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 DNA methylation clocks tick in naked mole rats but queens age more slowly than nonbreeders

Nature Aging ◽  
2021 ◽  
Author(s):  
Steve Horvath ◽  
Amin Haghani ◽  
Nicholas Macoretta ◽  
Julia Ablaeva ◽  
Joseph A. Zoller ◽  
...  
Keyword(s):  
Pluripotent Stem Cells ◽  
Mammalian Species ◽  
Aging Effects ◽  
Eusocial Insects ◽  
Age Related ◽  
Physiological Capacity ◽  
Epigenetic Aging ◽  
Induced Pluripotent ◽  
Negligible Senescence ◽  
Kidney Liver

AbstractNaked 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.

scholarly journals A Genome-Wide Scan Reveals Important Roles of DNA Methylation in Human Longevity by Regulating Age-Related Disease Genes

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0120388 ◽  
Author(s):  
Fu-Hui Xiao ◽  
Yong-Han He ◽  
Qi-Gang Li ◽  
Huan Wu ◽  
Long-Hai Luo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Human Longevity ◽  
Disease Genes ◽  
Related Disease ◽  
Age Related ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Scan

scholarly journals Environmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sara Zocher ◽  
Rupert W. Overall ◽  
Mathias Lesche ◽  
Andreas Dahl ◽  
Gerd Kempermann
Keyword(s):  
Dna Methylation ◽  
Brain Function ◽  
Environmental Enrichment ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Aged Mouse ◽  
Lifestyle Interventions ◽  
Epigenetic Changes ◽  
Aging Effects ◽  
Age Related

AbstractThe decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment counteracts age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is critical to neuronal function. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the stimulating effects of environmental enrichment on hippocampal plasticity at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.

scholarly journals Changes of gene expression but not cytosine methylation are associated with plasticity of male parental care reflecting behavioural state, social context, and individual flexibility

2017 ◽  
Author(s):  
CB Cunningham ◽  
L Ji ◽  
EC McKinney ◽  
KM Benowitz ◽  
RJ Schmitz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Social Context ◽  
Parental Care ◽  
Individual Variation ◽  
Molecular Mechanisms ◽  
Cytosine Methylation ◽  
Burying Beetle ◽  
Behavioural State ◽  
Age Related

AbstractBehaviour is often on the front line of plasticity in response to different environments. At the genetic level, behavioural changes are likely to be associated with changes of gene expression. Most studies to date have focused on gene expression differences associated with discrete behavioural states reflecting development or age-related changes, such as honey bee castes. However, more rapidly flexible behaviour is often observed in response to social context or simple individual variation. The differences in genetic influences for the different forms of plasticity are poorly understood. In this study we contrasted gene expression during male parental care of the burying beetle, Nicrophorus vespilloides, in a factorial design. Male N. vespilloides males typically do not provide care when females are present. However, male care is inducible by the removing female and has parental effects equivalent to female care. We used this experimental manipulation to isolate gene expression and cytosine methylation associated with differences of behavioural state, differences of social context, or differences of individual flexibility for expressing care. The greatest number of differentially expressed genes was associated with behavioural state, followed by differences of social contexts, and lastly differences of individual variation. DNA methylation has been hypothesized to regulate the transcriptional architecture that regulates behavioural transitions. We tested this hypothesis by quantifying differences of cytosine methylation that were associated with differences of behavioural state and individual flexibility. Changes of cytosine methylation were not associated with changes of gene expression. Our results suggest a hierarchical association between gene expression and the different sources of variation that influence behaviour, but that this process is not controlled by DNA methylation despite reflecting levels of plasticity in behaviour. Our results further suggest that the extent that a behaviour is transient plays an underappreciated role in determining the molecular mechanisms that underpin the behaviour.

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 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 DNA methylation QTL analysis identifies new regulators of human longevity

2020 ◽  
Vol 29 (7) ◽  
pp. 1154-1167 ◽  
Author(s):  
Silke Szymczak ◽  
Janina Dose ◽  
Guillermo G Torres ◽  
Femke-Anouska Heinsen ◽  
Geetha Venkatesh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Complex Trait ◽  
Human Longevity ◽  
Reduced Representation ◽  
Age Related ◽  
Reduced Representation Bisulfite Sequencing ◽  
Genetic And Environmental Factors ◽  
Functional Relevance ◽  
Study Participants

Abstract Human longevity is a complex trait influenced by both genetic and environmental factors, whose interaction is mediated by epigenetic mechanisms like DNA methylation. Here, we generated genome-wide whole-blood methylome data from 267 individuals, of which 71 were long-lived (90–104 years), by applying reduced representation bisulfite sequencing. We followed a stringent two-stage analysis procedure using discovery and replication samples to detect differentially methylated sites (DMSs) between young and long-lived study participants. Additionally, we performed a DNA methylation quantitative trait loci analysis to identify DMSs that underlie the longevity phenotype. We combined the DMSs results with gene expression data as an indicator of functional relevance. This approach yielded 21 new candidate genes, the majority of which are involved in neurophysiological processes or cancer. Notably, two candidates (PVRL2, ERCC1) are located on chromosome 19q, in close proximity to the well-known longevity- and Alzheimer’s disease-associated loci APOE and TOMM40. We propose this region as a longevity hub, operating on both a genetic (APOE, TOMM40) and an epigenetic (PVRL2, ERCC1) level. We hypothesize that the heritable methylation and associated gene expression changes reported here are overall advantageous for the LLI and may prevent/postpone age-related diseases and facilitate survival into very old age.

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 Epigenetic rejuvenation of the hippocampus by environmental enrichment

2019 ◽  
Author(s):  
Sara Zocher ◽  
Rupert W. Overall ◽  
Mathias Lesche ◽  
Andreas Dahl ◽  
Gerd Kempermann
Keyword(s):  
Dna Methylation ◽  
Brain Function ◽  
Environmental Enrichment ◽  
Brain Aging ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Lifestyle Interventions ◽  
Epigenetic Changes ◽  
Aging Effects ◽  
Age Related

AbstractThe decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that environmental enrichment counteracted age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is known to control neuronal functions. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the rejuvenating effects of environmental enrichment at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.

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.

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