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1.  Geroncogenesis: Metabolic Changes during Aging as a Driver of Tumorigenesis 
Cancer cell  2014;25(1):12-19.
Why does cancer risk increase as we age? Frequently attributed to the multi-hit hypothesis and the time required to accumulate genomic mutations, this question is a matter of ongoing debate. Here, we propose that the normal decline in oxidative metabolism during aging constitutes an early and important “hit” that drives tumorigenesis. Central to these metabolic changes are the sirtuins, a family of NAD+-dependent deacylases that have evolved as coordinators of physiological responses to nutrient intake and energetic demand. Thus, the modulation of sirtuins might be a fruitful approach to reversing the age-related metabolic changes that could underlie tumorigenesis.
doi:10.1016/j.ccr.2013.12.005
PMCID: PMC3970212  PMID: 24434207
2.  Dietary restriction involves NAD+-dependent mechanisms and a shift toward oxidative metabolism 
Aging Cell  2014;13(6):1075-1085.
Interventions that slow aging and prevent chronic disease may come from an understanding of how dietary restriction (DR) increases lifespan. Mechanisms proposed to mediate DR longevity include reduced mTOR signaling, activation of the NAD+-dependent deacylases known as sirtuins, and increases in NAD+ that derive from higher levels of respiration. Here, we explored these hypotheses in Caenorhabditis elegans using a new liquid feeding protocol. DR lifespan extension depended upon a group of regulators that are involved in stress responses and mTOR signaling, and have been implicated in DR by some other regimens [DAF-16 (FOXO), SKN-1 (Nrf1/2/3), PHA-4 (FOXA), AAK-2 (AMPK)]. Complete DR lifespan extension required the sirtuin SIR-2.1 (SIRT1), the involvement of which in DR has been debated. The nicotinamidase PNC-1, a key NAD+ salvage pathway component, was largely required for DR to increase lifespan but not two healthspan indicators: movement and stress resistance. Independently of pnc-1, DR increased the proportion of respiration that is coupled to ATP production but, surprisingly, reduced overall oxygen consumption. We conclude that stress response and NAD+-dependent mechanisms are each critical for DR lifespan extension, although some healthspan benefits do not require NAD+ salvage. Under DR conditions, NAD+-dependent processes may be supported by a DR-induced shift toward oxidative metabolism rather than an increase in total respiration.
doi:10.1111/acel.12273
PMCID: PMC4244309  PMID: 25257342
aging; dietary restriction; C. elegans; stress response; sirtuins; NAD+
3.  Preventing malaria in international travellers: an evaluation of published English-language guidelines 
BMC Public Health  2014;14(1):1129.
Background
People intending to travel may seek information on malaria prevention from a range of sources. To ensure the best protection, this information needs to be reliable, up-to-date, consistent, and useful to their decision making. This study appraises current international and national guidelines written in English for malaria prevention in travellers, and whether any recommendations conflict.
Methods
We systematically identified national or international English-language guidelines on malaria prevention in travellers to July 2013 using standard and multiple searching methods. We critically appraised guidelines using the AGREE II tool, and report inconsistent recommendations within guidelines.
Results
We identified five sets of English-language guidelines on preventing malaria for travellers. Assessment against AGREE II indicate that all of the guidelines fall short of internationally accepted standards in guideline development: none include a transparent description of methods; only one describes sources of funding or potential conflicts of interest; and only one includes formal presentation of the evidence alongside transparent assessment of the quality of that evidence. There were a number of important discrepancies between guidelines, and some omit information about effectiveness, safety and adverse effects of chemoprophylaxis options.
