The process of aging and circadian rhythms are intimately intertwined, but how peripheral clocks involved in metabolic homeostasis contribute to aging remains unknown. Importantly, caloric ...restriction (CR) extends lifespan in several organisms and rewires circadian metabolism. Using young versus old mice, fed ad libitum or under CR, we reveal reprogramming of the circadian transcriptome in the liver. These age-dependent changes occur in a highly tissue-specific manner, as demonstrated by comparing circadian gene expression in the liver versus epidermal and skeletal muscle stem cells. Moreover, de novo oscillating genes under CR show an enrichment in SIRT1 targets in the liver. This is accompanied by distinct circadian hepatic signatures in NAD+-related metabolites and cyclic global protein acetylation. Strikingly, this oscillation in acetylation is absent in old mice while CR robustly rescues global protein acetylation. Our findings indicate that the clock operates at the crossroad between protein acetylation, liver metabolism, and aging.
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•Aging reprograms clockwork with distinct modalities in the liver versus stem cells•Liver circadian genomic signatures of aging are reverted by caloric restriction (CR)•Cyclic protein acetylation is lost in old mice while CR results in hyperacetylation•CR reorganizes circadian metabolic pathway linked to NAD+-SIRT1-AceCS1 in the liver
Aging reprograms the circadian transcriptome in a highly tissue-specific manner
Nicotinamide riboside (NR) is in wide use as an NAD
precursor vitamin. Here we determine the time and dose-dependent effects of NR on blood NAD
metabolism in humans. We report that human blood NAD
...can rise as much as 2.7-fold with a single oral dose of NR in a pilot study of one individual, and that oral NR elevates mouse hepatic NAD
with distinct and superior pharmacokinetics to those of nicotinic acid and nicotinamide. We further show that single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD
metabolome in the first clinical trial of NR pharmacokinetics in humans. We also report that nicotinic acid adenine dinucleotide (NAAD), which was not thought to be en route for the conversion of NR to NAD
, is formed from NR and discover that the rise in NAAD is a highly sensitive biomarker of effective NAD
repletion.
Animal studies suggest a positive role for nicotinamide riboside (NR) on insulin sensitivity and hepatic steatosis in models of obesity and type 2 diabetes. NR, an NAD+ precursor, is a member of the ...vitamin B-3 family now available as an over-the-counter supplement. Although data from preclinical trials appear consistent, potential effects and safety need to be evaluated in human clinical trials.
The aim of this study was to test the safety of dietary NR supplementation over a 12-wk period and potential to improve insulin sensitivity and other metabolic parameters in obese, insulin-resistant men.
In an investigator-initiated randomized, placebo-controlled, double-blinded, and parallel-group designed clinical trial, forty healthy, sedentary men with a body mass index (BMI) > 30 kg/m2, age-range 40–70 y were randomly assigned to 12 wk of NR (1000 mg twice daily) or placebo. We determined the effects of NR supplementation on insulin sensitivity by a hyperinsulinemic euglycemic clamp and substrate metabolism by indirect calorimetry and labeled substrates of tritiated glucose and palmitate. Body composition and fat mass distribution were determined by whole-body dual-energy X-ray absorptiometry (DXA) and MRI scans, and measurements of intrahepatic lipid content were obtained by MR spectroscopy.
Insulin sensitivity, endogenous glucose production, and glucose disposal and oxidation were not improved by NR supplementation. Similarly, NR supplementation had no effect on resting energy expenditure, lipolysis, oxidation of lipids, or body composition. No serious adverse events due to NR supplementation were observed and safety blood tests were normal.
12 wk of NR supplementation in doses of 2000 mg/d appears safe, but does not improve insulin sensitivity and whole-body glucose metabolism in obese, insulin-resistant men. This trial was registered at clinicaltrials.gov as NCT02303483.
Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known ...poly(ADP-ribosylating) (PARylating) PARPs primarily function in the DNA damage response, many noncanonical mono(ADP-ribosylating) (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust up-regulation of several PARPs following infection with murine hepatitis virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly up-regulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while down-regulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+ and NADP+. Finally, we show that NAMPT activation, NAM, and NR dramatically decrease the replication of an MHV that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses.
AbstractObjectiveTo understand the epidemiology and burden of severe coronavirus disease 2019 (covid-19) during the first epidemic wave on the west coast of the United States.DesignProspective cohort ...study.SettingKaiser Permanente integrated healthcare delivery systems serving populations in northern California, southern California, and Washington state.Participants1840 people with a first acute hospital admission for confirmed covid-19 by 22 April 2020, among 9 596 321 healthcare plan enrollees. Analyses of hospital length of stay and clinical outcomes included 1328 people admitted by 9 April 2020 (534 in northern California, 711 in southern California, and 83 in Washington).Main outcome measuresCumulative incidence of first acute hospital admission for confirmed covid-19, and subsequent probabilities of admission to an intensive care unit (ICU) and mortality, as well as duration of hospital stay and ICU stay. The effective reproduction number (RE) describing transmission dynamics was estimated for each region.ResultsAs of 22 April 2020, cumulative incidences of a first acute hospital admission for covid-19 were 15.6 per 100 000 cohort members in northern California, 23.3 per 100 000 in southern California, and 14.7 per 100 000 in Washington. Accounting for censoring of incomplete hospital stays among those admitted by 9 April 2020, the estimated median duration of stay among survivors was 9.3 days (with 95% staying 0.8 to 32.9 days) and among non-survivors was 12.7 days (1.6 to 37.7 days). The censoring adjusted probability of ICU admission for male patients was 48.5% (95% confidence interval 41.8% to 56.3%) and for female patients was 32.0% (26.6% to 38.4%). For patients requiring critical care, the median duration of ICU stay was 10.6 days (with 95% staying 1.3 to 30.8 days). The censoring adjusted case fatality ratio was 23.5% (95% confidence interval 19.6% to 28.2%) among male inpatients and 14.9% (11.8% to 18.6%) among female inpatients; mortality risk increased with age for both male and female patients. Reductions in RE were identified over the study period within each region.ConclusionsAmong residents of California and Washington state enrolled in Kaiser Permanente healthcare plans who were admitted to hospital with covid-19, the probabilities of ICU admission, of long hospital stay, and of mortality were identified to be high. Incidence rates of new hospital admissions have stabilized or declined in conjunction with implementation of social distancing interventions.
