A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging

Zhang, Weiqi; Li, Jingyi; Suzuki, Keiichiro; Qu, Jing; Wang, Ping; Zhou, Junzhi; Liu, Xiaomeng; Ren, Rui; Xu, Xiuling; Ocampo, Alejandro; Yuan, Tingting; Yang, Jiping; Liu, Ying; Shi, Liang; Guan, Dee; Pan, Huize; Duan, Shunlei; Ding, Zicheng; Li, Mo; Yi, Fei; Bai, Ruijun; Wang, Yayu; Chang, Chen; Yang, Fuquan; Li, Xiaoyu; Wang, Zimei; Aizawa, Emi; Goebl, April; Soligalla, Rupa Devi; Reddy, Pradeep; Esteban, Concepción Rodrı́guez; Tang, Fuchou; Liu, Guanghui; Belmonte, Juan Carlos Izpisúa

doi:10.1126/science.aaa1356

Cited by 470 publications

(549 citation statements)

References 47 publications

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“…We next investigated whether the metformin‐Nrf2‐GPx7 pathway also functions in HMSCs. We observed that the expression levels of Nrf2 and GPx7 decreased in both replicative senescent HMSCs and premature senescent HMSCs (Werner syndrome‐specific: WRN ‐deficient) (Li et al., 2016; Zhang et al., 2015) (Figure 5a). High levels of GPx7 were also observed in HMSCs genetically bearing an endogenous NRF2 nucleotide variation (A254G, referred to as HMSC‐ NRF2 AG/AG ) (Yang et al., 2017) (Figure 5b), which encodes a constitutively activated Nrf2 protein (Fig.…”

Section: Resultsmentioning

confidence: 99%

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

et al. 2018

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SummaryMetformin, an FDA‐approved antidiabetic drug, has been shown to elongate lifespan in animal models. Nevertheless, the effects of metformin on human cells remain unclear. Here, we show that low‐dose metformin treatment extends the lifespan of human diploid fibroblasts and mesenchymal stem cells. We report that a low dose of metformin upregulates the endoplasmic reticulum‐localized glutathione peroxidase 7 (GPx7). GP×7 expression levels are decreased in senescent human cells, and GPx7 depletion results in premature cellular senescence. We also indicate that metformin increases the nuclear accumulation of nuclear factor erythroid 2‐related factor 2 (Nrf2), which binds to the antioxidant response elements in the GPX7 gene promoter to induce its expression. Moreover, the metformin‐Nrf2‐GPx7 pathway delays aging in worms. Our study provides mechanistic insights into the beneficial effects of metformin on human cellular aging and highlights the importance of the Nrf2‐GPx7 pathway in pro‐longevity signaling.

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Section: Resultsmentioning

confidence: 99%

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

et al. 2018

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“…The ligand‐based target list for metformin also contained several chromatin‐modifying epigenetic regulators including lysine‐specific demethylases 4A (KDM4A) and 4C (KDM4C), Jumonji 2 proteins that demethylate di‐ and trimethylated histone 3 lysine 9 (H3K9me2/3) and H3K36me3, two epigenetic markers closely related to the aging process (Sen et al., 2015; Zhang et al., 2015). Moreover, when the default similarity score of 0.8 used for ligand‐based VP was reduced to 0.65–0.7, a number of histone lysine demethylases including KDM2A, KDM5A/C, KDM4B/D/E, KDM7, KDM5C, KDM6A/UTX, KDM6B/JMJD3, and LSD1 (KDM1A) emerged as new putative targets of metformin.…”

Section: Resultsmentioning

confidence: 99%

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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SummaryMetformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure‐ and ligand‐based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3‐specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low‐density lipoprotein receptor‐deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft‐bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

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“…In addition, mutations in LMNA and ZMPSTE24 in patients lead to metabolic dysfunction, including type 2 diabetes and hepatic steatosis (Galant et al., 2016; Shackleton et al., 2000). Moreover, a recent report has implicated disorganization of heterochromatin at the lamina as a driver of human aging (Zhang et al., 2015). Numerous enzymes associated with H3K9me3, the mark associated with heterochromatin, including acetyltransferases (SRC‐1/ Ncoa1 ), deacetylases (Hdac3), methyltransferases (Suv39 h1 and G9a/ Ehmt2 ), and demethylases (Jhmdh2a/Kdm3a, Jmjd2c/Kdm4c), have been linked to fatty liver, diabetes, and obesity (Picard et al., 2002; Sun et al., 2012; Tateishi et al., 2009; Wang et al., 2013).…”

Section: Discussionmentioning

confidence: 99%

“…A recent report implicated disorganization of heterochromatin at the lamina as a driver of human aging (Zhang et al., 2015). Mutations in LMNA , encoding the nuclear structural protein lamin A/C, result in disturbed nuclear architecture and cause the premature aging syndrome Hutchinson‐Gilford progeria (HGPS).…”

Section: Introductionmentioning

confidence: 99%

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

et al. 2018

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SummaryIncreasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age‐dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina‐associated domains (LADs) using lamin B1 ChIP‐Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1‐associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24‐deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de‐repression of PPAR‐ and LXR‐dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de‐repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis.

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A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging

Cited by 470 publications

References 47 publications

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

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