Epigenetic Aging Clock Research Articles

Epigenetic aging of the demographically non-aging naked mole-rat

The naked mole-rat (NMR) is an exceptionally long-lived rodent that shows no increase of mortality with age, defining it as a demographically non-aging mammal. Here, we perform bisulfite sequencing of the blood of > 100 NMRs, assessing > 3 million common CpG sites. Unsupervised clustering based on sites whose methylation correlates with age reveals an age-related methylome remodeling, and we also observe a methylome information loss, suggesting that NMRs age. We develop an epigenetic aging clock that accurately predicts the NMR age. We show that these animals age much slower than mice and much faster than humans, consistent with their known maximum lifespans. Interestingly, patterns of age-related changes of clock sites in Tert and Prpf19 differ between NMRs and mice, but there are also sites conserved between the two species. Together, the data indicate that NMRs, like other mammals, epigenetically age even in the absence of demographic aging of this species.

DNA methylation aging and transcriptomic studies in horses

Cytosine methylation patterns have not yet been thoroughly studied in horses. Here, we profile n = 333 samples from 42 horse tissue types at loci that are highly conserved between mammalian species using a custom array (HorvathMammalMethylChip40). Using the blood and liver tissues from horses, we develop five epigenetic aging clocks: a multi-tissue clock, a blood clock, a liver clock and two dual-species clocks that apply to both horses and humans. In addition, using blood methylation data from three additional equid species (plains zebra, Grevy’s zebras and Somali asses), we develop another clock that applies across all equid species. Castration does not significantly impact the epigenetic aging rate of blood or liver samples from horses. Methylation and RNA data from the same tissues define the relationship between methylation and RNA expression across horse tissues. We expect that the multi-tissue atlas will become a valuable resource.

Late-life exercise mitigates skeletal muscle epigenetic aging.

There are functional benefits to exercise in muscle, even when performed late in life, but the contributions of epigenetic factors to late‐life exercise adaptation are poorly defined. Using reduced representation bisulfite sequencing (RRBS), ribosomal DNA (rDNA) and mitochondrial‐specific examination of methylation, targeted high‐resolution methylation analysis, and DNAge™ epigenetic aging clock analysis with a translatable model of voluntary murine endurance/resistance exercise training (progressive weighted wheel running, PoWeR), we provide evidence that exercise may mitigate epigenetic aging in skeletal muscle. Late‐life PoWeR from 22–24 months of age modestly but significantly attenuates an age‐associated shift toward promoter hypermethylation. The epigenetic age of muscle from old mice that PoWeR‐trained for eight weeks was approximately eight weeks younger than 24‐month‐old sedentary counterparts, which represents ~8% of the expected murine lifespan. These data provide a molecular basis for exercise as a therapy to attenuate skeletal muscle aging.

Systems aging clock: A novel epigenetic aging clock modeled from organ & bodily function based mortality indices

BackgroundCurrent evidence on the effects of Care Coordination (CC) on older adults’ well-being and health service utilization is inconsistent. Previous studies are mostly limited to regional data and focus mostly on nurse-led CC instead of layperson Care Coordinators like family caregivers. This study explores the effects of having CC in a national sample of U.S. older adults and whether the coordinators’ professionalism impacts the effect of having CC on multidimensional health outcomes (Health outcomes were conceptualized as physical health, healthcare utilization, and care encounters).MethodsData were from the 2016 and 2018 waves of the Health and Retirement Study (HRS) (n=1,372). Multivariate regression models were used to examine the effects of CC on multidimensional health outcomes in 2016 and the longitudinal effects of having CC. We also tested the effect of Care Coordinators’ professionalism on the multidimensional health outcomes. All models controlled for sociodemographic characteristics and health status.ResultsFindings suggest that having CC doesn’t have a positive effect on older adults’ health outcomes. Having CC was associated with an increased number of acute diseases (β = 0.16, p < .001) and nonacute diseases (β = 0.21, p < .01) in longterm. The results regarding cross-sectional effects show that receiving care from a Coordinator was related to increased health service utilization. Participants with professional Care Coordinators were more likely to report receiving person-centered care (OR=1.60, p<.05).ConclusionThis study demonstrates the limited effects of CCs on older adults’ physical health outcomes, and emphasized the importance of care coordinators’ qualifications.

An Epigenetic Aging Clock for Cattle Using Portable Sequencing Technology.