Conclusions
The methods used for developing guidelines for malaria prevention in travellers lags behind current internationally recognized standards. Healthcare professionals as well as travellers themselves could be better informed if guidelines were more systematic and transparent summaries of the current knowledge on drug interventions in relation to effects, safety, administration and contra-indications.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-1129) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2458-14-1129
PMCID: PMC4226897  PMID: 25367677
Malaria; Travellers; Chemoprophylaxis; Prevention
4.  A matrix model for valuing anesthesia service with the resource-based relative value system 
Background
The purpose of this study was to propose a new crosswalk using the resource-based relative value system (RBRVS) that preserves the time unit component of the anesthesia service and disaggregates anesthesia billing into component parts (preoperative evaluation, intraoperative management, and postoperative evaluation). The study was designed as an observational chart and billing data review of current and proposed payments, in the setting of a preoperative holing area, intraoperative suite, and post anesthesia care unit. In total, 1,195 charts of American Society of Anesthesiology (ASA) physical status 1 through 5 patients were reviewed. No direct patient interventions were undertaken.
Results
Spearman correlations between the proposed RBRVS billing matrix payments and the current ASA relative value guide methodology payments were strong (r=0.94–0.96, P<0.001 for training, test, and overall). The proposed RBRVS-based billing matrix yielded payments that were 3.0%±1.34% less than would have been expected from commercial insurers, using standard rates for commercial ASA relative value units and RBRVS relative value units. Compared with current Medicare reimbursement under the ASA relative value guide, reimbursement would almost double when converting to an RBRVS billing model. The greatest increases in Medicare reimbursement between the current system and proposed billing model occurred as anesthetic management complexity increased.
Conclusion
The new crosswalk correlates with existing evaluation and management and intensive care medicine codes in an essentially revenue neutral manner when applied to the market-based rates of commercial insurers. The new system more highly values delivery of care to more complex patients undergoing more complex surgery and better represents the true value of anesthetic case management.
doi:10.2147/JMDH.S68671
PMCID: PMC4199848  PMID: 25336964
payment reform; billing; crosswalk
5.  SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass 
Aging Cell  2014;13(5):787-796.
Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density, and insulin sensitivity associated with higher mitochondrial content and decreased inflammation. Short-term SRT2104 treatment preserves bone and muscle mass in an experimental model of atrophy. These results demonstrate it is possible to design a small molecule that can slow aging and delay multiple age-related diseases in mammals, supporting the therapeutic potential of SIRT1 activators in humans.
doi:10.1111/acel.12220
PMCID: PMC4172519  PMID: 24931715
healthspan; inflammation; lifespan; muscle wasting; osteoporosis; sirtuins
6.  Carboxamide SIRT1 inhibitors block DBC1 binding via an acetylation-independent mechanism 
Cell Cycle  2013;12(14):2233-2240.
SIRT1 is an NAD+-dependent deacetylase that counteracts multiple disease states associated with aging and may underlie some of the health benefits of calorie restriction. Understanding how SIRT1 is regulated in vivo could therefore lead to new strategies to treat age-related diseases. SIRT1 forms a stable complex with DBC1, an endogenous inhibitor. Little is known regarding the biochemical nature of SIRT1-DBC1 complex formation, how it is regulated and whether or not it is possible to block this interaction pharmacologically. In this study, we show that critical residues within the catalytic core of SIRT1 mediate binding to DBC1 via its N-terminal region, and that several carboxamide SIRT1 inhibitors, including EX-527, can completely block this interaction. We identify two acetylation sites on DBC1 that regulate its ability to bind SIRT1 and suppress its activity. Furthermore, we show that DBC1 itself is a substrate for SIRT1. Surprisingly, the effect of EX-527 on SIRT1-DBC1 binding is independent of DBC1 acetylation. Together, these data show that protein acetylation serves as an endogenous regulatory mechanism for SIRT1-DBC1 binding and illuminate a new path to developing small-molecule modulators of SIRT1.
doi:10.4161/cc.25268
PMCID: PMC3755073  PMID: 23892437
SIRT1 inhibitors; DBC1; SIRT1-DBC1 complex regulation; DBC1 acetylation; DBC1 localization
7.  Role of Sirtuins in Lifespan Regulation is Linked to Methylation of Nicotinamide 
Nature chemical biology  2013;9(11):693-700.
