scholarly journals Mammalian Co-methylation Network Analysis of Species Characteristics

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 676-676
Author(s):  
Amin Haghani ◽  
Steve Horvath
Keyword(s):  
Dna Methylation ◽  
Network Analysis ◽  
Growth Hormone Receptor ◽  
Mammalian Species ◽  
Tissue Type ◽  
Maximum Lifespan ◽  
Age Related ◽  
Species Analysis ◽  
Species Characteristics ◽  
Highly Correlated

Abstract The comparative cross-species analysis is a powerful tool to resolve the mysteries of evolution and phenotypic disparities among animals. This is the first network analysis of 10,000 DNA methylome data from 176 mammalian species to identify co-methylation modules that relate to individual (age, sex, tissue type) and species characteristics (e.g. phylogenetic order, maximum lifespan, adult weight). The unexpected correlation between DNA methylation and species were sufficiently strong to allow the construction of phyloepigenetic trees that parallel the phylogenetic tree. Weighted correlation network analysis identified 55 distinct co-methylation modules, i.e. sets of highly correlated CpGs. 31 of these modules are readily interpretable in terms of their relationship to age, maximum lifespan, tissue type etc. An age-related module was perturbed by gold standard anti-aging interventions in mice such as caloric restriction or growth hormone receptor knock outs. Our module-based analysis greatly enhances our biological understanding of age-related changes in DNA methylation across many species.

scholarly journals Epigenetic clock and methylation studies in elephants

2020 ◽  
Author(s):  
Natalia A. Prado ◽  
Janine L. Brown ◽  
Joseph A. Zoller ◽  
Amin Haghani ◽  
Mingjia Yao ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Association Studies ◽  
Mammalian Species ◽  
Epigenetic Clock ◽  
African Elephants ◽  
Asian Elephants ◽  
Age Related ◽  
Elephant Conservation ◽  
Organismal Development ◽  
Polycomb Repressive Complexes

ABSTRACTAge-associated DNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age (“epigenetic clocks”) in humans, mice, dogs, and other species. Here we present epigenetic clocks for African and Asian elephants. These clocks were developed using novel DNA methylation profiles of 140 elephant blood samples of known age, at loci that are highly conserved between mammalian species, using a custom Infinium array (HorvathMammalMethylChip40). We present epigenetic clocks for Asian elephants (Elephas maximus), African elephants (Loxodonta africana), and both elephant species combined. Two additional human-elephant clocks were constructed by combing human and elephant samples. Epigenome-wide association studies identified elephant age-related CpGs and their proximal genes. The products of these genes play important roles in cellular differentiation, organismal development, metabolism, and circadian rhythms. Intracellular events observed to change with age included the methylation of bivalent chromatin domains, targets of polycomb repressive complexes, and TFAP2C binding sites. These readily available epigenetic clocks can be used for elephant conservation efforts where accurate estimates of age are needed to predict demographic trends.

scholarly journals EPIGENETIC PROFILES OF ALZHEIMER’S DISEASE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S937-S937
Author(s):  
Kyra Thrush ◽  
Morgan E Levine
Keyword(s):  
Network Analysis ◽  
Brain Regions ◽  
Machine Learning Techniques ◽  
Clear Understanding ◽  
Clinical Biomarkers ◽  
Age Related ◽  
Epigenetic Age ◽  
Lifestyle Choices ◽  
Level Information ◽  
Highly Correlated

Abstract Although age is highly correlated with incidence of Alzheimer’s Dementia (AD), the field continues to lack a clear understanding of how either normal and/or pathological aging processes drive neurodegeneration. As such, there remains a clear lack of valid and reliable clinical biomarkers to predict that disease’s future development and severity. Epigenetic age based on DNA methylation (DNAm) in brain have been shown to relate to AD neuropathology and cognitive decline. However, they were not initially designed as AD biomarkers. We hypothesized that supervised and unsupervised machine learning techniques (e.g. network analysis, clustering, and regressed-based techniques) could be used to build composite scoring variables from DNAm data that are predictive of AD progression. This work analyzes the methylation of 3 brain regions (cerebellum (CBM), prefrontal cortex (PFC), striatum (ST))—totaling 1,047 brain methylation samples. The samples contain neuropathologically confirmed AD cases and controls, and is enriched for APOE4+ carriers. Detailed subject-level information concerning cognitive measures, lifestyle choices, medications, and neuropathology at death were also considered. Based on epigenome-wide association study (EWAS), we identified a CpG in AIMP2 that is a robust predictor of AD-related phenotypes. Using network analysis, we have also identified co-methylation modules that relate to multifactorial AD phenotypes. Following validation, we intend to follow-up on the biological processes and molecular pathways associated with these epigenetic signatures. In moving forward, predictors of AD diagnosis and prognostication have major implications for early detection and treatment of this major age-related disease.

