but not others. Through analysis of mouse single-cell transcriptome data across diverse tissues and ages, we find that cellular age explains a large proportion of the variation in the age-related increase in transcriptome variance. We further show that long-lived cells are characterized by relatively high expression of genes associated with proteostasis and that the transcriptome of long-lived cells shows greater evolutionary constraint than short-lived cells. In contrast, in short-lived cell types, the transcriptome is enriched for genes associated with DNA repair. Based on these observations, we develop a novel heuristic model that explains how and why aging rates differ among cell types.
RESUMEN
The motivation to reproduce is a potent natural drive, and the social behaviors that induce it can severely impact animal health and lifespan. Indeed, in Drosophila males, accelerated aging associated with reproduction arises not from the physical act of courtship or copulation but instead from the motivational drive to court and mate. To better understand the mechanisms underlying social effects on aging, we studied male choosiness for mates. We found that increased activity of insulin-producing cells (IPCs) of the fly brain potentiated choosiness without consistently affecting courtship activity. Surprisingly, this effect was not caused by insulins themselves, but instead by drosulfakinin (DSK), another neuropeptide produced in a subset of the IPCs, acting through one of the two DSK receptors, CCKLR-17D1. Activation of Dsk+ IPC neurons also decreased food consumption, while activation of Dsk+ neurons outside of IPCs affected neither choosiness nor feeding, suggesting an overlap between Dsk+neurons modulating choosiness and those influencing satiety. Broader activation of Dsk+ neurons (both within and outside of the IPCs) was required to rescue the detrimental effect of female pheromone exposure on male lifespan, as was the function of both DSK receptors. The same broad set of Dsk+ neurons was found to reinforce normally aversive feeding interactions, but only after exposure to female pheromones, suggesting that perception of the opposite sex gates rewarding properties of these neurons. We speculate that broad Dsk+ neuron activation is associated with states of satiety and social experience, which under stressful conditions is rewarding and beneficial for lifespan.
Asunto(s)
Proteínas de Drosophila , Neuropéptidos , Animales , Masculino , Femenino , Drosophila melanogaster/fisiología , Proteínas de Drosophila/genética , Neuropéptidos/química , Drosophila , Percepción Social , Envejecimiento , Conducta Sexual Animal/fisiologíaRESUMEN
[This corrects the article DOI: 10.1371/journal.pgen.1008835.].
RESUMEN
The evolutionary context of why caloric restriction (CR) activates physiological mechanisms that slow the process of aging remains unclear. The main goal of this analysis was to identify, using metabolomics, the common pathways that are modulated across multiple tissues (brown adipose tissue, liver, plasma, and brain) to evaluate two alternative evolutionary models: the "disposable soma" and "clean cupboards" ideas. Across the four tissues, we identified more than 10,000 different metabolic features. CR altered the metabolome in a graded fashion. More restriction led to more changes. Most changes, however, were tissue specific, and in some cases, metabolites changed in opposite directions in different tissues. Only 38 common metabolic features responded to restriction in the same way across all four tissues. Fifty percent of the common altered metabolites were carboxylic acids and derivatives, as well as lipids and lipid-like molecules. The top five modulated canonical pathways were l-carnitine biosynthesis, NAD (nicotinamide adenine dinucleotide) biosynthesis from 2-amino-3-carboxymuconate semialdehyde, S-methyl-5'-thioadenosine degradation II, NAD biosynthesis II (from tryptophan), and transfer RNA (tRNA) charging. Although some pathways were modulated in common across tissues, none of these reflected somatic protection, and each tissue invoked its own idiosyncratic modulation of pathways to cope with the reduction in incoming energy. Consequently, this study provides greater support for the clean cupboards hypothesis than the disposable soma interpretation.
