Dena E. Cohen

SIRT1 transgenic mice show phenotypes resembling calorie restriction.

We generated mice that overexpress the sirtuin, SIRT1. Transgenic mice have been generated by knocking in SIRT1 cDNA into the β‐actin locus. Mice that are hemizygous for this transgene express normal levels of β‐actin and higher levels of SIRT1 protein in several tissues. Transgenic mice display some phenotypes similar to mice on a calorie‐restricted diet: they are leaner than littermate controls; are more metabolically active; display reductions in blood cholesterol, adipokines, insulin and fasted glucose; and are more glucose tolerant. Furthermore, transgenic mice perform better on a rotarod challenge and also show a delay in reproduction. Our findings suggest that increased expression of SIRT1 in mice elicits beneficial phenotypes that may be relevant to human health and longevity.

SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10

A hallmark of Alzheimer’s disease (AD) is the accumulation of plaques of Ab 1–40 and 1–42 peptides, which result from the sequential cleavage of APP by the b and g-secretases. The production of Ab peptides is avoided by alternate cleavage of APP by the a and g-secretases. Here we show that production of b-amyloid and plaques in a mouse model of AD are reduced by overexpressing the NAD-dependent deacetylase SIRT1 in brain, and are increased by knocking out SIRT1 in brain. SIRT1 directly activates the transcription of the gene encoding the a-secretase, ADAM10. SIRT1 deacetylates and coactivates the retinoic acid receptor b, a known regulator of ADAM10 transcription. ADAM10 activation by SIRT1 also induces the Notch pathway, which is known to repair neuronal damage in the brain. Our findings indicate SIRT1 activation is a viable strategy to combat AD and perhaps other neurodegenerative diseases.

RETRACTED: SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10

A hallmark of Alzheimers disease (AD) is the accumulation of plaques of Abeta 1-40 and 1-42 peptides, which result from the sequential cleavage of APP by the beta and gamma-secretases. The production of Abeta peptides is avoided by alternate cleavage of APP by the alpha and gamma-secretases. Here we show that production of beta-amyloid and plaques in a mouse model of AD are reduced by overexpressing the NAD-dependent deacetylase SIRT1 in brain, and are increased by knocking out SIRT1 in brain. SIRT1 directly activates the transcription of the gene encoding the alpha-secretase, ADAM10. SIRT1 deacetylates and coactivates the retinoic acid receptor beta, a known regulator of ADAM10 transcription. ADAM10 activation by SIRT1 also induces the Notch pathway, which is known to repair neuronal damage in the brain. Our findings indicate SIRT1 activation is a viable strategy to combat AD and perhaps other neurodegenerative diseases.

Turning straw into gold: directing cell fate for regenerative medicine

Regenerative medicine offers the hope that cells for disease research and therapy might be created from readily available sources. To fulfil this promise, the cells available need to be converted into the desired cell types. We review two main approaches to accomplishing this goal: in vitro directed differentiation, which is used to push pluripotent stem cells, including embryonic stem cells or induced pluripotent stem cells, through steps similar to those that occur during embryonic development; and reprogramming (also known as transdifferentiation), in which a differentiated cell is converted directly into the cell of interest without proceeding through a pluripotent intermediate. We analyse the status of progress made using these strategies and highlight challenges that must be overcome to achieve the goal of cell-replacement therapy.

Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restriction

Mammalian life span can be extended by both calorie restriction (CR) and mutations that diminish somatotropic signaling. Sirt1 is a mediator of many effects of CR in mammals, but any role in controlling somatotropic signaling has not been shown. Since the somatotropic axis is controlled by the brain, we created mice lacking Sirt1 specifically in the brain and examined the impacts of this manipulation on somatotropic signaling and the CR response. These mutant mice displayed defects in somatotropic signaling when fed ad libitum, and defects in the endocrine and behavioral responses to CR. We conclude that Sirt1 in the brain is a link between somatotropic signaling and CR in mammals.

SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive.