Sirtuins, a family of histone deacetylases, have a fiercely debated role in regulating lifespan. Contrasting recent observations, we here find that overexpression of sir-2.1, the orthologue of mammalian SirT1, does extend C. elegans lifespan. Sirtuins mandatorily convert NAD+ into nicotinamide (NAM). We here find that NAM and its metabolite, 1-methylnicotinamide (MNA), extend C. elegans lifespan, even in the absence of sir-2.1. We identify anmt-1 to encode a C. elegans orthologue of nicotinamide-N-methyltransferase (NNMT), the enzyme that methylates NAM to generate MNA. Disruption and overexpression of anmt-1 have opposing effects on lifespan independent of sirtuins, with loss of anmt-1 fully inhibiting sir-2.1-mediated lifespan extension. MNA serves as a substrate for a newly identified aldehyde oxidase, GAD-3, to generate hydrogen peroxide acting as a mitohormetic ROS signal to promote C. elegans longevity. Taken together, sirtuin-mediated lifespan extension depends on methylation of NAM, providing an unexpected mechanistic role for sirtuins beyond histone deacetylation.
doi:10.1038/nchembio.1352
PMCID: PMC4076143  PMID: 24077178
8.  Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging 
Cell  2013;155(7):1624-1638.
SUMMARY
Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD+ and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.
doi:10.1016/j.cell.2013.11.037
PMCID: PMC4076149  PMID: 24360282
9.  Aging-like Phenotype and Defective Lineage Specification in SIRT1-Deleted Hematopoietic Stem and Progenitor Cells 
Stem Cell Reports  2014;3(1):44-59.
Summary
Aging hematopoietic stem cells (HSCs) exhibit defective lineage specification that is thought to be central to increased incidence of myeloid malignancies and compromised immune competence in the elderly. Mechanisms underlying these age-related defects remain largely unknown. We show that the deacetylase Sirtuin (SIRT)1 is required for homeostatic HSC maintenance. Differentiation of young SIRT1-deleted HSCs is skewed toward myeloid lineage associated with a significant decline in the lymphoid compartment, anemia, and altered expression of associated genes. Combined with HSC accumulation of damaged DNA and expression patterns of age-linked molecules, these have striking overlaps with aged HSCs. We further show that SIRT1 controls HSC homeostasis via the longevity transcription factor FOXO3. These findings suggest that SIRT1 is essential for HSC homeostasis and lineage specification. They also indicate that SIRT1 might contribute to delaying HSC aging.
Graphical Abstract
Highlights
•SIRT1 deacetylase is essential for homeostatic maintenance of HSCs•SIRT1 regulates HSC homeostasis via the longevity factor FOXO3•SIRT1 is essential for HSC lineage specification•Young SIRT1-deleted HSCs have overlapping features with old HSCs
SIRT1 deacetylase is essential for homeostatic maintenance of HSCs and for HSC lineage specification. Differentiation of young SIRT1-deleted HSCs is myeloid biased, defective in lymphoid cell production, leads to anemia, and recapitulates the main features of aged HSCs, suggesting that SIRT1 might contribute to delaying HSC aging. The longevity transcription factor FOXO3 mediates the SIRT1 effects on HSC homeostasis.
doi:10.1016/j.stemcr.2014.04.015
PMCID: PMC4110778  PMID: 25068121
10.  Germline energetics, aging and female infertility 
Cell metabolism  2013;17(6):838-850.
SUMMARY
The role of metabolism in ovarian aging is poorly described, despite the fact that ovaries fail earlier than most other organs. Growing interest in ovarian function is being driven by recent evidence that mammalian females routinely generate new oocytes during adult life through the activity of germline stem cells. In this perspective, we overview the female reproductive system as a powerful and clinically relevant model to understand links between aging and metabolism, and we discuss new concepts for how oocytes and their precursor cells might be altered metabolically to sustain or increase ovarian function and fertility in women.
doi:10.1016/j.cmet.2013.05.007
PMCID: PMC3756096  PMID: 23747243
11.  Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy 
Angiogenesis  2013;16(4):985-992.
