RESUMO
With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice.
Assuntos
Envelhecimento , Longevidade , Humanos , BiomarcadoresRESUMO
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.
Assuntos
Peixes Listrados/fisiologia , Animais , Feminino , Humanos , MasculinoRESUMO
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.
Assuntos
Envelhecimento/fisiologia , Cães/fisiologia , Disseminação de Informação , Animais de Estimação/fisiologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Biomarcadores , Ambiente Construído , Ensaios Clínicos Veterinários como Assunto , Estudos Transversais , Coleta de Dados , Cães/genética , Feminino , Fragilidade/veterinária , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Objetivos , Envelhecimento Saudável/efeitos dos fármacos , Humanos , Inflamação/veterinária , Consentimento Livre e Esclarecido , Estilo de Vida , Longevidade/efeitos dos fármacos , Longevidade/genética , Longevidade/fisiologia , Estudos Longitudinais , Masculino , Modelos Animais , Multimorbidade , Animais de Estimação/genética , Privacidade , Sirolimo/farmacologiaRESUMO
In nearly every organism studied, reduced caloric intake extends life span. In yeast, span extension from dietary restriction is thought to be mediated by the highly conserved, nutrient-responsive target of rapamycin (TOR), protein kinase A (PKA), and Sch9 kinases. These kinases coordinately regulate various cellular processes including stress responses, protein turnover, cell growth, and ribosome biogenesis. Here we show that a specific reduction of 60S ribosomal subunit levels slows aging in yeast. Deletion of genes encoding 60S subunit proteins or processing factors or treatment with a small molecule, which all inhibit 60S subunit biogenesis, are each sufficient to significantly increase replicative life span. One mechanism by which reduced 60S subunit levels leads to life span extension is through induction of Gcn4, a nutrient-responsive transcription factor. Genetic epistasis analyses suggest that dietary restriction, reduced 60S subunit abundance, and Gcn4 activation extend yeast life span by similar mechanisms.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Subunidades Ribossômicas Maiores de Eucariotos/fisiologia , Proteínas de Saccharomyces cerevisiae/fisiologia , Saccharomyces cerevisiae/fisiologia , Fatores de Transcrição/fisiologia , Fatores de Transcrição de Zíper de Leucina Básica , Deleção de Genes , Histona Desacetilases/fisiologia , Proteínas Ribossômicas/fisiologia , Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae/fisiologia , Sirtuína 2 , Sirtuínas/fisiologiaRESUMO
Epigenetic mechanisms, including histone post-translational modifications, control longevity in diverse organisms. Relatedly, loss of proper transcriptional regulation on a global scale is an emerging phenomenon of shortened life span, but the specific mechanisms linking these observations remain to be uncovered. Here, we describe a life span screen in Saccharomyces cerevisiae that is designed to identify amino acid residues of histones that regulate yeast replicative aging. Our results reveal that lack of sustained histone H3K36 methylation is commensurate with increased cryptic transcription in a subset of genes in old cells and with shorter life span. In contrast, deletion of the K36me2/3 demethylase Rph1 increases H3K36me3 within these genes, suppresses cryptic transcript initiation, and extends life span. We show that this aging phenomenon is conserved, as cryptic transcription also increases in old worms. We propose that epigenetic misregulation in aging cells leads to loss of transcriptional precision that is detrimental to life span, and, importantly, this acceleration in aging can be reversed by restoring transcriptional fidelity.
Assuntos
Epigênese Genética/fisiologia , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histonas/metabolismo , Longevidade/genética , Animais , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/genética , Epigênese Genética/genética , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Metilação , Mutação , Processamento de Proteína Pós-Traducional/genética , Proteínas Repressoras/genética , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMO
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.
Assuntos
Envelhecimento/genética , Reparo do DNA/genética , Longevidade/genética , Neoplasias/genética , Envelhecimento/patologia , Reparo de Erro de Pareamento de DNA/genética , Replicação do DNA/genética , Genótipo , Humanos , Mutação/genética , Acúmulo de Mutações , Taxa de Mutação , Neoplasias/patologia , Fenótipo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Sequenciamento Completo do GenomaRESUMO
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.