Extensively grazed cattle are often mustered only once a year. Therefore, birthdates are typically unknown or inaccurate. Birthdates would be useful for deriving important traits (growth rate; calving interval), breed registrations, and making management decisions. Epigenetic clocks use methylation of DNA to predict an individual’s age. An epigenetic clock for cattle could provide a solution to the challenges of industry birthdate recording. Here we derived the first epigenetic clock for tropically adapted cattle using portable sequencing devices from tail hair, a tissue which is widely used in industry for genotyping. Cattle (n = 66) with ages ranging from 0.35 to 15.7 years were sequenced using Oxford Nanopore Technologies MinION and methylation was called at CpG sites across the genome. Sites were then filtered and used to calculate a covariance relationship matrix based on methylation state. Best linear unbiased prediction was used with 10-fold cross validation to predict age. A second methylation relationship matrix was also calculated that contained sites associated with genes used in the dog and human epigenetic clocks. The correlation between predicted age and actual age was 0.71 for all sites and 0.60 for dog and human gene epigenetic clock sites. The mean absolute deviation was 1.4 years for animals aged less than 3 years of age, and 1.5 years for animals aged 3–10 years. This is the first reported epigenetic clock using industry relevant samples in cattle.

Accelerated hematopoietic mitotic aging measured by DNA methylation, blood cell lineage, and Parkinson\u2019s disease

BackgroundAging and inflammation are important components of Parkinson’s disease (PD) pathogenesis and both are associated with changes in hematopoiesis and blood cell composition. DNA methylation (DNAm) presents a mechanism to investigate inflammation, aging, and hematopoiesis in PD, using epigenetic mitotic aging and aging clocks. Here, we aimed to define the influence of blood cell lineage on epigenetic mitotic age and then investigate mitotic age acceleration with PD, while considering epigenetic age acceleration biomarkers.ResultsWe estimated epigenetic mitotic age using the “epiTOC” epigenetic mitotic clock in 10 different blood cell populations and in a population-based study of PD with whole-blood. Within subject analysis of the flow-sorted purified blood cell types DNAm showed a clear separation of epigenetic mitotic age by cell lineage, with the mitotic age significantly lower in myeloid versus lymphoid cells (p = 2.1e-11). PD status was strongly associated with accelerated epigenetic mitotic aging (AccelEpiTOC) after controlling for cell composition (OR = 2.11, 95 % CI = 1.56, 2.86, p = 1.6e-6). AccelEpiTOC was also positively correlated with extrinsic epigenetic age acceleration, a DNAm aging biomarker related to immune system aging (with cell composition adjustment: R = 0.27, p = 6.5e-14), and both were independently associated with PD. Among PD patients, AccelEpiTOC measured at baseline was also associated with longitudinal motor and cognitive symptom decline.ConclusionsThe current study presents a first look at epigenetic mitotic aging in PD and our findings suggest accelerated hematopoietic cell mitosis, possibly reflecting immune pathway imbalances, in early PD that may also be related to motor and cognitive progression.

Epigenetic aging biomarkers and occupational exposure to benzene, trichloroethylene and formaldehyde

Epigenetic aging biomarkers are associated with increased morbidity and mortality. We evaluated if occupational exposure to three established chemical carcinogens is associated with acceleration of epigenetic aging. We studied workers in China occupationally exposed to benzene, trichloroethylene (TCE) or formaldehyde by measuring personal air exposures prior to blood collection. Unexposed controls matched by age and sex were selected from nearby factories. We measured leukocyte DNA methylation (DNAm) in peripheral white blood cells using the Infinium HumanMethylation450 BeadChip to calculate five epigenetic aging clocks and DNAmTL, a biomarker associated with leukocyte telomere length and cell replication. We tested associations between exposure intensity and epigenetic age acceleration (EAA), defined as the residuals of regressing the DNAm aging biomarker on chronological age, matching factors and potential confounders. Median differences in EAA between exposure groups were tested using a permutation test with exact p-values. Epigenetic clocks were strongly correlated with age (Spearman r > 0.8) in all three occupational studies. There was a positive exposure-response relationship between benzene and the Skin-Blood Clock EAA biomarker: median EAA was −0.91 years in controls (n = 44), 0.78 years in workers exposed to <10 ppm (n = 41; mean benzene = 1.35 ppm; p = 0.034 vs. controls), and 2.10 years in workers exposed to ≥10 ppm (n = 9; mean benzene = 27.3 ppm; p = 0.019 vs. controls; ptrend = 0.0021). In the TCE study, control workers had a median Skin-Blood Clock EAA of −0.54 years (n = 71) compared to 1.63 years among workers exposed to <10 ppm of TCE (n = 27; mean TCE = 4.22 ppm; p = 0.035). We observed no evidence of EAA associations with formaldehyde exposure (39 controls, 31 exposed). Occupational benzene and TCE exposure were associated with increased epigenetic age acceleration measured by the Skin-Blood Clock. For TCE, there was some evidence of epigenetic age acceleration for lower exposures compared to controls. Our results suggest that some chemical carcinogens may accelerate epigenetic aging.

