Current perspectives on the cellular and molecular features of epigenetic ageing

Raj, Ken; Horvath, Steve

doi:10.1177/1535370220918329

Cited by 40 publications

(24 citation statements)

References 117 publications

(24 reference statements)

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“…Collectively, these features indicate that epigenetic aging is intimately associated with the process of development and homeostatic maintenance of the body post-maturity. While most organs of the body turn-over during the lifetime of the host, albeit at different rates, the brain appears at best to do this at a very much slower rate 27,47 . While most tissues harbor stem cells that are necessary for replenishment and turnover, stem cells in adult brain have only been detected in a defined and very limited area of the subventricular zone, olfactory bulb (in rats), hippocampus and hypothalamic proliferative region 48 .…”

Section: Plasma Fraction Treatmentmentioning

confidence: 99%

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

Horvath

Singh

Raj

et al. 2020

Preprint

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Young 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.

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“…Although this assumption is understandably intuitive, it remains to be proven. It is theoretically possible that some interventions that extend life, may not delay or slow-down ageing [37][38][39] . This intriguing possibility remains to be tested in primates, and if the marmoset cohort on rapamycin is eventually observed to have extended lifespan, this may be a possible indication.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation age analysis of rapamycin in common marmosets

Horvath

Zoller

Haghani

et al. 2020

Preprint

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Human DNA methylation data have previously been used to develop highly accurate biomarkers of aging (“epigenetic clocks”). Subsequent studies demonstrate that similar epigenetic clocks can also be developed for mice and many other mammals. Here, we describe epigenetic clocks for common marmosets (Callithrix jacchus) based on novel DNA methylation data generated from highly conserved mammalian CpGs that were profiled using a custom Infinium array (HorvathMammalMethylChip40). From these, we developed and present here, two epigenetic clocks for marmosets that are applicable to whole blood samples. We find that the human-marmoset clock for relative age exhibits moderately high age correlations in two other non-human primate species: vervet monkeys and rhesus macaques. In a separate cohort of marmosets, we tested whether intervention with rapamycin, a drug shown to extend lifespan in mice, would alter the epigenetic age of marmosets, as measured by the marmoset epigenetic clocks. These clocks did not detect significant effects of rapamycin on the epigenetic age of marmoset blood. The common marmoset stands out from other mammals in that it is not possible to build accurate estimators of sex based on DNA methylation data: the accuracy of a random forest predictor of sex (66%) was substantially lower than that observed for other mammals (which is close to 100%). Overall, the epigenetic clocks developed here for the common marmoset are expected to be useful for age estimation of wild-born animals and for anti-aging studies in this species.

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“…Epigenetic changes are understood to be core features of the biological process of aging (51,52). Yet, the methylation measurements we studied are only correlates of the unobserved processes of biological aging, not direct observations of it (53).…”

Section: Discussionmentioning

confidence: 99%

Analysis of socioeconomic disadvantage and pace of aging measured in saliva DNA methylation of children and adolescents

Raffington

Belsky

Malanchini

et al. 2020

Preprint

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Children who grow up in socioeconomically disadvantaged families face increased burden of disease and disability as they mature into adulthood. One hypothesized mechanism for this increased burden is that early-life disadvantage and its associated psychological stress accelerate biological processes of aging, increasing vulnerability to subsequent disease. In order to evaluate this hypothesis and the potential impact of preventive interventions, measures to quantify the early acceleration of biological aging in childhood are needed. Here, we evaluated a novel DNAmethylation measure of the pace of aging, DunedinPoAm, and compared DunedinPoAm results with results for several published epigenetic clocks. Data on saliva DNA-methylation and socioeconomic circumstances were collected from N = 600 children and adolescents aged 8-to 18-years-old (48% female) participating in the Texas Twin Project. Participants living in more disadvantaged families and neighborhoods exhibited faster pace of aging (r = 0.18, p = 0.001 for both). Latinx-identifying children exhibited faster DunedinPoAm compared to both White-and Latinx-White-identifying children, consistent with higher levels of disadvantage in this group.Children with more advanced pubertal development and those with had higher body-mass index also exhibited faster DunedinPoAm, but these covariates did not account for the observed socioeconomic gradient in methylation pace of aging. In contrast to findings for DunedinPoAm, we did not detect associations of socioeconomic disadvantage with five published epigenetic clocks. Findings suggest that DNA-methylation pace-of-aging measures may prove more sensitive to health damaging effects of adversity, particularly when measurements are taken early in the life course, before substantial aging has occurred.

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“…4 The estimated age by DNA methylation analysis is called DNAmAge. 2,3 The first minireview by Raj and Horvath 5 overviews the recent progress of the understanding of the mechanism of DNAm age progression. This article explains the history and the background of the discovery of Horvath’s multi-tissue age estimators, and the authors concisely overview the most up-to-date understanding of the significance and the mechanism of epigenetic aging.…”

Section: Mechanism Of Age-dependent Changesmentioning

confidence: 99%

Mechanisms of aging, age-associated diseases, and lifespan determination

Matsuyama

2020

Exp Biol Med (Maywood)

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“…Some of the first studies reporting epigenetic change with age reported the random loss of epigenetic information over time, or epigenetic drift (35). In contrast, epigenetic clocks rely on non-random changes to the DNA methylome over time, suggestive of a process independent of epigenetic drift (36). Recent work demonstrates that DNA damage, namely the induction of DNA double stranded breaks (DSBs), plays an important role in the acceleration of epigenetic age (37).…”

Section: Introductionmentioning

confidence: 99%

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

Bertucci

Mason

Rhodes

et al. 2021

Preprint

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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.

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Current perspectives on the cellular and molecular features of epigenetic ageing

Cited by 40 publications

References 117 publications

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

DNA methylation age analysis of rapamycin in common marmosets

Analysis of socioeconomic disadvantage and pace of aging measured in saliva DNA methylation of children and adolescents

Mechanisms of aging, age-associated diseases, and lifespan determination

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

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