We previously reported that hsa-miR-520d-5p is functionally involved in the induction of the epithelial–mesenchymal transition and stemness-mediated processes in normal cells and cancer cells, respectively. On the basis of the synergistic effect of p53 upregulation and demethylation induced by 520d-5p, the current study investigated the effect of this miRNA on apoptotic induction by ultraviolet B (UVB) light in normal human dermal fibroblast (NHDF) cells. 520d-5p was lentivirally transfected into NHDF cells either before or after a lethal dose of UVB irradiation (302 nm) to assess its preventive or therapeutic effects, respectively. The methylation level, gene expression, production of type I collagen and cell cycle distribution were estimated in UV-irradiated cells. NHDF cells transfected with 520d-5p prior to UVB irradiation had apoptotic characteristics, and the transfection exerted no preventive effects. However, transfection with 520d-5p into NHDF cells after UVB exposure resulted in the induction of reprogramming in damaged fibroblasts, the survival of CD105-positive cells, an extended cell lifespan and prevention of cellular damage or malfunction; these outcomes were similar to the effects observed in 520d-5p-transfected NHDF cells (520d/NHDF). The gene expression of c-Abl (Abelson murine leukemia viral oncogene homolog 1), ATR (ataxia telangiectasia and Rad3-related protein), and BRCA1 (breast cancer susceptibility gene I) in transfectants was transcriptionally upregulated in order. These mechanistic findings indicate that ATR-dependent DNA damage repair was activated under this stressor. In conclusion, 520d-5p exerted a therapeutic effect on cells damaged by UVB and restored them to a normal senescent state following functional restoration via survival of CD105-positive cells through c-Abl-ATR-BRCA1 pathway activation, p53 upregulation, and demethylation. As hsa-miR-520d-5p has an innovating effect of reversion of undifferentiated cancer cells to benign or normal status via a stemness-mediated process, we attempted to examine its reprogramming effect on differentiated normal cells (dermal fibroblasts). We found that miR-520d-5p has a restoration effect on fibroblasts exposed to lethal ultraviolet B irradiation and that it induced these cells to the mesenchymal status with CD105 expression. The therapeutic effect indicates that miR-520d-5p is deeply involved in DNA repair (non-canonical pathway against nuclear stress), and it may function as the main regulator in the response mechanism to fragmented DNA and severely damaged nucleic acids. Therefore, this study may pave the way to elucidating a new mechanism because miRNA may play a role in the biogenesis of cells that are getting lethal due to cell damage or aging.
{"title":"Hsa-miR-520d-5p promotes survival in human dermal fibroblasts exposed to a lethal dose of UV irradiation","authors":"Yoshitaka Ishihara, Satoshi Tsuno, Bingqiong Ping, Taichiro Ashizaki, Masahiro Nakashima, Keigo Miura, Yugo Miura, Taro Yamashita, Junichi Hasegawa, Norimasa Miura","doi":"10.1038/npjamd.2016.29","DOIUrl":"10.1038/npjamd.2016.29","url":null,"abstract":"We previously reported that hsa-miR-520d-5p is functionally involved in the induction of the epithelial–mesenchymal transition and stemness-mediated processes in normal cells and cancer cells, respectively. On the basis of the synergistic effect of p53 upregulation and demethylation induced by 520d-5p, the current study investigated the effect of this miRNA on apoptotic induction by ultraviolet B (UVB) light in normal human dermal fibroblast (NHDF) cells. 520d-5p was lentivirally transfected into NHDF cells either before or after a lethal dose of UVB irradiation (302 nm) to assess its preventive or therapeutic effects, respectively. The methylation level, gene expression, production of type I collagen and cell cycle distribution were estimated in UV-irradiated cells. NHDF cells transfected with 520d-5p prior to UVB irradiation had apoptotic characteristics, and the transfection exerted no preventive effects. However, transfection with 520d-5p into NHDF cells after UVB exposure resulted in the induction of reprogramming in damaged fibroblasts, the survival of CD105-positive cells, an extended cell lifespan and prevention of cellular damage or malfunction; these outcomes were similar to the effects observed in 520d-5p-transfected NHDF cells (520d/NHDF). The gene expression of c-Abl (Abelson murine leukemia viral oncogene homolog 1), ATR (ataxia telangiectasia and Rad3-related protein), and BRCA1 (breast cancer susceptibility gene I) in transfectants was transcriptionally upregulated in order. These mechanistic findings indicate that ATR-dependent DNA damage repair was activated under this stressor. In conclusion, 520d-5p exerted a therapeutic effect on cells damaged by UVB and restored them to a normal senescent state following functional restoration via survival of CD105-positive cells through c-Abl-ATR-BRCA1 pathway activation, p53 upregulation, and