Regeneration of blood vessels in ischemic neuronal tissue is critical to reduce tissue damage in diseases. In proliferative retinopathy, initial vessel loss leads to retinal ischemia, which can induce either regrowth of vessels to restore normal metabolism and minimize damage, or progress to hypoxia-induced sight-threatening pathologic vaso-proliferation. It is not well understood how retinal neurons mediate regeneration of vascular growth in response to ischemic insults. In this study we aim to investigate the potential role of Sirtuin 1 (Sirt1), a metabolically-regulated protein deacetylase, in mediating the response of ischemic neurons to regulate vascular regrowth in a mouse model of oxygen-induced ischemic retinopathy (OIR). We found that Sirt1 is highly induced in the avascular ischemic retina in OIR. Conditional depletion of neuronal Sirt1 leads to significantly decreased retinal vascular regeneration into the avascular zone and increased hypoxia-induced pathologic vascular growth. This effect is likely independent of PGC-1α, a known Sirt1 target, as absence of PGC-1α in knockout mice does not impact vascular growth in retinopathy. We found that neuronal Sirt1 controls vascular regrowth in part through modulating deacetylation and stability of hypoxia-induced factor 1α and 2α, and thereby modulating expression of angiogenic factors. These results indicate that ischemic neurons induce Sirt1 to promote revascularization into ischemic neuronal areas, suggesting a novel role of neuronal Sirt1 in mediating vascular regeneration in ischemic conditions, with potential implications beyond retinopathy.
doi:10.1007/s10456-013-9374-5
PMCID: PMC4006695  PMID: 23912262
Acetylation; Hypoxia-induced factor; Ischemic retinopathy; Neovascularization; Retinal ganglion cell; Revascularization; Sirtuin1
12.  Safety of 8-aminoquinolines given to people with G6PD deficiency: protocol for systematic review of prospective studies 
BMJ Open  2014;4(5):e004664.
Introduction
A single dose or short course of primaquine given to people infected with malaria may reduce transmission of Plasmodium falciparum through its effects on gametocytes. Primaquine is also known to cause haemolysis in people with variants of glucose-6-phosphate dehydrogenase (G6PD) deficiency. The objective of this systematic review was to assess the risk of adverse effects in people with G6PD deficiency given primaquine or other 8-aminoquinoline (8AQ) as a single dose or short course (less than 7 days).
Methods and analysis
We will search the following databases: Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS. Prospective cohort studies, randomised and quasi-randomised trials that evaluated 8AQs for whatever reason in adults or children with a known G6PD deficiency will be included. Two authors will independently assess each study for eligibility, risk of bias and extract data.
Ethics and dissemination
This systematic review will be published in a peer-reviewed journal. Brief reports of the review findings will be disseminated directly to the appropriate audiences and the WHO Technical Expert Group in Malaria Chemotherapy. As no primary data collection will be undertaken, no additional formal ethical assessment and informed consent are required.
Protocol registration in PROSPERO
The protocol is registered with PROSPERO, registration number CRD42013006518.
doi:10.1136/bmjopen-2013-004664
PMCID: PMC4024606  PMID: 24833685
Preventive Medicine; Public Health; Infectious Diseases
13.  Small-Molecule Allosteric Activators of Sirtuins 
The mammalian sirtuins (SIRT1–7) are NAD+-dependent lysine deacylases that play central roles in cell survival, inflammation, energy metabolism, and aging. Members of this family of enzymes are considered promising pharmaceutical targets for the treatment of age-related diseases including cancer, type 2 diabetes, inflammatory disorders, and Alzheimer’s disease. SIRT1-activating compounds (STACs), which have been identified from a variety of chemical classes, provide health benefits in animal disease models. Recent data point to a common mechanism of allosteric activation by natural and synthetic STACs that involves the binding of STACs to a conserved N-terminal domain in SIRT1. Compared with polyphenols such as resveratrol, the synthetic STACs show greater potency, solubility, and target selectivity. Although considerable progress has been made regarding SIRT1 allosteric activation, key questions remain, including how the molecular contacts facilitate SIRT1 activation, whether other sirtuin family members will be amenable to activation, and whether STACs will ultimately prove safe and efficacious in humans.
doi:10.1146/annurev-pharmtox-010611-134657
PMCID: PMC4018738  PMID: 24160699
aging; sirtuin; NAD; allosteric activation; HDAC
14.  The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet 
Cell reports  2014;6(5):836-843.
