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1.
Nat Commun ; 11(1): 4796, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963231

RESUMO

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/ß-catenin, TGF-ß and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.


Assuntos
Envelhecimento/genética , Encéfalo , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Doenças Neurodegenerativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estruturas Cromossômicas , Cognição , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
2.
Nat Commun ; 11(1): 4618, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934233

RESUMO

The identification of genes and interventions that slow or reverse aging is hampered by the lack of non-invasive metrics that can predict the life expectancy of pre-clinical models. Frailty Indices (FIs) in mice are composite measures of health that are cost-effective and non-invasive, but whether they can accurately predict health and lifespan is not known. Here, mouse FIs are scored longitudinally until death and machine learning is employed to develop two clocks. A random forest regression is trained on FI components for chronological age to generate the FRIGHT (Frailty Inferred Geriatric Health Timeline) clock, a strong predictor of chronological age. A second model is trained on remaining lifespan to generate the AFRAID (Analysis of Frailty and Death) clock, which accurately predicts life expectancy and the efficacy of a lifespan-extending intervention up to a year in advance. Adoption of these clocks should accelerate the identification of longevity genes and aging interventions.


Assuntos
Envelhecimento/fisiologia , Camundongos/fisiologia , Envelhecimento/genética , Animais , Relógios Biológicos , Feminino , Fragilidade , Humanos , Expectativa de Vida , Aprendizado de Máquina , Masculino , Camundongos/genética , Camundongos/crescimento & desenvolvimento , Camundongos Endogâmicos C57BL
3.
Nat Commun ; 11(1): 4075, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796847

RESUMO

Hematopoietic ageing involves declining erythropoiesis and lymphopoiesis, leading to frequent anaemia and decreased adaptive immunity. How intrinsic changes to the hematopoietic stem cells (HSCs), an altered microenvironment and systemic factors contribute to this process is not fully understood. Here we use bone marrow stromal cells as sensors of age-associated changes to the bone marrow microenvironment, and observe up-regulation of IL-6 and TGFß signalling-induced gene expression in aged bone marrow stroma. Inhibition of TGFß signalling leads to reversal of age-associated HSC platelet lineage bias, increased generation of lymphoid progenitors and rebalanced HSC lineage output in transplantation assays. In contrast, decreased erythropoiesis is not an intrinsic property of aged HSCs, but associated with decreased levels and functionality of erythroid progenitor populations, defects ameliorated by TGFß-receptor and IL-6 inhibition, respectively. These results show that both HSC-intrinsic and -extrinsic mechanisms are involved in age-associated hematopoietic decline, and identify therapeutic targets that promote their reversal.


Assuntos
Envelhecimento/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Interleucina-6/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Envelhecimento/genética , Animais , Medula Óssea , Ciclo Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Células Precursoras Eritroides , Eritropoese/genética , Eritropoese/fisiologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hematopoese , Interleucina-6/genética , Linfopoese/genética , Linfopoese/fisiologia , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides , Transdução de Sinais , Nicho de Células-Tronco , Fator de Crescimento Transformador beta1/genética
4.
Protein Cell ; 11(10): 740-770, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32780218

RESUMO

Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.


Assuntos
Envelhecimento/imunologia , Betacoronavirus , Infecções por Coronavirus/imunologia , Sistema Imunitário/imunologia , Pandemias , Pneumonia Viral/imunologia , Análise de Célula Única , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Linfócitos T CD4-Positivos/metabolismo , Linhagem da Célula , Montagem e Desmontagem da Cromatina , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/biossíntese , Citocinas/genética , Suscetibilidade a Doenças , Citometria de Fluxo/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Rearranjo Gênico , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/crescimento & desenvolvimento , Imunocompetência/genética , Inflamação/genética , Inflamação/imunologia , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Análise de Sequência de RNA , Transcriptoma , Adulto Jovem
5.
PLoS One ; 15(8): e0237006, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750074

