DNA-Methylation Changes in Replicative Senescence and Aging: Two Sides of the Same Coin?

Wagner, Wolfgang; Fernández-Rebollo, Eduardo; Frobel, Joana

doi:10.2217/epi.15.100

Cited by 11 publications

(11 citation statements)

References 25 publications

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“…DNA demethylation is an important process that maintains transcriptional activity of genes (Avrahami et al., 2015; Bigot et al., 2015; Wagner, Fernandez‐Rebollo & Frobel, 2016; Zinovkina & Zinovkin, 2015). An increase in methylation in the promoter region of a gene diminishes the promoter activity and gene transcription (Wagner et al., 2016; Zinovkina & Zinovkin, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…An increase in methylation in the promoter region of a gene diminishes the promoter activity and gene transcription (Wagner et al., 2016; Zinovkina & Zinovkin, 2015). Numerous studies showed that DNA methylation is increased with age (Alvares, Mayberry, Joyner, Lakowski & Ahmed, 2014; Avrahami et al., 2015; Bigot et al., 2015; Wagner et al., 2016; Zinovkina & Zinovkin, 2015). Coincidently, the prevalence of arterial stiffness and hypertension also increases with age (Sun, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Whether increased methylation led to arterial stiffening has never been determined. Physiologically, an appropriate methylation level is maintained by the balanced methyltransferase and demethylase activity (Wagner et al., 2016). In this study, we assessed if activation of the demethylase affects arterial stiffening and hypertension in aged mice.…”

Section: Introductionmentioning

confidence: 99%

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Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Chen

Sun

2018

Aging Cell

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Summary DNA methylation increases with age. The objective of this study was to investigate whether compound H, a potential activator of DNA demethylases, attenuates aging‐related arterial stiffness and hypertension. Aged mice (24–27 months) and adult mice (12 months) were used. Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) were increased significantly in aged mice. Notably, daily treatments with compound H (15 mg/kg, IP) for 2 weeks significantly attenuated the aging‐related increases in PWV and BP. Compound H abolished aging‐associated downregulation of secreted Klotho (SKL) levels in both kidneys and serum likely by enhancing DNA demethylase activity and decreasing DNA methylation. Aging‐related arterial stiffness was associated with accumulation of stiffer collagen and degradation of compliant elastin which are accompanied by increased expression of MMP2, MMP9, TGF‐β1, and TGF‐β3. These changes were effectively attenuated by compound H, suggesting rejuvenation of aged arteries. Compound H also rescued downregulation of Sirt1 deacetylase, AMPKα, and eNOS activities in aortas of aged mice. In cultured smooth muscle cells (SMCc) Klotho‐deficient serum upregulated expression of MMPs and TGFβ which, however, was not affected by compound H. In conclusion, compound H attenuates aging‐associated arterial stiffness and hypertension by activation of DNA demethylase which increases renal SKL expression and consequently circulating SKL levels leading to activation of the Sirt1‐AMPK‐eNOS pathway in aortas of aged mice.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Chen

Sun

2018

Aging Cell

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“…There is a growing perception that culture expansion toward replicative senescence and aging are both reflected by specific modifications in the DNAm pattern, which might indicate that they are evoked by epigenetic processes (Wagner et al, 2016). DNAm plays a crucial role in mammalian development (Meissner et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The Link Between Epigenetic Clocks for Aging and Senescence

Wagner

2019

Front. Genet.

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Replicative senescence of cells in vitro is often considered as counterpart for aging of the organism in vivo . In fact, both processes are associated with functional decay and similar molecular modifications. On epigenetic level, replicative senescence and aging evoke characteristic modifications in the DNA methylation (DNAm) pattern, but at different sites in the genome. Various epigenetic signatures, which are often referred to as epigenetic clocks, provide useful biomarkers: Senescence-associated epigenetic modifications can be used for quality control of cell preparations or to elucidate effects of culture conditions on the state of cellular aging. Age-associated epigenetic modifications hold high expectations to determine chronological age in forensics or to identify parameters that impact on biological aging. Despite these differences, there are some striking similarities between senescence- and age-associated DNAm, such as complete rejuvenation during reprogramming into induced pluripotent stem cells (iPSCs). It is yet unclear what makes epigenetic clocks tick, but there is evidence that the underlying mechanisms of both processes are related to similar modifications in the histone code or higher order chromatin. Replicative senescence therefore appears to be a suitable model system to gain better insight into how organismal aging might be governed epigenetically.

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“…Alternatively, cellular senescence can be induced by DNA damage through external stress like reactive oxygen species or the activation of oncogenes [5,6]. Cellular senescence is often considered to be a hallmark of aging, suggesting that the two processes might be related [7].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Modifications upon Senescence of Mesenchymal Stem Cells

2016

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Cellular senescence is a continuous and highly organized process that alters the intricate genomic network in order to maintain cellular homeostasis. It occurs in all primary cell cultures-including mesenchymal stem cells (MSCs), which are concurrently tested for a wide variety of clinical applications. Differentiation potential as well as paracrine secretion of MSCs is severely affected by cellular senescence. There is a growing perception that nuclear reorganization and epigenetic modifications contribute to trigger and maintain functional differences in long-term culture. In this review, we discuss molecular and epigenetic aspects that evoke functional changes in cellular aging-indicating that the underlying process is not only an accumulation of cellular defects, but rather epigenetically orchestrated.

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DNA-Methylation Changes in Replicative Senescence and Aging: Two Sides of the Same Coin?

Cited by 11 publications

References 25 publications

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

The Link Between Epigenetic Clocks for Aging and Senescence

Epigenetic Modifications upon Senescence of Mesenchymal Stem Cells

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