Asunto(s)
Restricción Calórica , Carnitina/biosíntesis , Metabolismo Energético/fisiología , NAD/biosíntesis , ARN de Transferencia/metabolismo , Alimentación Animal/análisis , Animales , Dieta/veterinaria , Regulación de la Expresión Génica/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , ARN de Transferencia/genética , Distribución Aleatoria , Distribución TisularRESUMEN
Cognitive deficits are a major biomedical challenge-and engagement of the brain in stimulating tasks improves cognition in aged individuals (Wilson et al., 2002; Gates et al., 2011) and rodents (Aidil-Carvalho et al., 2017), through unknown mechanisms. Whether cognitive stimulation alters specific metabolic pathways in the brain is unknown. Understanding which metabolic processes are involved in cognitive stimulation is important because it could lead to pharmacologic intervention that promotes biological effects of a beneficial behavior, toward the goal of effective medical treatments for cognitive deficits. Here we show using male mice that cognitive stimulation induced metabolic remodeling of the mouse hippocampus, and that pharmacologic treatment with the longevity hormone α-klotho (KL), mediated by its KL1 domain, partially mimicked this alteration. The shared, metabolic signature shared between cognitive stimulation and treatment with KL or KL1 closely correlated with individual mouse cognitive performance, indicating a link between metabolite levels and learning and memory. Importantly, the treatment of mice with KL1, an endogenous circulating factor that more closely mimicked cognitive stimulation than KL, acutely increased synaptic plasticity, a substrate of cognition. KL1 also improved cognition, itself, in young mice and countered deficits in old mice. Our data show that treatments or interventions mimicking the hippocampal metabolome of cognitive stimulation can enhance brain functions. Further, we identify the specific domain by which klotho promotes brain functions, through KL1, a metabolic mimic of cognitive stimulation.SIGNIFICANCE STATEMENT Cognitive deficits are a major biomedical challenge without truly effective pharmacologic treatments. Engaging the brain through cognitive tasks benefits cognition. Mimicking the effects of such beneficial behaviors through pharmacological treatment represents a highly valuable medical approach to treating cognitive deficits. We demonstrate that brain engagement through cognitive stimulation induces metabolic remodeling of the hippocampus that was acutely recapitulated by the longevity factor klotho, mediated by its KL1 domain. Treatment with KL1, a close mimic of cognitive stimulation, enhanced cognition and countered cognitive aging. Our findings shed light on how cognition metabolically alters the brain and provide a plausible therapeutic intervention for mimicking these alterations that, in turn, improves cognition in the young and aging brain.
Asunto(s)
Glucuronidasa , Longevidad , Envejecimiento , Animales , Cognición/fisiología , Glucuronidasa/química , Glucuronidasa/metabolismo , Hidrolasas/metabolismo , Proteínas Klotho , Masculino , Metaboloma , RatonesRESUMEN
Comparative phylogenetic studies offer a powerful approach to study the evolution of complex traits. Although much effort has been devoted to the evolution of the genome and to organismal phenotypes, until now relatively little work has been done on the evolution of the metabolome, despite the fact that it is composed of the basic structural and functional building blocks of all organisms. Here we explore variation in metabolite levels across 50 My of evolution in the genus Drosophila, employing a common garden design to measure the metabolome within and among 11 species of Drosophila. We find that both sex and age have dramatic and evolutionarily conserved effects on the metabolome. We also find substantial evidence that many metabolite pairs covary after phylogenetic correction, and that such metabolome coevolution is modular. Some of these modules are enriched for specific biochemical pathways and show different evolutionary trajectories, with some showing signs of stabilizing selection. Both observations suggest that functional relationships may ultimately cause such modularity. These coevolutionary patterns also differ between sexes and are affected by age. We explore the relevance of modular evolution to fitness by associating modules with lifespan variation measured in the same common garden. We find several modules associated with lifespan, particularly in the metabolome of older flies. Oxaloacetate levels in older females appear to coevolve with lifespan, and a lifespan-associated module in older females suggests that metabolic associations could underlie 50 My of lifespan evolution.
Asunto(s)
Drosophila , Metaboloma , Animales , Evolución Biológica , Drosophila/genética , Drosophila/metabolismo , Femenino , Longevidad/genética , Fenotipo , FilogeniaRESUMEN
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.
