Biology subjects

Haghani, A.

Publications and source records attributed to Haghani, A..

46 records · Page 3Linked to original sources

bioRxiv2020

Castration delays epigenetic aging and feminises DNA methylation at androgen-regulated loci

In mammals, females generally live longer than males. Nevertheless, the mechanisms underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful biological biomarkers capable of precisely estimating chronological age using only DNA methylation data. These clocks have been used to identify novel factors influencing the aging rate, but few studies have examined the performance of epigenetic clocks in divergent mammalian species. In this study, we developed the first epigenetic clock for domesticated sheep (Ovis aries), and using 185 CpG sites can predict chronological age with a median absolute error of 5.1 months from ear punch and blood samples. We have discovered that castrated male sheep have a decelerated aging rate compared to intact males, mediated at least in part by the removal of androgens. Furthermore, we identified several androgen-sensitive CpG dinucleotides that become progressively hypomethylated with age in intact males, but remain stable in castrated males and females. Many of these androgen sensitive demethylating sites are regulatory in nature and located in genes with known androgen-dependent regulation, such as MKLN1, LMO4 and FN1. Comparable sex-specific methylation differences in MKLN1 also exist in mouse muscle (p=0.003) but not blood, indicating that androgen dependent demethylation exists in multiple mammalian groups, in a tissue-specific manner. In characterising these sites, we identify biologically plausible mechanisms explaining how androgens drive male-accelerated aging.

developmental biology↗

bioRxiv2020

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

DNA-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 minipigs 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.

developmental biology↗

bioRxiv2020

Pair bonding slows epigenetic aging and alters methylation in brains of prairie voles

The quality of romantic relationships can be predictive of health consequences related to aging. DNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how pair bonding impacts aging. Prairie voles (Microtus ochrogaster) have emerged as a model to study social attachment among adult pairs. Here we describe DNA methylation-based estimators of age for prairie voles based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for voles was trained on 3 tissue sources (ear, liver, and samples of brain tissue from within the pair bonding circuit). A novel dual species human-vole clock accurately measured relative age defined as the ratio of chronological age to maximum age. According to the human-vole clock of relative age, sexually inexperienced voles exhibit accelerated epigenetic aging in brain tissue (p = 0.02) when compared to pair bonded animals of the same chronological age. Epigenome wide association studies identified CpGs in four genes that were strongly associated with pair bonding across the three tissue types (brain, ear, and liver): Hnrnph1, Fancl, Fam13b, and Fzd1. Further, four CpGs (near the Bmp4 exon, Eif4g2 3 prime UTR, Robo1 exon, and Nfat5 intron) exhibited a convergent methylation change between pair bonding and aging. This study describes highly accurate DNA methylation-based estimators of age in prairie voles and provides evidence that pair bonding status modulates the methylome.

developmental biology↗

bioRxiv2020

Epigenetic clock and DNA methylation studies of roe deer in the wild

DNA methylation-based biomarkers of aging (epigenetic clocks) promise to lead to new insights in the evolutionary biology of ageing. Relatively little is known about how the natural environment affects epigenetic aging effects in wild species. In this study, we took advantage of a unique long-term (>40 years) longitudinal monitoring of individual roe deer (Capreolus capreolus) living in two wild populations (Chize and Trois Fontaines, France) facing different ecological contexts to investigate the relationship between chronological age and levels of DNA methylation (DNAm). We generated novel DNA methylation data from n=90 blood samples using a custom methylation array (HorvathMammalMethylChip40). We present three DNA methylation-based estimators of age (DNAm or epigenetic age), which were trained in males, females, and both sexes combined. We investigated how sex differences influenced the relationship between DNAm age and chronological age through the use of sex-specific epigenetic clocks. Our results highlight that both populations and sex influence the epigenetic age, with the bias toward a stronger male average age acceleration (i.e. differences between epigenetic age and chronological ages) particularly pronounced in the population facing harsh environmental conditions. Further, we identify the main sites of epigenetic alteration that have distinct aging patterns across the two sexes. These findings open the door to promising avenues of research at the crossroad of evolutionary biology and biogerontology.