Disrupted sleep-wake and molecular circadian rhythms are a feature of aging associated with metabolic disease and reduced levels of NAD+, yet whether changes in nucleotide metabolism control ...circadian behavioral and genomic rhythms remains unknown. Here, we reveal that supplementation with the NAD+ precursor nicotinamide riboside (NR) markedly reprograms metabolic and stress-response pathways that decline with aging through inhibition of the clock repressor PER2. NR enhances BMAL1 chromatin binding genome-wide through PER2K680 deacetylation, which in turn primes PER2 phosphorylation within a domain that controls nuclear transport and stability and that is mutated in human advanced sleep phase syndrome. In old mice, dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity are restored by NAD+ repletion to youthful levels with NR. These results reveal effects of NAD+ on metabolism and the circadian system with aging through the spatiotemporal control of the molecular clock.
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•NAD+ induces transcription of stress and metabolic genes through the circadian clock•BMAL1 is required for chromatin remodeling and HSF1 recruitment in response to NAD+•NAD+ regulates PER2 acetylation and localization to control feedback repression•NAD+ counters age-related decline in circadian function
Aging is associated with disrupted circadian rhythms through signals that remain unidentified. Levine et al. show that NAD+ controls global circadian transcription through post-translational modification of PER2 and feedback repression. Raising NAD+ restores youthful transcription and mitochondrial rhythms in old age, revealing that NAD+ governs both behavior and metabolic health.
Nicotinamide adenine dinucleotide (NAD+) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide ...riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR.
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•NR supplementation in aged subjects augments the skeletal muscle NAD+ metabolome•NR supplementation does not affect skeletal muscle mitochondrial bioenergetics•NR supplementation reduces levels of circulating inflammatory cytokines
Elhassan et al. show that oral nicotinamide riboside increases the NAD+ metabolome in aged human skeletal muscle, without apparently altering mitochondrial bioenergetics. Measures of muscle and whole-body metabolism are also unchanged. Nicotinamide riboside reduces the levels of circulating inflammatory cytokines. Studies in relevant human disease models are warranted.
Axon degeneration, a hallmark of chemotherapy-induced peripheral neuropathy (CIPN), is thought to be caused by a loss of the essential metabolite nicotinamide adenine dinucleotide (NAD⁺) via the ...prodegenerative protein SARM1. Some studies challenge this notion, however, and suggest that an aberrant increase in a direct precursor of NAD⁺, nicotinamide mononucleotide (NMN), rather than loss of NAD⁺, is responsible. In support of this idea, blocking NMN accumulation in neurons by expressing a bacterial NMN deamidase protected axons from degeneration. We hypothesized that protection could similarly be achieved by reducing NMN production pharmacologically. To achieve this, we took advantage of an alternative pathway for NAD⁺ generation that goes through the intermediate nicotinic acid mononucleotide (NAMN), rather than NMN. We discovered that nicotinic acid riboside (NAR), a precursor of NAMN, administered in combination with FK866, an inhibitor of the enzyme nicotinamide phosphoribosyltransferase that produces NMN, protected dorsal root ganglion (DRG) axons against vincristine-induced degeneration as well as NMN deamidase. Introducing a different bacterial enzyme that converts NAMN to NMN reversed this protection. Collectively, our data indicate that maintaining NAD⁺ is not sufficient to protect DRG neurons from vincristine-induced axon degeneration, and elevating NMN, by itself, is not sufficient to cause degeneration. Nonetheless, the combination of FK866 and NAR, which bypasses NMN formation, may provide a therapeutic strategy for neuroprotection.
Cost information is critical to ease managers' decisions in daily business, but its provision is informationally demanding and error prone. Effective design choices for costing systems that can ...reduce errors are the subject of a growing body of research. The computational model by Anand, Balakrishnan, and Labro (2019) collates previous research in a unifying framework, turning it into a potential standard for future studies. This paper uses this framework and aims to investigate the mechanism behind the well-documented empirical pattern of product cost cross-subsidization in a large-scale simulation experiment. According to this pattern, volume-based costing systems bias the costs of high-volume products upward and of low-volume products downward. Although this pattern has important implications for firms and is discussed extensively in the literature, it has not yet been investigated with computational models. As the first objective of this paper, we replicate the original model by following a pattern-oriented model replication approach. The second objective is to study the mechanism behind the pattern of product cost cross-subsidization. We are unable to reproduce it systematically with the original model. However, the pattern emerges when we extend the model to include a simple cost hierarchy with distinct resource consumption types and volume-based cost drivers. This allows us to specify the likely mechanism behind it. Building on these results, we further extend the model with empirical and theory-based ABC cost hierarchies and assess their effect on product cost cross-subsidization. Our results suggest that production environments underpin more diverse cost hierarchies in practice than previously implemented in the model. Overall, we argue that our extension provides relevant insights into the pattern of product cost cross-subsidization, while our replication and extension strengthen the models' credibility and usability for future research.
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