Epigenetic clock and methylation studies in gray short-tailed opossums

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 tissues including blood, liver, and tail. We contrast age-related changes in the opossum methylome to those of C57BL/6J mice. 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. These human-opossum epigenetic clocks are expected to provide a significant boost to the attractiveness of opossum as a biological model.

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Epigenetic clock and DNA methylation analysis of porcine models of aging and obesity

10.1101/2020.09.29.319509 ◽

2020 ◽

Author(s):

Kyle M. Schachtschneider ◽

Lawrence B Schook ◽

Jennifer J. Meudt ◽

Dhanansayan Shanmuganayagam ◽

Joseph A. Zoller ◽

...

Keyword(s):

Dna Methylation ◽

Tissue Type ◽

Epigenetic Clock ◽

Miniature Swine ◽

Methylation Array ◽

Domestic Pigs ◽

Relative Age ◽

Sus Scrofa Domesticus ◽

Kidney Liver

AbstractDNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age, epigenetic clocks, for many species. Using a custom methylation array, we generated DNA methylation data from n=238 porcine tissues including blood, bladder, frontal cortex, kidney, liver and lung, from domestic pigs (Sus scrofa domesticus) and minipigs (Wisconsin Miniature Swine™). We present 4 epigenetic clocks for pigs that are distinguished by their compatibility with tissue type (pan-tissue and blood clock) and species (pig and human). Two dual-species human-pig pan-tissue clocks accurately measure chronological age and relative age, respectively. We also characterized CpGs that differ between minipigs and domestic pigs. Strikingly, several genes implicated by our epigenetic studies of minipig status overlap with genes (ADCY3, TFAP2B, SKOR1, and GPR61) implicated by genetic studies of body mass index in humans. In addition, CpGs with different levels of methylation between the two pig breeds were identified proximal to genes involved in blood LDL levels and cholesterol synthesis, of particular interest given the minipig’s increased susceptibility to cardiovascular disease compared to domestic pigs. Thus, inbred differences of domestic and minipigs may potentially help to identify biological mechanisms underlying weight gain and aging-associated diseases. Our porcine clocks are expected to be useful for elucidating the role of epigenetics in aging and obesity, and the testing of anti-aging interventions.

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Epigenetic clock and DNA methylation analysis of porcine models of aging and obesity

GeroScience ◽

10.1007/s11357-021-00439-6 ◽

2021 ◽

Author(s):

Kyle M. Schachtschneider ◽

Lawrence B. Schook ◽

Jennifer J. Meudt ◽

Dhanansayan Shanmuganayagam ◽

Joseph A. Zoller ◽

...

Keyword(s):

Dna Methylation ◽

Tissue Type ◽

Epigenetic Clock ◽

Miniature Swine ◽

Large White ◽

Methylation Array ◽

Domestic Pigs ◽

Kidney Liver ◽

Crossbred Pigs

AbstractDNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age, epigenetic clocks, for many species. Using a custom methylation array, we generated DNA methylation data from n = 238 porcine tissues including blood, bladder, frontal cortex, kidney, liver, and lung, from domestic pigs (Sus scrofa domesticus) and minipigs (Wisconsin Miniature Swine™). Samples used in this study originated from Large White X Landrace crossbred pigs, Large White X Minnesota minipig crossbred pigs, and Wisconsin Miniature Swine™. We present 4 epigenetic clocks for pigs that are distinguished by their compatibility with tissue type (pan-tissue and blood clock) and species (pig and human). Two dual-species human-pig pan-tissue clocks accurately measure chronological age and relative age, respectively. We also characterized CpGs that differ between minipigs and domestic pigs. Strikingly, several genes implicated by our epigenetic studies of minipig status overlap with genes (ADCY3, TFAP2B, SKOR1, and GPR61) implicated by genetic studies of body mass index in humans. In addition, CpGs with different levels of methylation between the two pig breeds were identified proximal to genes involved in blood LDL levels and cholesterol synthesis, of particular interest given the minipig’s increased susceptibility to cardiovascular disease compared to domestic pigs. Thus, breed-specific differences of domestic and minipigs may potentially help to identify biological mechanisms underlying weight gain and aging-associated diseases. Our porcine clocks are expected to be useful for elucidating the role of epigenetics in aging and obesity, and the testing of anti-aging interventions.

