Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer

Herranz, Daniel; Muñoz‐Martín, Maribel; Cañamero, Marta; Mulero, Francisca; Martínez-Pastor, Bárbara; Fernández-Capetillo, Óscar; Serrano, Manuel

doi:10.1038/ncomms1001

Cited by 556 publications

(440 citation statements)

References 42 publications

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“…In addition, we observed an overall decline in the physiological condition of SirT7 −/− mice, including reduced circulating IGF‐1 protein, increased p16INK4 expression, altered HSC compartment, and leukopenia (Fig 2D–H). SIRT1 overexpression in mice results in a delayed onset of age‐related pathologies that correlate with reduced p16INK4 expression (Herranz et al , 2010). Progeroid mouse models, including SirT6 −/− mice (Mostoslavsky et al , 2006), display a systemic reduction in IGF‐1 levels, which might be related to the optimization of energy resources in response to cellular stress.…”

Section: Discussionmentioning

confidence: 99%

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

et al. 2016

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Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N‐terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7‐knockout mice suffer from partial embryonic lethality and a progeroid‐like phenotype. Consistently, SIRT7‐deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1‐dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double‐strand breaks (DSBs), thereby influencing the efficiency of non‐homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7‐mediated H3K18 deacetylation and the maintenance of genome integrity.

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Section: Discussionmentioning

confidence: 99%

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

et al. 2016

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“…SIRT1 transgenic mice (SIRT1Tg mice) were a gift from Manuel Serrano. 5 The animals were killed, and the tissues were recovered and stored at − 80°C. All of the methods employed in this study were in accordance with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publications No.…”

Section: Discussionmentioning

confidence: 99%

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

et al. 2015

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Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired. Cell Death and Differentiation (2015) 22, 1742-1753 doi:10.1038/cdd.2015; published online 27 March 2015Sirtuins are highly conserved NAD + -dependent deacetylases with a critical impact on metabolic adaptive responses. In mammals, among the seven members of the sirtuin family (SIRT1-SIRT7), SIRT1 has been the most extensively characterized. 1 SIRT1 promotes the generation of new mitochondria through the activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), which orchestrates the mitochondrial biogenesis program through the transcriptional activation of nuclear respiratory factors (NRF-1 and NRF-2) and mitochondrial transcription factor A (TFAM). 2 SIRT1 activity is finely regulated not only by gene expression and protein levels but also by posttranslational modifications, its oligomeric status, the interaction with the DBC1 and AROS proteins, and the levels of NAD + /NADH/NAM. 3 In addition, SIRT1 activity is modulated by several synthetic or natural molecules such as the polyphenol resveratrol (3,4',5-trihydroxystilbene: RSV). 4 The activation of SIRT1 by transgenic overexpression or pharmacologically with RSV has been shown to prevent the pathology in diseases commonly associated with mitochondrial dysfunction such as the metabolic syndrome and neurodegenerative disorders, 1,5,6 albeit recent findings cast doubts on the universal validity of the results. 7,8 Although prominent axonal pathology often precedes cell body loss in many neurodegenerative diseases, 9 the potential of SIRT1 activation in axonal degeneration has not been addressed in depth. In this work, we take advantage of the cellular and animal models of the rare monogenic neurodegenerative disease named X-linked adrenoleukodystrophy (X-ALD, (McKusick No.300100)) to evaluate the impact of SIRT1 function on axonal degeneration. X-ALD is the most prevalent peroxisomal disorder (minimum incidence 1:17 000 newborns), characterized by brain inflammatory demyelination and/or axonopathy of long tracts in spinal cords, adrenal insufficiency and a pathognomonic accumulation of very longchain fatty acids (VLCFA) in plasma and tissues, in particular hexacosanoic acid (C26:0). 10,11 The disease phenotypes range from adrenal ...

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“…For example, Herranz and colleagues showed that transgenic animals overexpressing SIRT1 are protected against diethylnitrosamine/high fat dietinduced liver carcinogenesis compared with nontransgenic controls (27). The protective effect was explained, in part, by SIRT1-mediated regulation of NF-kB activity; SIRT1 overexpression reduced NF-kB-mediated inflammation and hepatic cell malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

“…40). However, it still needs to be determined if SIRT1 overexpression is indeed an initiating event, as no tumors were reported to be induced in SIRT1 overexpressing transgenic mice, in fact, these mice had fewer spontaneous carcinomas and sarcomas (27,41). Further investigations may reveal that as important as SIRT1 overexpression is, perhaps equally important is loss of expression of other family members, for example SIRT3 and SIRT6 in promoting tumor growth in HCC.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Effect of SIRT1 Inhibition in Human HCC Tumor Models In Vitro and In Vivo

Portmann

Fahrner

Lechleiter

et al. 2013

Molecular Cancer Therapeutics

101

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Sirtuins (SIRT1-7) are a highly conserved family of NAD þ -dependent enzymes that control the activity of histone and nonhistone regulatory proteins. SIRT1 is purposed to promote longevity and to suppress the initiation of some cancers. Nevertheless, SIRT1 is reported to function as a tumor suppressor as well as an oncogenic protein. Our data show that compared with normal liver or surrounding tumor tissue, SIRT1 is strongly overexpressed in human hepatocellular carcinoma (HCC). In addition, human HCC cell lines (Hep3B, HepG2, HuH7, HLE, HLF, HepKK1, skHep1) were screened for the expression of the sirtuin family members and only SIRT1 was consistently overexpressed compared with normal hepatocytes. To determine its effect on HCC growth, SIRT1 activity was inhibited either with lentiviruses expressing short hairpin RNAs or with the small molecule inhibitor, cambinol. Knockdown or inhibition of SIRT1 activity had a cytostatic effect, characterized by an altered morphology, impaired proliferation, an increased expression of differentiation markers, and cellular senescence. In an orthotopic xenograft model, knockdown of SIRT1 resulted in 50% fewer animals developing tumors and cambinol treatment resulted in an overall lower tumor burden. Taken together, our data show that inhibition of SIRT1 in HCC cells impairs their proliferation in vitro and tumor formation in vivo. These data suggest that SIRT1 expression positively influences the growth of HCC and support further studies aimed to block its activity alone or in combination as a novel treatment strategy. Mol Cancer Ther; 12(4); 499-508. Ó2013 AACR.

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Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer

Cited by 556 publications

References 42 publications

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

Antitumor Effect of SIRT1 Inhibition in Human HCC Tumor Models In Vitro and In Vivo

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