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Impaired autophagy is known to cause mitochondrial dysfunction and heart failure, in part due to altered mitophagy and protein quality control. However, whether additional mechanisms are involved in the development of mitochondrial dysfunction and heart failure in the setting of deficient autophagic flux remains poorly explored. Here, we show that impaired autophagic flux reduces nicotinamide adenine dinucleotide (NAD+) availability in cardiomyocytes. NAD+ deficiency upon autophagic impairment is attributable to the induction of nicotinamide N-methyltransferase (NNMT), which methylates the NAD+ precursor nicotinamide (NAM) to generate N-methyl-nicotinamide (MeNAM). The administration of nicotinamide mononucleotide (NMN) or inhibition of NNMT activity in autophagy-deficient hearts and cardiomyocytes restores NAD+ levels and ameliorates cardiac and mitochondrial dysfunction. Mechanistically, autophagic inhibition causes the accumulation of SQSTM1, which activates NF-κB signaling and promotes NNMT transcription. In summary, we describe a novel mechanism illustrating how autophagic flux maintains mitochondrial and cardiac function by mediating SQSTM1-NF-κB-NNMT signaling and controlling the cellular levels of NAD+. Synopsis: How autophagy safeguards cardiac structure and function to prevent heart failure remains unclear. This genetic work links a novel connection between deficient autophagic flux in cardiomyocytes to reduced availability of the cellular metabolite NAD+, suggesting novel tractable avenues for intervention. Depletion of autophagy-related protein 3 (ATG3) in cardiomyocytes causes cardiac dysfunction and early mortality in mice. ATG3 depletion reduces mitochondrial metabolism and biogenesis, preceding age-dependent cardiac dysfunction. Reduced autophagy leads to accumulation of SQSTM1, activation of NF-κB subunit RELA, and increased transcription of the NAD+ metabolic enzyme NNMT. Increased NNMT catalyzes the competing conversion of NAD+ precursor NAM to MeNAM, leading to NAD+ deficiency. Autophagy induction prevents NNMT induction and NNMT inhibition or NMN supplementation restore cardiac and mitochondrial dysfunction when autophagy is defective. Deficient autophagy reduces NAD+ availability in cardiomyocytes via a SQSTM1-NF-κB-NNMT axis, contributing to mitochondrial dysfunction and heart failure. [ABSTRACT FROM AUTHOR]

BACKGROUND. Fasting and [NAD.sup.+]-boosting compounds, including [NAD.sup.+] precursor nicotinamide riboside (NR), confer antiinflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined. METHODS. We explored the underlying biology in myeloid cells from healthy volunteers following in vivo placebo or NR administration and subsequently tested the findings in vitro in monocytes extracted from patients with systemic lupus erythematosus (SLE). RESULTS. RNA-Seq of unstimulated and LPS-activated monocytes implicated NR in the regulation of autophagy and type I IFN signaling. In primary monocytes, NR blunted LPS-induced IFN-[beta] production, and genetic or pharmacological disruption of autophagy phenocopied this effect. Given that [NAD.sup.+] is a coenzyme in oxidoreductive reactions, metabolomics was performed and identified that NR increased the inosine level. Inosine supplementation similarly blunted autophagy and IFN-[beta] release. Finally, because SLE exhibits type I IFN dysregulation, we assessed the NR effect on monocytes from patients with SLE and found that NR reduced autophagy and IFN-[beta] release. CONCLUSION. We conclude that NR, in an [NAD.sup.+]-dependent manner and in part via inosine signaling, mediated suppression of autophagy and attenuated type I IFN in myeloid cells, and we identified NR as a potential adjunct for SLE management. TRIAL REGISTRATION. ClinicalTrials.gov registration numbers NCT02812238, NCT00001846, and NCT00001372. FUNDING. This work was supported by the NHLBI and NIAMS Intramural Research divisions., Introduction Caloric restriction, intermittent fasting, time-restricted feeding, and fasting mimetic diets confer immunomodulatory effects, including amelioration of inflammatory diseases (1-6) and blunting of the NLRP3 inflammasome, circulating cytokines, and acute-phase [...]