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Epigenetic clock and methylation studies in the rhesus macaque

GeroScience ◽

10.1007/s11357-021-00429-8 ◽

2021 ◽

Author(s):

Steve Horvath ◽

Joseph A. Zoller ◽

Amin Haghani ◽

Anna J. Jasinska ◽

Ken Raj ◽

...

Keyword(s):

Cerebral Cortex ◽

Rhesus Macaque ◽

Mammalian Species ◽

Vervet Monkey ◽

Chronological Age ◽

Biological Research ◽

Epigenetic Clock ◽

Methylation Array ◽

Tissue Samples ◽

Age Related

AbstractMethylation levels at specific CpG positions in the genome have been used to develop accurate estimators of chronological age in humans, mice, and other species. Although epigenetic clocks are generally species-specific, the principles underpinning them appear to be conserved at least across the mammalian class. This is exemplified by the successful development of epigenetic clocks for mice and several other mammalian species. Here, we describe epigenetic clocks for the rhesus macaque (Macaca mulatta), the most widely used nonhuman primate in biological research. Using a custom methylation array (HorvathMammalMethylChip40), we profiled n = 281 tissue samples (blood, skin, adipose, kidney, liver, lung, muscle, and cerebral cortex). From these data, we generated five epigenetic clocks for macaques. These clocks differ with regard to applicability to different tissue types (pan-tissue, blood, skin), species (macaque only or both humans and macaques), and measure of age (chronological age versus relative age). Additionally, the age-based human-macaque clock exhibits a high age correlation (R = 0.89) with the vervet monkey (Chlorocebus sabaeus), another Old World species. Four CpGs within the KLF14 promoter were consistently altered with age in four tissues (adipose, blood, cerebral cortex, skin). Future studies will be needed to evaluate whether these epigenetic clocks predict age-related conditions in the rhesus macaque.

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Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex

Brain ◽

10.1093/brain/awaa334 ◽

2020 ◽

Author(s):

Gemma L Shireby ◽

Jonathan P Davies ◽

Paul T Francis ◽

Joe Burrage ◽

Emma M Walker ◽

...

Keyword(s):

Dna Methylation ◽

Age Distribution ◽

Biological Age ◽

Supervised Machine Learning ◽

Tissue Type ◽

Chronological Age ◽

Epigenetic Clock ◽

Methylation Data ◽

Human Cortex ◽

Dna Methylation Age

Abstract Human DNA methylation data have been used to develop biomarkers of ageing, referred to as ‘epigenetic clocks’, which have been widely used to identify differences between chronological age and biological age in health and disease including neurodegeneration, dementia and other brain phenotypes. Existing DNA methylation clocks have been shown to be highly accurate in blood but are less precise when used in older samples or in tissue types not included in training the model, including brain. We aimed to develop a novel epigenetic clock that performs optimally in human cortex tissue and has the potential to identify phenotypes associated with biological ageing in the brain. We generated an extensive dataset of human cortex DNA methylation data spanning the life course (n = 1397, ages = 1 to 108 years). This dataset was split into ‘training’ and ‘testing’ samples (training: n = 1047; testing: n = 350). DNA methylation age estimators were derived using a transformed version of chronological age on DNA methylation at specific sites using elastic net regression, a supervised machine learning method. The cortical clock was subsequently validated in a novel independent human cortex dataset (n = 1221, ages = 41 to 104 years) and tested for specificity in a large whole blood dataset (n = 1175, ages = 28 to 98 years). We identified a set of 347 DNA methylation sites that, in combination, optimally predict age in the human cortex. The sum of DNA methylation levels at these sites weighted by their regression coefficients provide the cortical DNA methylation clock age estimate. The novel clock dramatically outperformed previously reported clocks in additional cortical datasets. Our findings suggest that previous associations between predicted DNA methylation age and neurodegenerative phenotypes might represent false positives resulting from clocks not robustly calibrated to the tissue being tested and for phenotypes that become manifest in older ages. The age distribution and tissue type of samples included in training datasets need to be considered when building and applying epigenetic clock algorithms to human epidemiological or disease cohorts.

