Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 347
Filtrar
1.
Mol Psychiatry ; 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35705636

RESUMO

Chronic heavy alcohol consumption is associated with increased mortality and morbidity and often leads to premature aging; however, the mechanisms of alcohol-associated cellular aging are not well understood. In this study, we used DNA methylation derived telomere length (DNAmTL) as a novel approach to investigate the role of alcohol use on the aging process. DNAmTL was estimated by 140 cytosine phosphate guanines (CpG) sites in 372 individuals with alcohol use disorder (AUD) and 243 healthy controls (HC) and assessed using various endophenotypes and clinical biomarkers. Validation in an independent sample of DNAmTL on alcohol consumption was performed (N = 4219). Exploratory genome-wide association studies (GWAS) on DNAmTL were also performed to identify genetic variants contributing to DNAmTL shortening. Top GWAS findings were analyzed using in-silico expression quantitative trait loci analyses and related to structural MRI hippocampus volumes of individuals with AUD. DNAmTL was 0.11-kilobases shorter per year in AUD compared to HC after adjustment for age, sex, race, and blood cell composition (p = 4.0 × 10-12). This association was partially attenuated but remained significant after additionally adjusting for BMI, and smoking status (0.06 kilobases shorter per year, p = 0.002). DNAmTL shortening was strongly associated with chronic heavy alcohol use (ps < 0.001), elevated gamma-glutamyl transferase (GGT), and aspartate aminotransferase (AST) (ps < 0.004). Comparison of DNAmTL with PCR-based methods of assessing TL revealed positive correlations (R = 0.3, p = 2.2 × 10-5), highlighting the accuracy of DNAmTL as a biomarker. The GWAS meta-analysis identified a single nucleotide polymorphism (SNP), rs4374022 and 18 imputed ones in Thymocyte Expressed, Positive Selection Associated 1(TESPA1), at the genome-wide level (p = 3.75 × 10-8). The allele C of rs4374022 was associated with DNAmTL shortening, lower hippocampus volume (p < 0.01), and decreased mRNA expression in hippocampus tissue (p = 0.04). Our study demonstrates DNAmTL-related aging acceleration in AUD and suggests a functional role for TESPA1 in regulating DNAmTL length, possibly via the immune system with subsequent biological effects on brain regions negatively affected by alcohol and implicated in aging.

2.
Aging Cell ; : e13652, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35661546

RESUMO

Accelerated aging is a hallmark of Down syndrome (DS), with adults experiencing early-onset Alzheimer's disease and premature aging of the skin, hair, and immune and endocrine systems. Accelerated epigenetic aging has been found in the blood and brain tissue of adults with DS but when premature aging in DS begins remains unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth. We assessed the association between age acceleration and DS using five epigenetic clocks in 346 newborns with DS and 567 newborns without DS using Illumina MethylationEPIC DNA methylation array data. We compared two epigenetic aging clocks (DNAmSkinBloodClock and pan-tissue DNAmAge) and three epigenetic gestational age clocks (Haftorn, Knight, and Bohlin) between DS and non-DS newborns using linear regression adjusting for observed age, sex, batch, deconvoluted blood cell proportions, and genetic ancestry. Targeted sequencing of GATA1 was performed in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis. DS was significantly associated with increased DNAmSkinBloodClock (effect estimate = 0.2442, p < 0.0001), with an epigenetic age acceleration of 244 days in newborns with DS after adjusting for potential confounding factors (95% confidence interval: 196-292 days). We also found evidence of epigenetic age acceleration associated with somatic GATA1 mutations among newborns with DS (p = 0.015). DS was not associated with epigenetic gestational age acceleration. We demonstrate that accelerated epigenetic aging in the blood of DS patients begins prenatally, with implications for the pathophysiology of immunosenescence and other aging-related traits in DS.