RESUMO

Biological aging reflects decline in physiological functions and is an effective indicator of morbidity and mortality. Numerous epigenetic age calculators are available, however biological aging calculators based on transcription remain scarce. Here, we introduce RNAAgeCalc, a versatile across-tissue and tissue-specific transcriptional age calculator. By performing a meta-analysis of transcriptional age signature across multi-tissues using the GTEx database, we identify 1,616 common age-related genes, as well as tissue-specific age-related genes. Based on these genes, we develop new across-tissue and tissue-specific age predictors. We show that our transcriptional age calculator outperforms other prior age related gene signatures as indicated by the higher correlation with chronological age as well as lower median and median error. Our results also indicate that both racial and tissue differences are associated with transcriptional age. Furthermore, we demonstrate that the transcriptional age acceleration computed from our within-tissue predictor is significantly correlated with mutation burden, mortality risk and cancer stage in several types of cancer from the TCGA database, and offers complementary information to DNA methylation age. RNAAgeCalc is available at http://www.ams.sunysb.edu/~pfkuan/softwares.html#RNAAgeCalc, both as Bioconductor and Python packages, accompanied by a user-friendly interactive Shiny app.


Assuntos
Envelhecimento/genética , Metilação de DNA , Epigenômica , Software , Feminino , Humanos , Aprendizado de Máquina , Masculino , Modelos Genéticos , Neoplasias/genética , Transcrição Genética
6.
PLoS Med ; 17(8): e1003289, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32817639

RESUMO

BACKGROUND: The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of ß-amyloid peptide (A, ß-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. METHODS AND FINDINGS: This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1-5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4-31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. CONCLUSIONS: In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.


Assuntos
Envelhecimento/líquido cefalorraquidiano , Envelhecimento/genética , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Apolipoproteína E4/líquido cefalorraquidiano , Apolipoproteína E4/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
7.
Nature ; 585(7824): 283-287, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32814897

RESUMO

The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards1-6. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy2,3,7,8. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing9-12. Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.


Assuntos
Envelhecimento/metabolismo , Progressão da Doença , Ácido Metilmalônico/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/patologia , Adulto , Idoso , Envelhecimento/sangue , Envelhecimento/genética , Animais , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Ácido Metilmalônico/sangue , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Neoplasias/sangue , Neoplasias/genética , Fatores de Transcrição SOXC/metabolismo , Transdução de Sinais , Transcriptoma/genética , Fator de Crescimento Transformador beta/metabolismo
8.
Proc Natl Acad Sci U S A ; 117(29): 17094-17103, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32611817

RESUMO

Declining ejaculate performance with male age is taxonomically widespread and has broad fitness consequences. Ejaculate success requires fully functional germline (sperm) and soma (seminal fluid) components. However, some aging theories predict that resources should be preferentially diverted to the germline at the expense of the soma, suggesting differential impacts of aging on sperm and seminal fluid and trade-offs between them or, more broadly, between reproduction and lifespan. While harmful effects of male age on sperm are well known, we do not know how much seminal fluid deteriorates in comparison. Moreover, given the predicted trade-offs, it remains unclear whether systemic lifespan-extending interventions could ameliorate the declining performance of the ejaculate as a whole. Here, we address these problems using Drosophila melanogaster. We demonstrate that seminal fluid deterioration contributes to male reproductive decline via mating-dependent mechanisms that include posttranslational modifications to seminal proteins and altered seminal proteome composition and transfer. Additionally, we find that sperm production declines chronologically with age, invariant to mating activity such that older multiply mated males become infertile principally via reduced sperm transfer and viability. Our data, therefore, support the idea that both germline and soma components of the ejaculate contribute to male reproductive aging but reveal a mismatch in their aging patterns. Our data do not generally support the idea that the germline is prioritized over soma, at least, within the ejaculate. Moreover, we find that lifespan-extending systemic down-regulation of insulin signaling results in improved late-life ejaculate performance, indicating simultaneous amelioration of both somatic and reproductive aging.