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Age-associated changes in granulosa cell transcript abundance in equine preovulatory follicles

Reproduction Fertility and Development ◽

10.1071/rd14467 ◽

2015 ◽

Vol 27 (6) ◽

pp. 906 ◽

Cited By ~ 10

Author(s):

Dawn R. Sessions-Bresnahan ◽

Elaine M. Carnevale

Keyword(s):

Regulatory Protein ◽

Transcript Abundance ◽

Tissue Type ◽

Gene Transcript ◽

Tissue Remodelling ◽

Paracrine Signalling ◽

Age Related ◽

Preovulatory Follicles ◽

Steroidogenic Acute Regulatory ◽

Age Related Changes

Age-related changes in follicle paracrine signalling are not defined, and follicular gene transcript abundance could predict oocyte viability. Granulosa cells from preovulatory follicles of mares considered Young (n = 12; 4–14 years), Mid-aged (n = 9; 15–19 years) and Old (n = 14; 20–27 years) were evaluated for transcript abundance related to systemic and follicle-specific pathways. Gene transcript abundance for receptors of insulin, adiponectin and peroxisome proliferating factor-γ were higher or tended to be higher in Mid-aged or Old than Young mares. Transcript abundance for interleukin (IL)-6 was elevated in Old versus Young mares, and IL-6 signal transducer was elevated in Old versus younger groups. Expression of tumour necrosis factor (TNF) receptor superfamily member 1A was higher in Mid-aged than Young mares, whereas TNF-inducible gene 6 protein mRNA tended to decrease in Mid-aged versus Young and Old mares. Genes for LH receptor and steroidogenic acute regulatory protein tended to be increased in Old versus Mid-aged and Young mares, respectively. Young and Old mares had higher mRNA for tissue-type plasminogen activator than Mid-aged mares. Thioredoxin-2 mRNA was higher in Old than younger groups. We observed age-related changes in mRNA of receptors for metabolic hormones, inflammatory processes, steroidogenic hormones, tissue remodelling and mitochondrial function, which could contribute to and/or mark alterations in follicular function and fertility.

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Age-dependent changes in mean and variance of gene expression across tissues in a twin cohort

10.1101/063883 ◽

2016 ◽

Cited By ~ 3

Author(s):

Ana Viñuela ◽

Andrew A Brown ◽

Alfonso Buil ◽

Pei-Chien Tsai ◽

Matthew N Davies ◽

...

Keyword(s):

Gene Expression ◽

Healthy Aging ◽

Process Analysis ◽

Strong Relationship ◽

Methylation Array ◽

Age Related ◽

Age Dependent ◽

Mean And Variance ◽

The Relationship ◽

Age Related Changes

AbstractGene expression changes with age have consequences for healthy aging and disease development. Here we investigate age-related changes in gene expression measured by RNA-seq in four tissues and the interplay between genotypes and age-related changes in expression. Using concurrently measured methylation array data from fat we also investigate the relationship between methylation, gene expression and age. We identified age-dependent changes in mean levels of gene expression in 5,631 genes and in splicing of 904 genes. Age related changes were widely shared across tissues, with up to 60% of age-related changes in expression and 47% on splicing in multi-exonic genes shared; amongst these we highlight effects on genes involved in diseases such as Alzheimer and cancer. We identified 137 genes with age-related changes in variance and 42 genes with age-dependent discordance between genetically identical individuals; implying the latter are driven by environmental effects. We also give four examples where genetic control of expression is affected by the aging process. Analysis of methylation observed a widespread and stronger effect of age on methylation than expression; however we did not find a strong relationship between age-related changes in both expression and methylation. In summary, we quantified aging affects in splicing, level and variance of gene expression, and show that these processes can be both environmentally and genetically influenced.

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Recalibrating the Epigenetic Clock: Implications for Assessing Biological Age in the Human Cortex

10.1101/2020.04.27.063719 ◽

2020 ◽

Cited By ~ 5

Author(s):

Gemma L Shireby ◽

Jonathan P Davies ◽

Paul T Francis ◽

Joe Burrage ◽

Emma M Walker ◽

...

