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 , HumanosRESUMO
Exercise is a potent stimulus for combatting skeletal muscle ageing. To study the effects of exercise on muscle in a preclinical setting, we developed a combined endurance-resistance training stimulus for mice called progressive weighted wheel running (PoWeR). PoWeR improves molecular, biochemical, cellular and functional characteristics of skeletal muscle and promotes aspects of partial epigenetic reprogramming when performed late in life (22-24 months of age). In this investigation, we leveraged pan-mammalian DNA methylome arrays and tandem mass-spectrometry proteomics in skeletal muscle to provide detailed information on late-life PoWeR adaptations in female mice relative to age-matched sedentary controls (n = 7-10 per group). Differential CpG methylation at conserved promoter sites was related to transcriptional regulation genes as well as Nr4a3, Hes1 and Hox genes after PoWeR. Using a holistic method of -omics integration called binding and expression target analysis (BETA), methylome changes were associated with upregulated proteins related to global and mitochondrial translation after PoWeR (P = 0.03). Specifically, BETA implicated methylation control of ribosomal, mitoribosomal, and mitochondrial complex I protein abundance after training. DNA methylation may also influence LACTB, MIB1 and UBR4 protein induction with exercise - all are mechanistically linked to muscle health. Computational cistrome analysis predicted several transcription factors including MYC as regulators of the exercise trained methylome-proteome landscape, corroborating prior late-life PoWeR transcriptome data. Correlating the proteome to muscle mass and fatigue resistance revealed positive relationships with VPS13A and NPL levels, respectively. Our findings expose differential epigenetic and proteomic adaptations associated with translational regulation after PoWeR that could influence skeletal muscle mass and function in aged mice. KEY POINTS: Late-life combined endurance-resistance exercise training from 22-24 months of age in mice is shown to improve molecular, biochemical, cellular and in vivo functional characteristics of skeletal muscle and promote aspects of partial epigenetic reprogramming and epigenetic age mitigation. Integration of DNA CpG 36k methylation arrays using conserved sites (which also contain methylation ageing clock sites) with exploratory proteomics in skeletal muscle extends our prior work and reveals coordinated and widespread regulation of ribosomal, translation initiation, mitochondrial ribosomal (mitoribosomal) and complex I proteins after combined voluntary exercise training in a sizeable cohort of female mice (n = 7-10 per group and analysis). Multi-omics integration predicted epigenetic regulation of serine ß-lactamase-like protein (LACTB - linked to tumour resistance in muscle), mind bomb 1 (MIB1 - linked to satellite cell and type 2 fibre maintenance) and ubiquitin protein ligase E3 component N-recognin 4 (UBR4 - linked to muscle protein quality control) after training. Computational cistrome analysis identified MYC as a regulator of the late-life training proteome, in agreement with prior transcriptional analyses. Vacuolar protein sorting 13 homolog A (VPS13A) was positively correlated to muscle mass, and the glycoprotein/glycolipid associated sialylation enzyme N-acetylneuraminate pyruvate lyase (NPL) was associated to in vivo muscle fatigue resistance.