3.
Proc Natl Acad Sci U S A ; 119(21): e2120887119, 2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35580182

RESUMO

DNA methylation profiles have been used to develop biomarkers of aging known as epigenetic clocks, which predict chronological age with remarkable accuracy and show promise for inferring health status as an indicator of biological age. Epigenetic clocks were first built to monitor human aging, but their underlying principles appear to be evolutionarily conserved, as they have now been successfully developed for many mammalian species. Here, we describe reliable and highly accurate epigenetic clocks shown to apply to 93 domestic dog breeds. The methylation profiles were generated using the mammalian methylation array, which utilizes DNA sequences that are conserved across all mammalian species. Canine epigenetic clocks were constructed to estimate age and also average time to death. We also present two highly accurate human­dog dual species epigenetic clocks (R = 0.97), which may facilitate the ready translation from canine to human use (or vice versa) of antiaging treatments being developed for longevity and preventive medicine. Finally, epigenome-wide association studies here reveal individual methylation sites that may underlie the inverse relationship between breed weight and lifespan. Overall, we describe robust biomarkers to measure aging and, potentially, health status in canines.


Assuntos
Metilação de DNA , Epigênese Genética , Envelhecimento/genética , Animais , DNA , Metilação de DNA/genética , Cães , Epigenômica , Humanos
4.
Geroscience ; 44(3): 1861-1869, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35585300

RESUMO

Telomere length (TL) and DNA methylation-based epigenetic clocks are markers of biological age, but the relationship between the two is not fully understood. Here, we used multivariable regression models to evaluate the relationships between leukocyte TL (LTL; measured by qPCR [n = 635] or flow FISH [n = 144]) and five epigenetic clocks (Hannum, DNAmAge pan-tissue, PhenoAge, SkinBlood, or GrimAge clocks), or their epigenetic age acceleration measures in healthy adults (age 19-61 years). LTL showed statistically significant negative correlations with all clocks (qPCR: r = - 0.26 to - 0.32; flow FISH: r = - 0.34 to - 0.49; p < 0.001 for all). Yet, models adjusted for age, sex, and race revealed significant associations between three of five clocks (PhenoAge, GrimAge, and Hannum clocks) and LTL by flow FISH (p < 0.01 for all) or qPCR (p < 0.001 for all). Significant associations between age acceleration measures for the same three clocks and qPCR or flow FISH TL were also found (p < 0.01 for all). Additionally, LTL (by qPCR or flow FISH) showed significant associations with extrinsic epigenetic age acceleration (EEAA: p < 0.0001 for both), but not intrinsic epigenetic age acceleration (IEAA; p > 0.05 for both). In conclusion, the relationships between LTL and epigenetic clocks were limited to clocks reflecting phenotypic age. The observed association between LTL and EEAA reflects the ability of both measures to detect immunosenescence. The observed modest correlations between LTL and epigenetic clocks highlight a possible benefit from incorporating both measures in understanding disease etiology and prognosis.

5.
Psychoneuroendocrinology ; 141: 105748, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35397259

RESUMO

OBJECTIVE: Subjective social status (SSS), an individual's assessment of their own social status in relation to others, is associated with health and mortality independently of objective SES; however, no studies have tested whether SSS influences epigenetic aging. The current study examines if SSS is associated with epigenetic age acceleration in both Black and White women, independently of objective SES measured during both childhood and adulthood. METHOD: For 9- and 10-year-old Black and White girls, parental education and annual household income was obtained. At ages 39-42, 361 participants (175 Black, 186 White) reported their current education, household income, and SSS, and provided saliva to assess age acceleration using the GrimAge epigenetic clock. Linear regression estimated the association of SSS with epigenetic age acceleration, controlling for objective SES (current education, current income, parents' education, income during childhood), smoking, and counts of cell types. RESULTS: When all objective SES variables were included in the model, SSS remained significantly associated with epigenetic age acceleration, b = - 0.31, p = .003, ß = - 0.15. Black women had significantly greater age acceleration than White women, (t(359) = 5.20, p > .001, d = 0.55) but race did not moderate the association between SSS and epigenetic age acceleration. CONCLUSIONS: Women who rated themselves lower in SSS had greater epigenetic age acceleration, regardless of income and education. There was no difference by race for this association.