Keyword(s):

Dna Methylation ◽

Age Distribution ◽

Biological Age ◽

Supervised Machine Learning ◽

Tissue Type ◽

Chronological Age ◽

Epigenetic Clock ◽

Methylation Data ◽

Human Cortex ◽

Dna Methylation Age

AbstractHuman DNA-methylation data have been used to develop biomarkers of ageing - referred to ‘epigenetic clocks’ - that have been widely used to identify differences between chronological age and biological age in health and disease including neurodegeneration, dementia and other brain phenotypes. Existing DNA methylation clocks are highly accurate in blood but are less precise when used in older samples or on brain tissue. We aimed to develop a novel epigenetic clock that performs optimally in human cortex tissue and has the potential to identify phenotypes associated with biological ageing in the brain. We generated an extensive dataset of human cortex DNA methylation data spanning the life-course (n = 1,397, ages = 1 to 104 years). This dataset was split into ‘training’ and ‘testing’ samples (training: n = 1,047; testing: n = 350). DNA methylation age estimators were derived using a transformed version of chronological age on DNA methylation at specific sites using elastic net regression, a supervised machine learning method. The cortical clock was subsequently validated in a novel human cortex dataset (n = 1,221, ages = 41 to 104 years) and tested for specificity in a large whole blood dataset (n = 1,175, ages = 28 to 98 years). We identified a set of 347 DNA methylation sites that, in combination optimally predict age in the human cortex. The sum of DNA methylation levels at these sites weighted by their regression coefficients provide the cortical DNA methylation clock age estimate. The novel clock dramatically out-performed previously reported clocks in additional cortical datasets. Our findings suggest that previous associations between predicted DNA methylation age and neurodegenerative phenotypes might represent false positives resulting from clocks not robustly calibrated to the tissue being tested and for phenotypes that become manifest in older ages. The age distribution and tissue type of samples included in training datasets need to be considered when building and applying epigenetic clock algorithms to human epidemiological or disease cohorts.

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Development of Epigenetic Clocks for Key Ruminant Species

Genes ◽

10.3390/genes13010096 ◽

2021 ◽

Vol 13 (1) ◽

pp. 96

Author(s):

Alex Caulton ◽

Ken G. Dodds ◽

Kathryn M. McRae ◽

Christine Couldrey ◽

Steve Horvath ◽

...

Keyword(s):

Large Body ◽

Ovis Aries ◽

Farm Animal ◽

Tissue Type ◽

Capra Hircus ◽

Chronological Age ◽

Individual Species ◽

Epigenetic Clock ◽

Cpg Sites ◽

Age Related

Robust biomarkers of chronological age have been developed in humans and model mammalian species such as rats and mice using DNA methylation data. The concept of these so-called “epigenetic clocks” has emerged from a large body of literature describing the relationship between genome-wide methylation levels and age. Epigenetic clocks exploit this phenomenon and use small panels of differentially methylated cytosine (CpG) sites to make robust predictions of chronological age, independent of tissue type. Here, we present highly accurate livestock epigenetic clocks for which we have used the custom mammalian methylation array “HorvathMammalMethyl40” to construct the first epigenetic clock for domesticated goat (Capra hircus), cattle (Bos taurus), Red (Cervus elaphus) and Wapiti deer (Cervus canadensis) and composite-breed sheep (Ovis aries). Additionally, we have constructed a ‘farm animal clock’ for all species included in the study, which will allow for robust predictions to be extended to various breeds/strains. The farm animal clock shows similarly high accuracy to the individual species’ clocks (r > 0.97), utilizing only 217 CpG sites to estimate age (relative to the maximum lifespan of the species) with a single mathematical model. We hypothesise that the applications of this livestock clock could extend well beyond the scope of chronological age estimates. Many independent studies have demonstrated that a deviation between true age and clock derived molecular age is indicative of past and/or present health (including stress) status. There is, therefore, untapped potential to utilize livestock clocks in breeding programs as a predictor for age-related production traits.

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