Asunto(s)
Envejecimiento/genética , Proteínas de Drosophila/genética , Longevidad/genética , Metaboloma/genética , Receptores Acoplados a Proteínas G/genética , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Restricción Calórica , Dieta , Drosophila melanogaster/genética , Drosophila melanogaster/crecimiento & desarrollo , Regulación del Desarrollo de la Expresión Génica/genética , Insulina/genética , Metabolómica , Mutación/genética , Transducción de Señal/genéticaRESUMEN
An enormous amount of work has been done on aging in Drosophila melanogaster, a classical genetic and molecular model system, but also in numerous other insects. However, these two extensive bodies of work remain poorly integrated to date. Studies in Drosophila often explore genetic, developmental, physiological, and nutrition-related aspects of aging in the lab, while studies in other insects often explore ecological, social, and somatic aspects of aging in both lab and natural populations. Alongside exciting genomic and molecular research advances in aging in Drosophila, many new studies have also been published on aging in various other insects, including studies on aging in natural populations of diverse species. However, no broad synthesis of these largely separate bodies of work has been attempted. In this review, we endeavor to synthesize these two semi-independent literatures to facilitate collaboration and foster the exchange of ideas and research tools. While lab studies of Drosophila have illuminated many fundamental aspects of senescence, the stunning diversity of aging patterns among insects, especially in the context of their rich ecology, remains vastlyunderstudied. Coupled with field studies and novel, more easily applicable molecular methods, this represents a major opportunity for deepening our understanding of the biology of aging in insects and beyond.
Asunto(s)
Envejecimiento , Drosophila melanogaster , Insectos , Animales , Drosophila melanogaster/fisiología , Insectos/fisiologíaRESUMEN
Mutations accumulate within somatic cells and have been proposed to contribute to aging. It is unclear what level of mutation burden may be required to consistently reduce cellular lifespan. Human cancers driven by a mutator phenotype represent an intriguing model to test this hypothesis, since they carry the highest mutation burdens of any human cell. However, it remains technically challenging to measure the replicative lifespan of individual mammalian cells. Here, we modeled the consequences of cancer-related mutator phenotypes on lifespan using yeast defective for mismatch repair (MMR) and/or leading strand (Polε) or lagging strand (Polδ) DNA polymerase proofreading. Only haploid mutator cells with significant lifetime mutation accumulation (MA) exhibited shorter lifespans. Diploid strains, derived by mating haploids of various genotypes, carried variable numbers of fixed mutations and a range of mutator phenotypes. Some diploid strains with fewer than two mutations per megabase displayed a 25% decrease in lifespan, suggesting that moderate numbers of random heterozygous mutations can increase mortality rate. As mutation rates and burdens climbed, lifespan steadily eroded. Strong diploid mutator phenotypes produced a form of genetic anticipation with regard to aging, where the longer a lineage persisted, the shorter lived cells became. Using MA lines, we established a relationship between mutation burden and lifespan, as well as population doubling time. Our observations define a threshold of random mutation burden that consistently decreases cellular longevity in diploid yeast cells. Many human cancers carry comparable mutation burdens, suggesting that while cancers appear immortal, individual cancer cells may suffer diminished lifespan due to accrued mutation burden.
Asunto(s)
Envejecimiento/genética , Reparación del ADN/genética , Longevidad/genética , Neoplasias/genética , Envejecimiento/patología , Reparación de la Incompatibilidad de ADN/genética , Replicación del ADN/genética , Genotipo , Humanos , Mutación/genética , Acumulación de Mutaciones , Tasa de Mutación , Neoplasias/patología , Fenotipo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Secuenciación Completa del GenomaRESUMEN
BACKGROUND: Differential correlation networks are increasingly used to delineate changes in interactions among biomolecules. They characterize differences between omics networks under two different conditions, and can be used to delineate mechanisms of disease initiation and progression. RESULTS: We present a new R package, CorDiffViz, that facilitates the estimation and visualization of differential correlation networks using multiple correlation measures and inference methods. The software is implemented in R, HTML and Javascript, and is available at https://github.com/sqyu/CorDiffViz . Visualization has been tested for the Chrome and Firefox web browsers. A demo is available at https://diffcornet.github.io/CorDiffViz/demo.html . CONCLUSIONS: Our software offers considerable flexibility by allowing the user to interact with the visualization and choose from different estimation methods and visualizations. It also allows the user to easily toggle between correlation networks for samples under one condition and differential correlations between samples under two conditions. Moreover, the software facilitates integrative analysis of cross-correlation networks between two omics data sets.