Assuntos
Envelhecimento , Drosophila melanogaster , Proteínas de Plasma Seminal , Espermatozoides , Envelhecimento/genética , Envelhecimento/fisiologia , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Feminino , Fertilidade/genética , Fertilidade/fisiologia , Infertilidade Masculina/genética , Infertilidade Masculina/fisiopatologia , Masculino , Proteoma/análise , Proteoma/genética , Proteoma/fisiologia , Proteínas de Plasma Seminal/análise , Proteínas de Plasma Seminal/fisiologia , Comportamento Sexual Animal/fisiologia , Espermatozoides/química , Espermatozoides/fisiologia
9.
PLoS Biol ; 18(7): e3000745, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32667908

RESUMO

Mutations create genetic variation for other evolutionary forces to operate on and cause numerous genetic diseases. Nevertheless, how de novo mutations arise remains poorly understood. Progress in the area is hindered by the fact that error rates of conventional sequencing technologies (1 in 100 or 1,000 base pairs) are several orders of magnitude higher than de novo mutation rates (1 in 10,000,000 or 100,000,000 base pairs per generation). Moreover, previous analyses of germline de novo mutations examined pedigrees (and not germ cells) and thus were likely affected by selection. Here, we applied highly accurate duplex sequencing to detect low-frequency, de novo mutations in mitochondrial DNA (mtDNA) directly from oocytes and from somatic tissues (brain and muscle) of 36 mice from two independent pedigrees. We found mtDNA mutation frequencies 2- to 3-fold higher in 10-month-old than in 1-month-old mice, demonstrating mutation accumulation during the period of only 9 mo. Mutation frequencies and patterns differed between germline and somatic tissues and among mtDNA regions, suggestive of distinct mutagenesis mechanisms. Additionally, we discovered a more pronounced genetic drift of mitochondrial genetic variants in the germline of older versus younger mice, arguing for mtDNA turnover during oocyte meiotic arrest. Our study deciphered for the first time the intricacies of germline de novo mutagenesis using duplex sequencing directly in oocytes, which provided unprecedented resolution and minimized selection effects present in pedigree studies. Moreover, our work provides important information about the origins and accumulation of mutations with aging/maturation and has implications for delayed reproduction in modern human societies. Furthermore, the duplex sequencing method we optimized for single cells opens avenues for investigating low-frequency mutations in other studies.


Assuntos
Envelhecimento/genética , Mamíferos/genética , Mitocôndrias/genética , Mutação/genética , Oócitos/metabolismo , Especificidade de Órgãos/genética , Animais , Análise Mutacional de DNA , DNA Mitocondrial/genética , Feminino , Frequência do Gene/genética , Deriva Genética , Células Germinativas/metabolismo , Padrões de Herança/genética , Modelos Logísticos , Masculino , Camundongos , Modelos Genéticos , Taxa de Mutação , Nucleotídeos/genética , Linhagem
10.
Nature ; 583(7817): 596-602, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32669715

RESUMO

Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified-such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1-these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2-or 'Mouse Ageing Cell Atlas'-which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.


Assuntos
Envelhecimento/genética , Envelhecimento/fisiologia , Regulação da Expressão Gênica , Especificidade de Órgãos/genética , Animais , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/genética , Feminino , Cadeias J de Imunoglobulina/genética , Cadeias J de Imunoglobulina/metabolismo , Masculino , Camundongos , Plasmócitos/citologia , Plasmócitos/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/genética , RNA-Seq , Análise de Célula Única , Linfócitos T/citologia , Linfócitos T/metabolismo , Fatores de Tempo , Transcriptoma
11.
PLoS One ; 15(7): e0236045, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692766