Analysis of Methylation Dynamics Reveals a Tissue-Specific, Age-Dependent Decline in 5-Methylcytosine Within the Genome of the Vertebrate Aging Model Nothobranchius furzeri.

Erosion of the epigenetic DNA methylation landscape is a widely recognized hallmark of aging. Emerging advances in high throughput sequencing techniques, in particular DNA methylation data analysis, have resulted in the establishment of precise human and murine age prediction tools. In vertebrates, methylation of cytosine at the C5 position of CpG dinucleotides is executed by DNA methyltransferases (DNMTs) whereas the process of enzymatic demethylation is highly dependent on the activity of the ten-eleven translocation methylcytosine dioxygenase (TET) family of enzymes. Here, we report the identification of the key players constituting the DNA methylation machinery in the short-lived teleost aging model Nothobranchius furzeri. We present a comprehensive spatio-temporal expression profile of the methylation-associated enzymes from embryogenesis into late adulthood, thereby covering the complete killifish life cycle. Data mining of the N. furzeri genome produced five dnmt gene family orthologues corresponding to the mammalian DNMTs (DNMT1, 2, 3A, and 3B). Comparable to other teleost species, N. furzeri harbors multiple genomic copies of the de novo DNA methylation subfamily. A related search for the DNMT1 recruitment factor UHRF1 and TET family members resulted in the identification of N. furzeri uhrf1, tet1, tet2, and tet3. Phylogenetic analysis revealed high cross-species similarity on the amino acid level of all individual dnmts, tets, and uhrf1, emphasizing a high degree of functional conservation. During early killifish development all analyzed dnmts and tets showed a similar expression profile characterized by a strong increase in transcript levels after fertilization, peaking either at embryonic day 6 or at the black eye stage of embryonic development. In adult N. furzeri, DNA methylation regulating enzymes showed a ubiquitous tissue distribution. Specifically, we observed an age-dependent downregulation of dnmts, and to some extent uhrf1, which correlated with a significant decrease in global DNA methylation levels in the aging killifish liver and muscle. The age-dependent DNA methylation profile and spatio-temporal expression characteristics of its enzymatic machinery reported here may serve as an essential platform for the identification of an epigenetic aging clock in the new vertebrate model system N. furzeri.

Multi-species and multi-tissue methylation clocks for age estimation in toothed whales and dolphins

The development of a precise blood or skin tissue DNA Epigenetic Aging Clock for Odontocete (OEAC) would solve current age estimation inaccuracies for wild odontocetes. Therefore, we determined genome-wide DNA methylation profiles using a custom array (HorvathMammalMethyl40) across skin and blood samples (n = 446) from known age animals representing nine odontocete species within 4 phylogenetic families to identify age associated CG dinucleotides (CpGs). The top CpGs were used to create a cross-validated OEAC clock which was highly correlated for individuals (r = 0.94) and for unique species (median r = 0.93). Finally, we applied the OEAC for estimating the age and sex of 22 wild Norwegian killer whales. DNA methylation patterns of age associated CpGs are highly conserved across odontocetes. These similarities allowed us to develop an odontocete epigenetic aging clock (OEAC) which can be used for species conservation efforts by provide a mechanism for estimating the age of free ranging odontocetes from either blood or skin samples.

Postpartum sleep loss and accelerated epigenetic aging

BackgroundInsufficient sleep has been linked to accelerated biological aging in adults, providing a possible mechanism through which sleep may influence disease risk. In the current paper, we test the hypothesis that short sleep in postpartum would predict older biological age in women one year post birth, as indicated by accelerated epigenetic aging. MethodsAs part of a larger study of pregnancy and postpartum health (Healthy Babies Before Birth, HB3), 33 mothers provided blood samples for epigenetic aging clock estimates. intrinsic epigenetic age acceleration (IEAA), extrinsic apigenetic age acceleration, phenotypic epigenetic age acceleration (PEAA), GrimAge, DNAmPAI-1, and DNAm telomere length (TL) were calculated using established protocols. Sleep duration was categorized as insufficient sleep (<7 hours per night) or healthy sleep duration (7+ hours per night). Sleep quality was determined using the Pittsburgh Sleep Quality Index (Global score >5). ResultsMaternal postpartum sleep duration at 6 months, but not 12 months, following a birth was predictive of older 12-month IEAA, B (SE) = 3.0 (1.2), P = .02, PEAA, B (SE) = 7.3 (2.0), P = .002, and DNAmTL, B (SE) = −0.18 (0.07), P = .01, but not other indices, all P> .127. Self-reported poor sleep quality at 6 and 12 months was not significantly related to epigenetic age. ConclusionsThese findings suggest that insufficient sleep duration during the early postpartum period is associated with accelerated biological aging. As the sample size is small, additional research is warranted with a larger sample size to replicate these findings.