Asunto(s)
Programas Informáticos , Navegador WebRESUMEN
The yeast genome becomes unstable during stress, which often results in adaptive aneuploidy, allowing rapid activation of protective mechanisms that restore cellular homeostasis. In this study, we performed a genetic screen in Saccharomyces cerevisiae to identify genome adaptations that confer resistance to tunicamycin-induced endoplasmic reticulum (ER) stress. Whole-genome sequencing of tunicamycin-resistant mutants revealed that ER stress resistance correlated significantly with gains of chromosomes II and XIII. We found that chromosome duplications allow adaptation of yeast cells to ER stress independently of the unfolded protein response, and that the gain of an extra copy of chromosome II alone is sufficient to induce protection from tunicamycin. Moreover, the protective effect of disomic chromosomes can be recapitulated by overexpression of several genes located on chromosome II. Among these genes, overexpression of UDP-N-acetylglucosamine-1-P transferase (ALG7), a subunit of the 20S proteasome (PRE7), and YBR085C-A induced tunicamycin resistance in wild-type cells, whereas deletion of all three genes completely reversed the tunicamycin-resistance phenotype. Together, our data demonstrate that aneuploidy plays a critical role in adaptation to ER stress by increasing the copy number of ER stress protective genes. While aneuploidy itself leads to proteotoxic stress, the gene-specific effects of chromosome II aneuploidy counteract the negative effect resulting in improved protein folding.
Asunto(s)
Adaptación Fisiológica/genética , Aneuploidia , Estrés del Retículo Endoplásmico/genética , Regulación Fúngica de la Expresión Génica/fisiología , Saccharomyces cerevisiae/fisiología , Cromosomas Fúngicos/genética , Farmacorresistencia Fúngica/genética , Fosfotransferasas (Aceptor del Grupo Fosfato)/genética , Fosfotransferasas (Aceptor del Grupo Fosfato)/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Pliegue de Proteína , Tunicamicina/farmacología , Respuesta de Proteína Desplegada/fisiologíaRESUMEN
BACKGROUND: Genetic association studies that seek to explain the inheritance of complex traits typically fail to explain a majority of the heritability of the trait under study. Thus, we are left with a gap in the map from genotype to phenotype. Several approaches have been used to fill this gap, including those that attempt to map endophenotype such as the transcriptome, proteome or metabolome, that underlie complex traits. Here we used metabolomics to explore the nature of genetic variation for hydrogen peroxide (H2O2) resistance in the sequenced inbred Drosophila Genetic Reference Panel (DGRP). RESULTS: We first studied genetic variation for H2O2 resistance in 179 DGRP lines and along with identifying the insulin signaling modulator u-shaped and several regulators of feeding behavior, we estimate that a substantial amount of phenotypic variation can be explained by a polygenic model of genetic variation. We then profiled a portion of the aqueous metabolome in subsets of eight 'high resistance' lines and eight 'low resistance' lines. We used these lines to represent collections of genotypes that were either resistant or sensitive to the stressor, effectively modeling a discrete trait. Across the range of genotypes in both populations, flies exhibited surprising consistency in their metabolomic signature of resistance. Importantly, the resistance phenotype of these flies was more easily distinguished by their metabolome profiles than by their genotypes. Furthermore, we found a metabolic response to H2O2 in sensitive, but not in resistant genotypes. Metabolomic data further implicated at least two pathways, glycogen and folate metabolism, as determinants of sensitivity to H2O2. We also discovered a confounding effect of feeding behavior on assays involving supplemented food. CONCLUSIONS: This work suggests that the metabolome can be a point of convergence for genetic variation influencing complex traits, and can efficiently elucidate mechanisms underlying trait variation.
