Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-Related Hearing Loss under Caloric Restriction

Someya, Shinichi; Yu, Wei; Hallows, William C.; Xu, Jinze; Vann, James M.; Leeuwenburgh, Christiaan; Tanokura, Masaru; Denu, John M.; Prolla, Tomas A.

doi:10.1016/j.cell.2010.10.002

Cited by 995 publications

(975 citation statements)

References 67 publications

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“…For example, NMN may have influenced the activity of additional sirtuins, such as mitochondrial SIRT3, which is associated with decreased oxidative stress and enhanced physiological function (Someya et al ., 2010). It is also possible that NMN enhanced metabolic flux through the tricarboxylic acid cycle and electron transport chain, thus reducing cellular reactive oxygen species (Nakamura et al ., 2012).…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

et al. 2016

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SummaryWe tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD + intermediate, increases arterial SIRT1 activity and reverses age‐associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid artery endothelium‐dependent dilation (EDD) (60 ± 5% vs. 84 ± 2%), a measure of endothelial function, and nitric oxide (NO)‐mediated EDD (37 ± 4% vs. 66 ± 6%), compared with young mice (YC). This age‐associated impairment in EDD was restored in OC by the superoxide (O2−) scavenger TEMPOL (82 ± 7%). OC also had increased aortic pulse wave velocity (aPWV, 464 ± 31 cm s−1 vs. 337 ± 3 cm s−1) and elastic modulus (EM, 6407 ± 876 kPa vs. 3119 ± 471 kPa), measures of large elastic artery stiffness, compared with YC. OC had greater aortic O2− production (2.0 ± 0.1 vs. 1.0 ± 0.1 AU), nitrotyrosine abundance (a marker of oxidative stress), and collagen‐I, and reduced elastin and vascular SIRT1 activity, measured by the acetylation status of the p65 subunit of NFκB, compared with YC. Supplementation with NMN in old mice restored EDD (86 ± 2%) and NO‐mediated EDD (61 ± 5%), reduced aPWV (359 ± 14 cm s−1) and EM (3694 ± 315 kPa), normalized O2− production (0.9 ± 0.1 AU), decreased nitrotyrosine, reversed collagen‐I, increased elastin, and restored vascular SIRT1 activity. Acute NMN incubation in isolated aortas increased NAD + threefold and manganese superoxide dismutase (MnSOD) by 50%. NMN supplementation may represent a novel therapy to restore SIRT1 activity and reverse age‐related arterial dysfunction by decreasing oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

et al. 2016

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“…For example, in response to CR, Sirt3 activated superoxide dismutase 2 (Sod2) (Qiu et al ., 2010). Moreover, Sirt3 activated isocitrate dehydrogenase 2 (Idh2), thereby increasing NADPH levels in mitochondria, leading to suppression of oxidative stress (Someya et al ., 2010). Therefore, Srebp‐1c‐dependent upregulation of Sirt3 protein, as well as enhanced GSH biosynthesis, may be vital for CR‐associated suppression of oxidative stress in WAT.…”

Section: Discussionmentioning

confidence: 99%

Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

et al. 2017

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SummaryCaloric restriction (CR) can delay onset of several age‐related pathophysiologies and extend lifespan in various species, including rodents. CR also induces metabolic remodeling involved in activation of lipid metabolism, enhancement of mitochondrial biogenesis, and reduction of oxidative stress in white adipose tissue (WAT). In studies using genetically modified mice with extended lifespans, WAT characteristics influenced mammalian lifespans. However, molecular mechanisms underlying CR‐associated metabolic remodeling of WAT remain unclear. Sterol regulatory element‐binding protein‐1c (Srebp‐1c), a master transcription factor of fatty acid (FA) biosynthesis, is responsible for the pathogenesis of fatty liver (steatosis). Our study showed that, under CR conditions, Srebp‐1c enhanced mitochondrial biogenesis via increased expression of peroxisome proliferator‐activated receptor gamma coactivator‐1α (Pgc‐1α) and upregulated expression of proteins involved in FA biosynthesis within WAT. However, via Srebp‐1c, most of these CR‐associated metabolic alterations were not observed in other tissues, including the liver. Moreover, our data indicated that Srebp‐1c may be an important factor both for CR‐associated suppression of oxidative stress, through increased synthesis of glutathione in WAT, and for the prolongevity action of CR. Our results strongly suggested that Srebp‐1c, the primary FA biosynthesis‐promoting transcriptional factor implicated in fatty liver disease, is also the food shortage‐responsive factor in WAT. This indicated that Srebp‐1c is a key regulator of metabolic remodeling leading to the beneficial effects of CR.

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“…SIRTs (mammalian homolog of silent mating type information regulation 2 homolog in yeast) are a family of epigenetic mediators that play various functions in aging, chromatin integrity, metabolic regulation, and longevity (Kim et al ., 2007; Hirschey et al ., 2010). Among sirtuins, SIRT1 has been mostly widely studied and its level is changed in AD brains (Shi et al ., 2005; Someya et al ., 2010; Kim et al ., 2011). …”

Section: Introductionmentioning

confidence: 99%

“…It regulates mitochondrial activity by ROS in many cell types and modulates CREB phosphorylation and fat metabolism (Shi et al ., 2005; Hirschey et al ., 2010; Kim et al ., 2010). Importantly, SIRT3 has an essential role in enhancing the mitochondrial antioxidant glutathione, which could contribute to reduce aging in mammals (Someya et al ., 2010). Recently, it is reported that SIRT3 acts as a pro‐survival factor in neurons exposed to NMDA‐induced excitotoxic injury (Kim et al ., 2011).…”

Section: Introductionmentioning

confidence: 99%

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

et al. 2017

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SummaryAlzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD‐dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac‐p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53‐induced mitochondrial dysfunction and neuronal damage in a deacetylase activity‐dependent manner. Notably, mitochondrially targeted p53 (mito‐p53) directly reduced mitochondria DNA‐encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53‐ChIP analysis verified the presence of p53‐binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito‐p53 activity. Our results indicate that SIRT3 dysfunction leads to p53‐mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD.

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Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-Related Hearing Loss under Caloric Restriction

Cited by 995 publications

References 67 publications

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

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