Alzheimer's Disease (AD) is an aging-associated neurodegenerative disorder, threatening millions of people worldwide. The onset and progression of AD can be accelerated by environmental risk factors, such as bacterial and viral infections. Human herpesviruses are ubiquitous infectious agents that underpin numerous inflammatory disorders including neurodegenerative diseases. Published studies concerning human herpesviruses in AD imply an active role HSV-1 in the pathogenesis of AD. This review will summarize the current understanding of HSV-1 infection in AD and highlight some barriers to advance this emerging field. [ABSTRACT FROM AUTHOR]

Approximately two million students matriculate into American colleges and universities per year. Almost 20% of these students begin taking a series of courses specified by advisers of health preprofessionals. The single most important influence on health profession advisers and on course selection for this huge population of learners is the Medical College Admissions Test (MCAT), which was last revised in 1991, 10 years before publication of the first draft human genome sequence. In preparation for the 2015 MCAT, there is a broad discussion among stakeholders of how best to revise undergraduate and medical education in the molecular sciences to prepare researchers and doctors to acquire, analyze and use individual genomic and metabolomic data in the coming decades. Getting these changes right is among the most important educational problems of our era.

Introduction: Cancer inequity is one of the most critical public health issues faced by ethnic minorities and people of lower socioeconomic status. The disparate burden of cancer is caused by poor access to care and inadequate delivery of cancer treatment, as well as comorbid and co-occurring conditions. Diabetes is a common and serious comorbid condition of cancer. Methods: To better understand diabetes prevalence among diverse cancer patients, this study analyzed and described characteristics of cancer patients with diabetes from local-level Service Planning Area (SPA) data using City of Hope Comprehensive Cancer Center data, and United States national-level data from The National Health Interview Survey. Results: Findings from national level data showed that patients in racial/ethnic minority groups had a higher occurrence of being diagnosed with diabetes, especially for non-Hispanic Blacks (OR=1.76, 95% CI=1.51, 2.03) and Hispanic/ Latino individuals (OR=1.34, 95% CI=1.18, 1.52). Cancer patients who are older, ethnic minority, overweight/obese and with lower educational levels were more likely to have co-occurring diabetes. SPA-level patient data found similar results. Discussion: In response to our findings and other reports, clinicians and health system including health coverage organizations should routinely assess cancer patients for cooccurring chronic illnesses, in particular diabetes. Interventions improving coordinated care that integrates oncology, endocrinology and primary care, targeting cancer patients -especially racial/ethnic minorities, overweight/obese, and older patients who are at increased risk for diabetes - ought to be considered as best practice Whole Person care. With coordinated care management, ethnic disparities in cancer may be better addressed and reduced. Additionally, policymakers can contribute by enacting policies improving access to and coverage of integrated oncology, chronic disease prevention, and associated specialty care i.e., endocrinology to equalize quality care for ethnic minority, lower educated, overweight/obese and older cancer patients who are more likely to suffer greater comorbidity, and inadequate oncology and coordinated care to reduce disparities. [ABSTRACT FROM AUTHOR]

Background: Mice with deletion of complex I subunit Ndufs4 develop mitochondrial encephalomyopathy resembling Leigh syndrome (LS). The metabolic derangement and underlying mechanisms of cardio‐encephalomyopathy in LS remains incompletely understood. Methods: We performed echocardiography, electrophysiology, confocal microscopy, metabolic and molecular/morphometric analysis of the mice lacking Ndufs4. HEK293 cells, human iPS cells‐derived cardiomyocytes and neurons were used to determine the mechanistic role of mitochondrial complex I deficiency. Results: LS mice develop severe cardiac bradyarrhythmia and diastolic dysfunction. Human‐induced pluripotent stem cell‐derived cardiomyocytes (iPS‐CMs) with Ndufs4 deletion recapitulate LS cardiomyopathy. Mechanistically, we demonstrate a direct link between complex I deficiency, decreased intracellular (nicotinamide adenine dinucleotide) NAD+/NADH and bradyarrhythmia, mediated by hyperacetylation of the cardiac sodium channel NaV1.5, particularly at K1479 site. Neuronal apoptosis in the cerebellar and midbrain regions in LS mice was associated with hyperacetylation of p53 and activation of microglia. Targeted metabolomics revealed increases in several amino acids and citric acid cycle intermediates, likely due to impairment of NAD+‐dependent dehydrogenases, and a substantial decrease in reduced Glutathione (GSH). Metabolic rescue by nicotinamide riboside (NR) supplementation increased intracellular NAD+/ NADH, restored metabolic derangement, reversed protein hyperacetylation through NAD+‐dependent Sirtuin deacetylase, and ameliorated cardiomyopathic phenotypes, concomitant with improvement of NaV1.5 current and SERCA2a function measured by Ca2+‐transients. NR also attenuated neuronal apoptosis and microglial activation in the LS brain and human iPS‐derived neurons with Ndufs4 deletion. Conclusions: Our study reveals direct mechanistic explanations of the observed cardiac bradyarrhythmia, diastolic dysfunction and neuronal apoptosis in mouse and human induced pluripotent stem cells (iPSC) models of LS. [ABSTRACT FROM AUTHOR]

