Are sirtuins viable targets for improving healthspan and lifespan?

Baur, Joseph A.; Ungvári, Zoltán; Minor, Robin K.; Couteur, David G. Le; Cabo, Rafael de

doi:10.1038/nrd3738

Cited by 356 publications

(295 citation statements)

References 284 publications

(390 reference statements)

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“…We found that, in ob/ob mice, the SIRT1 level was lower in ECs recovered from both ischemic and nonischemic muscles of saline mice, while it increased upon a UnAG challenge. A number of SIRT1 targets have been described in mammals (44), and tumor suppressor p53 is included (38). Transcription factor p53 is involved in DNA damage mechanisms (45).…”

Section: Discussionmentioning

confidence: 99%

Unacylated Ghrelin Induces Oxidative Stress Resistance in a Glucose Intolerance and Peripheral Artery Disease Mouse Model by Restoring Endothelial Cell miR-126 Expression

et al. 2014

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Reactive oxygen species (ROS) are crucial in longterm diabetes complications, including peripheral artery disease (PAD). In this study, we have investigated the potential clinical impact of unacylated ghrelin (UnAG) in a glucose intolerance and PAD mouse model. We demonstrate that UnAG is able to protect skeletal muscle and endothelial cells (ECs) from ROS imbalance in hind limb ischemiasubjected ob/ob mice. This effect translates into reductions in hind limb functional impairment. We show that UnAG rescues sirtuin 1 (SIRT1) activity and superoxide dismutase-2 (SOD-2) expression in ECs. This leads to SIRT1-mediated p53 and histone 3 lysate 56 deacetylation and results in reduced EC senescence in vivo. We demonstrate, using small interfering RNA technology, that SIRT1 is also crucial for SOD-2 expression. UnAG also renews micro-RNA (miR)-126 expression, resulting in the posttranscriptional regulation of vascular cell adhesion molecule 1 expression and a reduced number of infiltrating inflammatory cells in vivo. Loss-of-function experiments that target miR-126 demonstrate that miR-126 also controls SIRT1 and SOD-2 expression, thus confirming its role in driving UnAG-mediated EC protection against ROS imbalance. These results indicate that UnAG protects vessels from ROS imbalance in ob/ob mice by rescuing miR-126 expression, thus emphasizing its potential clinical impact in avoiding limb loss in PAD.

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Section: Discussionmentioning

confidence: 99%

Unacylated Ghrelin Induces Oxidative Stress Resistance in a Glucose Intolerance and Peripheral Artery Disease Mouse Model by Restoring Endothelial Cell miR-126 Expression

et al. 2014

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“…Perhaps no compound has created greater debate on its effects on lifespan and health, on its precise mode of action and on its potential as a DR mimetic as the polyphenol resveratrol has (126)(127)(128) . Resveratrol has been shown to increased lifespan in yeast, C. elegans and Drosophila apparently through the activation of NAD-dependent histone deacetylases called sirtuins (129,130) , with SIRT1 activation reported to underlie the effects of DR in mammals (130) .…”

Section: Resveratrolmentioning

confidence: 99%

Dietary restriction and the pursuit of effective mimetics

Selman

2014

Proc. Nutr. Soc.

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Dietary restriction (DR) has been shown to extend both median and maximum lifespan in a range of animals, although recent findings suggest that these effects are not universally enjoyed across all animals. In particular, the lifespan effect following DR in mice is highly strain-specific and there is little current evidence that DR induces a positive effect on all-cause mortality in non-human primates. However, the positive effects of DR on health appear to be highly conserved across the vast majority of species, including human subjects. Despite these effects on health, it is highly unlikely that DR will become a realistic or popular life choice for most human subjects given the level of restraint required. Consequently significant research is focusing on identifying compounds that will bestow the benefits of DR without the obligation to adhere to stringent reductions in daily food intake. Several such compounds, including rapamycin, metformin and resveratrol, have been identified as potential DR mimetics. Although these compounds show significant promise, there is a need to properly understand the mechanisms through which these drugs act. This review will discuss the importance in understanding the role that genetic background and heterogeneity play in mediating the lifespan and healthspan effects of DR. It will also provide an overview of the most promising current DR mimetics and their effects on healthy lifespan.

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“…They have been implicated in diverse biological events, such as aging, energy control, circadian clocks, and mitochondrial biogenesis (Baur, Ungvari, Minor, Le Couteur, & de Cabo, 2012; Preyat & Leo, 2013; Wood et al., 2004). Of them, Sirt2 is associated with mitotic structures, beginning with the centrosome in mitotic prophase, the spindle in metaphase, and the midbody during cytokinesis, presumably to ensure normal cell division (North & Verdin, 2007).…”

Section: Introductionmentioning

confidence: 99%

Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

et al. 2017

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SummaryThe level of Sirt2 protein is reduced in oocytes from aged mice, while exogenous expression of Sirt2 could ameliorate the maternal age‐associated meiotic defects. To date, the underlying mechanism remains unclear. Here, we confirmed that specific depletion of Sirt2 disrupts maturational progression and spindle/chromosome organization in mouse oocytes, with compromised kinetochore–microtubule attachments. Candidate screening revealed that acetylation state of lysine 243 on BubR1 (BubR1‐K243, an integral part of the spindle assembly checkpoint complex) functions during oocyte meiosis, and acetylation‐mimetic mutant BubR1‐K243Q results in the very similar phenotypes as Sirt2‐knockdown oocytes. Furthermore, we found that nonacetylatable‐mimetic mutant BubR1‐K243R partly prevents the meiotic deficits in oocytes depleted of Sirt2. Importantly, BubR1‐K243R overexpression in oocytes derived from aged mice markedly suppresses spindle/chromosome anomalies and thereupon lowers the incidence of aneuploid eggs. In sum, our data suggest that Sirt2‐dependent BubR1 deacetylation involves in the regulation of meiotic apparatus in normal oocytes and mediates the effects of advanced maternal age on oocyte quality.

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Are sirtuins viable targets for improving healthspan and lifespan?

Cited by 356 publications

References 284 publications

Unacylated Ghrelin Induces Oxidative Stress Resistance in a Glucose Intolerance and Peripheral Artery Disease Mouse Model by Restoring Endothelial Cell miR-126 Expression

Unacylated Ghrelin Induces Oxidative Stress Resistance in a Glucose Intolerance and Peripheral Artery Disease Mouse Model by Restoring Endothelial Cell miR-126 Expression

Dietary restriction and the pursuit of effective mimetics

Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

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