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Exercise promotes functional improvements in aged tissues, but the extent to which it simulates partial molecular reprogramming is unknown. Using transcriptome profiling from (1) a skeletal muscle-specific in vivo Oct3/4, Klf4, Sox2 and Myc (OKSM) reprogramming-factor expression murine model; (2) an in vivo inducible muscle-specific Myc induction murine model; (3) a translatable high-volume hypertrophic exercise training approach in aged mice; and (4) human exercise muscle biopsies, we collectively defined exercise-induced genes that are common to partial reprogramming. Late-life exercise training lowered murine DNA methylation age according to several contemporary muscle-specific clocks. A comparison of the murine soleus transcriptome after late-life exercise training to the soleus transcriptome after OKSM induction revealed an overlapping signature that included higher JunB and Sun1. Also, within this signature, downregulation of specific mitochondrial and muscle-enriched genes was conserved in skeletal muscle of long-term exercise-trained humans; among these was muscle-specific Abra/Stars. Myc is the OKSM factor most induced by exercise in muscle and was elevated following exercise training in aged mice. A pulse of MYC rewired the global soleus muscle methylome, and the transcriptome after a MYC pulse partially recapitulated OKSM induction. A common signature also emerged in the murine MYC-controlled and exercise adaptation transcriptomes, including lower muscle-specific Melusin and reactive oxygen species-associated Romo1. With Myc, OKSM and exercise training in mice, as well habitual exercise in humans, the complex I accessory subunit Ndufb11 was lower; low Ndufb11 is linked to longevity in rodents. Collectively, exercise shares similarities with genetic in vivo partial reprogramming. KEY POINTS: Advances in the last decade related to cellular epigenetic reprogramming (e.g. DNA methylome remodelling) toward a pluripotent state via the Yamanaka transcription factors Oct3/4, Klf4, Sox2 and Myc (OKSM) provide a window into potential mechanisms for combatting the deleterious effects of cellular ageing. Using global gene expression analysis, we compared the effects of in vivo OKSM-mediated partial reprogramming in skeletal muscle fibres of mice to the effects of late-life murine exercise training in muscle. Myc is the Yamanaka factor most induced by exercise in skeletal muscle, and so we compared the MYC-controlled transcriptome in muscle to Yamanaka factor-mediated and exercise adaptation mRNA landscapes in mice and humans. A single pulse of MYC is sufficient to remodel the muscle methylome. We identify partial reprogramming-associated genes that are innately altered by exercise training and conserved in humans, and propose that MYC contributes to some of these responses.
Assuntos
Envelhecimento , Reprogramação Celular , Exercício Físico , Músculo Esquelético , Animais , Humanos , Camundongos , Reprogramação Celular/genética , Modelos Animais de Doenças , Metilação de DNA , Exercício Físico/fisiologia , Perfilação da Expressão Gênica , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Envelhecimento/genética , Envelhecimento/fisiologiaRESUMO
Geographically isolated populations, specifically island-mainland counterparts, tend to exhibit phenotypic variation in many species. The so-called island syndrome occurs when different environmental pressures lead to insular divergence from mainland populations. This phenomenon can be seen in an island population of Nova Scotia masked shrews (Sorex cinereus), which have developed a specialized feeding habit and digestive enzyme compared to their mainland counterparts. Epigenetic modifications, such as DNA methylation (DNAm), can impact phenotypes by altering gene expression without changing the DNA sequence. Here, we used a de novo masked shrew genome assembly and a mammalian methylation array profiling 37 thousand conserved CpGs to investigate morphological and DNA methylation patterns between island and mainland populations. Island shrews were morphologically and epigenetically different than their mainland counterparts, exhibiting a smaller body size. A gene ontology enrichment analyses of differentially methylated CpGs implicated developmental and digestive system related pathways. Based on our shrew epigenetic clock, island shrews might also be aging faster than their mainland counterparts. This study provides novel insight on phenotypic and epigenetic divergence in island-mainland mammal populations and suggests an underlying role of methylation in island-mainland divergence.
Assuntos
Epigênese Genética , Musaranhos , Animais , Musaranhos/genética , Tamanho Corporal , Sequência de Bases , Metilação de DNA/genéticaRESUMO
Little is known of gene-environment interactions for Alzheimer's disease (AD) risk factors. Apolipoprotein E (APOE) and neighbors on chromosome 19q13.3 have variants associated with risks of AD, but with unknown mechanism. This study describes novel links among the APOE network, air pollution, and age-related diseases. Mice exposed to air pollution nano-sized particulate matter (nPM) had coordinate responses of Apoe-Apoc1-Tomm40 in the cerebral cortex. In humans, the AD vulnerable hippocampus and amygdala had stronger age decline in APOE cluster expression than the AD-resistant cerebellum and hypothalamus. Using consensus weighted gene co-expression network, we showed that APOE has a conserved co-expressed network in rodent and primate brains. SOX1, which has AD-associated single nucleotide polymorphisms, was among the co-expressed genes in the human hippocampus. Humans and mice shared 87% of potential binding sites for transcription factors in APOE cluster promoter, suggesting similar inducibility and a novel link among environment, APOE cluster, and risk of AD.