The prevention or delay of the onset of age-related diseases prolongs survival and improves quality of life while reducing the burden on the health care system. Activation of sirtuin 1 (SIRT1), an NAD+ deacetylase, improves metabolism and confers protection against physiological and cognitive disturbances in old age. SRT1720 is a specific SIRT1 activator that has health and lifespan benefits in adult mice fed a high-fat diet. We found extension in lifespan, delayed onset of age-related metabolic diseases, and improved general health in mice fed a standard diet after SRT1720 supplementation. Inhibition of pro-inflammatory gene expression both in the liver and muscle of SRT1720-treated animals was noted. SRT1720 lowered phosphorylation of NF-κB pathway regulators in vitro only when SIRT1 was functionally present. Combined with our previous work, the current study further supports the beneficial effects of SRT1720 on health across the lifespan in mice.
doi:10.1016/j.celrep.2014.01.031
PMCID: PMC4010117  PMID: 24582957
SRT1720; healthspan; standard diet; mice; longevity; SIRT1
15.  Immediate fluid management of children with severe febrile illness and signs of impaired circulation in low-income settings: a contextualised systematic review 
BMJ Open  2014;4(4):e004934.
Objective
To evaluate the effects of intravenous fluid bolus compared to maintenance intravenous fluids alone as part of immediate emergency care in children with severe febrile illness and signs of impaired circulation in low-income settings.
Design
Systematic review of randomised controlled trials (RCTs), and observational studies, including retrospective analyses, that compare fluid bolus regimens with maintenance fluids alone. The primary outcome measure was predischarge mortality.
Data sources and synthesis
We searched PubMed, The Cochrane Library (to January 2014), with complementary earlier searches on, Google Scholar and Clinical Trial Registries (to March 2013). As studies used different clinical signs to define impaired circulation we classified patients into those with signs of severely impaired circulation, or those with any signs of impaired circulation. The quality of evidence for each outcome was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Findings are presented as risk ratios (RRs) with 95% CIs.
Results
Six studies were included. Two were RCTs, one large trial (n=3141 children) from a low-income country and a smaller trial from a middle-income country. The remaining studies were from middle-income or high-income settings, observational, and with few participants (34–187 children).
Severely impaired circulation
The large RCT included a small subgroup with severely impaired circulation. There were more deaths in those receiving bolus fluids (20–40 mL/kg/h, saline or albumin) compared to maintenance fluids (2.5–4 mL/kg/h; RR 2.40, 95% CI 0.84 to 6.88, p=0.054, 65 participants, low quality evidence). Three additional observational studies, all at high risk of confounding, found mixed effects on mortality (very low quality evidence).
Any signs of impaired circulation
The large RCT included children with signs of both severely and non-severely impaired circulation. Overall, bolus fluids increased 48 h mortality compared to maintenance fluids with an additional 3 deaths per 100 children treated (RR 1.45, 95% CI 1.13 to 1.86, 3141 participants, high quality evidence). In a second small RCT from India, no difference in 72 h mortality was detected between children who received 20–40 mL/kg Ringers lactate over 15 min and those who received 20 mL over 20 min up to a maximum of 60 mL/kg over 1 h (147 participants, low quality evidence). In one additional observational study, resuscitation consistent with Advanced Paediatric Life Support (APLS) guidelines, including fluids, was not associated with reduced mortality in the small subgroup with septic shock (very low quality evidence).
Signs of impaired circulation, but not severely impaired
Only the large RCT allowed an analysis for children with some signs of impaired circulation who would not meet the criteria for severe impairment. Bolus fluids increased 48 h mortality compared to maintenance alone (RR 1.36, 95% CI 1.05 to 1.76, high quality evidence).
