Development of a novel epigenetic clock resistant to changes in immune cell composition

Tomusiak, Alan; Floro, Ariel; Tiwari, Ritesh; Riley, Rebeccah; Matsui, Hiroyuki; Andrews, Nicolas; Kasler, Herbert G.; Verdin, Eric

doi:10.1101/2023.03.01.530561

Cited by 14 publications

(14 citation statements)

References 143 publications

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“…Even though the role of various factors contributing to tissue DNAm changes has been extensively discussed [10][11][12][13][14] , epigenetic aging clocks are still lacking an exhaustive mechanistic explanation. The observed internal age-related changes across all cells could be confounded by multiple factors, such as changes in cell-type composition [15][16][17] and errors in DNAm maintenance during cell division and clonal expansion [18][19][20][21][22] . An important advance in this area is the development of a single-cell DNA methylation (scDNAm) clock known as scAge 23 , relying on tissue DNAm data for calibration.…”

Section: Introductionmentioning

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: Introductionmentioning

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 mitotic clocks were calculated using the epiTOC2 function from the meffonym package. Finally, the IntrinClock was calculated as described elsewhere [53].…”

Section: Methodsmentioning

confidence: 99%

“…For instance, previous studies have shown that human naive CD8+ T cells can exhibit an epigenetic age 15-20 years younger than effector memory CD8+ T cells from the same individual. This means that previous epigenetic clocks measure two independent variables, aging and immune cell composition [53]. To analyze if immune changes were responsible for the first-generation epigenetic clock acceleration, we calculated immune EAA and adjusted by all the immune cells that were significantly associated to the clocks (CD4T naive and memory cells, B naive and memory cells, CD8T naive and memory cells, natural killers, and neutrophils).…”

Section: Clinical and Dnam Proteomic Surrogate Analysismentioning

confidence: 99%

Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions

Lee,

Carreras-Gallo,

Lopez

et al. 2023

Preprint

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Senolytics, small molecules targeting cellular senescence, have emerged as potential therapeutics to enhance health span. However, their impact on epigenetic age remains unstudied. This study aimed to assess the effects of Dasatinib and Quercetin (DQ) senolytic treatment on DNA methylation (DNAm), epigenetic age, and immune cell subsets. In a Phase I pilot study, 19 participants received DQ for 6 months, with DNAm measured at baseline, 3 months, and 6 months. Significant increases in epigenetic age acceleration were observed in first-generation epigenetic clocks and mitotic clocks at 3 and 6 months, along with a notable decrease in telomere length. However, no significant differences were observed in second and third-generation clocks. Building upon these findings, a subsequent investigation evaluated the combination of DQ with Fisetin (DQF), a well-known antioxidant and antiaging senolytic molecule. After one year, 19 participants (including 10 from the initial study) received DQF for 6 months, with DNAm assessed at baseline and 6 months. Remarkably, the addition of Fisetin to the treatment resulted in non-significant increases in epigenetic age acceleration, suggesting a potential mitigating effect of Fisetin on the impact of DQ on epigenetic aging. Furthermore, our analyses unveiled notable differences in immune cell proportions between the DQ and DQF treatment groups, providing a biological basis for the divergent patterns observed in the evolution of epigenetic clocks. These findings warrant further research to validate and comprehensively understand the implications of these combined interventions.

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Development of a novel epigenetic clock resistant to changes in immune cell composition

Cited by 14 publications

References 143 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

Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions

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