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Poluição do Ar/efeitos adversos , Doença de Alzheimer/genética , Apolipoproteína C-I/genética , Apolipoproteínas E/genética , Expressão Gênica , Envelhecimento/fisiologia , Animais , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Camundongos , Família Multigênica , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Exposure to traffic-related air pollution (TRAP) is associated with accelerated cognitive aging and higher dementia risk in human populations. Rodent brains respond to TRAP with activation of astrocytes and microglia, increased inflammatory cytokines, and neurite atrophy. A role for Toll-like receptor 4 (TLR4) was suggested in mouse TLR4-knockouts, which had attenuated lung macrophage responses to air pollution. METHODS: To further analyze these mechanisms, we examined mixed glial cultures (astrocytes and microglia) for RNA responses to nanoscale particulate matter (nPM; diameter <0.2 µm), a well-characterized nanoscale particulate matter subfraction of TRAP collected from a local freeway (Morgan et al. Environ Health Perspect 2011; 119,1003-1009, 2011). The nPM was compared with responses to the endotoxin lipopolysaccharide (LPS), a classic TLR4 ligand, using Affymetrix whole genome microarray in rats. Expression patterns were analyzed by significance analysis of microarrays (SAM) for fold change and by weighted gene co-expression network analysis (WGCNA) to identify modules of shared responses between nPM and LPS. Finally, we examined TLR4 activation in hippocampal tissue from mice chronically exposed to nPM. RESULTS: SAM and WGCNA analyses showed strong activation of TLR4 and NF-κB by both nPM and LPS. TLR4 siRNA attenuated TNFα and other inflammatory responses to nPM in vitro, via the MyD88-dependent pathway. In vivo, mice chronically exposed to nPM showed increased TLR4, MyD88, TNFα, and TNFR2 RNA, and decreased NF-κB and TRAF6 RNA TLR4 and NF-κB responses in the hippocampus. CONCLUSIONS: These results show TLR4 activation is integral in brain inflammatory responses to air pollution, and warrant further study of TLR4 in accelerated cognitive aging by air pollution.
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Poluição do Ar/efeitos adversos , Mediadores da Inflamação/metabolismo , Neuroglia/metabolismo , Material Particulado/efeitos adversos , Receptor 4 Toll-Like/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Feminino , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/genéticaRESUMO
BACKGROUND: There are two biotypes of feline coronavirus (FCoV): the self-limiting feline enteric coronavirus (FECV) and the feline infectious peritonitis virus (FIPV), which causes feline infectious peritonitis (FIP), a fatal disease associated with cats living in multi-cat environments. This study provides an insight on the various immune mediators detected in FCoV-positive cats which may be responsible for the development of FIP. RESULTS: In this study, using real-time PCR and multiplex bead-based immunoassay, the expression profiles of several immune mediators were examined in Crandell-Reese feline kidney (CRFK) cells infected with the feline coronavirus (FCoV) strain FIPV 79-1146 and in samples obtained from FCoV-positive cats. CRFK cells infected with FIPV 79-1146 showed an increase in the expression of interferon-related genes and pro-inflammatory cytokines such as MX1, viperin, CXCL10, CCL8, RANTES, KC, MCP1, and IL8. In addition, an increase in the expression of the above cytokines as well as GM-CSF and IFNγ was also detected in the PBMC, serum, and peritoneal effusions of FCoV-positive cats. Although the expression of MX1 and viperin genes was variable between cats, the expression of these two genes was relatively higher in cats having peritoneal effusion compared to cats without clinically obvious effusion. Higher viral load was also detected in the supernatant of peritoneal effusions compared to in the plasma of FCoV-positive cats. As expected, the secretion of IL1ß, IL6 and TNFα was readily detected in the supernatant of peritoneal effusions of the FCoV-positive cats. CONCLUSIONS: This study has identified various pro-inflammatory cytokines and interferon-related genes such as MX1, viperin, CXCL10, CCL8, RANTES, KC, MCP1, IL8, GM-CSF and IFNγ in FCoV-positive cats. With the exception of MX1 and viperin, no distinct pattern of immune mediators was observed that distinguished between FCoV-positive cats with and without peritoneal effusion. Further studies based on definitive diagnosis of FIP need to be performed to confirm the clinical importance of this study.