RESUMO

Epigenetic age acceleration-the difference between an individual's DNA methylation age and chronological age-is associated with many diseases including cancer. This study aims to evaluate epigenetic age acceleration as a prognostic biomarker for gliomas. DNA methylation data of gliomas patients (516 low-grade and intermediate-grade gliomas and 140 glioblastoma) were obtained from The Cancer Genome Atlas (TCGA) and patient epigenetic ages were computed using Horvath's age prediction model. We used multivariate linear regression to assess the association of epigenetic age acceleration with tumor molecular subtypes, including Codel, Classic-like, G-CIMP-high, G-CIMP-low, Mesenchymal-like and PA-like. Compared with Codel subtype, epigenetic ages in other molecular subtypes show deceleration after controlling age and race. Age deceleration for Classic-like, G-CIMP-high, G-CIMP-low, Mesenchymal-like and PA-like were 15.42 years (CI: 7.98-22.86, p = 5.38E-05), 25.00 years (CI: 20.79-29.22, p = 4.06E-28), 28.56 years (CI: 14.37-42.74, p = 8.75E-05), 45.34 years (CI: 38.80-51.88, p = 2.15E-36), and 53.58 years (CI: 44.90-62.26, p = 4.81E-30), respectively. Then, Cox proportional hazards regression was used to assess the association of epigenetic age acceleration with patient overall survival. Our results show epigenetic age acceleration is positively associated with patient overall survival (per 10-year age acceleration, HR = 0.89; 95%CI: 0.82-0.97; p = 9.04E-03) in multivariate analysis. When stratified by molecular subtypes, epigenetic age acceleration remains positively associated with patient survival after adjusting age and tumor grade. In conclusion, epigenetic age acceleration is significantly associated with molecular subtypes and patient overall survival in gliomas, indication that epigenetic age acceleration has potential as a quantitative prognostic biomarker for gliomas.


Assuntos
Envelhecimento/genética , Epigênese Genética , Glioma/diagnóstico , Glioma/genética , Adulto , Metilação de DNA , Feminino , Glioma/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida
12.
Mol Cell ; 79(5): 824-835.e5, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32649882

RESUMO

DNA-protein crosslinks (DPCs) are highly toxic DNA lesions that threaten genomic integrity. Recent findings highlight that SPRTN, a specialized DNA-dependent metalloprotease, is a central player in proteolytic cleavage of DPCs. Previous studies suggest that SPRTN deubiquitination is important for its chromatin association and activation. However, the regulation and consequences of SPRTN deubiquitination remain unclear. Here we report that, in response to DPC induction, the deubiquitinase VCPIP1/VCIP135 is phosphorylated and activated by ATM/ATR. VCPIP1, in turn, deubiquitinates SPRTN and promotes its chromatin relocalization. Deubiquitination of SPRTN is required for its subsequent acetylation, which promotes SPRTN relocation to the site of chromatin damage. Furthermore, Vcpip1 knockout mice are prone to genomic instability and premature aging. We propose a model where two sequential post-translational modifications (PTMs) regulate SPRTN chromatin accessibility to repair DPCs and maintain genomic stability and a healthy lifespan.


Assuntos
Envelhecimento/genética , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Acetilação , Envelhecimento/metabolismo , Animais , Linhagem Celular , Dano ao DNA , Proteínas de Ligação a DNA/genética , Enzimas Desubiquitinantes/metabolismo , Endopeptidases/metabolismo , Feminino , Instabilidade Genômica , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Domínios Proteicos , Processamento de Proteína Pós-Traducional , Ubiquitinação
13.
PLoS Genet ; 16(7): e1008835, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32644988

RESUMO

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


Assuntos
Envelhecimento/genética , Proteínas de Drosophila/genética , Longevidade/genética , Metaboloma/genética , Receptores Acoplados a Proteínas-G/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Restrição Calórica , Dieta , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/genética , Insulina/genética , Metabolômica , Mutação/genética , Transdução de Sinais/genética
14.
Nat Commun ; 11(1): 3570, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32678081