Asunto(s)
Drosophila melanogaster/fisiología , Peróxido de Hidrógeno/metabolismo , Metaboloma , Estrés Oxidativo/genética , Animales , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Femenino , Ácido Fólico/metabolismo , Genes de Insecto/genética , Variación Genética , Genoma de los Insectos/genética , Genotipo , Glucógeno/metabolismo , Redes y Vías Metabólicas/genética , Herencia Multifactorial , FenotipoRESUMEN
Inbreeding poses a real or potential threat to nearly every species of conservation concern. Inbreeding leads to loss of diversity at the individual level, which can cause inbreeding depression, and at the population level, which can hinder ability to respond to a changing environment. In closed populations such as endangered species and ex situ breeding programs, some degree of inbreeding is inevitable. It is therefore vital to understand how different patterns of breeding and inbreeding can affect fitness in real animals. Domestic dogs provide an excellent model, showing dramatic variation in degree of inbreeding and in lifespan, an important aspect of fitness that is known to be impacted by inbreeding in other species. There is a strong negative correlation between body size and lifespan in dogs, but it is unknown whether the higher rate of aging in large dogs is due to body size per se or some other factor associated with large size. We used dense genome-wide SNP array data to calculate average inbreeding for over 100 dog breeds based on autozygous segment length and found that large breeds tend to have higher coefficients of inbreeding than small breeds. We then used data from the Veterinary medical Database and other published sources to estimate life expectancies for pure and mixed breed dogs. When controlling for size, variation in inbreeding was not associated with life expectancy across breeds. When comparing mixed versus purebred dogs, however, mixed breed dogs lived about 1.2 years longer on average than size-matched purebred dogs. Furthermore, individual pedigree coefficients of inbreeding and lifespans for over 9000 golden retrievers showed that inbreeding does negatively impact lifespan at the individual level. Registration data from the American Kennel Club suggest that the molecular inbreeding patterns observed in purebred dogs result from specific breeding practices and/or founder effects and not the current population size. Our results suggest that recent inbreeding, as reflected in variation within a breed, is more likely to affect fitness than historic inbreeding, as reflected in variation among breeds. Our results also indicate that occasional outcrosses, as in mixed breed dogs, can have a substantial positive effect on fitness.
RESUMEN
Individuals choose their mates so as to maximize reproductive success, and one important component of this choice is assessment of traits reflecting mate quality. Little is known about why specific traits are used for mate quality assessment nor about how they reflect it. We have previously shown that global manipulation of insulin signaling, a nutrient-sensing pathway governing investment in survival versus reproduction, affects female sexual attractiveness in the fruit fly, Drosophila melanogaster. Here we demonstrate that these effects on attractiveness derive from insulin signaling in the fat body and ovarian follicle cells, whose signals are integrated by pheromone-producing cells called oenocytes. Functional ovaries were required for global insulin signaling effects on attractiveness, and manipulations of insulin signaling specifically in late follicle cells recapitulated effects of global manipulations. Interestingly, modulation of insulin signaling in the fat body produced opposite effects on attractiveness, suggesting a competitive relationship with the ovary. Furthermore, all investigated tissue-specific insulin signaling manipulations that changed attractiveness also changed fecundity in the corresponding direction, pointing to insulin pathway activity as a reliable link between fecundity and attractiveness cues. The cues themselves, cuticular hydrocarbons, responded distinctly to fat body and follicle cell manipulations, indicating independent readouts of the pathway activity from these two tissues. Thus, here we describe a system in which female attractiveness results from an apparent connection between attractiveness cues and an organismal state of high fecundity, both of which are created by lowered insulin signaling in the fat body and increased insulin signaling in late follicle cells.