Assuntos
Adaptação Fisiológica/genética , Aneuploidia , Estresse do Retículo Endoplasmático/genética , Regulação Fúngica da Expressão Gênica/fisiologia , Saccharomyces cerevisiae/fisiologia , Cromossomos Fúngicos/genética , Farmacorresistência Fúngica/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Dobramento de Proteína , Tunicamicina/farmacologia , Resposta a Proteínas não Dobradas/fisiologiaRESUMO
All organisms age, but the extent to which all organisms age the same way remains a fundamental unanswered question in biology. Across species, it is now clear that at least some aspects of aging are highly conserved and are perhaps universal, but other mechanisms of aging are private to individual species or sets of closely related species. Within the same species, however, it has generally been assumed that the molecular mechanisms of aging are largely invariant from one individual to the next. With the development of new tools for studying aging at the individual cell level in budding yeast, recent data has called this assumption into question. There is emerging evidence that individual yeast mother cells may undergo fundamentally different trajectories of aging. Individual trajectories of aging are difficult to study by traditional population level assays, but through the application of systems biology approaches combined with novel microfluidic technologies, it is now possible to observe and study these phenomena in real time. Understanding the spectrum of mechanisms that determine how different individuals age is a necessary step toward the goal of personalized geroscience, where healthy longevity is optimized for each individual.
Assuntos
Envelhecimento , Senescência Celular , Saccharomyces cerevisiae/citologia , Biologia de Sistemas/métodos , Animais , Humanos , Longevidade , Técnicas Analíticas Microfluídicas/métodos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Análise de Célula Única/métodos , Especificidade da EspécieRESUMO
Leigh Syndrome (LS) is a mitochondrial disorder defined by progressive focal neurodegenerative lesions in specific regions of the brain. Defects in NDUFS4, a subunit of complex I of the mitochondrial electron transport chain, cause LS in humans; the Ndufs4 knockout mouse (Ndufs4(KO)) closely resembles the human disease. Here, we probed brain region-specific molecular signatures in pre-symptomatic Ndufs4(KO) to identify factors which underlie focal neurodegeneration. Metabolomics revealed that free amino acid concentrations are broadly different by region, and glucose metabolites are increased in a manner dependent on both region and genotype. We then tested the impact of the mTOR inhibitor rapamycin, which dramatically attenuates LS in Ndufs4(KO), on region specific metabolism. Our data revealed that loss of Ndufs4 drives pathogenic changes to CNS glutamine/glutamate/α-ketoglutarate metabolism which are rescued by mTOR inhibition Finally, restriction of the Ndufs4 deletion to pre-synaptic glutamatergic neurons recapitulated the whole-body knockout. Together, our findings are consistent with mTOR inhibition alleviating disease by increasing availability of α-ketoglutarate, which is both an efficient mitochondrial complex I substrate in Ndufs4(KO) and an important metabolite related to neurotransmitter metabolism in glutamatergic neurons.