scholarly journals DNA methylation clocks show slower progression of aging in naked mole-rat queens

2021 ◽  
Author(s):  
Steve Horvath ◽  
Amin Haghani ◽  
Nicholas Macoretta ◽  
Julia Ablaeva ◽  
Joseph Alan Zoller ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cytosine Methylation ◽  
Mammalian Species ◽  
Human Longevity ◽  
Aging Effects ◽  
Metabolic Processes ◽  
Eusocial Insects ◽  
Age Related ◽  
Physiological Capacity ◽  
Mole Rat

Naked mole-rats (NMRs) live an exceptionally long life, appear not to exhibit age-related decline in physiological capacity, and are seemingly 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 generated DNA methylation profiles from 329 tissues from animals of known age, at loci that are highly conserved between mammalian species, using a custom Infinium array (HorvathMammalMethylChip40). We observed strong aging effects on NMR DNA methylation, from which we developed seven highly accurate age estimators (epigenetic clocks) for several tissues (pan-tissue, blood, kidney clock, liver clock, skin clock) and two dual species (human-NMR) clocks. By identifying age-related cytosine methylation that are shared between NMR and humans, but not with the mouse, we identified genes and cellular pathways that impinge on developmental and metabolic processes that are potentially involved in NMR and human longevity. The NMR epigenetic clocks revealed that breeding NMR queens age more slowly than non-breeders, a feature that is also observed in some eusocial insects. CpGs associated with queen status were located near developmental genes and those that are regulated by the LHX3 transcription factor that controls pituitary development. In summary, our study demonstrates that despite a phenotype of reduced senescence, the NMR ages epigenetically through developmental and metabolic processes, and that NMR queens age more slowly than non-breeders.

scholarly journals Epigenetic predictors of maximum lifespan and other life history traits in mammals

2021 ◽  
Author(s):  
Caesar Z. Li ◽  
Amin Haghani ◽  
Todd R. Robeck ◽  
Diego Villar ◽  
Ake T. Lu ◽  
...  
Keyword(s):  
Life History ◽  
Sexual Maturity ◽  
Life History Traits ◽  
Growth Hormone Receptor ◽  
Cytosine Methylation ◽  
Mammalian Species ◽  
Maximum Lifespan ◽  
Transcriptional Regulatory ◽  
Extended Lifespan ◽  
Methylation Patterns

Maximum lifespan of a species is the oldest that individuals can survive, reflecting the genetic limit of longevity in an ideal environment. Here we report methylation-based models that accurately predict maximum lifespan (r=0.89), gestational time (r=0.96), and age at sexual maturity (r=0.87), using cytosine methylation patterns collected from over 12,000 samples derived from 192 mammalian species. Our epigenetic maximum lifespan predictor corroborated the extended lifespan in growth hormone receptor knockout mice and rapamycin treated mice. Across dog breeds, epigenetic maximum lifespan correlates positively with breed lifespan but negatively with breed size. Lifespan-related cytosines are located in transcriptional regulatory regions, such as bivalent chromatin promoters and polycomb-repressed regions, which were hypomethylated in long-lived species. The epigenetic estimators of maximum lifespan and other life history traits will be useful for characterizing understudied species and for identifying interventions that extend lifespan.

scholarly journals Universal DNA Methylation Age Across Mammalian Tissues

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 412-412
Author(s):  
Zhe Fei ◽  
Ken Raj ◽  
Steve Horvath ◽  
Ake Lu
Keyword(s):  
Dna Methylation ◽  
Aging Process ◽  
Mammalian Species ◽  
The Body ◽  
Cellular Damage ◽  
Developmental Processes ◽  
Age Related ◽  
Evolutionarily Conserved ◽  
Mammalian Tissues ◽  
Dna Methylation Age