Underlying features of epigenetic aging clocks in vivo and in vitro.

Epigenetic clocks, developed using DNA methylation data, have been widely used to quantify biological aging in multiple tissues/cells. However, many existing epigenetic clocks are weakly correlated with each other, suggesting they may capture different biological processes. We utilize multi‐omics data from diverse human tissue/cells to identify shared features across eleven existing epigenetic clocks. Despite the striking lack of overlap in CpGs, multi‐omics analysis suggested five clocks (Horvath1, Horvath2, Levine, Hannum, and Lin) share transcriptional associations conserved across purified CD14+ monocytes and dorsolateral prefrontal cortex. The pathways enriched in the shared transcriptional association suggested links between epigenetic aging and metabolism, immunity, and autophagy. Results from in vitro experiments showed that two clocks (Levine and Lin) were accelerated in accordance with two hallmarks of aging—cellular senescence and mitochondrial dysfunction. Finally, using multi‐tissue data to deconstruct the epigenetic clock signals, we developed a meta‐clock that demonstrated improved prediction for mortality and robustly related to hallmarks of aging in vitro than single clocks.

Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1

BackgroundEpigenetic clocks are mathematical models that predict the biological age of an individual using DNA methylation data and have emerged in the last few years as the most accurate biomarkers of the aging process. However, little is known about the molecular mechanisms that control the rate of such clocks. Here, we have examined the human epigenetic clock in patients with a variety of developmental disorders, harboring mutations in proteins of the epigenetic machinery.ResultsUsing the Horvath epigenetic clock, we perform an unbiased screen for epigenetic age acceleration in the blood of these patients. We demonstrate that loss-of-function mutations in the H3K36 histone methyltransferase NSD1, which cause Sotos syndrome, substantially accelerate epigenetic aging. Furthermore, we show that the normal aging process and Sotos syndrome share methylation changes and the genomic context in which they occur. Finally, we found that the Horvath clock CpG sites are characterized by a higher Shannon methylation entropy when compared with the rest of the genome, which is dramatically decreased in Sotos syndrome patients.ConclusionsThese results suggest that the H3K36 methylation machinery is a key component of the epigenetic maintenance system in humans, which controls the rate of epigenetic aging, and this role seems to be conserved in model organisms. Our observations provide novel insights into the mechanisms behind the epigenetic aging clock and we expect will shed light on the different processes that erode the human epigenetic landscape during aging.

Epigenetic Aging Clocks in Ecology and Evolution

The development of 'epigenetic clocks' is changing how biomedical scientists approach age-associated disease and leads to new insights and questions of wider significance. We highlight recent findings concerning epigenetic aging and discuss their relevance to life history evolution and their potential for advancing the field of ecological and evolutionary aging.

The lifespan quantitative trait locus gene Securin controls hematopoietic progenitor cell function.

The percentage of murine hematopoietic stem and progenitor cells, which present with a loss of function upon treatment with the genotoxic agent hydroxyurea, is inversely correlated to the mean lifespan of inbred mice, including the long-lived C57BL/6 and short-lived DBA/2 strains. Quantitative trait locus mapping in BXD recombinant inbred strains identified a region spanning 12.5 cM on the proximal part of chromosome 11 linked to both the percentage of dysfunctional hematopoietic stem and progenitor cells as well as regulation of lifespan. By generating and analyzing reciprocal congenic mice for this locus, we demonstrate that this region indeed determines the sensitivity of hematopoietic stem and progenitor cells to hydroxyurea. These cells do not present, as previously anticipated, with differences in cell cycle distribution, and also not with changes in the frequency of cells undergoing apoptosis, senescence, replication stalling and re-initiation activity, excluding that variations in proliferation, replication or viability underlie the distinct response of these cells from the congenic and parental strains. An epigenetic aging clock in blood cells was accelerated in C57BL/6 mice congenic for the DBA/2 version of the locus. We verified pituitary tumor-transforming gene-1 (pttg1)/securin as the quantitative trait gene regulating the differential response of hematopoietic stem and progenitor cells to hydroxyurea treatment and which might thus likely be linked to the regulation of lifespan.