Conclusions
Prior to the publication of the large RCT, the global evidence base for bolus fluid therapy in children with severe febrile illness and signs of impaired circulation was of very low quality. This large study provides robust evidence that in low-income settings fluid boluses increase mortality in children with severe febrile illness and impaired circulation, and this increased risk is consistent across children with severe and less severe circulatory impairment.
doi:10.1136/bmjopen-2014-004934
PMCID: PMC4010848  PMID: 24785400
Paediatrics
17.  Type 5 Adenylyl Cyclase Increases Oxidative Stress by Transcriptional Regulation of MnSOD via the SIRT1/FoxO3a Pathway 
Circulation  2013;127(16):1692-1701.
Background
For reasons that remain unclear, whether type 5 AC (AC5), one of two major AC isoforms in heart, is protective or deleterious in response to cardiac stress is controversial. To reconcile this controversy we examined the cardiomyopathy induced by chronic isoproterenol (ISO) in AC5 transgenic (Tg) mice and the signaling mechanisms involved.
Methods and Results
Chronic ISO increased oxidative stress and induced more severe cardiomyopathy in AC5 Tg, as left ventricular (LV) ejection fraction fell 1.9 fold more than wild type (WT), along with greater LV dilation and increased fibrosis, apoptosis and hypertrophy. Oxidative stress induced by chronic ISO, detected by 8-OhDG was 15% greater, p=0.007, in AC5 Tg hearts, while protein expression of MnSOD was reduced by 38%, indicating that the susceptibility of AC5 Tg to cardiomyopathy may be due to decreased MnSOD expression. Consistent with this, susceptibility of the AC5 Tg to cardiomyopathy was suppressed by overexpression of MnSOD, whereas protection afforded by the AC5 KO was lost in AC5 KO×MnSOD+/− mice. Elevation of MnSOD was eliminated by both sirtuin and MEK inhibitors, suggesting both the SIRT1/FoxO3a and MEK/ERK pathway are involved in MnSOD regulation by AC5.
Conclusion
Overexpression of AC5 exacerbates the cardiomyopathy induced by chronic catecholamine stress by altering regulation of SIRT1/FoxO3a, MEK/ERK and MnSOD, resulting in oxidative stress intolerance, thereby shedding light on new approaches for treatment of heart failure.
doi:10.1161/CIRCULATIONAHA.112.001212
PMCID: PMC3980473  PMID: 23536361
Adenylyl cyclase; Adrenergic; Cardiomyopathy; Oxidative Stress
18.  Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38 
Diabetes  2013;62(4):1084-1093.
Metabolic syndrome is a growing health problem worldwide. It is therefore imperative to develop new strategies to treat this pathology. In the past years, the manipulation of NAD+ metabolism has emerged as a plausible strategy to ameliorate metabolic syndrome. In particular, an increase in cellular NAD+ levels has beneficial effects, likely because of the activation of sirtuins. Previously, we reported that CD38 is the primary NAD+ase in mammals. Moreover, CD38 knockout mice have higher NAD+ levels and are protected against obesity and metabolic syndrome. Here, we show that CD38 regulates global protein acetylation through changes in NAD+ levels and sirtuin activity. In addition, we characterize two CD38 inhibitors: quercetin and apigenin. We show that pharmacological inhibition of CD38 results in higher intracellular NAD+ levels and that treatment of cell cultures with apigenin decreases global acetylation as well as the acetylation of p53 and RelA-p65. Finally, apigenin administration to obese mice increases NAD+ levels, decreases global protein acetylation, and improves several aspects of glucose and lipid homeostasis. Our results show that CD38 is a novel pharmacological target to treat metabolic diseases via NAD+-dependent pathways.
doi:10.2337/db12-1139
PMCID: PMC3609577  PMID: 23172919
19.  Communicating Hydrocephalus and Vestibular Schwannomas: Etiology, Treatment, and Long-Term Follow-Up 
Background Large vestibular schwannomas (VSs) can cause hydrocephalus by obstructing the fourth ventricle. Little is known about the communicating hydrocephalus that is seen with a smaller VS.