Assuntos
Doenças do Gato/virologia , Coronavirus Felino/imunologia , Peritonite Infecciosa Felina/imunologia , Animais , Líquido Ascítico/imunologia , Líquido Ascítico/virologia , Doenças do Gato/imunologia , Gatos , Linhagem Celular , Citocinas/metabolismoRESUMO
BACKGROUND: Edible Bird's Nest (EBN) as a popular traditional Chinese medicine is believed to have health enhancing and antiviral activities against influenza A virus (IAV); however, the molecular mechanism behind therapeutic effects of EBN is not well characterized. METHODS: In this study, EBNs that underwent different enzymatic preparation were tested against IAV infected cells. 50% cytotoxic concentration (CC50) and 50% inhibitory concentration (IC50) of the EBNs against IAV strain A/Puerto Rico/8/1934(H1N1) were determined by HA and MTT assays. Subsequently, the sialic acid content of the used EBNs were analyzed by fluorometric HPLC. Western Blotting and immunofluorescent staining were used to investigate the effects of EBNs on early endosomal trafficking and autophagy process of influenza virus. RESULTS: This study showed that post inoculations of EBNs after enzymatic preparations have the highest efficacy to inhibit IAV. While CC50 of the tested EBNs ranged from 27.5-32 mg/ml, the IC50 of these compounds ranged between 2.5-4.9 mg/ml. EBNs could inhibit IAV as efficient as commercial antiviral agents, such as amantadine and oseltamivir with different mechanisms of action against IAV. The antiviral activity of these EBNs correlated with the content of N-acetyl neuraminic acid. EBNs could affect early endosomal trafficking of the virus by reducing Rab5 and RhoA GTPase proteins and also reoriented actin cytoskeleton of IAV infected cells. In addition, for the first time this study showed that EBNs can inhibit intracellular autophagy process of IAV life cycle as evidenced by reduction of LC3-II and increasing of lysosomal degradation. CONCLUSIONS: The results procured in this study support the potential of EBNs as supplementary medication or alternative to antiviral agents to inhibit influenza infections. Evidently, EBNs can be a promising antiviral agent; however, these natural compounds should be screened for their metabolites prior to usage as therapeutic approach.
Assuntos
Antivirais/farmacologia , Fatores Biológicos/farmacologia , Aves , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/virologia , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Animais , Antivirais/análise , Antivirais/metabolismo , Fatores Biológicos/análise , Fatores Biológicos/metabolismo , Aves/metabolismo , Humanos , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A/fisiologia , Influenza Humana/metabolismo , Proteínas rab5 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
Apoptosis has been postulated to play an important role during feline infectious peritonitis virus (FIPV) infection; however, its mechanism is not well characterized. This study is focused on apoptosis and transcriptional profiling of FIPV-infected cells following in vitro infection of CRFK cells with FIPV 79-1146 WSU. Flow cytometry was used to determine mode of cell death in first 42 h post infection (hpi). FIPV infected cells underwent early apoptosis at 9 hpi (p < 0.05) followed by late apoptosis at 12 hpi (p < 0.05) and necrosis from 24 hpi (p < 0.05). Then, next generation sequencing was performed on 9 hpi and control uninfected cells by Illumina analyzer. An aggregate of 4546 genes (2229 down-regulated and 2317 up-regulated) from 17 cellular process, 11 molecular functions and 130 possible biological pathways were affected by FIPV. 131 genes from apoptosis cluster (80 down-regulated and 51 up-regulated) along with increase of apoptosis, p53, p38 MAPK, VEGF and chemokines/cytokines signaling pathways were probably involved in apoptosis process. Six of the de-regulated genes expression (RASSF1, BATF2, MAGEB16, PDCD5, TNFα and TRAF2) and TNFα protein concentration were analyzed by RT-qPCR and ELISA, respectively, at different time-points. Up-regulations of both pro-apoptotic (i.e. PDCD5) and anti-apoptotic (i.e. TRAF2) were detected from first hpi and continuing to deregulate during apoptosis process in the infected cells.