RESUMO

Ageing phenotypes, such as years lived in good health (healthspan), total years lived (lifespan), and survival until an exceptional old age (longevity), are of interest to us all but require exceptionally large sample sizes to study genetically. Here we combine existing genome-wide association summary statistics for healthspan, parental lifespan, and longevity in a multivariate framework, increasing statistical power, and identify 10 genomic loci which influence all three phenotypes, of which five (near FOXO3, SLC4A7, LINC02513, ZW10, and FGD6) have not been reported previously at genome-wide significance. The majority of these 10 loci are associated with cardiovascular disease and some affect the expression of genes known to change their activity with age. In total, we implicate 78 genes, and find these to be enriched for ageing pathways previously highlighted in model organisms, such as the response to DNA damage, apoptosis, and homeostasis. Finally, we identify a pathway worthy of further study: haem metabolism.


Assuntos
Envelhecimento/genética , Heme/metabolismo , Locos de Características Quantitativas , Envelhecimento/metabolismo , Expressão Gênica , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Longevidade/genética , Herança Multifatorial , Pais , Fenótipo , Fatores Sexuais
15.
Cytogenet Genome Res ; 160(5): 225-237, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32659775

RESUMO

Loss of chromosome Y (LOY) is a mosaic aneuploidy that can be detected mainly in blood samples of male individuals. Usually, LOY occurrence increases with chronological age in healthy men. Moreover, recently LOY has been reported in association with several diseases, such as cancer, where its frequency is even higher. The Y chromosome is one of the shortest chromosomes of the human karyotype, and it is crucial for correct male development. This chromosome has functions beyond the male reproductive system, and loss of its genes or even LOY can have consequences for the male body that are yet to be elucidated. Analyses of the Y chromosome are largely applied in forensic contexts such as paternity testing, ancestry studies, and sexual assault cases, among others. Thus, LOY can be a disadvantage, limiting laboratory methods and result interpretation. However, as an advantage, LOY detection could be used as a biological age biomarker due to its association with the aging process. The potential application of LOY as biomarker highlights the necessity to clarify the molecular mechanism behind its occurrence and its possible applications in both health and forensic studies.


Assuntos
Aneuploidia , Cromossomos Humanos Y/genética , Medicina Legal , Marcadores Genéticos/genética , Saúde , Mosaicismo , Envelhecimento/genética , Haplótipos/genética , Humanos , Masculino , Paternidade , Delitos Sexuais
16.
BMC Evol Biol ; 20(1): 83, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32660486

RESUMO

BACKGROUND: We have described the diversity of complete mtDNA sequences from 'relic' groups of the Russian Far East, primarily the Nivkhi (who speak a language isolate with no clear relatedness to any others) and Oroki of Sakhalin, as well as the sedentary Koryak from Kamchatka and the Udegey of Primorye. Previous studies have shown that most of their traditional territory was dramatically reshaped by the expansion of Tungusic-speaking groups. RESULTS: Overall, 285 complete mitochondrial sequences were selected for phylogenetic analyses of published, revised and new mitogenomes. To highlight the likely role of Neolithic expansions in shaping the phylogeographical landscape of the Russian Far East, we focus on the major East Eurasian maternal lineages (Y1a, G1b, D4m2, D4e5, M7a2, and N9b) that are restricted to the coastal area. To obtain more insight into autochthonous populations, we removed from the phylogeographic analysis the G2a, G3a2, M8a1, M9a1, and C4b1 lineages, also found within our samples, likely resulting from admixture between the expanding proto-Tungus and the indigenous Paleoasiatic groups with whom they assimilated. Phylogenetic analysis reveals that unlike the relatively diverse lineage spectrum observed in the Amur estuary and northwestern Sakhalin, the present-day subpopulation on the northeastern coast of the island is relatively homogenous: a sole Y1a sublineage, conspicuous for its nodal mutation at m.16189 T > C!, includes different haplotypes. Sharing of the Y1a-m.16189 T > C! sublineages and haplotypes among the Nivkhi, Ulchi and sedentary Koryak is also evident. Aside from Y1a, the entire tree approach expands our understanding of the evolutionary history of haplogroups G1, D4m, N9b, and M7a2. Specifically, we identified the novel haplogroup N9b1 in Primorye, which implies a link between a component of the Udegey ancestry and the Hokkaido Jomon. CONCLUSIONS: Through a comprehensive dataset of mitochondrial genomes retained in autochthonous populations along the coast between Primorye and the Bering Strait, we considerably extended the sequence diversity of these populations to provide new features based on the number and timing of founding lineages. We emphasize the value of integrating genealogical information with genetic data for reconstructing the population history of indigenous groups dramatically impacted by twentieth century resettlement and social upheavals.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Extinção Biológica , Genoma Mitocondrial , Grupos Populacionais/genética , Envelhecimento/genética , DNA Mitocondrial/genética , Genética Populacional , Geografia , Haplótipos/genética , Humanos , Ilhas , Filogenia , Filogeografia , Federação Russa
17.
Neuron ; 107(3): 496-508.e6, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32526197