Assuntos
Classe Social , Adulto , Envelhecimento/genética , Criança , Epigênese Genética/genética , Feminino , Humanos
6.
Geroscience ; 44(3): 1609-1620, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35411474

RESUMO

Epigenetic clocks based on patterns of DNA methylation have great importance in understanding aging and disease; however, there are basic questions to be resolved in their application. It remains unknown whether epigenetic age acceleration (EAA) within an individual shows strong correlation between different primary tissue sites, the extent to which tissue pathology and clinical illness correlate with EAA in the target organ, and if EAA variability across tissues differs according to sex. Considering the outsized role of age-related illness in Human Immunodeficiency Virus-1 (HIV), these questions were pursued in a sample enriched for tissue from HIV-infected individuals. We used a custom methylation array to generate DNA methylation data from 661 samples representing 11 human tissues (adipose, blood, bone marrow, heart, kidney, liver, lung, lymph node, muscle, spleen and pituitary gland) from 133 clinically characterized, deceased individuals, including 75 infected with HIV. We developed a multimorbidity index based on the clinical disease history. Epigenetic age was moderately correlated across tissues. Blood had the greatest number and degree of correlation, most notably with spleen and bone marrow. However, blood did not correlate with epigenetic age of liver. EAA in liver was weakly correlated with EAA in kidney, adipose, lung and bone marrow. Clinically, hypertension was associated with EAA in several tissues, consistent with the multiorgan impacts of this illness. HIV infection was associated with positive age acceleration in kidney and spleen. Male sex was associated with increased epigenetic acceleration in several tissues. Preliminary evidence indicates that amyotrophic lateral sclerosis is associated with positive EAA in muscle tissue. Finally, greater multimorbidity was associated with greater EAA across all tissues. Blood alone will often fail to detect EAA in other tissues. While hypertension is associated with increased EAA in several tissues, many pathologies are associated with organ-specific age acceleration.

7.
Geroscience ; 44(3): 1825-1845, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35449380

RESUMO

The opossum (Monodelphis domestica), with its sequenced genome, ease of laboratory care and experimental manipulation, and unique biology, is the most used laboratory marsupial. Using the mammalian methylation array, we generated DNA methylation data from n = 100 opossum samples from the ear, liver, and tail. We contrasted postnatal development and later aging effects in the opossum methylome with those in mouse (Mus musculus, C57BL/6 J strain) and other marsupial species such as Tasmanian devil, kangaroos, and wallabies. While the opossum methylome is similar to that of mouse during postnatal development, it is distinct from that shared by other mammals when it comes to the age-related gain of methylation at target sites of polycomb repressive complex 2. Our immunohistochemical staining results provide additional support for the hypothesis that PRC2 activity increases with later aging in mouse tissues but remains constant in opossum tissues. We present several epigenetic clocks for opossums that are distinguished by their compatibility with tissue type (pan-tissue and blood clock) and species (opossum and human). Two dual-species human-opossum pan-tissue clocks accurately measure chronological age and relative age, respectively. The human-opossum epigenetic clocks are expected to provide a significant boost to the attractiveness of opossum as a biological model. Additional epigenetic clocks for Tasmanian devil, red kangaroos and other species of the genus Macropus may aid species conservation efforts.

8.
Elife ; 112022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35389339

RESUMO

Changes in DNA methylation (DNAm) are linked to aging. Here, we profile highly conserved CpGs in 339 predominantly female mice belonging to the BXD family for which we have deep longevity and genomic data. We use a 'pan-mammalian' microarray that provides a common platform for assaying the methylome across mammalian clades. We computed epigenetic clocks and tested associations with DNAm entropy, diet, weight, metabolic traits, and genetic variation. We describe the multifactorial variance of methylation at these CpGs and show that high-fat diet augments the age-related changes. Entropy increases with age. The progression to disorder, particularly at CpGs that gain methylation over time, was predictive of genotype-dependent life expectancy. The longer-lived BXD strains had comparatively lower entropy at a given age. We identified two genetic loci that modulate epigenetic age acceleration (EAA): one on chromosome (Chr) 11 that encompasses the Erbb2/Her2 oncogenic region, and the other on Chr19 that contains a cytochrome P450 cluster. Both loci harbor genes associated with EAA in humans, including STXBP4, NKX2-3, and CUTC. Transcriptome and proteome analyses revealed correlations with oxidation-reduction, metabolic, and immune response pathways. Our results highlight concordant loci for EAA in humans and mice, and demonstrate a tight coupling between the metabolic state and epigenetic aging.