We analyzed mitochondrial DNA (mtDNA), Y-chromosome single nucleotide polymorphisms (Y-SNP), and autosomal short tandem repeats (STR) of three skeletons found in a 2,000-year-old Xiongnu elite cemetery in Duurlig Nars of Northeast Mongolia. This study is one of the first reports of the detailed genetic analysis of ancient human remains using the three types of genetic markers. The DNA analyses revealed that one subject was an ancient male skeleton with maternal U2e1 and paternal R1a1 haplogroups. This is the first genetic evidence that a male of distinctive Indo-European lineages (R1a1) was present in the Xiongnu of Mongolia. This might indicate an Indo European migration into Northeast Asia 2,000 years ago. Other specimens are a female with mtDNA haplogroup D4 and a male with Y-SNP haplogroup C3 and mtDNA haplogroup D4. Those haplogroups are common in Northeast Asia. There was no close kinship among them. The genetic evidence of U2el and R1a1 may help to clarify the migration patterns of Indo-Europeans and ancient East-West contacts of the Xiongnu Empire. Artifacts in the tombs suggested that the Xiongnu had a system of the social stratification. The West Eurasian male might show the racial tolerance of the Xiongnu Empire and some insight into the Xiongnu society. Am J Phys Anthropol 142:429-440, 2010. [c]2010 Wiley-Liss, Inc. KEY WORDS Xiongnu; R1a1; Indo-European migration; Northeast Asia; ancient DNA DOI 10.1002/ajpa.21242

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2007.03.024 Byline: Peter Belenky (1), Frances G. Racette (2), Katrina L. Bogan (1), Julie M. McClure (2), Jeffrey S. Smith (2), Charles Brenner (1) Abstract: Although NAD.sup.+ biosynthesis is required for Sir2 functions and replicative lifespan in yeast, alterations in NAD.sup.+ precursors have been reported to accelerate aging but not to extend lifespan. In eukaryotes, nicotinamide riboside is a newly discovered NAD.sup.+ precursor that is converted to nicotinamide mononucleotide by specific nicotinamide riboside kinases, Nrk1 and Nrk2. In this study, we discovered that exogenous nicotinamide riboside promotes Sir2-dependent repression of recombination, improves gene silencing, and extends lifespan without calorie restriction. The mechanism of action of nicotinamide riboside is totally dependent on increased net NAD.sup.+ synthesis through two pathways, the Nrk1 pathway and the Urh1/Pnp1/Meu1 pathway, which is Nrk1 independent. Additionally, the two nicotinamide riboside salvage pathways contribute to NAD.sup.+ metabolism in the absence of nicotinamide-riboside supplementation. Thus, like calorie restriction in the mouse, nicotinamide riboside elevates NAD.sup.+ and increases Sir2 function. Author Affiliation: (1) Departments of Genetics and Biochemistry and the Norris Cotton Cancer Center, Dartmouth Medical School, Rubin 733-HB7937, Lebanon, NH 03756, USA (2) Department of Biochemistry and Molecular Genetics, University of Virginia Health System, Charlottesville, VA 22908, USA Article History: Received 11 December 2006; Revised 7 February 2007; Accepted 16 March 2007 Article Note: (miscellaneous) Published: May 3, 2007

Nicotinamide adenine dinucleotide ([NAD.sup.+]) is both a coenzyme for hydride-transfer enzymes and a substrate for [NAD.sup.+]-consuming enzymes, which include ADP-ribose transferases, poly(ADP-ribose) polymerases, cADP-ribose synthases and sirtuins. Recent results establish protective roles for [NAD.sup.+] that might be applicable therapeutically to prevent neurodegenerative conditions and to fight Candida glabrata infection. In addition, the contribution that [NAD.sup.+] metabolism makes to lifespan extension in model systems indicates that therapies to boost [NAD.sup.+] might promote some of the beneficial effects of calorie restriction. Nicotinamide riboside, the recently discovered nucleoside precursor of [NAD.sup.+] in eukaryotic systems, might have advantages as a therapy to elevate [NAD.sup.+] without inhibiting sirtuins, which is associated with high-dose nicotinamide, or incurring the unpleasant side-effects of high-dose nicotinic acid.