RESUMO

Here, we perform a genome-wide screen for variants that regulate the expression of gene co-expression modules in the aging human brain; we discover and replicate such variants in the TMEM106B and RBFOX1 loci. The TMEM106B haplotype is known to influence the accumulation of TAR DNA-binding protein 43 kDa (TDP-43) proteinopathy, and the haplotype's large-scale transcriptomic effects include the dysregulation of lysosomal genes and alterations in synaptic gene splicing that are also seen in the pathophysiology of TDP-43 proteinopathy. Further, a variant near GRN, another TDP-43 proteinopathy susceptibility gene, shows concordant effects with the TMEM106B haplotype. Leveraging neuropathology data from the same participants, we also show that TMEM106B and APOE-amyloid-ß effects converge to alter myelination and lysosomal gene expression, which then contributes to TDP-43 accumulation. These results advance our mechanistic understanding of the TMEM106B TDP-43 risk haplotype and uncover a transcriptional program that mediates the converging effects of APOE-amyloid-ß and TMEM106B on TDP-43 aggregation in older adults.


Assuntos
Envelhecimento/genética , Encéfalo/metabolismo , Regulação da Expressão Gênica/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Progranulinas/genética , Fatores de Processamento de RNA/genética , Proteinopatias TDP-43/genética , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/psicologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Encéfalo/patologia , Estudos de Coortes , Proteínas de Ligação a DNA/metabolismo , Feminino , Haplótipos , Humanos , Lisossomos , Masculino , Bainha de Mielina , Locos de Características Quantitativas , Proteinopatias TDP-43/psicologia
18.
Neuron ; 106(6): 899-911, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32553207

RESUMO

In recent years, the nuclear pore complex (NPC) has emerged as a key player in genome regulation and cellular homeostasis. New discoveries have revealed that the NPC has multiple cellular functions besides mediating the molecular exchange between the nucleus and the cytoplasm. In this review, we discuss non-transport aspects of the NPC focusing on the NPC-genome interaction, the extreme longevity of the NPC proteins, and NPC dysfunction in age-related diseases. The examples summarized herein demonstrate that the NPC, which first evolved to enable the biochemical communication between the nucleus and the cytoplasm, now doubles as the gatekeeper of cellular identity and aging.


Assuntos
Envelhecimento/metabolismo , Esclerose Amiotrófica Lateral/metabolismo , Diferenciação Celular , Regulação da Expressão Gênica , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Poro Nuclear/metabolismo , Transporte Ativo do Núcleo Celular , Envelhecimento/genética , Senilidade Prematura/genética , Senilidade Prematura/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Esclerose Amiotrófica Lateral/genética , Animais , Proteína de Ligação a CREB/metabolismo , Senescência Celular , Genoma , Humanos , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Poro Nuclear/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética
19.
Nature ; 584(7819): 130-135, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581364

