Sirt1 Extends Life Span and Delays Aging in Mice through the Regulation of Nk2 Homeobox 1 in the DMH and LH

Satoh, Akira; Brace, Cynthia S.; Rensing, Nick; Cliften, Paul; Wozniak, David F.; Herzog, Erik D.; Yamada, Kelvin A.; Imai, Shin‐ichiro

doi:10.1016/j.cmet.2013.07.013

Cited by 630 publications

(538 citation statements)

References 31 publications

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“…DMH and lateral hypothalamus (LH) neurons are responsible for phenotypes observed in aged BRASTO mice (Satoh et al., 2013). In particular, Sirt1 in the DMH plays a critical role in maintaining physical activity.…”

Section: Resultsmentioning

confidence: 99%

“…NMJ analyses were thus performed 3 weeks after stereotactic injections of shRNA‐ Sirt1 or shRNA‐Ctr into the DMH of 3‐month‐old WT mice. The efficiency of the lentiviral knockdown was noted to be a 65% reduction in mRNA (data not shown) and similar to previous reports (Satoh et al., 2013). DMH‐specific Sirt1 knockdown accelerated age‐associated NMJ morphologic changes compared to age‐matched controls (Figures 5 and 6).…”

Section: Resultsmentioning

confidence: 99%

“…Stereotactic injection of Sirt1 ‐expressing lentiviruses into the dorsomedial hypothalamus (DMH) of aged adult wild‐type (WT) mice ameliorates age‐associated declines in physical activity and body temperature, supporting the notion that the hypothalamus, specifically the DMH, is one of the control centers for mammalian aging and longevity (Satoh et al., 2010, 2013). Mice with brain‐specific overexpression of Sirt1 (BRASTO) show a significant delay in aging with extended lifespans in both males and females (Satoh et al., 2013). Specifically, skeletal muscle in BRASTO mice maintains youthful morphology and mitochondrial function during the aging process due to enhanced sympathetic nervous tone during the dark period.…”

Section: Introductionmentioning

confidence: 99%

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Hypothalamic Sirt1 protects terminal Schwann cells and neuromuscular junctions from age‐related morphological changes

et al. 2018

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SummaryNeuromuscular decline occurs with aging. The neuromuscular junction (NMJ), the interface between motor nerve and muscle, also undergoes age‐related changes. Aging effects on the NMJ components—motor nerve terminal, acetylcholine receptors (AChRs), and nonmyelinating terminal Schwann cells (tSCs)—have not been comprehensively evaluated. Sirtuins delay mammalian aging and increase longevity. Increased hypothalamic Sirt1 expression results in more youthful physiology, but the relationship between NMJ morphology and hypothalamic Sirt1 was previously unknown. In wild‐type mice, all NMJ components showed age‐associated morphological changes with ~80% of NMJs displaying abnormalities by 17 months of age. Aged mice with brain‐specific Sirt1 overexpression (BRASTO) had more youthful NMJ morphologic features compared to controls with increased tSC numbers, increased NMJ innervation, and increased numbers of normal AChRs. Sympathetic NMJ innervation was increased in BRASTO mice. In contrast, hypothalamic‐specific Sirt1 knockdown led to tSC abnormalities, decreased tSC numbers, and more denervated endplates compared to controls. Our data suggest that hypothalamic Sirt1 functions to protect NMJs in skeletal muscle from age‐related changes via sympathetic innervation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hypothalamic Sirt1 protects terminal Schwann cells and neuromuscular junctions from age‐related morphological changes

et al. 2018

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“…Silent information regulator T1 (SIRT1) plays an important role in the regulation of aging and longevity in mammals (Alcendor et al., 2007; Satoh et al., 2013; Wang, Chen, Lv & Liu, 2013). There exist cross‐talks between SIRT1‐ and AMP‐activated protein kinase (AMPK)/eNOS, which are involved in the control of the senescence program (Wang, Liang & Vanhoutte, 2011).…”

