DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging

Hayano, Motoshi; Yang, Jae-Hyun; Bonkowski, Michael S.; Amorim, João A.; Ross, Jaime M.; Coppotelli, Giuseppe; Griffin, Patrick; Chew, Yap Ching; Guo, Wei; Yang, Xiaojing; Vera, Daniel; Salfati, Elias; Das, Abhirup; Thakur, Sachin; Kane, Alice E.; Mitchell, Sarah J.; Mohri, Yasuaki; Nishimura, Emi K.; Schaevitz, Laura; Garg, Neha; Balta, Ana-Maria; Rego, Meghan A.; Gregory-Ksander, Meredith; Jakobs, Tatjana C.; Zhong, Lei; Wakimoto, Hiroko; Mostoslavsky, Raúl; Wagers, Amy J.; Tsubota, Kazuo; Bonasera, Stephen J.; Palmeira, Carlos M.; Seidman, Jonathan G.; Seidman, Christine E.; Wolf, Norman S.; Kreiling, Jill A.; Sedivy, John M.; Murphy, Gëorge F.; Oberdoerffer, Philipp; Ksander, Bruce R.; Rajman, Luis A.; Sinclair, David

doi:10.2139/ssrn.3466338

Cited by 28 publications

(48 citation statements)

References 36 publications

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“…We can only begin to address this question after having first understood what epigenetic aging entails. As it stands, our knowledge in this area remains limited, but it is nevertheless clear that: (a) epigenetic aging is distinct from the process of cellular senescence and telomere attrition 41 , (b) several types of tissue stem cells are epigenetically younger than non-stem cells of the same tissue 42,43 , (c) a considerable number of age-related methylation sites, including some clock CpGs, are proximal to genes whose proteins are involved in the process of development 44 , (d) epigenetic clocks are associated with developmental timing 22,45 , and (e) relate to an epigenomic maintenance system 20,46 . Collectively, these features indicate that epigenetic aging is intimately associated with the process of development and homeostatic maintenance of the body post-maturity.…”

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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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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show abstract

“…David Sinclair, Harvard, USA, showed that DSBs may drive age-dependent epigenetic alterations and loss of cellular identity. Using a transgenic mouse system for inducible creation of DSBs, he revealed that loss of epigenetic structures, an accumulation of epigenetic noise and increased predicted DNA methylation changes increase with age and DNA damage [42,43]. Importantly, the introduction of an engineered vector expressing Yamanaka transcription factors, excluding c-Myc, regenerated axons after optic nerve crush injury and restored vision in old mice [44].…”

Section: Genome Maintenance In Aging and Longevitymentioning

confidence: 99%

ARDD 2020: from aging mechanisms to interventions

Mkrtchyan

Abdelmohsen

Andreux

et al. 2020

Aging

Self Cite

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“…Nevertheless, both can be linked because DNA double‐strand breaks induce epigenetic drift that in turn produces aging phenotypes. [ 47 ] Thus, increased epigenomic variation could occur with age because of defects in restoration of the epigenome after DNA replication or repair that result in the progressive alteration of methylation and histone modification patterns. This suggests that DNA damage is a conserved cause of aging.…”

Section: Increased Cell‐to‐cell Gene Expression Heterogeneity Is Seenmentioning

confidence: 99%

Tissue‐disruption‐induced cellular stochasticity and epigenetic drift: Common origins of aging and cancer?

Capp

Thomas

2020

BioEssays

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Age-related and cancer-related epigenomic modifications have been associated with enhanced cell-to-cell gene expression variability that characterizes increased cellular stochasticity. Since gene expression variability appears to be highly reduced byand epigenetic and phenotypic stability acquired through-direct or long-range cellular interactions during cell differentiation, we propose a common origin for aging and cancer in the failure to control cellular stochasticity by cell-cell interactions. Tissuedisruption-induced cellular stochasticity associated with epigenetic drift would be at the origin of organ dysfunction because of an increase in phenotypic variation among cells, ultimately leading to cell death and organ failure through a loss of coordination in cellular functions, and eventually to cancerization. We propose mechanistic research perspectives to corroborate this hypothesis and explore its evolutionary consequences, highlighting a positive correlation between the median age of mass loss onset (a proxy for the onset of organ aging) and the median age at cancer diagnosis.

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DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging

Cited by 28 publications

References 36 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

ARDD 2020: from aging mechanisms to interventions

Tissue‐disruption‐induced cellular stochasticity and epigenetic drift: Common origins of aging and cancer?

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