Abstract Aging is often perceived as a degenerative process caused by random accrual of cellular damage over time. In spite of this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, it is difficult to ignore the likelihood that a defined and shared mechanism instead, underlies the aging process. To address this, we generated over 10,000 methylation arrays, each profiling up to 37,000 cytosines in highly-conserved stretches of DNA, from over 59 tissue-types derived from 128 mammalian species. From these, we identified and characterized specific cytosines, whose methylation levels change with age across mammalian species. Genes associated with these cytosines are greatly enriched in mammalian developmental processes and implicated in age-associated diseases. From the methylation profiles of these age-related cytosines, we successfully constructed three highly accurate universal mammalian clocks for eutherians, and one universal clock for marsupials. The universal clocks for eutherians are similarly accurate for estimating ages (r>0.96) of any mammalian species and tissue with a single mathematical formula. Collectively, these new observations support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species - a notion that was long-debated without the benefit of this new and compelling evidence.

scholarly journals Universal DNA methylation age across mammalian tissues

2021 ◽  
Author(s):  
◽  
Ake T. Lu ◽  
Zhe Fei ◽  
Amin Haghani ◽  
Todd R. Robeck ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Aging Process ◽  
Mammalian Species ◽  
The Body ◽  
Cellular Damage ◽  
Developmental Processes ◽  
Age Related ◽  
Evolutionarily Conserved ◽  
Mammalian Tissues ◽  
Dna Methylation Age

ABSTRACTAging is often perceived as a degenerative process caused by random accrual of cellular damage over time. In spite of this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, it is difficult to ignore the likelihood that a defined and shared mechanism instead, underlies the aging process. To address this, we generated 10,000 methylation arrays, each profiling up to 37,000 cytosines in highly-conserved stretches of DNA, from over 59 tissue-types derived from 128 mammalian species. From these, we identified and characterized specific cytosines, whose methylation levels change with age across mammalian species. Genes associated with these cytosines are greatly enriched in mammalian developmental processes and implicated in age-associated diseases. From the methylation profiles of these age-related cytosines, we successfully constructed three highly accurate universal mammalian clocks for eutherians, and one universal clock for marsupials. The universal clocks for eutherians are similarly accurate for estimating ages (r>0.96) of any mammalian species and tissue with a single mathematical formula. Collectively, these new observations support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species - a notion that was long-debated without the benefit of this new and compelling evidence.

scholarly journals DNA methylation aging and transcriptomic studies in horses

2021 ◽  
Author(s):  
Steve Horvath ◽  
Amin Haghani ◽  
Sichong Peng ◽  
Erin N. Hales ◽  
Joseph A. Zoller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Sequences ◽  
Mammalian Species ◽  
Body Parts ◽  
Developmental Genes ◽  
Chromatin Domains ◽  
Biomarkers Of Aging ◽  
Age Related ◽  
Expression Atlas

ABSTRACTHuman DNA methylation profiles have been used successfully to develop highly accurate biomarkers of aging (“epigenetic clocks”). Here, we describe epigenetic clocks for horses, based on methylation profiles of CpGs with flanking DNA sequences that are highly conserved between multiple mammalian species. Methylation levels of these CpGs were measured using a custom-designed Infinium array (HorvathMammalMethylChip40). We generated 336 DNA methylation profiles from 42 different horse tissues and body parts, which we used to develop five epigenetic clocks for horses: a multi-tissue clock, a blood clock, a liver clock and two dual-species clocks that apply to both horses and humans. Epigenetic age measured by these clocks show that while castration affects the basal methylation levels of individual cytosines, it does not exert a significant impact on the epigenetic aging rate of the horse. We observed that most age-related CpGs are adjacent to developmental genes. Consistently, these CpGs reside in bivalent chromatin domains and polycomb repressive targets, which are elements that control expression of developmental genes. The availability of an RNA expression atlas of these tissues allowed us to correlate CpG methylation, their corresponding contextual chromatin features and gene expression. This analysis revealed that while increased methylation of CpGs in enhancers is likely to repress gene expression, methylation of CpGs in bivalent chromatin domains on the other hand is likely to stimulate expression of the corresponding downstream loci, which are often developmental genes. This supports the notion that aging may be accompanied by increased expression of developmental genes. It is expected that the epigenetic clocks will be useful for identifying and validating anti-aging interventions for horses.