Methods The clinicopathological findings and follow up of three patients with communicating hydrocephalus associated with a small VS are presented.
Results Four patients aged 40 to 66 years (mean: 57.7) presented with ataxia, dementia, and urinary incontinence. The VS were 2.0 to 2.4 cm. The cerebrospinal fluid (CSF) protein was elevated in three patients in whom it was measured (1.7 to 6 times normal). The VS was resected in two patients. All of the patients required ventriculoperitoneal shunting (VPS). All of the patients were asymptomatic or improved at follow-up at 9 months to 13 years.
Conclusion Communicating hydrocephalus associated with a VS can occur in younger patients than was previously thought. An elevated CSF protein appears to be important, but other factors may be involved. A shunting procedure is often required to relieve the symptoms of hydrocephalus even if the tumor is resected. Possible etiological causes of communicating hydrocephalus in patients with a small VS are discussed.
doi:10.1055/s-0033-1333621
PMCID: PMC3699216  PMID: 24436891
vestibular schwannoma; communicating hydrocephalus
20.  Metformin improves healthspan and lifespan in mice 
Nature communications  2013;4:2192.
Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced LDL and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging.
doi:10.1038/ncomms3192
PMCID: PMC3736576  PMID: 23900241
21.  Analysis of 41 cancer cell lines reveals excessive allelic loss and novel mutations in the SIRT1 gene 
Cell Cycle  2013;12(2):263-270.
SIRT1 is an evolutionarily conserved protein deacetylase that modulates stress response, cellular metabolism and aging in model organisms. While SIRT1 exerts beneficial effects in protecting against age-related diseases, the role of SIRT1 in cancer has been controversial. SIRT1 promotes cell survival by deacetylating, and thereby negatively regulating the activity of important tumor suppressors such as p53. In this regard, SIRT1 has been considered to be a potential oncogene, and SIRT1 inhibitors have been studied for possible anticancer therapeutic effects. In contrast, it has been shown that SIRT1 deficiency leads to increased genomic instability and tumorigenesis, and that overexpression of SIRT1 attenuates cancer formation in mice, suggesting it may also act as a tumor suppressor. Based on this evidence, SIRT1-activating molecules could act as candidate chemotherapeutic drugs. In order to gain insight into the role of SIRT1 in cancer, we performed a comprehensive resequencing analysis of the SIRT1 gene in 41 tumor cell lines and found an unusually excessive homozygosity, which was confirmed to be allelic loss by microsatellite analysis. Furthermore, we found two novel SIRT1 mutations (D739Y and R65_A72del) in addition to the known, rare non-synonymous variation resulting in I731V. In vitro assays using purified SIRT1 protein showed that these mutations do not alter SIRT1 deacetylase activity or telomerase activity, which was shown to be regulated by SIRT1. We conclude that allelic loss or mutations in the SIRT1 gene occur prevalently during tumorigenesis, supporting the assertion that SIRT1 may serve as a tumor suppressor.
doi:10.4161/cc.23056
PMCID: PMC3575455  PMID: 23255128
SIRT1; breast cancer; cell line; allelic loss; gene mutation; tumor suppressor
22.  Sirtuin1 Over-Expression Does Not Impact Retinal Vascular and Neuronal Degeneration in a Mouse Model of Oxygen-Induced Retinopathy 
PLoS ONE  2014;9(1):e85031.
