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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.

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 [...]

The Distance Learning Partnership in Gerontology involves eight Georgia state universities in a videoconferencing network for gerontology education. Design features include multilevel administration and a multimethod, multimeasure evaluation plan. Challenges include the diversity of faculty and students and enabling faculty autonomy within a collaborative framework. (SK)

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 vincristineinduced 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 vincristineinduced 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. [ABSTRACT FROM AUTHOR]