Synchrony and asynchrony between an epigenetic clock and developmental timing

Epigenetic changes have been used to estimate chronological age across the lifespan, and some studies suggest that epigenetic “aging” clocks may already operate in developing tissue. To better understand the relationship between developmental stage and epigenetic age, we utilized the highly regular sequence of development found in the mammalian neural retina and a well-established epigenetic aging clock based on DNA methylation. Our results demonstrate that the epigenetic age of fetal retina is highly correlated with chronological age. We further establish that epigenetic aging progresses normally in vitro, suggesting that epigenetic aging is a property of individual tissues. This correlation is also retained in stem cell-derived retinal organoids, but is accelerated in individuals with Down syndrome, a progeroid-like condition. Overall, our results suggest that epigenetic aging begins as early as a few weeks post-conception, in fetal tissues, and the mechanisms underlying the phenomenon of epigenetic aging might be studied in developing organs.

Can Aging be Programmed?

Aging diminishes individual fitness, and aging could never evolve as an adaptive program according to the most prevalent model of evolutionary theory. On the other hand, some mechanisms of aging have been found to be conserved since the Cambrian explosion, and the physiology of aging sometimes looks like programmed self-destruction. Biostatisticians find evidence of an epigenetic aging clock, extending the clock that controls the growth and development into a realm of inexorably increasing mortality. These and other observations have suggested to some biologists that our understanding of aging is being constrained by restrictive evolutionary paradigms. Several computational models have been proposed; but evolution of an aging program requires group selection on a scale that goes beyond the theory of multilevel selection, a perspective that is already controversial. So, the question whether plausible models exist that can account for aging as a group-selected adaptation is central to our understanding of what aging is, where it comes from and, importantly, how anti-aging medicine might most propitiously be pursued. In a 2016 Aging Cell article, Kowald and Kirkwood reviewed computational models that evolve aging as an adaptation. They find fault with each of these models in turn, based on theory alone, and on this basis, they endorse the standing convention that aging must be understood in terms of trade-off models. But consideration of the corpus of experimental evidence creates a picture that stands in counterpoint to the conclusions of that review. Presented herein is a broad summary of that evidence, together with a description of one model that Kowald and Kirkwood omitted, the demographic theory of aging, which may be the most conservative, and therefore most plausible of the alternative evolutionary theories, and which is the subject of a book by the present author, published contemporaneously with Kowald and Kirkwood.

Epigenetic aging clocks in mice and men

Epigenetic clocks provide powerful tools to evaluate nutritional, hormonal, and genetic effects on aging. What can we learn from differences between species in how these clocks tick?Please see related Research articles: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1203-5, http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1186-2, http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1187-1 and http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1185-3

An epigenetic aging clock for dogs and wolves.

Several articles describe highly accurate age estimation methods based on human DNA-methylation data. It is not yet known whether similar epigenetic aging clocks can be developed based on blood methylation data from canids. Using Reduced Representation Bisulfite Sequencing, we assessed blood DNA-methylation data from 46 domesticated dogs (Canis familiaris) and 62 wild gray wolves (C. lupus). By regressing chronological dog age on the resulting CpGs, we defined highly accurate multivariate age estimators for dogs (based on 41 CpGs), wolves (67 CpGs), and both combined (115 CpGs). Age related DNA methylation changes in canids implicate similar gene ontology categories as those observed in humans suggesting an evolutionarily conserved mechanism underlying age-related DNA methylation in mammals.

Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels.

Age of Huntington's disease (HD) motoric onset is strongly related to the number of CAG trinucleotide repeats in the huntingtin gene, suggesting that biological tissue age plays an important role in disease etiology. Recently, a DNA methylation based biomarker of tissue age has been advanced as an epigenetic aging clock. We sought to inquire if HD is associated with an accelerated epigenetic age. DNA methylation data was generated for 475 brain samples from various brain regions of 26 HD cases and 39 controls. Overall, brain regions from HD cases exhibit a significant epigenetic age acceleration effect (p=0.0012). A multivariate model analysis suggests that HD status increases biological age by 3.2 years. Accelerated epigenetic age can be observed in specific brain regions (frontal lobe, parietal lobe, and cingulate gyrus). After excluding controls, we observe a negative correlation (r=−0.41, p=5.5×10−8) between HD gene CAG repeat length and the epigenetic age of HD brain samples. Using correlation network analysis, we identify 11 co-methylation modules with a significant association with HD status across 3 broad cortical regions. In conclusion, HD is associated with an accelerated epigenetic age of specific brain regions and more broadly with substantial changes in brain methylation levels.