Aging clocks, entropy, and the limits of age-reversal

Tarkhov, Andrei E.; Denisov, Kirill A.; Федичев, П. О.

doi:10.1101/2022.02.06.479300

Cited by 11 publications

(8 citation statements)

References 74 publications

(104 reference statements)

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“…1h ), thus resembling exponential-decay-like changes in the average methylation levels within the defined dynamics of DNAm changes. This is consistent with the aging-related increase in entropy metrics based on various molecular and functional readouts 12,31–34 .…”

Section: Resultssupporting

confidence: 85%

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: Resultssupporting

confidence: 85%

Nature of epigenetic aging from a single-cell perspective

Tarkhov

Lindstrom-Vautrin

Zhang

et al. 2022

Preprint

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“…Previous studies found an accelerated increase in DNA methylation Shannon entropy with adult age 21,33,34 , which is in line with the notion of accumulation of age-related damage. Using skin and embryo DNA methylation data, we examined the dynamics of methylation entropy in the frog.…”

Section: Profiling Dna Methylation During Aging and Embryonic Develop...supporting

confidence: 86%

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

Zhang

Tarkhov

Ratzan

et al. 2022

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Recent studies suggest the existence of a natural rejuvenation event during early embryonic development of mice, followed by epigenetic aging. Here, by profiling embryonic DNA methylation in the African clawed frog, Xenopus laevis, we found that the epigenetic entropy basepoint maps to the gastrulation stage of embryogenesis and corresponds to a rapid increase in embryo transcript abundance. We further developed a frog aging clock, revealing that this species epigenetically ages. Application of this clock to developmental stages identified a decrease in epigenetic age during early embryogenesis, with the minimal age reached around gastrulation. By examining individual developmental trajectories of 6,457 embryos, we found that this stage is also accompanied by a higher incidence of disrupted development. Taken together, our data point to gastrulation as a critical stage for aging and natural rejuvenation, characterized by the lowest epigenetic age, increased mortality, nadir of DNA methylation entropy and rapid increase in embryo transcript abundance, defining aging ground zero as the basepoint where rejuvenation ends and the aging process begins.

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“…To deepen the mechanistic understanding of epigenetic aging clocks, Levine et al deconstructed epigenetic clock CpG sites from 12 different clocks into distinct modules and showed that while some modules might be driven by entropic alterations and regress to a methylation state of 0.5, most might be distinct and changing systematically with time 19 . Recently, Tarkhov et al showed that aging singlecell DNA methylation changes are predominantly affected by a stochastic component 20 , and that a single stochastic variable (thermodynamic biological age) can track entropic aging 21 .…”

Section: Introductionmentioning

confidence: 99%

Accurate aging clocks based on accumulating stochastic variation

Schumacher

Meyer

2023

Preprint

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Aging clocks have provided one of the most significant recent breakthroughs in the biology of aging. Such clocks allow the determination of chronological and increasingly also biological age, which is prerequisite for assessing the effectiveness of interventions in the aging process and preventive treatments of age-related diseases. The most advanced aging clocks are based on age-dependent changes in DNA methylation pattern. The reproducibility of such changes over the life course has reinvigorated the debate whether a programmed process underlies aging. A programmed aging process, however, is incompatibly with the evolutionary theory of aging. Aging occurs as a consequence of a vanishing force of selective pressure post-reproduction as no fitness benefit is provided by immortality of the soma. In fact, stochastic events have been observed to increasingly occur during the aging process. Here, we test whether aging clocks could be built with entirely stochastic variation. We find that accumulating stochastic variation is sufficient to accurately predict chronological and biological age. Moreover, current aging clocks are entirely compatible with random alterations in the methylation or transcriptomic patterns. Our analysis unifies the clock measure of aging with the evolutionary theory of aging and predicts that any set of data that have a ground state at the age zero with accumulating stochastic variation could be used for building accurate aging clocks.

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Aging clocks, entropy, and the limits of age-reversal

Cited by 11 publications

References 74 publications

Nature of epigenetic aging from a single-cell perspective

Nature of epigenetic aging from a single-cell perspective

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

Accurate aging clocks based on accumulating stochastic variation

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