scholarly journals Reversing age: dual species measurement of epigenetic age with a single clock

2020 ◽  
Author(s):  
Steve Horvath ◽  
Kavita Singh ◽  
Ken Raj ◽  
Shraddha Khairnar ◽  
Akshay Sanghavi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Training Data ◽  
Rat Tissues ◽  
Epigenetic Clock ◽  
Tissue Samples ◽  
Beneficial Effects ◽  
Biomarkers Of Aging ◽  
Plasma Fraction ◽  
Epigenetic Aging ◽  
Epigenetic Age

AbstractYoung blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.

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

2020 ◽  
Author(s):  
Jean-François Lemaître ◽  
Benjamin Rey ◽  
Jean-Michel Gaillard ◽  
Corinne Régis ◽  
Emmanuelle Gilot ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Evolutionary Biology ◽  
Roe Deer ◽  
Chronological Age ◽  
Epigenetic Clock ◽  
Aging Effects ◽  
Methylation Array ◽  
Biomarkers Of Aging ◽  
Epigenetic Age ◽  
The Relationship

AbstractDNA 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 (Chizé 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.

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

2020 ◽  
Author(s):  
Lindsay L. Sailer ◽  
Amin Haghani ◽  
Joseph A. Zoller ◽  
Caesar Z. Li ◽  
Alexander G. Ophir ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Tissue ◽  
Association Studies ◽  
Chronological Age ◽  
Epigenetic Clock ◽  
Pair Bonding ◽  
Prairie Voles ◽  
Relative Age ◽  
Biomarkers Of Aging ◽  
Epigenetic Aging

ABSTRACTThe 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.

scholarly journals Dysfunctional epigenetic aging of the normal colon and colorectal cancer risk

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Ting Wang ◽  
Sean K. Maden ◽  
Georg E. Luebeck ◽  
Christopher I. Li ◽  
Polly A. Newcomb ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Risk Group ◽  
Risk Groups ◽  
Biological Age ◽  
Chronological Age ◽  
Epigenetic Clock ◽  
Normal Colon ◽  
Epigenetic Aging ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration

Abstract Background Chronological age is a prominent risk factor for many types of cancers including colorectal cancer (CRC). Yet, the risk of CRC varies substantially between individuals, even within the same age group, which may reflect heterogeneity in biological tissue aging between people. Epigenetic clocks based on DNA methylation are a useful measure of the biological aging process with the potential to serve as a biomarker of an individual’s susceptibility to age-related diseases such as CRC. Methods We conducted a genome-wide DNA methylation study on samples of normal colon mucosa (N = 334). Subjects were assigned to three cancer risk groups (low, medium, and high) based on their personal adenoma or cancer history. Using previously established epigenetic clocks (Hannum, Horvath, PhenoAge, and EpiTOC), we estimated the biological age of each sample and assessed for epigenetic age acceleration in the samples by regressing the estimated biological age on the individual’s chronological age. We compared the epigenetic age acceleration between different risk groups using a multivariate linear regression model with the adjustment for gender and cell-type fractions for each epigenetic clock. An epigenome-wide association study (EWAS) was performed to identify differential methylation changes associated with CRC risk. Results Each epigenetic clock was significantly correlated with the chronological age of the subjects, and the Horvath clock exhibited the strongest correlation in all risk groups (r > 0.8, p < 1 × 10−30). The PhenoAge clock (p = 0.0012) revealed epigenetic age deceleration in the high-risk group compared to the low-risk group. Conclusions Among the four DNA methylation-based measures of biological age, the Horvath clock is the most accurate for estimating the chronological age of individuals. Individuals with a high risk for CRC have epigenetic age deceleration in their normal colons measured by the PhenoAge clock, which may reflect a dysfunctional epigenetic aging process.