demethylation. As hsa-miR-520d-5p has an innovating effect of reversion of undifferentiated cancer cells to benign or normal status via a stemness-mediated process, we attempted to examine its reprogramming effect on differentiated normal cells (dermal fibroblasts). We found that miR-520d-5p has a restoration effect on fibroblasts exposed to lethal ultraviolet B irradiation and that it induced these cells to the mesenchymal status with CD105 expression. The therapeutic effect indicates that miR-520d-5p is deeply involved in DNA repair (non-canonical pathway against nuclear stress), and it may function as the main regulator in the response mechanism to fragmented DNA and severely damaged nucleic acids. Therefore, this study may pave the way to elucidating a new mechanism because miRNA may play a role in the biogenesis of cells that are getting lethal due to cell damage or aging.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2016-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.29","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anne-Laure Egesipe, Sophie Blondel, Alessandra Lo Cicero, Anne-Laure Jaskowiak, Claire Navarro, Annachiara De Sandre-Giovannoli, Nicolas Levy, Marc Peschanski, Xavier Nissan
Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder that causes systemic accelerated aging in children. This syndrome is due to a mutation in the LMNA gene that leads to the production of a truncated and toxic form of lamin A called progerin. Because the balance between the A-type lamins is controlled by the RNA-binding protein SRSF1, we have hypothesized that its inhibition may have therapeutic effects for HGPS. For this purpose, we evaluated the antidiabetic drug metformin and demonstrated that 48 h treatment with 5 mmol/l metformin decreases SRSF1 and progerin expression in mesenchymal stem cells derived from HGPS induced pluripotent stem cells (HGPS MSCs). The effect of metformin on progerin was then confirmed in several in vitro models of HGPS, i.e., human primary HGPS fibroblasts, LmnaG609G/G609G mouse fibroblasts and healthy MSCs previously treated with a PMO (phosphorodiamidate morpholino oligonucleotide) that induces progerin. This was accompanied by an improvement in two in vitro phenotypes associated with the disease: nuclear shape abnormalities and premature osteoblastic differentiation of HGPS MSCs. Overall, these results suggest a novel approach towards therapeutics for HGPS that can be added to the currently assayed treatments that target other molecular defects associated with the disease. A diabetes drug with a proven track record in the clinic may also offer an alternative treatment for a rare ''premature aging'' disorder. A genetic mutation in patients with Hutchinson-Gilford progeria syndrome (HGPS) produces a defective protein called progerin, which causes children to develop skeletal, cardiovascular and other symptoms normally seen in the elderly. Researchers led by Xavier Nissan at I-Stem in France have demonstrated that metformin triggers a biochemical ''switch'' that causes cells to decrease their production of progerin, and instead generate an alternative, non-toxic protein. Relative to untreated cells, metformin-treated cells were less prone to develop structural abnormalities or undergo premature maturation. Importantly, doctors have used metformin for over 20 years, suggesting that such a treatment approach should be safe for HGPS patients.
{"title":"Metformin decreases progerin expression and alleviates pathological defects of Hutchinson–Gilford progeria syndrome cells","authors":"Anne-Laure Egesipe, Sophie Blondel, Alessandra Lo Cicero, Anne-Laure Jaskowiak, Claire Navarro, Annachiara De Sandre-Giovannoli, Nicolas Levy, Marc Peschanski, Xavier Nissan","doi":"10.1038/npjamd.2016.26","DOIUrl":"10.1038/npjamd.2016.26","url":null,"abstract":"Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder that causes systemic accelerated aging in children. This syndrome is due to a mutation in the LMNA gene that leads to the production of a truncated and toxic form of lamin A called progerin. Because the balance between the A-type lamins is controlled by the RNA-binding protein SRSF1, we have hypothesized that its inhibition may have therapeutic effects for HGPS. For this purpose, we evaluated the antidiabetic drug metformin and demonstrated that 48 h treatment with 5 mmol/l metformin decreases SRSF1 and progerin expression in mesenchymal stem cells derived from HGPS induced pluripotent stem cells (HGPS MSCs). The effect of metformin on progerin was then confirmed in several in vitro models of HGPS, i.e., human primary HGPS fibroblasts, LmnaG609G/G609G mouse fibroblasts and healthy MSCs previously treated with a PMO (phosphorodiamidate morpholino oligonucleotide) that induces progerin. This was accompanied by an improvement in two in vitro phenotypes associated with the disease: nuclear shape abnormalities and premature osteoblastic differentiation of HGPS MSCs. Overall, these results suggest a novel