Sirtuin 6 activation rescues the age-related decline in DNA damage repair in primary human chondrocytes
Michaela E. CoppJacqueline ShineHannon L. BrownKirti R. NimmalaOliver B. HansenS. ChubinskayaJohn A. CollinsRichard F. LoeserBrian O. Diekman
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Sirtuin 1
Primary (astronomy)
Sirtuin is a type of deacetylase acted on histone. Sirtuin 1 （SIRT1） is the most homologous to the homologue of silent information regulator 2 （SIR2） in mammals. Its main function is to regulate the body energy metabolism, cell senescence and response to stress. SIRT1 inhibits apoptosis through the interaction of several transcription factors involving in stress response. It is a neuroprotective agent.
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sirtuin; neuroprotective agents; apoptosis
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【目的】Sirtuin-1（SIRT1）はヒストン脱アセチル酵素であり，神経保護や脂質代謝などへの関与が報告されている．本研究ではヒト単球のIL-10制御におけるSIRT1の役割を検討した．【方法】健常者末梢血から精製した単球を用いLPSまたはIFNβで刺激後にSIRT1遺伝子発現を定量した．健常者，無治療multiple sclerosis（MS）患者，IFNβ治療MS患者の単球におけるSIRT1発現を定量した．単球のIL-10産生に対するresveratrol（SIRT1活性化剤），EX527（同抑制剤）の作用を検討した．【結果】単球におけるSIRT1発現はLPSで低下した一方，IFNβで上昇した．単球におけるSIRT1発現に健常者と無治療MS患者間で差は確認できなかったが，IFNβ治療患者で無治療患者より高い傾向が見られた．ResveratrolはLPS刺激に対する単球のIL-10産生を増強した．IFNβは単球からのIL-10産生を増強したが，この作用はEX527によりキャンセルされた．【結論】SIRT1は単球のIL-10制御に関与しており，IFNβによるIL-10産生増強にも関与することが示唆された．SIRT1は神経変性疾患動物モデルにおいて神経保護作用が報告されており，神経と免疫双方が関与する疾患であるMSにとって有用な治療標的であると予想される．
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The silent information regulator sirtuin 1 (SIRT1) protein, a highly conserved NAD + -dependent deacetylase belonging to the sirtuin family, is a post-translational regulator that plays a role in modulating inflammation. SIRT1 affects multiple biological processes by deacetylating a variety of proteins including histones and non-histone proteins. Recent studies have revealed intimate links between SIRT1 and inflammation, while alterations to SIRT1 expression and activity have been linked to inflammatory diseases. In this review, we summarize the mechanisms that regulate SIRT1 expression, including upstream activators and suppressors that operate on the transcriptional and post-transcriptional levels. We also summarize factors that influence SIRT1 activity including the NAD + /NADH ratio, SIRT1 binding partners, and post-translational modifications. Furthermore, we underscore the role of SIRT1 in the development of inflammation by commenting on the proteins that are targeted for deacetylation by SIRT1. Finally, we highlight the potential for SIRT1-based therapeutics for inflammatory diseases.
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SOS response
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SirT1 is a deacetylase whose expression and activity increases during times of caloric restriction (CR). CR has been implicated lifespan extension in rodents, flies and worms, and SirT1 appears to be required for this increased longevity. Sirtuins have also been implicated in the regulation of transcriptional events, apoptosis, and energy efficiency. Many of the sirtuin proteins are similar in function, although they vary in cellular location. Interestingly, numerous studies demonstrated SirT1 activity during CR, but CR effects on the remaining six sirtuin proteins remains relatively unknown. This study aims to analyze the expression of sirtuins in a variety of tissues from mice subjected to a two week 60% CR. We hypothesize that CR will cause increases in mRNA levels of multiple sirtuins. Male and female mice were monitored daily to determine their individual food intake for two weeks and were then given 60% of their normal daily intake for two weeks. Animals were euthanized and tissues snap frozen and stored until further processing. We will present data showing the levels of SirT1–7 as well as other important metabolic and reproductive genes in response to CR. This work is supported by NIH grants U54 HD012303 and T32 DK007494.
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Abstract Mammalian ovarian follicular development is an intricate, elaborate, and well‐organized phenomenon regulated by various signaling pathways; however, the underlying mechanism remains unclear. Mammalian sirtuins (sirtuin 1 to sirtuin 7) are a group of NAD + ‐dependent deacetylases implicated in various physiological processes including cell proliferation, apoptosis, cell cycle progression, and insulin signaling. Mammalian ovarian sirtuins have been studied using adult and aged bovine, porcine, and murine models. However, limited information is available regarding their precise expression patterns and the localization of follicle development in mice. This study aimed to assess the dynamic expression and localization of all seven sirtuins in early postnatal mouse ovaries through real‐time polymerase chain reaction analysis and immunohistochemistry, respectively. During postnatal ovarian follicle development, sirtuin 1, sirtuin 4, and sirtuin 6 were downregulated compared with those in 1‐day postnatal mouse ovaries ( p < .05), indicating that these three sirtuin genes may be markers of follicular development. Combining their localization in granulosa cells through immunohistochemical studies, sirtuin 1, sirtuin 4, and sirtuin 6 are suggested to play negative regulatory roles in mammal ovarian follicular granulosa cell development. Furthermore, we found that sirtuin 2 ( p < .05) and sirtuin 7 ( p < .05) mRNA were constantly upregulated relative to sirtuin 1, although limited information is available regarding sirtuin 7. Among all sirtuins in mouse ovaries, sirtuin 1 was relatively and steadily downregulated. Upon sirtuin 1 overexpression in 1‐day postnatal mouse ovaries via sirtuin 1‐harboring adenoviruses in vitro, the emergence of primary follicles was delayed, as was the emergence of secondary follicles in 4‐day postnatal ovaries. Further studies on KGN cell lines reported that interfering with sirtuin 1 expression in granulosa cell significantly affected granulosa cell proliferation and the expression of mitochondrial genes. This study presents the first systemic analysis of dynamic patterns of sirtuin family expression in early postnatal mice ovaries, laying the foundation for further studies on less discussed sirtuin subtypes, such as sirtuin 5 and sirtuin 7.
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DNA Damage Repair
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