RESUMO

The extent to which the biology of oncogenesis and ageing are shaped by factors that distinguish human populations is unknown. Haematopoietic clones with acquired mutations become common with advancing age and can lead to blood cancers1-10. Here we describe shared and population-specific patterns of genomic mutations and clonal selection in haematopoietic cells on the basis of 33,250 autosomal mosaic chromosomal alterations that we detected in 179,417 Japanese participants in the BioBank Japan cohort and compared with analogous data from the UK Biobank. In this long-lived Japanese population, mosaic chromosomal alterations were detected in more than 35.0% (s.e.m., 1.4%) of individuals older than 90 years, which suggests that such clones trend towards inevitability with advancing age. Japanese and European individuals exhibited key differences in the genomic locations of mutations in their respective haematopoietic clones; these differences predicted the relative rates of chronic lymphocytic leukaemia (which is more common among European individuals) and T cell leukaemia (which is more common among Japanese individuals) in these populations. Three different mutational precursors of chronic lymphocytic leukaemia (including trisomy 12, loss of chromosomes 13q and 13q, and copy-neutral loss of heterozygosity) were between two and six times less common among Japanese individuals, which suggests that the Japanese and European populations differ in selective pressures on clones long before the development of clinically apparent chronic lymphocytic leukaemia. Japanese and British populations also exhibited very different rates of clones that arose from B and T cell lineages, which predicted the relative rates of B and T cell cancers in these populations. We identified six previously undescribed loci at which inherited variants predispose to mosaic chromosomal alterations that duplicate or remove the inherited risk alleles, including large-effect rare variants at NBN, MRE11 and CTU2 (odds ratio, 28-91). We suggest that selective pressures on clones are modulated by factors that are specific to human populations. Further genomic characterization of clonal selection and cancer in populations from around the world is therefore warranted.


Assuntos
Envelhecimento/genética , Aberrações Cromossômicas , Cromossomos Humanos/genética , Células Clonais/metabolismo , Genoma Humano/genética , Células-Tronco Hematopoéticas/metabolismo , Mutação , Idoso de 80 Anos ou mais , Alelos , Linhagem da Célula , Células Clonais/citologia , Células Clonais/patologia , Estudos de Coortes , Feminino , Loci Gênicos/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/patologia , Humanos , Japão , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia de Células T/genética , Leucemia de Células T/patologia , Masculino , Mosaicismo , Reino Unido
20.
Arterioscler Thromb Vasc Biol ; 40(7): e193-e202, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32404005

RESUMO

Vascular calcification is a ubiquitous pathology of aging. Oxidative stress, persistent DNA damage, and senescence are major pathways driving both cellular and tissue aging, and emerging evidence suggests that these pathways are activated, and even accelerated, in patients with vascular calcification. The DNA damage response-a complex signaling platform that maintains genomic integrity-is induced by oxidative stress and is intimately involved in regulating cell death and osteogenic differentiation in both bone and the vasculature. Unexpectedly, a posttranslational modification, PAR (poly[ADP-ribose]), which is a byproduct of the DNA damage response, initiates biomineralization by acting to concentrate calcium into spheroidal structures that can nucleate apatitic mineral on the ECM (extracellular matrix). As we start to dissect the molecular mechanisms driving aging-associated vascular calcification, novel treatment strategies to promote healthy aging and delay pathological change are being unmasked. Drugs targeting the DNA damage response and senolytics may provide new avenues to tackle this detrimental and intractable pathology.


Assuntos
Envelhecimento/patologia , Artérias/patologia , Aterosclerose/patologia , Dano ao DNA , Estresse Oxidativo , Placa Aterosclerótica , Calcificação Vascular/patologia , Fatores Etários , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Apatitas/metabolismo , Artérias/efeitos dos fármacos , Artérias/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Senescência Celular , Dano ao DNA/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos , Mediadores da Inflamação/metabolismo , Osteogênese , Estresse Oxidativo/efeitos dos fármacos , Poli Adenosina Difosfato Ribose/metabolismo , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/genética , Calcificação Vascular/metabolismo
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