Assuntos
Encéfalo/patologia , Complexo I de Transporte de Elétrons/fisiologia , Ácido Glutâmico/metabolismo , Ácidos Cetoglutáricos/metabolismo , Doença de Leigh/patologia , Metaboloma , Doenças Mitocondriais/patologia , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Doença de Leigh/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Doenças Mitocondriais/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Mitochondrial dysfunction can increase oxidative stress and extend lifespan in Caenorhabditis elegans. Homeostatic mechanisms exist to cope with disruptions to mitochondrial function that promote cellular health and organismal longevity. Previously, we determined that decreased expression of the cytosolic pentose phosphate pathway (PPP) enzyme transaldolase activates the mitochondrial unfolded protein response (UPRmt) and extends lifespan. Here we report that transaldolase (tald-1) deficiency impairs mitochondrial function in vivo, as evidenced by altered mitochondrial morphology, decreased respiration, and increased cellular H2O2 levels. Lifespan extension from knockdown of tald-1 is associated with an oxidative stress response involving p38 and c-Jun N-terminal kinase (JNK) MAPKs and a starvation-like response regulated by the transcription factor EB (TFEB) homolog HLH-30. The latter response promotes autophagy and increases expression of the flavin-containing monooxygenase 2 (fmo-2). We conclude that cytosolic redox established through the PPP is a key regulator of mitochondrial function and defines a new mechanism for mitochondrial regulation of longevity.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Longevidade/genética , Oxigenases/genética , Transaldolase/genética , Envelhecimento/genética , Envelhecimento/patologia , Animais , Autofagia/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Peróxido de Hidrogênio/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/biossíntese , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Mitocôndrias/genética , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Oxigenases/biossíntese , Inanição , Transaldolase/antagonistas & inibidores , Resposta a Proteínas não Dobradas/genética , Proteínas Quinases p38 Ativadas por Mitógeno/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR). The human mitochondrial disorder MELAS/MIDD (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes/Maternally Inherited Diabetes and Deafness) shares many phenotypic characteristics with Leigh syndrome. MELAS/MIDD often leads to organ failure and transplantation and there are currently no effective treatments. To examine the therapeutic potential of mTOR inhibition in human mitochondrial disease, four kidney transplant recipients with MELAS/MIDD were switched from calcineurin inhibitors to mTOR inhibitors for immunosuppression. Primary fibroblast lines were generated from patient dermal biopsies and the impact of rapamycin was studied using cell-based end points. Metabolomic profiles of the four patients were obtained before and after the switch. pS6, a measure of mTOR signaling, was significantly increased in MELAS/MIDD cells compared to controls in the absence of treatment, demonstrating mTOR overactivation. Rapamycin rescued multiple deficits in cultured cells including mitochondrial morphology, mitochondrial membrane potential, and replicative capacity. Clinical measures of health and mitochondrial disease progression were improved in all four patients following the switch to an mTOR inhibitor. Metabolomic analysis was consistent with mitochondrial function improvement in all patients.
Assuntos
Surdez/cirurgia , Diabetes Mellitus Tipo 2/cirurgia , Rejeição de Enxerto/prevenção & controle , Imunossupressores/farmacologia , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Síndrome MELAS/cirurgia , Doenças Mitocondriais/cirurgia , Adulto , Aloenxertos/citologia , Aloenxertos/efeitos dos fármacos , Aloenxertos/patologia , Animais , Inibidores de Calcineurina/farmacologia , Inibidores de Calcineurina/uso terapêutico , Células Cultivadas , Surdez/complicações , Surdez/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Progressão da Doença , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Humanos , Imunossupressores/uso terapêutico , Rim/citologia , Rim/efeitos dos fármacos , Rim/patologia , Falência Renal Crônica/etiologia , Falência Renal Crônica/patologia , Síndrome MELAS/complicações , Síndrome MELAS/patologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Doenças Mitocondriais/complicações , Doenças Mitocondriais/patologia , Cultura Primária de Células , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/imunologia , Resultado do TratamentoRESUMO
Many experts in the biology of ageing believe that pharmacological interventions to slow ageing are a matter of 'when' rather than 'if'. A leading target for such interventions is the nutrient response pathway defined by the mechanistic target of rapamycin (mTOR). Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies in humans.
Assuntos
Envelhecimento/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Envelhecimento/patologia , Animais , Humanos , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Longevidade/genética , Transdução de SinaisRESUMO
Flavin-containing monooxygenases (FMOs) are primarily studied as xenobiotic metabolizing enzymes with a prominent role in drug metabolism. In contrast, endogenous functions and substrates of FMOs are less well understood. A growing body of recent evidence, however, implicates FMOs in aging, several diseases, and metabolic pathways. The evidence suggests an important role for these well-conserved proteins in multiple processes and raises questions about the endogenous substrate(s) and regulation of FMOs. Here, we present an overview of evidence for FMOs' involvement in aging and disease, discussing the biological context and arguing for increased investigation into the function of these enzymes.
Assuntos
Dinitrocresóis/metabolismo , Evolução Molecular , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Animais , HumanosRESUMO
[This corrects the article DOI: 10.1371/journal.pbio.1002131.].