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

2020 ◽  
Author(s):  
Paweł Kordowitzki ◽  
Amin Haghani ◽  
Joseph A. Zoller ◽  
Caesar Z. Li ◽  
Ken Raj ◽  
...  
Keyword(s):  
Association Studies ◽  
Gestation Length ◽  
Epigenetic Clock ◽  
Reproductive Aging ◽  
Aging Effects ◽  
Biomarkers Of Aging ◽  
Reproductive Axis ◽  
Epigenetic Aging ◽  
Epigenetic Age ◽  
Epigenetic Signatures

ABSTRACTCattle 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.

scholarly journals Epigenetic clock and methylation studies in vervet monkeys

2020 ◽  
Author(s):  
Anna J. Jasinska ◽  
Amin Haghani ◽  
Joseph A. Zoller ◽  
Caesar Z. Li ◽  
Adriana Arneson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Primate Species ◽  
Chronological Age ◽  
Epigenetic Clock ◽  
Vervet Monkeys ◽  
Maximum Lifespan ◽  
Primate Model ◽  
Tissue Samples ◽  
Relative Age ◽  
Biomarkers Of Aging

ABSTRACTDNA 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.

scholarly journals Epigenetic clock and methylation studies in vervet monkeys

GeroScience ◽  
2021 ◽  
Author(s):  
Anna J. Jasinska ◽  
Amin Haghani ◽  
Joseph A. Zoller ◽  
Caesar Z. Li ◽  
Adriana Arneson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Primate Species ◽  
Chronological Age ◽  
Epigenetic Clock ◽  
Vervet Monkeys ◽  
Maximum Lifespan ◽  
Primate Model ◽  
Tissue Samples ◽  
Relative Age ◽  
Biomarkers Of Aging

AbstractDNA 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, we developed 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 that gain methylation 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 anti-aging studies in vervets.

scholarly journals The aging DNA methylome reveals environment-by-aging interactions in a model teleost

2021 ◽  
Author(s):  
Emily M Bertucci ◽  
Marilyn W Mason ◽  
Olin E Rhodes ◽  
Benjamin B Parrott
Keyword(s):  
Dna Methylation ◽  
Environmental Factors ◽  
Environmental Drivers ◽  
Chronological Age ◽  
Epigenetic Clock ◽  
Ongoing Research ◽  
Dna Methylome ◽  
Age Related ◽  
Epigenetic Aging ◽  
Epigenetic Age

The rate at which individuals age underlies variation in life history and attendant health and disease trajectories. Age specific patterning of the DNA methylome (epigenetic aging) is strongly correlated with chronological age in humans and can be modeled to produce epigenetic age predictors. However, epigenetic age estimates vary among individuals of the same age, and this mismatch is correlated to the onset of age-related disease and all-cause mortality. Yet, the origins of epigenetic-to-chronological age discordance are not resolved. In an effort to develop a tractable model in which environmental drivers of epigenetic aging can be assessed, we investigate the relationship between aging and DNA methylation in a small teleost, medaka (Oryzias latipes). We find that age-associated DNA methylation patterning occurs broadly across the genome, with the majority of age-related changes occurring during early life. By modeling the stereotypical nature of age-associated DNA methylation dynamics, we built an epigenetic clock, which predicts chronological age with a mean error of 29.1 days (~4% of average lifespan). Characterization of clock loci suggests that aspects of epigenetic aging are functionally similar across vertebrates. To understand how environmental factors interact with epigenetic aging, we exposed medaka to four doses of ionizing radiation for seven weeks, hypothesizing that exposure to such an environmental stressor would accelerate epigenetic aging. While the epigenetic clock was not significantly affected, radiation exposure accelerated and decelerated patterns of normal epigenetic aging, with radiation-induced epigenetic alterations enriched at loci that become hypermethylated with age. Together, our findings advance ongoing research attempting to elucidate the functional role of DNA methylation in integrating environmental factors into the rate of biological aging.

scholarly journals DEVELOPMENT OF EPIGENETIC MEASURES FOR GEROSCIENCE CLINICAL TRIALS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S746-S746
Author(s):  
Morgan E Levine
Keyword(s):  
Dna Methylation ◽  
Clinical Trials ◽  
Surrogate Endpoints ◽  
Methylation Data ◽  
Biomarkers Of Aging ◽  
Age Related ◽  
Epigenetic Age ◽  
Human And Mouse ◽  
Promising Avenue