Proliferative retinopathy is a leading cause of blindness, including retinopathy of prematurity (ROP) in children and diabetic retinopathy in adults. Retinopathy is characterized by an initial phase of vessel loss, leading to tissue ischemia and hypoxia, followed by sight threatening pathologic neovascularization in the second phase. Previously we found that Sirtuin1 (Sirt1), a metabolically dependent protein deacetylase, regulates vascular regeneration in a mouse model of oxygen-induced proliferative retinopathy (OIR), as neuronal depletion of Sirt1 in retina worsens retinopathy. In this study we assessed whether over-expression of Sirtuin1 in retinal neurons and vessels achieved by crossing Sirt1 over-expressing flox mice with Nestin-Cre mice or Tie2-Cre mice, respectively, may protect against retinopathy. We found that over-expression of Sirt1 in Nestin expressing retinal neurons does not impact vaso-obliteration or pathologic neovascularization in OIR, nor does it influence neuronal degeneration in OIR. Similarly, increased expression of Sirt1 in Tie2 expressing vascular endothelial cells and monocytes/macrophages does not protect retinal vessels in OIR. In addition to the genetic approaches, dietary supplement with Sirt1 activators, resveratrol or SRT1720, were fed to wild type mice with OIR. Neither treatment showed significant vaso-protective effects in retinopathy. Together these results indicate that although endogenous Sirt1 is important as a stress-induced protector in retinopathy, over-expression of Sirt1 or treatment with small molecule activators at the examined doses do not provide additional protection against retinopathy in mice. Further studies are needed to examine in depth whether increasing levels of Sirt1 may serve as a potential therapeutic approach to treat or prevent retinopathy.
doi:10.1371/journal.pone.0085031
PMCID: PMC3885684  PMID: 24416337
23.  Evaluation of Resveratrol, Green Tea Extract, Curcumin, Oxaloacetic Acid, and Medium-Chain Triglyceride Oil on Life Span of Genetically Heterogeneous Mice 
The National Institute on Aging Interventions Testing Program (ITP) was established to evaluate agents that are hypothesized to increase life span and/or health span in genetically heterogeneous mice. Each compound is tested in parallel at three test sites. It is the goal of the ITP to publish all results, negative or positive. We report here on the results of lifelong treatment of mice, beginning at 4 months of age, with each of five agents, that is, green tea extract (GTE), curcumin, oxaloacetic acid, medium-chain triglyceride oil, and resveratrol, on the life span of genetically heterogeneous mice. Each agent was administered beginning at 4 months of age. None of these five agents had a statistically significant effect on life span of male or female mice, by log-rank test, at the concentrations tested, although a secondary analysis suggested that GTE might diminish the risk of midlife deaths in females only.
doi:10.1093/gerona/gls070
PMCID: PMC3598361  PMID: 22451473
Longevity; aging; mice; diet; Interventions
24.  Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators 
Science (New York, N.Y.)  2013;339(6124):1216-1219.
A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu230, located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.
doi:10.1126/science.1231097
PMCID: PMC3799917  PMID: 23471411
25.  A High-Confidence Interaction Map Identifies SIRT1 as a Mediator of Acetylation of USP22 and the SAGA Coactivator Complex 
Molecular and Cellular Biology  2013;33(8):1487-1502.
Although many functions and targets have been attributed to the histone and protein deacetylase SIRT1, a comprehensive analysis of SIRT1 binding proteins yielding a high-confidence interaction map has not been established. Using a comparative statistical analysis of binding partners, we have assembled a high-confidence SIRT1 interactome. Employing this method, we identified the deubiquitinating enzyme ubiquitin-specific protease 22 (USP22), a component of the deubiquitinating module (DUBm) of the SAGA transcriptional coactivating complex, as a SIRT1-interacting partner. We found that this interaction is highly specific, requires the ZnF-UBP domain of USP22, and is disrupted by the inactivating H363Y mutation within SIRT1. Moreover, we show that USP22 is acetylated on multiple lysine residues and that alteration of a single lysine (K129) within the ZnF-UBP domain is sufficient to alter interaction of the DUBm with the core SAGA complex. Furthermore, USP22-mediated recruitment of SIRT1 activity promotes the deacetylation of individual SAGA complex components. Our results indicate an important role of SIRT1-mediated deacetylation in regulating the formation of DUBm subcomplexes within the larger SAGA complex.
doi:10.1128/MCB.00971-12
PMCID: PMC3624249  PMID: 23382074

Results 1-25 (75)