Assuntos
Epigênese Genética , Epigenômica , Envelhecimento/genética , Animais , Metilação de DNA , Epigenômica/métodos , Feminino , Loci Gênicos , Masculino , Mamíferos/genética , Camundongos
9.
NPJ Breast Cancer ; 8(1): 48, 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35418123

RESUMO

Estrogen promotes breast tissue proliferation and telomerase activation. We investigated the effects of reproductive history on cell cycling and telomere length using a DNA methylation-based estimate of telomere length (DNAmTL) in breast and blood from healthy women donors. We demonstrate that DNAmTL is shorter in breast than in blood, and that nulliparous women have longer age-adjusted DNAmTL in both breast and blood, potentially explaining their higher risk of breast cancer.

10.
Nat Aging ; 2(1): 46-59, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35368774

RESUMO

Naked mole rats (NMRs) live an exceptionally long life, appear not to exhibit age-related decline in physiological capacity and are resistant to age-related diseases. However, it has been unknown whether NMRs also evade aging according to a primary hallmark of aging: epigenetic changes. To address this question, we profiled n = 385 samples from 11 tissue types at loci that are highly conserved between mammalian species using a custom array (HorvathMammalMethylChip40). We observed strong epigenetic aging effects and developed seven highly accurate epigenetic clocks for several tissues (pan-tissue, blood, kidney, liver, skin clocks) and two dual-species (human-NMR) clocks. The skin clock correctly estimated induced pluripotent stem cells derived from NMR fibroblasts to be of prenatal age. The NMR epigenetic clocks revealed that breeding NMR queens age more slowly than nonbreeders, a feature that is also observed in some eusocial insects. Our results show that despite a phenotype of negligible senescence, the NMR ages epigenetically.

11.
Nat Ecol Evol ; 6(4): 418-426, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35256811

RESUMO

Species that hibernate generally live longer than would be expected based solely on their body size. Hibernation is characterized by long periods of metabolic suppression (torpor) interspersed by short periods of increased metabolism (arousal). The torpor-arousal cycles occur multiple times during hibernation, and it has been suggested that processes controlling the transition between torpor and arousal states cause ageing suppression. Metabolic rate is also a known correlate of longevity; we thus proposed the 'hibernation-ageing hypothesis' whereby ageing is suspended during hibernation. We tested this hypothesis in a well-studied population of yellow-bellied marmots (Marmota flaviventer), which spend 7-8 months per year hibernating. We used two approaches to estimate epigenetic age: the epigenetic clock and the epigenetic pacemaker. Variation in epigenetic age of 149 samples collected throughout the life of 73 females was modelled using generalized additive mixed models (GAMM), where season (cyclic cubic spline) and chronological age (cubic spline) were fixed effects. As expected, the GAMM using epigenetic ages calculated from the epigenetic pacemaker was better able to detect nonlinear patterns in epigenetic ageing over time. We observed a logarithmic curve of epigenetic age with time, where the epigenetic age increased at a higher rate until females reached sexual maturity (two years old). With respect to circannual patterns, the epigenetic age increased during the active season and essentially stalled during the hibernation period. Taken together, our results are consistent with the hibernation-ageing hypothesis and may explain the enhanced longevity in hibernators.