Asunto(s)
Drosophila melanogaster/fisiología , Cuerpo Adiposo/fisiología , Insulina/fisiología , Folículo Ovárico/fisiología , Conducta Sexual Animal , Transducción de Señal , Adiposidad , Animales , Células Epiteliales/fisiología , Femenino , Fertilidad/fisiología , Hidrocarburos/sangre , Masculino , Feromonas/fisiología , ReproducciónRESUMEN
Recently, the common marmoset has been proposed as a non-human primate model of aging. Their short lifespan coupled with pathologies that are similar to humans make them an ideal model to understand the genetic, metabolic, and environmental factors that influence aging and longevity. However, many of the underlying physiological changes that occur with age in the marmoset are unknown. Here, we attempt to determine if individual metabolites are predictive of future death and to recapitulate past metabolomic results after a change in environment (move across the country) was imposed on a colony of marmosets. We first determined that low levels of tryptophan metabolism metabolites were associated with risk of death in a 2-year follow-up in the animals, suggesting these metabolites may be used as future biomarkers of mortality. We also discovered that betaine metabolism and methionine metabolism are associated with aging regardless of environment for the animals, or of metabolomic assay technique. These two metabolic pathways are therefore of particular interest to examine as future targets for health and lifespan extending interventions. Many of the pathways associated with age in our first study of marmoset metabolomics were not found to have significant age effects in our second study, suggesting more work is needed to understand the reproducibility of large scale metabolomic studies in mammalian models. Overall, we were able to show that while several metabolomics markers show promise in understanding health and lifespan relationships with aging, it is possible that choice of technique for assay and reproducibility in these types of studies are still issues that need to be examined further.
Asunto(s)
Biomarcadores/sangre , Callithrix/metabolismo , Metaboloma , Mortalidad , Envejecimiento , Crianza de Animales Domésticos , Animales , Betaína/metabolismo , Callithrix/sangre , Femenino , Masculino , Metaboloma/fisiología , Metionina/metabolismo , Triptófano/metabolismoRESUMEN
The questions and methods of molecular biology and evolutionary biology are clearly distinct, yet a unified approach can lead to deep insights. Unfortunately, attempts to unify these approaches are fraught with pitfalls. In this informal series of questions and answers, we offer the mechanistically oriented biologist a set of steps to come up with evolutionarily reasonable and meaningful hypotheses. We emphasize the critical power and importance of carefully constructed null hypotheses, and we illustrate our ideas with examples representing a range of topics, from the biology of aging, to protein structure, to speciation, and more. We also stress the importance of mathematics as the lingua franca for biologists of all stripes, and encourage mechanistic biologists to seek out quantitative collaborators to build explicit mathematical models, making their assumptions explicit, and their logic clear and testable. Biologists in all realms of inquiry stand to gain from strong bridges between our disciplines.
Asunto(s)
Evolución Biológica , Envejecimiento/genética , Animales , Humanos , Conformación Proteica , Proteínas/genética , Proteínas/metabolismoRESUMEN
The angiotensin-converting enzyme (ACE) is a peptidase that is involved in the synthesis of Angiotensin II, the bioactive component of the renin-angiotensin system. A growing body of literature argues for a beneficial impact of ACE inhibitors (ACEi) on age-associated metabolic disorders, mediated by cellular changes in reactive oxygen species (ROS) that improve mitochondrial function. Yet, our understanding of the relationship between ACEi therapy and metabolic parameters is limited. Here, we used three genetically diverse strains of Drosophila melanogaster to show that Lisinopril treatment reduces thoracic ROS levels and mitochondrial respiration in young flies, and increases mitochondrial content in middle-aged flies. Using untargeted metabolomics analysis, we also showed that Lisinopril perturbs the thoracic metabolic network structure by affecting metabolic pathways involved in glycogen degradation, glycolysis, and mevalonate metabolism. The Lisinopril-induced effects on mitochondrial and metabolic parameters, however, are genotype-specific and likely reflect the drug's impact on nutrient-dependent fitness traits. Accordingly, we found that Lisinopril negatively affects survival under nutrient starvation, an effect that can be blunted by genotype and age in a manner that partially mirrors the drug-induced changes in mitochondrial respiration. In conclusion, our results provide novel and important insights into the role of ACEi in cellular metabolism.