Assuntos
Apoptose , Doenças do Gato/genética , Infecções por Coronavirus/veterinária , Coronavirus Felino/fisiologia , Animais , Doenças do Gato/fisiopatologia , Doenças do Gato/virologia , Gatos , Infecções por Coronavirus/genética , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Coronavirus Felino/genética , Transcrição Gênica , Proteína Supressora de Tumor p53/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
The oocyte is considered to be the largest cell in mammalian species. Women hoping to become pregnant face a ticking biological clock. This is becoming increasingly challenging as an increase in life expectancy is accompanied by the tendency to conceive at older ages. With advancing maternal age, the fertilized egg will exhibit lower quality and developmental competence, which contributes to increased chances of miscarriage due to several causes such as aneuploidy, oxidative stress, epigenetics, or metabolic disorders. In particular, heterochromatin in oocytes and with it, the DNA methylation landscape undergoes changes. Further, obesity is a well-known and ever-increasing global problem as it is associated with several metabolic disorders. More importantly, both obesity and aging negatively affect female reproduction. However, among women, there is immense variability in age-related decline of oocytes' quantity, developmental competence, or quality. Herein, the relevance of obesity and DNA-methylation will be discussed as these aspects have a tremendous effect on female fertility, and it is a topic of continuous and widespread interest that has yet to be fully addressed for the mammalian oocyte.
Assuntos
Doenças Metabólicas , Oócitos , Gravidez , Animais , Feminino , Humanos , Oócitos/metabolismo , Envelhecimento , Idade Materna , Obesidade/metabolismo , Doenças Metabólicas/metabolismo , MamíferosRESUMO
To address how conserved DNA methylation-based epigenetic aging is in diverse branches of the tree of life, we generated DNA methylation data from African clawed frogs (Xenopus laevis) and Western clawed frogs (Xenopus tropicalis) and built multiple epigenetic clocks. Dual species clocks were developed that apply to both humans and frogs (human-clawed frog clocks), supporting that epigenetic aging processes are evolutionary conserved outside mammals. Highly conserved positively age-related CpGs are located in neural-developmental genes such as uncx, tfap2d as well as nr4a2 implicated in age-associated disease. We conclude that signatures of epigenetic aging are evolutionary conserved between frogs and mammals and that the associated genes relate to neural processes, altogether opening opportunities to employ Xenopus as a model organism to study aging.
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Envelhecimento , Metilação de DNA , Animais , Humanos , Xenopus laevis/genética , Metilação de DNA/genética , Xenopus/genética , Envelhecimento/genética , Epigênese Genética/genética , MamíferosRESUMO
The quality of romantic relationships can predict health consequences related to aging. DNA methylation-based biomarkers of aging accurately estimate chronological age. We developed several highly accurate epigenetic aging clocks, based on highly conserved mammalian CpGs, for the socially monogamous prairie vole (Microtus ochrogaster). In addition, our dual-species human-vole clock accurately measured relative age and illustrates high species conservation of epigenetic aging effects. Next, we assessed how pair bonding impacts epigenetic aging. We did not find evidence that pair-bonded voles exhibit accelerated or decelerated epigenetic aging effects in blood, ear, liver, or brain tissue. Our epigenome wide association study identified CpGs in five genes strongly associated with pair bonding: Foxp4, Phf2, Mms22l, Foxb1, and Eif1ad. Overall, we present accurate DNA methylation-based estimators of age for a species of great interest to researchers studying monogamy in animals. We did not find any evidence that sex-naive animals age differently from pair-bonded animals.
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Envelhecimento , Arvicolinae , Metilação de DNA , Epigênese Genética , Animais , Arvicolinae/genética , Envelhecimento/genética , Feminino , Masculino , Ligação do Par , Ilhas de CpGRESUMO
Several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (Ercc1, LAKI, Polg, and Xpg). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in Ercc1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. Similarly, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight that mouse models with deficiencies in DNA repair, unlike other premature aging models, display accelerated epigenetic age, suggesting a strong connection between DNA damage and epigenetic dysregulation during aging.