Assuntos
Hibernação , Marmota , Animais , Epigênese Genética , Feminino , Longevidade/genética , Marmota/genética , Marmota/metabolismo , Estações do Ano
13.
Elife ; 112022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35346416

RESUMO

Background: Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker. Methods: We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671-13,879; N controls = 173,493-372,016), FinnGen (N cases = 719-8401; N controls = 74,685-174,006) and several international cancer genetic consortia (N cases = 11,348-122,977; N controls = 15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach. Results: Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04-1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09-1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97-1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers. Conclusions: GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results. Funding: FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, Entrepreneurship & Innovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol.


Have you noticed that some people seem to get older faster than others? Scientists have previously found that a chemical tag on DNA known as DNA methylation can be used to predict an individual's chronological age. However, age predicted using DNA methylation (also known as biological or epigenetic age) does not always perfectly correspond to chronological age. Indeed, some people's biological age is higher than their years, while other people's is lower. When an individual's biological age is higher than their chronological age, they are said to be experiencing 'epigenetic age acceleration'. This type of accelerated ageing, which can be measured with 'epigenetic clocks' based on DNA methylation, has been associated with several adverse health outcomes, including cancer. This means that epigenetic clocks may improve our ability to predict cancer risk and detect cancer early. However, it is still unclear whether accelerated biological ageing causes cancer, or whether it simply correlates with the disease. Morales-Berstein et al. wanted to investigate whether epigenetic age acceleration, as measured by epigenetic clocks, plays a role in the development of several cancers. To do so, they used an approach known as Mendelian randomization. Using genetic variants as natural experiments, they studied the effect of different measures of epigenetic age acceleration on cancer risk. Their work focused on five types of cancer: breast, colorectal, prostate, ovarian and lung cancer. They used genetic association data from people of European ancestry to determine whether genetic variants that are strongly associated with accelerated ageing are also strongly associated with cancer. The results showed that one of the DNA methylation markers used as an estimate of biological ageing could be directly related to the risk of developing colorectal cancer. This work provides new insights into the relationship between markers of biological ageing and cancer. Similar relationships should also be studied in other groups of people and for other cancer sites. The results suggest that reversing biological ageing by altering DNA methylation could prevent or delay the development of colorectal cancer.


Assuntos
Neoplasias Colorretais , Análise da Randomização Mendeliana , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Epigênese Genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
14.
Clin Epigenetics ; 14(1): 16, 2022 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-35101102

RESUMO

BACKGROUND: GrimAge acceleration (GAA), an epigenetic marker that represents physiologic aging, is associated with atherosclerotic cardiovascular disease. However, the associations between early adulthood lipid levels and GAA in midlife are unknown. Also, it is unknown whether GAA mediates the associations between lipid levels in young adults and subclinical atherosclerosis in midlife. RESULTS: We estimated measures of epigenetic age acceleration in 1118 White and Black participants from the Coronary Artery Risk Development in Young Adults (CARDIA) Study at examination years (Y) 15 and 20. We used multivariable regression models to examine associations of Y15 and Y20 GAA estimates with plasma lipid levels measured at prior examination years (Y0, Y5, and Y10) and concurrently: triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels. Mediation analysis was used to assess the extent to which GAA may mediate associations between plasma lipids and coronary artery calcification (CAC). In our study each 1-SD higher cumulative TG level was associated with an average 0.73 ± 0.12 years older GAA. Each 1-SD higher cumulative HDL-C level was associated with an average 0.57 ± 0.17 years younger GAA. Stratified analyses showed that the associations between TG and GAA were stronger among female and Black participants and the associations between HDL-C and GAA were stronger among female and White participants. GAA statistically mediated 17.4% of the association of cumulative TG with CAC. CONCLUSIONS: High TG and low HDL-C in early adulthood are associated with accelerated epigenetic aging by midlife. Increased epigenetic age acceleration may partially mediate the associations between high TG levels and the presence of subclinical atherosclerosis.


