Epigenetic profiling and incidence of disrupted development point to gastrulation as aging ground zero in <i>Xenopus laevis</i>

Zhang, Bohan; Tarkhov, Andrei E.; Ratzan, Wil; Ying, Kejun; Moqri, Mahdi; Poganik, Jesse R.; Barré, Benjamin; Trapp, Alexandre; Zoller, Joseph A.; Haghani, Amin; Horvath, Steve; Peshkin, Leonid; Gladyshev, Vadim N.

doi:10.1101/2022.08.02.502559

Cited by 7 publications

(2 citation statements)

References 42 publications

(53 reference statements)

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“…Therefore, the multispecies epigenetic clocks 51 may work well because closely related species, such as mammals, share the associated developmental biology setting them into similar initial states of the epigenome. Overall, the effects of early embryonic development on aging need to be further investigated 30,52 .…”

Section: Discussionmentioning

confidence: 99%

Nature of epigenetic aging from a single-cell perspective

Tarkhov

Lindstrom-Vautrin

Zhang

et al. 2022

Preprint

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Age-related changes in DNA methylation (DNAm) form the basis for the development of most robust predictors of age, epigenetic clocks, but a clear mechanistic basis for what exactly they quantify is lacking. Here, to clarify the nature of epigenetic aging, we analyzed the aging dynamics of bulk-tissue and single-cell DNAm, together with single-cell DNAm changes during early development. We show that aging DNAm changes are widespread, but are relatively slow and small in amplitude, with DNAm levels trending towards intermediate values and showing increased heterogeneity with age. By considering dominant types of DNAm changes, we find that aging manifests in the exponential decay-like loss or gain of methylation with a universal rate, independent of the initial level of DNAm. We further show that aging is dominated by the stochastic component, yet co-regulated changes are also present during both development and adulthood. We support the finding of stochastic epigenetic aging by direct single-cell DNAm analyses and modeling of aging DNAm trajectories with a stochastic process akin to radiocarbon decay. Finally, we describe a single-cell algorithm for the identification of co-regulated CpG clusters that may provide new opportunities for targeting aging and evaluating longevity interventions.

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Section: Discussionmentioning

confidence: 99%

Nature of epigenetic aging from a single-cell perspective

Tarkhov

Lindstrom-Vautrin

Zhang

et al. 2022

Preprint

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“…In addition, there exist other factors associated with epigenetic aging that do not explicitly implicate somatic mutations. Some epigenetic changes clearly reflect alterations in tissue composition with age 81,82 , and other changes are associated with the expression of developmental genes [83][84][85][86][87][88][89] such as in the binding sites of the polycomb repressive complex 90,91 . Some of these factors may nonetheless relate to DNA mutations, for instance somatic mutations can drive alterations in tissue composition 92,93 .…”

Section: Discussionmentioning

confidence: 99%

Somatic mutation as an explanation for epigenetic aging

Koch,

Li,

Evans

et al. 2023

Preprint

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DNA methylation marks have recently been used to build models known as “epigenetic clocks” which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In analysis of multimodal data from 9,331 human individuals, we find that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but also with pervasive remodeling of the methylome out to ±10 kilobases. This one-to-many mapping enables mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging faster or slower than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life.

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The long and winding road of reprogramming-induced rejuvenation

Yücel,

Gladyshev

2024

Nat Commun

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Organismal aging is inherently connected to the aging of its constituent cells and systems. Reducing the biological age of the organism may be assisted by reducing the age of its cells - an approach exemplified by partial cell reprogramming through the expression of Yamanaka factors or exposure to chemical cocktails. It is crucial to protect cell type identity during partial reprogramming, as cells need to retain or rapidly regain their functions following the treatment. Another critical issue is the ability to quantify biological age as reprogrammed older cells acquire younger states. We discuss recent advances in reprogramming-induced rejuvenation and offer a critical review of this procedure and its relationship to the fundamental nature of aging. We further comparatively analyze partial reprogramming, full reprogramming and transdifferentiation approaches, assess safety concerns and emphasize the importance of distinguishing rejuvenation from dedifferentiation. Finally, we highlight translational opportunities that the reprogramming-induced rejuvenation approach offers.

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Epigenetic profiling and incidence of disrupted development point to gastrulation as aging ground zero in Xenopus laevis

Cited by 7 publications

References 42 publications

Nature of epigenetic aging from a single-cell perspective

Nature of epigenetic aging from a single-cell perspective

Somatic mutation as an explanation for epigenetic aging

The long and winding road of reprogramming-induced rejuvenation

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