Assuntos
Senilidade Prematura , Humanos , Camundongos , Animais , Senilidade Prematura/genética , Envelhecimento/genética , Reparo do DNA/genética , Metilação de DNA/genética , Proteínas/genética , Epigênese Genética , DNARESUMO
Several studies have indicated that interrupted epigenetic reprogramming using Yamanaka transcription factors (OSKM) can rejuvenate cells from old laboratory animals and humans. However, the potential of OSKM-induced rejuvenation in brain tissue has been less explored. Here, we aimed to restore cognitive performance in 25.3-month-old female Sprague-Dawley rats using OSKM gene therapy for 39 days. Their progress was then compared with the cognitive performance of untreated 3.5-month-old rats as well as old control rats treated with a placebo adenovector. The Barnes maze test, used to assess cognitive performance, demonstrated enhanced cognitive abilities in old rats treated with OSKM compared to old control animals. In the treated old rats, there was a noticeable trend towards improved spatial memory relative to the old controls. Further, OSKM gene expression did not lead to any pathological alterations within the 39 days. Analysis of DNA methylation following OSKM treatment yielded three insights. First, epigenetic clocks for rats suggested a marginally significant epigenetic rejuvenation. Second, chromatin state analysis revealed that OSKM treatment rejuvenated the methylome of the hippocampus. Third, an epigenome-wide association analysis indicated that OSKM expression in the hippocampus of old rats partially reversed the age-related increase in methylation. In summary, the administration of Yamanaka genes via viral vectors rejuvenates the functional capabilities and the epigenetic landscape of the rat hippocampus.
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By analyzing 15,000 samples from 348 mammalian species, we derive DNA methylation (DNAm) predictors of maximum life span (R = 0.89), gestation time (R = 0.96), and age at sexual maturity (R = 0.85). Our maximum life-span predictor indicates a potential innate longevity advantage for females over males in 17 mammalian species including humans. The DNAm maximum life-span predictions are not affected by caloric restriction or partial reprogramming. Genetic disruptions in the somatotropic axis such as growth hormone receptors have an impact on DNAm maximum life span only in select tissues. Cancer mortality rates show no correlation with our epigenetic estimates of life-history traits. The DNAm maximum life-span predictor does not detect variation in life span between individuals of the same species, such as between the breeds of dogs. Maximum life span is determined in part by an epigenetic signature that is an intrinsic species property and is distinct from the signatures that relate to individual mortality risk.
Assuntos
Metilação de DNA , Epigênese Genética , Longevidade , Mamíferos , Animais , Longevidade/genética , Mamíferos/genética , Feminino , Humanos , Masculino , Características de História de Vida , Especificidade da EspécieRESUMO
Aging is the major risk factor for most human diseases and represents a major socio-economical challenge for modern societies. Despite its importance, the process of aging remains poorly understood. Epigenetic dysregulation has been proposed as a key driver of the aging process. Modifications in transcriptional networks and chromatin structure might be central to age-related functional decline. A prevalent feature described during aging is the overall reduction in heterochromatin, specifically marked by the loss of repressive histone modification, Histone 3 lysine 9 trimethylation (H3K9me3). However, the role of H3K9me3 in aging, especially in mammals, remains unclear. Here we show using a novel mouse strain, (TKOc), carrying a triple knockout of three methyltransferases responsible for H3K9me3 deposition, that the inducible loss of H3K9me3 in adulthood results in premature aging. TKOc mice exhibit reduced lifespan, lower body weight, increased frailty index, multi-organ degeneration, transcriptional changes with significant upregulation of transposable elements, and accelerated epigenetic age. Our data strongly supports the concept that the loss of epigenetic information directly drives the aging process. These findings reveal the importance of epigenetic regulation in aging and suggest that interventions targeting epigenetic modifications could potentially slow down or reverse age-related decline. Understanding the molecular mechanisms underlying the process of aging will be crucial for developing novel therapeutic strategies that can delay the onset of age-associated diseases and preserve human health at old age specially in rapidly aging societies.