Assuntos
Envelhecimento/sangue , Doença da Artéria Coronariana/genética , Lipídeos/análise , Adolescente , Adulto , Envelhecimento/genética , Biomarcadores/análise , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Metilação de DNA/genética , Feminino , Humanos , Lipídeos/sangue , Masculino , Fatores de Risco
15.
Nat Commun ; 13(1): 783, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35145108

RESUMO

Infinium methylation arrays are not available for the vast majority of non-human mammals. Moreover, even if species-specific arrays were available, probe differences between them would confound cross-species comparisons. To address these challenges, we developed the mammalian methylation array, a single custom array that measures up to 36k CpGs per species that are well conserved across many mammalian species. We designed a set of probes that can tolerate specific cross-species mutations. We annotate the array in over 200 species and report CpG island status and chromatin states in select species. Calibration experiments demonstrate the high fidelity in humans, rats, and mice. The mammalian methylation array has several strengths: it applies to all mammalian species even those that have not yet been sequenced, it provides deep coverage of conserved cytosines facilitating the development of epigenetic biomarkers, and it increases the probability that biological insights gained in one species will translate to others.


Assuntos
Sequência Conservada , Metilação de DNA , Mamíferos/genética , Mamíferos/metabolismo , Processamento de Proteína Pós-Traducional/genética , Processamento de Proteína Pós-Traducional/fisiologia , Animais , Biomarcadores , Ilhas de CpG , Epigênese Genética , Humanos , Camundongos , Mutação , Ratos , Transcriptoma
16.
Neuron ; 110(7): 1173-1192.e7, 2022 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-35114102

RESUMO

In Huntington's disease (HD), the uninterrupted CAG repeat length, but not the polyglutamine length, predicts disease onset. However, the underlying pathobiology remains unclear. Here, we developed bacterial artificial chromosome (BAC) transgenic mice expressing human mutant huntingtin (mHTT) with uninterrupted, and somatically unstable, CAG repeats that exhibit progressive disease-related phenotypes. Unlike prior mHTT transgenic models with stable, CAA-interrupted, polyglutamine-encoding repeats, BAC-CAG mice show robust striatum-selective nuclear inclusions and transcriptional dysregulation resembling those in murine huntingtin knockin models and HD patients. Importantly, the striatal transcriptionopathy in HD models is significantly correlated with their uninterrupted CAG repeat length but not polyglutamine length. Finally, among the pathogenic entities originating from mHTT genomic transgenes and only present or enriched in the uninterrupted CAG repeat model, somatic CAG repeat instability and nuclear mHTT aggregation are best correlated with early-onset striatum-selective molecular pathogenesis and locomotor and sleep deficits, while repeat RNA-associated pathologies and repeat-associated non-AUG (RAN) translation may play less selective or late pathogenic roles, respectively.


Assuntos
Doença de Huntington , Proteínas do Tecido Nervoso , Animais , Cromossomos Artificiais Bacterianos/genética , Cromossomos Artificiais Bacterianos/metabolismo , Modelos Animais de Doenças , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética , Doença de Huntington/patologia , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Expansão das Repetições de Trinucleotídeos/genética
17.
Nat Commun ; 13(1): 355, 2022 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-35039495

RESUMO

The naked mole-rat (NMR) is an exceptionally long-lived rodent that shows no increase of mortality with age, defining it as a demographically non-aging mammal. Here, we perform bisulfite sequencing of the blood of > 100 NMRs, assessing > 3 million common CpG sites. Unsupervised clustering based on sites whose methylation correlates with age reveals an age-related methylome remodeling, and we also observe a methylome information loss, suggesting that NMRs age. We develop an epigenetic aging clock that accurately predicts the NMR age. We show that these animals age much slower than mice and much faster than humans, consistent with their known maximum lifespans. Interestingly, patterns of age-related changes of clock sites in Tert and Prpf19 differ between NMRs and mice, but there are also sites conserved between the two species. Together, the data indicate that NMRs, like other mammals, epigenetically age even in the absence of demographic aging of this species.