SIRT1 is a NAD(+)-dependent deacetylase that governs a number of genetic programs to cope with changes in the nutritional status of cells and organisms. Behavioral responses to food abundance are important for the survival of higher animals. Here we used mice with increased or decreased brain SIRT1 to show that this sirtuin regulates anxiety and exploratory drive by activating transcription of the gene encoding the monoamine oxidase A (MAO-A) to reduce serotonin levels in the brain. Indeed, treating animals with MAO-A inhibitors or selective serotonin reuptake inhibitors (SSRIs) normalized anxiety differences between wild-type and mutant animals. SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter. Both common and rare variations in the SIRT1 gene were shown to be associated with risk of anxiety in human population samples. Together these data indicate that SIRT1 mediates levels of anxiety, and this regulation may be adaptive in a changing environment of food availability.

Higher order chromatin structure at the X-inactivation center via looping DNA.

In mammals, the silencing step of the X-chromosome inactivation (XCI) process is initiated by the non-coding Xist RNA. Xist is known to be controlled by the non-coding Xite and Tsix loci, but the mechanisms by which Tsix and Xite regulate Xist are yet to be fully elucidated. Here, we examine the role of higher order chromatin structure across the 100-kb region of the mouse X-inactivation center (Xic) and map domains of specialized chromatin in vivo. By hypersensitive site mapping and chromosome conformation capture (3C), we identify two domains of higher order chromatin structure. Xite makes looping interactions with Tsix, while Xist makes contacts with Jpx/Enox, another non-coding gene not previously implicated in XCI. These regions interact in a developmentally-specific and sex-specific manner that is consistent with a regulatory role in XCI. We propose that dynamic changes in three-dimensional architecture leads to formation of separate chromatin hubs in Tsix and Xist that together regulate the initiation of X-chromosome inactivation.

Neurogenesis directed by Sirt1

Differentiation of neuronal stem cells into astrocytes or neurons is important in maintaining brain function. Oxidative stress and inflammation are now shown to bias differentiation toward astrocytes by modulating activity of the anti-ageing gene Sirt1. These findings link a longevity gene to the activity of neuronal stem cells and their response to stress.

Brief Report: VGLL4 Is a Novel Regulator of Survival in Human Embryonic Stem Cells

Human embryonic stem cells (hESCs) are maintained in a self‐renewing state by an interconnected network of mechanisms that sustain pluripotency, promote proliferation and survival, and prevent differentiation. We sought to find novel genes that could contribute to one or more of these processes using a gain‐of‐function screen of a large collection of human open reading frames. We identified Vestigial‐like 4 (VGLL4), a cotranscriptional regulator with no previously described function in hESCs, as a positive regulator of survival in hESCs. Specifically, VGLL4 overexpression in hESCs significantly decreases cell death in response to dissociation stress. Additionally, VGLL4 overexpression enhances hESC colony formation from single cells. These effects may be attributable, in part, to a decreased activity of initiator and effector caspases observed in the context of VGLL4 overexpression. Additionally, we show an interaction between VGLL4 and the Rho/Rock pathway, previously implicated in hESC survival. This study introduces a novel gain‐of‐function approach for studying hESC maintenance and presents VGLL4 as a previously undescribed regulator of this process. Stem Cells 2013;31:2833–2841

Retraction Notice to: SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10

Donmez et al. (2010) reported that SIRT1 suppressed Alzheimers disease in a mouse model by upregulating the ADAM 10 α-secretase gene via coactivation of the retinoic acid receptor, RARβ. Increased α-secretase bypassed the processing of APP by the β-secretase, thereby reducing the amyloid burden. It has come to our attention that several figures in the paper contain images in which gel lanes were spliced together without appropriate indication. There are also instances of image duplication. We believe that these errors do not affect the conclusions of experiments in the paper. Moreover, the finding that SIRT1 upregulates the ADAM 10 α-secretase in neurons was reported by Theendakara et al. (Theendakara, V., et al. [2013]. Proc. Natl. Acad. Sci. USA 110, 18303–18308), and the more detailed finding that SIRT1 and RARβ cooperate in neurons to activate ADAM 10 has also recently been reported by Lee et al. (Lee, H.R., et al. [2014]. J. Neurosci. Res. Published online June 5, 2014. http://dx.doi.org/10.1002/jnr23421), thereby supporting our main conclusions. However, the level of care in figure preparation in Donmez et al. falls well below the standard that we expect, and we are therefore retracting the paper. We offer our sincerest apologies to the scientific community for these errors and for any inconvenience they may have caused.