Abstract One of the major goals of the NIA is to oversee development of biomarkers of aging. In recent years, DNA methylation has emerged as a promising avenue from which to quantify biological age. We and others have shown that these measures track age across various tissues and cells, and further deviations between chronological and “epigenetic age” have been shown to confer risk for various aging outcomes. However, the usefulness of these measures will depend on both their modifiability and ability to capture known targetable hallmarks of aging. Using DNA methylation data from cell line experiments, we have recently generated epigenetic predictors of cellular senescence for both human and mouse that when assessed in vivo from bulk samples, show age-related increases and are associated with aging outcomes. In moving forward, measures such as these may serve as promising surrogate endpoints for assessing efficacy of senolytic drugs and/or other anti-aging therapeutics.

scholarly journals The costs of competition: high social status males experience accelerated epigenetic aging in wild baboons

2020 ◽  
Author(s):  
Jordan A. Anderson ◽  
Rachel A. Johnston ◽  
Amanda J. Lea ◽  
Fernando A. Campos ◽  
Tawni N. Voyles ◽  
...  
Keyword(s):  
Dominance Rank ◽  
Natural Populations ◽  
Life History Strategy ◽  
Male Dominance ◽  
Biological Aging ◽  
Epigenetic Clock ◽  
Epigenetic Aging ◽  
Epigenetic Age ◽  
Aging Rates ◽  
Young Life

AbstractAging, for virtually all life, is inescapable. However, within populations, biological aging rates vary. Understanding sources of variation in this process is central to understanding the biodemography of natural populations. We constructed a DNA methylation-based age predictor for an intensively studied wild baboon population in Kenya. Consistent with findings in humans, the resulting “epigenetic clock” closely tracks chronological age, but individuals are predicted to be somewhat older or younger than their known ages. Surprisingly, these deviations are not explained by the strongest predictors of lifespan in this population, early adversity and social integration. Instead, they are best predicted by male dominance rank: high-ranking males are predicted to be older than their true ages, and epigenetic age tracks changes in rank over time. Our results argue that achieving high rank for male baboons—the best predictor of reproductive success—imposes costs consistent with a “live fast, die young” life history strategy.

scholarly journals An epigenetic clock to estimate the age of living beluga whales

2020 ◽  
Author(s):  
Eleanor K. Bors ◽  
C. Scott Baker ◽  
Paul R. Wade ◽  
Kaimyn O’Neill ◽  
Kim E.W. Shelden ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Penalized Regression ◽  
Training Data ◽  
Delphinapterus Leucas ◽  
Epigenetic Clock ◽  
Calibration Data ◽  
Cook Inlet ◽  
Data Set ◽  
Beluga Whales ◽  
Skin Samples

ABSTRACTIntroductionDNA methylation data facilitate the development of accurate molecular estimators of chronological age, or ‘epigenetic clocks.’ We present a robust epigenetic clock for the beluga whale, Delphinapterus leucas, developed for an endangered population in Cook Inlet, Alaska, USA.Methods and ResultsWe used a custom methylation array to measure methylation levels at 37,491 cytosine-guanine sites (CpGs) from skin samples of dead whales (n = 67) whose chronological ages were estimated based on tooth growth layer groups. Using these calibration data, a penalized regression model selected 23 CpGs, providing an R2 = 0.92 for the training data; and an R2 = 0.74 and median absolute age error = 2.9 years for the leave one out cross-validation. We applied the epigenetic clock to an independent data set of 38 skin samples collected with a biopsy dart from living whales between 2016 and 2018. Age estimates ranged from 11 to 27 years. We also report sex correlations in CpG data and describe an approach of identifying the sex of an animal using DNA methylation.DiscussionThe epigenetic estimators of age and sex presented here have broad applications for conservation and management of Cook Inlet beluga whales and potentially other cetaceans.

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