evolutionary biology↗

bioRxiv2020

Epigenetic clock and methylation studies in the rhesus macaque

Methylation 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 regards 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). It is expected that the macaque clocks will reveal an epigenetic aging rate associated with a host of health conditions and thus lend themselves for identifying and validating anti-aging interventions.

developmental biology↗

bioRxiv2020

Epigenetic clock and methylation studies in elephants

Age-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.

developmental biology↗

bioRxiv2020

Epigenetic clock and methylation study of oocytes from a bovine model of reproductive aging

Cattle are an attractive animal model of fertility in women due to their high degree of similarity relative to follicle selection, embryo cleavage, blastocyst formation, and gestation length. To facilitate future studies of the epigenetic underpinnings of aging effects in the female reproductive axis, several DNA methylation-based biomarkers of aging (epigenetic clocks) for bovine oocytes are presented. One such clock was germane to only oocytes, while a dual-tissue clock was highly predictive of age in both oocytes and blood. Dual species clocks that apply to both humans and cattle were also developed and evaluated. These epigenetic clocks can be used to accurately estimate the chronological age of the oocyte donor. Both epigenetic clock studies and epigenome wide association studies revealed that blood and oocytes differ substantially with respect aging and the underlying epigenetic signatures that potentially influence the aging process. The rate of epigenetic aging was found to be slower in oocytes compared to blood, however, oocytes appeared to begin at an older epigenetic age. The epigenetic clocks for oocytes are expected to address questions in the field of reproductive aging, including the central question: how to slow aging of oocytes.

developmental biology↗

bioRxiv2020

Epigenetic clock and methylation studies in vervet monkeys

DNA methylation-based biomarkers of aging have been developed for many mammals but not yet for the vervet monkey (Chlorocebus sabaeus), which is a valuable non-human primate model for biomedical studies. We generated novel DNA methylation data from vervet cerebral cortex, blood, and liver using highly conserved mammalian CpGs represented on a custom array (HorvathMammalMethylChip40). We present six DNA methylation-based estimators of age: vervet multi-tissue epigenetic clock and tissue-specific clocks for brain cortex, blood, and liver. In addition, two dual species clocks (human-vervet clocks) for measuring chronological age and relative age, respectively. Relative age was defined as ratio of chronological age to maximum lifespan to address the species differences in maximum lifespan. The high accuracy of the human-vervet clocks demonstrates that epigenetic aging processes are evolutionary conserved in primates. When applying these vervet clocks to tissue samples from another primate species, rhesus macaque, we observed high age correlations but strong offsets. We characterized CpGs that correlate significantly with age in the vervet. CpG probes hypermethylated with age across tissues were located near the targets of Polycomb proteins SUZ12 and EED, and genes possessing the trimethylated H3K27 mark in their promoters. The epigenetic clocks are expected to be useful for age estimation of wild-born animals and anti-aging studies in vervets.

developmental biology↗

bioRxiv2020

Epigenetic clock and methylation studies in cats

Human DNA methylation profiles have been used successfully to develop highly accurate biomarkers of aging ("epigenetic clocks"). Although these human epigenetic clocks are not immediately applicable to all species of the animal kingdom, the principles underpinning them appear to be conserved even in animals that are evolutionarily far removed from humans. This is exemplified by recent development of epigenetic clocks for mice and other mammalian species. Here, we describe epigenetic clocks for the domestic cat (Felis catus), based on methylation profiles of CpGs with flanking DNA sequences that are highly conserved between multiple mammalian species. Methylation levels of these CpGs are measured using a custom-designed Infinium array (HorvathMammalMethylChip40). From these, we present 3 epigenetic clocks for cats; of which, one applies only to blood samples from cats, while the remaining two dual-species human-cat clocks apply both to cats and humans. As the rate of human epigenetic ageing is associated with a host of health conditions and pathologies, it is expected that these epigenetic clocks for cats would do likewise and possess the potential to be further developed for monitoring feline health as well as being used for identifying and validating anti-aging interventions.

developmental biology↗

bioRxiv2020

Genome Methylation Predicts Age and Longevity of Bats

Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression.

genomics↗