Epigenetic ageing is distinct from senescence-mediated ageing and is not prevented by telomerase expression

Kabacik, Sylwia; Horvath, Steve; Cohen, Howard A.; Raj, Kenneth

doi:10.18632/aging.101588

Cited by 75 publications

(86 citation statements)

References 52 publications

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“…Blood samples from the Cape Town Adolescent Antiretroviral Cohort study 53 . Skin and other primary cells provided by Kenneth Raj 41 . Ethics approval (IRB#15-001454, IRB#16-000471, IRB#18-000315, IRB#16-002028).…”

Section: Human Tissue Samplesmentioning

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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Section: Human Tissue Samplesmentioning

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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“…We used these high quality DNAm data to construct different epigenetic clocks for vervet only and for both human and vervet. For the construction of the dual human-vervet clock, we used the DNAm data previously generated with the HorvathMammalMethylChip40 in 852 human samples representing 16 tissues from individuals 0 to 93 years old (Morgello et al 2001;Kabacik et al 2018;Horvath, Stein, et al 2018). Our clocks for vervet monkeys can be distinguished along three dimensions (tissue type, species, and measure of age).…”

Section: Epigenetic Clocksmentioning

confidence: 99%

“…We developed two dual species clocks based on our vervet samples and previously characterized human tissues (Morgello et al 2001;Horvath, Stein, et al 2018;Kabacik et al 2018). The human-vervet clock for chronological age (R=0.99 for the human and vervet samples and R=0.98 for the vervet samples, Figure 1E,F) and relative age (R=0.98 for the human and vervet samples and R=0.97 for the vervet samples, Figure 1G,H).…”

Section: Epigenetic Clocksmentioning

confidence: 99%

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Epigenetic clock and methylation studies in vervet monkeys

Jasinska

Haghani²,

Zoller³

et al. 2020

Preprint

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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.

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“…Due to its multiple roles, researchers argue that there may be different types of cellular senescence (Tables I and II). For example, the expression of telomerase has been found to prevent cellular senescence, but not epigenetic aging or DNA methylation-based aging; Kabacik and colleagues 33) suggest that each senescent cell and paracrine cell may have different epigenetic aging backgrounds. In another study, senescent cells during development are removed by immune system such as macrophage and thought not to be associated with DNA damage response 22,34) .…”

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confidence: 99%

Stress-induced Cellular Senescence Contributes to Chronic Inflammation and Cancer Progression

et al. 2019

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Cellular senescence has long been considered to act as a tumor suppressor or tumor suppression mechanism and described as a phenomenon of irreversible cell cycle arrest. Cellular senescence, however, is now considered to have physiological functions other than tumor suppression; it has been found to be involved in embryogenesis, tissue/organ aging, and wound healing. Surprisingly, cellular senescence is also demonstrated to have a tumor progressive role in certain situations. Senescent cells exhibit secretory phenotypes called senescence-associated secretory phenotype (SASP), which secrete a variety of SASP factors including inflammatory cytokines, chemokines, and growth factors, as well as matrix remodeling factors that promote the alteration of neighboring tissue microenvironments. Such SASP factors have been known to drive the mechanisms underlying the pleiotropic features of cellular senescence. In this review, we examine current knowledge of cellular senescence at molecular and cellular levels, with a focus on chronic inflammation and tumor progression. senescence, senescence-associated secretory phenotype (SASP), reactive oxygen species (ROS), ionizing radiation, heat shock response (HSR) Hayflick and Moorhead 1) were the first to describe the limited divisions of cells and term this irreversible cell cycle arrest as cellular senescence. Senescent cells remain metabolically active, but their growth is irreversibly halted and their morphological characteristics altered as large, flat, and refractile 2,3). Irreversible cell cycle arrest is now thought to be dependent upon the shortening of telomeres; an expression of the catalytic subunit of the telomerase holo-enzyme (hTERT) is enough to bypass cellular senescence 4-6). Telomeres are folded d-loop/t-loop structures located at the ends of chromosomes that serve to mask DNA ends from being recognized as DNA double-strand-breaks (DSBs) 7,8). Telomerase activity is absent from most normal human somatic cells. After serial divisions, telomeres become too short to have sufficient binding sites for shelterin proteins (the latter being protein complexes known to protect telomeres) and are remodeled with a "capped" structure 9). Telomere shortening-related senescence is called replicative senescence. Nonetheless, mouse Current knowledge of molecular and cellular biology of cellular senescence S. Kobashigawa et al.

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Epigenetic ageing is distinct from senescence-mediated ageing and is not prevented by telomerase expression

Cited by 75 publications

References 52 publications

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

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

Epigenetic clock and methylation studies in vervet monkeys

Stress-induced Cellular Senescence Contributes to Chronic Inflammation and Cancer Progression

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