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DNA methylation is influenced by genetic and non-genetic factors. Here, we chart quantitative trait loci (QTLs) that modulate levels of methylation at highly conserved CpGs using liver methylome data from mouse strains belonging to the BXD family. A regulatory hotspot on chromosome 5 had the highest density of trans-acting methylation QTLs (trans-meQTLs) associated with multiple distant CpGs. We refer to this locus as meQTL.5a. Trans-modulated CpGs showed age-dependent changes and were enriched in developmental genes, including several members of the MODY pathway (maturity onset diabetes of the young). The joint modulation by genotype and ageing resulted in a more 'aged methylome' for BXD strains that inherited the DBA/2J parental allele at meQTL.5a. Further, several gene expression traits, body weight, and lipid levels mapped to meQTL.5a, and there was a modest linkage with lifespan. DNA binding motif and protein-protein interaction enrichment analyses identified the hepatic nuclear factor, Hnf1a (MODY3 gene in humans), as a strong candidate. The pleiotropic effects of meQTL.5a could contribute to variations in body size and metabolic traits, and influence CpG methylation and epigenetic ageing that could have an impact on lifespan.
Assuntos
Metilação de DNA , Locos de Características Quantitativas , Humanos , Animais , Camundongos , Idoso , Camundongos Endogâmicos DBA , Envelhecimento/genética , LongevidadeRESUMO
Epigenetic approaches for estimating the age of living organisms are revolutionizing studies of long-lived species. Molecular biomarkers that allow age estimates from small tissue biopsies promise to enhance studies of long-lived whales, addressing a fundamental and challenging parameter in wildlife management. DNA methylation (DNAm) can affect gene expression, and strong correlations between DNAm patterns and age have been documented in humans and nonhuman vertebrates and used to construct "epigenetic clocks". We present several epigenetic clocks for skin samples from two of the longest-lived cetaceans, killer whales and bowhead whales. Applying the mammalian methylation array to genomic DNA from skin samples we validate four different clocks with median errors of 2.3-3.7 years. These epigenetic clocks demonstrate the validity of using cytosine methylation data to estimate the age of long-lived cetaceans and have broad applications supporting the conservation and management of long-lived cetaceans using genomic DNA from remote tissue biopsies.
Assuntos
Envelhecimento , Metilação de DNA , Humanos , Animais , Envelhecimento/genética , Mamíferos , Biomarcadores , DNA , Epigênese GenéticaRESUMO
Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor growth, sun sensitivity, mild immunodeficiency, diabetes, and increased risk of cancer, most commonly leukemias. Interestingly, patients with BSyn do not have other signs of premature aging such as early, progressive hair loss and cataracts. We set out to determine epigenetic age in BSyn, which can be a better predictor of health and disease over chronological age. Our results show for the first time that patients with BSyn have evidence of accelerated epigenetic aging across several measures in blood lymphocytes, as compared to carriers. Additionally, homozygous Blm mice exhibit accelerated methylation age in multiple tissues, including brain, blood, kidney, heart, and skin, according to the brain methylation clock. Overall, we find that Bloom syndrome is associated with accelerated epigenetic aging effects in multiple tissues and more generally a strong effect on CpG methylation levels.
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Senilidade Prematura , Síndrome de Bloom , Humanos , Animais , Camundongos , Síndrome de Bloom/genética , Síndrome de Bloom/diagnóstico , Epigênese Genética , Envelhecimento/genética , Senilidade Prematura/genética , Metilação , Metilação de DNA/genéticaRESUMO
Age determination of wild animals, including pinnipeds, is critical for accurate population assessment and management. For most pinnipeds, current age estimation methodologies utilize tooth or bone sectioning which makes antemortem estimations problematic. We leveraged recent advances in the development of epigenetic age estimators (epigenetic clocks) to develop highly accurate pinniped epigenetic clocks. For clock development, we applied the mammalian methylation array to profile 37,492 cytosine-guanine sites (CpGs) across highly conserved stretches of DNA in blood and skin samples (n = 171) from primarily three pinniped species representing the three phylogenetic families: Otariidae, Phocidae and Odobenidae. We built an elastic net model with Leave-One-Out-Cross Validation (LOOCV) and one with a Leave-One-Species-Out-Cross-Validation (LOSOCV). After identifying the top 30 CpGs, the LOOCV produced a highly correlated (r = 0.95) and accurate (median absolute error = 1.7 years) age estimation clock. The LOSOCV elastic net results indicated that blood and skin clock (r = 0.84) and blood (r = 0.88) pinniped clocks could predict age of animals from pinniped species not used for clock development to within 3.6 and 4.4 years, respectively. These epigenetic clocks provide an improved and relatively non-invasive tool to determine age in skin or blood samples from all pinniped species.