scholarly journals DNA methylation differs extensively between strains of the same geographical origin and changes with age in Daphnia magna

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jack Hearn ◽  
Fiona Plenderleith ◽  
Tom J. Little
Keyword(s):  
Dna Methylation ◽  
Caloric Restriction ◽  
Daphnia Magna ◽  
Single Gene ◽  
Methylation Status ◽  
Strain Differences ◽  
Life History Trait ◽  
Food Level ◽  
Epigenetic Clock ◽  
Age Related

Abstract Background Patterns of methylation influence lifespan, but methylation and lifespan may also depend on diet, or differ between genotypes. Prior to this study, interactions between diet and genotype have not been explored together to determine their influence on methylation. The invertebrate Daphnia magna is an excellent choice for testing the epigenetic response to the environment: parthenogenetic offspring are identical to their siblings (making for powerful genetic comparisons), they are relatively short lived and have well-characterised inter-strain life-history trait differences. We performed a survival analysis in response to caloric restriction and then undertook a 47-replicate experiment testing the DNA methylation response to ageing and caloric restriction of two strains of D. magna. Results Methylated cytosines (CpGs) were most prevalent in exons two to five of gene bodies. One strain exhibited a significantly increased lifespan in response to caloric restriction, but there was no effect of food-level CpG methylation status. Inter-strain differences dominated the methylation experiment with over 15,000 differently methylated CpGs. One gene, Me31b, was hypermethylated extensively in one strain and is a key regulator of embryonic expression. Sixty-one CpGs were differentially methylated between young and old individuals, including multiple CpGs within the histone H3 gene, which were hypermethylated in old individuals. Across all age-related CpGs, we identified a set that are highly correlated with chronological age. Conclusions Methylated cytosines are concentrated in early exons of gene sequences indicative of a directed, non-random, process despite the low overall DNA methylation percentage in this species. We identify no effect of caloric restriction on DNA methylation, contrary to our previous results, and established impacts of caloric restriction on phenotype and gene expression. We propose our approach here is more robust in invertebrates given genome-wide CpG distributions. For both strain and ageing, a single gene emerges as differentially methylated that for each factor could have widespread phenotypic effects. Our data showed the potential for an epigenetic clock at a subset of age positions, which is exciting but requires confirmation.

scholarly journals Age-related differences in monocyte DNA methylation and immune function in healthy Kenyan adults and children

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Katherine R. Dobbs ◽  
Paula Embury ◽  
Emmily Koech ◽  
Sidney Ogolla ◽  
Stephen Munga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Young Adults ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Innate Immune ◽  
Inflammatory Gene Expression ◽  
Cpg Sites ◽  
Age Related ◽  
Adults And Children

Abstract Background Age-related changes in adaptive and innate immune cells have been associated with a decline in effective immunity and chronic, low-grade inflammation. Epigenetic, transcriptional, and functional changes in monocytes occur with aging, though most studies to date have focused on differences between young adults and the elderly in populations with European ancestry; few data exist regarding changes that occur in circulating monocytes during the first few decades of life or in African populations. We analyzed DNA methylation profiles, cytokine production, and inflammatory gene expression profiles in monocytes from young adults and children from western Kenya. Results We identified several hypo- and hyper-methylated CpG sites in monocytes from Kenyan young adults vs. children that replicated findings in the current literature of differential DNA methylation in monocytes from elderly persons vs. young adults across diverse populations. Differentially methylated CpG sites were also noted in gene regions important to inflammation and innate immune responses. Monocytes from Kenyan young adults vs. children displayed increased production of IL-8, IL-10, and IL-12p70 in response to TLR4 and TLR2/1 stimulation as well as distinct inflammatory gene expression profiles. Conclusions These findings complement previous reports of age-related methylation changes in isolated monocytes and provide novel insights into the role of age-associated changes in innate immune functions.

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