Assuntos
Envelhecimento/genética , Epigênese Genética , Ratos-Toupeira/crescimento & desenvolvimento , Ratos-Toupeira/genética , Envelhecimento/sangue , Animais , Relógios Biológicos/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Demografia , Regulação da Expressão Gênica , Humanos , Camundongos , Ratos-Toupeira/sangue , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Telomerase/genética , Telomerase/metabolismo
18.
Nat Commun ; 13(1): 40, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013267

RESUMO

Cytosine methylation patterns have not yet been thoroughly studied in horses. Here, we profile n = 333 samples from 42 horse tissue types at loci that are highly conserved between mammalian species using a custom array (HorvathMammalMethylChip40). Using the blood and liver tissues from horses, we develop five epigenetic aging clocks: a multi-tissue clock, a blood clock, a liver clock and two dual-species clocks that apply to both horses and humans. In addition, using blood methylation data from three additional equid species (plains zebra, Grevy's zebras and Somali asses), we develop another clock that applies across all equid species. Castration does not significantly impact the epigenetic aging rate of blood or liver samples from horses. Methylation and RNA data from the same tissues define the relationship between methylation and RNA expression across horse tissues. We expect that the multi-tissue atlas will become a valuable resource.


Assuntos
Envelhecimento/genética , Metilação de DNA , Cavalos/genética , Transcriptoma , Animais , Sangue , Epigênese Genética , Epigenômica , Equidae/genética , Técnicas Genéticas , Humanos , Fígado
19.
J Parkinsons Dis ; 12(2): 545-556, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34842194

RESUMO

BACKGROUND: Stochastic epigenetic mutations (SEM) reflect a deviation from normal site-specific methylation patterns. Epigenetic mutation load (EML) captures the accumulation of SEMs across an individual's genome and may reflect dysfunction of the epigenetic maintenance system in response to epigenetic challenges. OBJECTIVE: We investigate whether EML is associated with PD risk and time to events (i.e., death and motor symptom decline). METHODS: We employed logistic regression and Cox proportional hazards regression to assess the association between EML and several outcomes. Our analyses are based on 568 PD patients and 238 controls from the Parkinson's disease, Environment and Genes (PEG) study, for whom blood-based methylation data was available. RESULTS: We found an association for PD onset and EML in all genes (OR = 1.90; 95%CI 1.52-2.37) and PD-related genes (OR = 1.87; 95%CI 1.50-2.32). EML was also associated with time to a minimum score of 35 points on the motor UPDRS exam (OR = 1.28; 95%CI 1.06-1.56) and time to death (OR = 1.29, 95%CI 1.11-1.49). An analysis of PD related genes only revealed five intragenic hotspots of high SEM density associated with PD risk. CONCLUSION: Our findings suggest an enrichment of methylation dysregulation in PD patients in general and specifically in five PD related genes. EML may also be associated with time to death and motor symptom progression in PD patients.


Assuntos
Doença de Parkinson , Progressão da Doença , Epigênese Genética , Humanos , Mutação , Doença de Parkinson/genética
20.
Geroscience ; 44(1): 447-461, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34698996

RESUMO

DNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how stress factors impact aging. Deer mice (Peromyscus) are long-living rodents that have emerged as an informative model to study aging, adaptation to extreme environments, and monogamous behavior. In the present study, we have undertaken an exhaustive, genome-wide analysis of DNA methylation in Peromyscus, spanning different species, stocks, sexes, tissues, and age cohorts. We describe DNA methylation-based estimators of age for different species of deer mice based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for deer mice was trained on 3 tissues (tail, liver, and brain). Two human-Peromyscus clocks accurately measure age and relative age, respectively. We present CpGs and enriched pathways that relate to different conditions such as chronological age, high altitude, and monogamous behavior. Overall, this study provides a first step towards studying the epigenetic correlates of monogamous behavior and adaptation to high altitude in Peromyscus. The human-Peromyscus epigenetic clocks are expected to provide a significant boost to the attractiveness of Peromyscus as a biological model.


Assuntos
Epigênese Genética , Peromyscus , Envelhecimento/genética , Altitude , Animais , Metilação de DNA , Peromyscus/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...