SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

Yao, Hongwei; Chung, Sangwoon; Hwang, Jae-Woong; Saravanan, R.; Sundar, Isaac K.; Dean, David A.; McBurney, Michael W.; Guarente, Leonard; Gu, Wei; Rönty, Mikko; Kinnula, Vuokko L.; Rahman, Irfan

doi:10.1172/jci60132

Cited by 310 publications

(377 citation statements)

References 92 publications

(145 reference statements)

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“…In cultured primary cortical cultures, overexpression of SIRT1 in microglia protected against A␤ toxicity, most likely by inhibiting NF-B signaling . SIRT1 could also protect against cellular senescence by inactivating NF-B (Rovillain et al, 2011;Tilstra et al, 2012) or deacetylating the FOXO3 transcription factor (Yao et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

SIRT1 Deficiency in Microglia Contributes to Cognitive Decline in Aging and Neurodegeneration via Epigenetic Regulation of IL-1β

et al. 2015

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Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as the brain ages is an aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we report a mechanistic link between chronic inflammation and aging microglia and a causal role of aging microglia in neurodegenerative cognitive deficits. We showed that SIRT1 is reduced with the aging of microglia and that microglial SIRT1 deficiency has a causative role in aging-or tau-mediated memory deficits via IL-1␤ upregulation in mice. Interestingly, the selective activation of IL-1␤ transcription by SIRT1 deficiency is likely mediated through hypomethylating the specific CpG sites on IL-1␤ proximal promoter. In humans, hypomethylation of IL-1␤ is strongly associated with chronological age and with elevated IL-1␤ transcription. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in aging and neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 99%

SIRT1 Deficiency in Microglia Contributes to Cognitive Decline in Aging and Neurodegeneration via Epigenetic Regulation of IL-1β

et al. 2015

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“…Pulmonary emphysema may result from accelerated and premature aging of the lungs because of cellular senescence (19), consistent with the observation that most COPD patients develop disease at advanced ages. Deficiency of cellular guardian genes, such as SIRT1 (sirtuin 1) (20) and TLR4 (Toll receptor 4) (21), leads to spontaneous pulmonary emphysema in murine models because of increased oxidative stress and accelerated aging.…”

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confidence: 99%

Hhip haploinsufficiency sensitizes mice to age-related emphysema

Lao

Jiang

Yun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Genetic variants in Hedgehog interacting protein (HHIP) have consistently been associated with the susceptibility to develop chronic obstructive pulmonary disease and pulmonary function levels, including the forced expiratory volume in 1 s (FEV1), in general population samples by genome-wide association studies. However, in vivo evidence connecting Hhip to age-related FEV1 decline and emphysema development is lacking. Herein, using Hhip heterozygous mice (Hhip+/−), we observed increased lung compliance and spontaneous emphysema in Hhip+/− mice starting at 10 mo of age. This increase was preceded by increases in oxidative stress levels in the lungs of Hhip+/− vs. Hhip+/+ mice. To our knowledge, these results provide the first line of evidence that HHIP is involved in maintaining normal lung function and alveolar structures. Interestingly, antioxidant N-acetyl cysteine treatment in mice starting at age of 5 mo improved lung function and prevented emphysema development in Hhip+/− mice, suggesting that N-acetyl cysteine treatment limits the progression of age-related emphysema in Hhip+/− mice. Therefore, reduced lung function and age-related spontaneous emphysema development in Hhip+/− mice may be caused by increased oxidative stress levels in murine lungs as a result of haploinsufficiency of Hhip.

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“…SIRT1, a representative sirtuin, has been shown to be involved in COPD pathogenesis through prevention of stress-induced inflammation and premature cellular senescence (9,10). In terms of the regulation of autophagy, decreased SIRT1 expression in response to CS exposure has been postulated to correspond with increased autophagy activation, resulting in excessive apoptosis and COPD development (11).…”

mentioning

confidence: 99%

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

Takasaka

Araya

Hara

et al. 2014

The Journal of Immunology

162

145

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Cigarette smoke (CS)–induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.

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SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice

Cited by 310 publications

References 92 publications

SIRT1 Deficiency in Microglia Contributes to Cognitive Decline in Aging and Neurodegeneration via Epigenetic Regulation of IL-1β

SIRT1 Deficiency in Microglia Contributes to Cognitive Decline in Aging and Neurodegeneration via Epigenetic Regulation of IL-1β

Hhip haploinsufficiency sensitizes mice to age-related emphysema

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

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