Systemic regulation of mammalian ageing and longevity by brain sirtuins

Satoh, Akira; Imai, Shoichi

doi:10.1038/ncomms5211

Cited by 56 publications

(41 citation statements)

References 146 publications

(178 reference statements)

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“…Of the seven sirtuin family members, three of them, SIRT3, SIRT4, and SIRT5, are known to regulate mitochondrial function (Laurent et al, 2013; Yang et al, 2007; Zhang et al, 2015). Because other sirtuin family members have been shown to play crucial roles in regulating the survival of retinal cells (Jaliffa et al, 2009; Silberman et al, 2014) and because sirtuins depend on NAD + availability for optimal function (Satoh and Imai, 2014), we hypothesized that NAD + deficiency may also impair mitochondrial sirtuin activity, contributing to mitochondrial dysfunction.…”

Section: Resultsmentioning

confidence: 99%

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

et al. 2016

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SUMMARY Photoreceptor death is the endpoint of many blinding diseases. Identifying unifying pathogenic mechanisms in these diseases may offer global approaches for facilitating photoreceptor survival. We found that rod or cone photoreceptor-specific deletion of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the major NAD+ biosynthetic pathway beginning with nicotinamide, caused retinal degeneration. In both cases, we could rescue vision with nicotinamide mononucleotide (NMN). Significantly, retinal NAD+ deficiency was an early feature of multiple mouse models of retinal dysfunction, including light-induced degeneration, streptozotocin-induced diabetic retinopathy, and age-associated dysfunction. Mechanistically, NAD+ deficiency caused metabolic dysfunction and consequent photoreceptor death. We further demonstrate that the NAD+-dependent mitochondrial deacylases SIRT3/SIRT5 play important roles in retinal homeostasis and that NAD+ deficiency causes SIRT3 dysfunction. These findings demonstrate that NAD+ biosynthesis is essential for vision, provide a foundation for future work to further clarify the mechanisms involved, and identify a unifying therapeutic target for diverse blinding diseases.

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Section: Resultsmentioning

confidence: 99%

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

et al. 2016

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“…In the hypothalamus, SIRT1 regulates Ox2r expression, and this SIRT1-mediated signaling in the hypothalamus is critical to regulate physical activity of mice during the dark time and in response to fasting (Satoh et al, 2010; Satoh et al, 2013; Satoh and Imai, 2014). Given that levels of NAD + and Ox2r expression were significantly reduced in female ANKO hypothalami, we examined their physical activity during the dark time.…”

Section: Resultsmentioning

confidence: 99%

SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice

et al. 2015

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SUMMARY Nicotinamide phosphoribosyltransferase (NAMPT), the key NAD+ biosynthetic enzyme, has two different forms, intra- and extracellular (iNAMPT and eNAMPT), in mammals. However, the significance of eNAMPT secretion remains unclear. Here we demonstrate that deacetylation of iNAMPT by the mammalian NAD+-dependent deacetylase SIRT1 predisposes the protein to secretion in adipocytes. NAMPT mutants reveal that SIRT1 deacetylates lysine 53 and enhances eNAMPT activity and secretion. Adipose tissue-specific Nampt knockout and knockin (ANKO and ANKI) mice show reciprocal changes in circulating eNAMPT, affecting hypothalamic NAD+/SIRT1 signaling and physical activity accordingly. The defect in physical activity observed in ANKO mice is ameliorated by nicotinamide mononucleotide (NMN). Furthermore, administration of a NAMPT-neutralizing antibody decreases hypothalamic NAD+ production, and treating ex vivo hypothalamic explants with purified eNAMPT enhances NAD+, SIRT1 activity, and neural activation. Thus, our findings indicate a critical role of adipose tissue as a modulator for the regulation of NAD+ biosynthesis at a systemic level.

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“…In line with this, SIRT1 plays important roles in many aging-related biological processes such as growth regulation, energy metabolism, stress response, and endocrine signaling7. Evidence derived from in vivo studies further confirmed that SIRT1 mediates effects of CR in mice, including lifespan extension58910111213. In addition, SIRT1 protein levels are increased in response to CR, and genetic ablation of SIRT1 prevents many health benefits of a CR diet1415161718.…”

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confidence: 83%

Resveratrol serves as a protein-substrate interaction stabilizer in human SIRT1 activation

Hou

Rooklin

Fang

et al. 2016

Sci Rep

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Resveratrol is a natural compound found in red wine that has been suggested to exert its potential health benefit through the activation of SIRT1, a crucial member of the mammalian NAD+-dependent deacetylases. SIRT1 has emerged as an attractive therapeutic target for many aging related diseases, however, how its activity can only be activated toward some specific substrates by resveratrol has been poorly understood. Herein, by employing extensive molecular dynamics simulations as well as fragment-centric topographical mapping of binding interfaces, we have clarified current controversies in the literature and elucidated that resveratrol plays an important activation role by stabilizing SIRT1/peptide interactions in a substrate-specific manner. This new mechanism highlights the importance of the N-terminal domain in substrate recognition, explains the activity restoration role of resveratrol toward some “loose-binding” substrates of SIRT1, and has significant implications for the rational design of new substrate-specific SIRT1 modulators.

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Systemic regulation of mammalian ageing and longevity by brain sirtuins

Cited by 56 publications

References 146 publications

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice

Resveratrol serves as a protein-substrate interaction stabilizer in human SIRT1 activation

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