RESUMO
The field of aging research has progressed rapidly over the past few decades. Genetic modulators of aging rate that are conserved over a broad evolutionary distance have now been identified. Several physiological and environmental interventions have also been shown to influence the rate of aging in organisms ranging from yeast to mammals. Here we briefly review these conserved pathways and interventions and highlight some key unsolved challenges that remain. Although the molecular mechanisms by which these modifiers of aging act are only partially understood, interventions to slow aging are nearing clinical application, and it is likely that we will begin to reap the benefits of aging research prior to solving all of the mysteries that the biology of aging has to offer.
Assuntos
Envelhecimento , Animais , Humanos , PesquisaRESUMO
In this issue of Molecular Cell, Lim et al. (2010) show that SIRT1 deacetylates HIF-1alpha and regulates its ability to respond to hypoxia, revealing yet another important function of SIRT1 and suggesting a connection between HIF function in aging and sirtuin enzymes.
RESUMO
Budding yeast divides asymmetrically, giving rise to a mother cell that progressively ages and a daughter cell with full lifespan. It is generally assumed that mother cells retain damaged, lifespan limiting materials ("aging factors") through asymmetric division. However, the identity of these aging factors and the mechanisms through which they limit lifespan remain poorly understood. Using a flow cytometry-based, high-throughput approach, we quantified the asymmetric partitioning of the yeast proteome between mother and daughter cells during cell division, discovering 74 mother-enriched and 60 daughter-enriched proteins. While daughter-enriched proteins are biased toward those needed for bud construction and genome maintenance, mother-enriched proteins are biased towards those localized in the plasma membrane and vacuole. Deletion of 23 of the 74 mother-enriched proteins leads to lifespan extension, a fraction that is about six times that of the genes picked randomly from the genome. Among these lifespan-extending genes, three are involved in endosomal sorting/endosome to vacuole transport, and three are nitrogen source transporters. Tracking the dynamic expression of specific mother-enriched proteins revealed that their concentration steadily increases in the mother cells as they age, but is kept relatively low in the daughter cells via asymmetric distribution. Our results suggest that some mother-enriched proteins may increase to a concentration that becomes deleterious and lifespan-limiting in aged cells, possibly by upsetting homeostasis or leading to aberrant signaling. Our study provides a comprehensive resource for analyzing asymmetric cell division and aging in yeast, which should also be valuable for understanding similar phenomena in other organisms.
Assuntos
Proteoma/metabolismo , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo , Divisão Celular Assimétrica , Citometria de Fluxo , Ontologia Genética , Proteínas de Fluorescência Verde/metabolismo , Ensaios de Triagem em Larga Escala , Proteínas de Saccharomyces cerevisiae/metabolismo , Fatores de TempoRESUMO
Mitochondria play an important role in numerous diseases as well as normative aging. Severe reduction in mitochondrial function contributes to childhood disorders such as Leigh Syndrome, whereas mild disruption can extend the lifespan of model organisms. The Caenorhabditis elegans isp-1 gene encodes the Rieske iron-sulfur protein subunit of cytochrome c oxidoreductase (complex III of the electron transport chain). The partial loss of function allele, isp-1(qm150), leads to several pleiotropic phenotypes. To better understand the molecular mechanisms of ISP-1 function, we sought to identify genetic suppressors of the delayed development of isp-1(qm150) animals. Here we report a series of intragenic suppressors, all located within a highly conserved six amino acid tether region of ISP-1. These intragenic mutations suppress all of the evaluated isp-1(qm150) phenotypes, including developmental rate, pharyngeal pumping rate, brood size, body movement, activation of the mitochondrial unfolded protein response reporter, CO2 production, mitochondrial oxidative phosphorylation, and lifespan extension. Furthermore, analogous mutations show a similar effect when engineered into the budding yeast Rieske iron-sulfur protein Rip1, revealing remarkable conservation of the structure-function relationship of these residues across highly divergent species. The focus on a single subunit as causal both in generation and in suppression of diverse pleiotropic phenotypes points to a common underlying molecular mechanism, for which we propose a "spring-loaded" model. These observations provide insights into how gating and control processes influence the function of ISP-1 in mediating pleiotropic phenotypes including developmental rate, movement, sensitivity to stress, and longevity.