Section: Resultsmentioning

confidence: 99%

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Chen

Sun

2018

Aging Cell

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Summary DNA methylation increases with age. The objective of this study was to investigate whether compound H, a potential activator of DNA demethylases, attenuates aging‐related arterial stiffness and hypertension. Aged mice (24–27 months) and adult mice (12 months) were used. Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) were increased significantly in aged mice. Notably, daily treatments with compound H (15 mg/kg, IP) for 2 weeks significantly attenuated the aging‐related increases in PWV and BP. Compound H abolished aging‐associated downregulation of secreted Klotho (SKL) levels in both kidneys and serum likely by enhancing DNA demethylase activity and decreasing DNA methylation. Aging‐related arterial stiffness was associated with accumulation of stiffer collagen and degradation of compliant elastin which are accompanied by increased expression of MMP2, MMP9, TGF‐β1, and TGF‐β3. These changes were effectively attenuated by compound H, suggesting rejuvenation of aged arteries. Compound H also rescued downregulation of Sirt1 deacetylase, AMPKα, and eNOS activities in aortas of aged mice. In cultured smooth muscle cells (SMCc) Klotho‐deficient serum upregulated expression of MMPs and TGFβ which, however, was not affected by compound H. In conclusion, compound H attenuates aging‐associated arterial stiffness and hypertension by activation of DNA demethylase which increases renal SKL expression and consequently circulating SKL levels leading to activation of the Sirt1‐AMPK‐eNOS pathway in aortas of aged mice.

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“…Most prior studies have found that increased SIRT1 is involved in healthful aging (Herranz et al., 2010; Sasaki et al., 2014; Satoh et al., 2013), whereas the results for SIRT3 are more controversial (Bellizzi et al., 2005; De Rango et al., 2008; Lescai et al., 2009; McDonnell, Peterson, Bomze & Hirschey, 2015; Rose et al., 2003). However, decreases in SIRT1 have been associated with cancer protection, which also is involved in healthful aging (Chen et al., 2014; Ohanna et al., 2014).…”

Section: Discussionmentioning

confidence: 99%

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

et al. 2018

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SummaryDisruption of the regulator for G protein signaling 14 (RGS14) knockout (KO) in mice extends their lifespan and has multiple beneficial effects related to healthful aging, that is, protection from obesity, as reflected by reduced white adipose tissue, protection against cold exposure, and improved metabolism. The observed beneficial effects were mediated by improved mitochondrial function. But most importantly, the main mechanism responsible for the salutary properties of the RGS14 KO involved an increase in brown adipose tissue (BAT), which was confirmed by surgical BAT removal and transplantation to wild‐type (WT) mice, a surgical simulation of a molecular knockout. This technique reversed the phenotype of the RGS14 KO and WT, resulting in loss of the improved metabolism and protection against cold exposure in RGS14 KO and conferring this protection to the WT BAT recipients. Another mechanism mediating the salutary features in the RGS14 KO was increased SIRT3. This mechanism was confirmed in the RGS14 X SIRT3 double KO, which no longer demonstrated improved metabolism and protection against cold exposure. Loss of function of the Caenorhabditis elegans RGS‐14 homolog confirmed the evolutionary conservation of this mechanism. Thus, disruption of RGS14 is a model of healthful aging, as it not only enhances lifespan, but also protects against obesity and cold exposure and improves metabolism with a key mechanism of increased BAT, which, when removed, eliminates the features of healthful aging.

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Sirt1 Extends Life Span and Delays Aging in Mice through the Regulation of Nk2 Homeobox 1 in the DMH and LH

Cited by 630 publications

References 31 publications

Hypothalamic Sirt1 protects terminal Schwann cells and neuromuscular junctions from age‐related morphological changes

Hypothalamic Sirt1 protects terminal Schwann cells and neuromuscular junctions from age‐related morphological changes

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

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