approach towards therapeutics for HGPS that can be added to the currently assayed treatments that target other molecular defects associated with the disease. A diabetes drug with a proven track record in the clinic may also offer an alternative treatment for a rare ''premature aging'' disorder. A genetic mutation in patients with Hutchinson-Gilford progeria syndrome (HGPS) produces a defective protein called progerin, which causes children to develop skeletal, cardiovascular and other symptoms normally seen in the elderly. Researchers led by Xavier Nissan at I-Stem in France have demonstrated that metformin triggers a biochemical ''switch'' that causes cells to decrease their production of progerin, and instead generate an alternative, non-toxic protein. Relative to untreated cells, metformin-treated cells were less prone to develop structural abnormalities or undergo premature maturation. Importantly, doctors have used metformin for over 20 years, suggesting that such a treatment approach should be safe for HGPS patients.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2016-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.26","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The first human clinical study for NMN has started in Japan","authors":"Kazuo Tsubota","doi":"10.1038/npjamd.2016.21","DOIUrl":"10.1038/npjamd.2016.21","url":null,"abstract":"","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-1"},"PeriodicalIF":0.0,"publicationDate":"2016-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.21","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The classical renin–angiotensin system (RAS), known as the angiotensin (Ang)-converting enzyme (ACE)/Ang II/Ang II type 1 (AT1) receptor axis, induces various organ damages including cognitive decline. On the other hand, the ACE2/Ang-(1–7)/Mas receptor axis has been highlighted as exerting antagonistic actions against the classical RAS axis in the cardiovascular system. However, the roles of the ACE2/Ang-(1–7)/Mas axis in cognitive function largely remain to be elucidated, and we therefore examined possible roles of ACE2 in cognitive function. Male, 10-week-old C57BL6 (wild type, WT) mice and ACE2 knockout (KO) mice were subjected to the Morris water maze task and Y maze test to evaluate cognitive function. ACE2KO mice exhibited significant impairment of cognitive function, compared with that in WT mice. Superoxide anion production increased in ACE2KO mice, with increased mRNA levels of NADPH oxidase subunit, p22phox, p40phox, p67phox, and gp91phox in the hippocampus of ACE2KO mice compared with WT mice. The protein level of SOD3 decreased in ACE2KO mice compared with WT mice. The AT1 receptor mRNA level in the hippocampus was higher in ACE2KO mice compared with WT mice. In contrast, the AT2 receptor mRNA level in the hippocampus did not differ between the two strains. Mas receptor mRNA was highly expressed in the hippocampus compared with the cortex. Brain-derived neurotrophic factor (BDNF) mRNA and protein levels were lower in the hippocampus in ACE2KO mice compared with WT mice. Taken together, ACE2 deficiency resulted in impaired cognitive function, probably at least in part because of enhanced oxidative stress and a decrease in BDNF. Angiotensin-converting enzyme 2 (ACE2), an enzyme that regulates a cellular pathway linked to blood pressure regulation, is found to play an important role in maintaining normal cognitive functions. Masatsugu Horiuchi and his colleagues from the medical school of Ehime University in Japan, using classical behavioral tests, compared the cognitive functions of mice without ACE2 with those of normal mice, and found impaired spatial learning and memory in the former. Among the ACE2-deficient mice, the researchers observed an increased production of free radicals and a decrease of an important learning-related nerve growth factor, which might explain their impaired cognitive functions. The study helps elucidate cognitive effects of the protective arm of the hormone system that regulates blood pressure, with potential applications in the prevention of cognitive decline in diseases such as hypertension and diabetes.
{"title":"Deficiency of angiotensin-converting enzyme 2 causes deterioration of cognitive function","authors":"Xiao-Li Wang, Jun Iwanami, Li-Juan Min, Kana Tsukuda, Hirotomo Nakaoka, Hui-Yu Bai, Bao-Shuai Shan, Harumi Kan-no, Masayoshi Kukida, Toshiyuki Chisaka, Toshifumi Yamauchi, Akinori Higaki, Masaki Mogi, Masatsugu Horiuchi","doi":"10.1038/npjamd.2016.24","DOIUrl":"10.1038/npjamd.2016.24","url":null,"abstract":"The classical renin–angiotensin system (RAS), known as the angiotensin (Ang)-converting enzyme (ACE)/Ang II/Ang II type 1 (AT1) receptor axis, induces various organ damages including cognitive decline. On the other hand, the ACE2/Ang-(1–7)/Mas receptor axis has been highlighted as exerting antagonistic actions against the classical RAS axis in the cardiovascular system. However, the roles of the ACE2/Ang-(1–7)/Mas axis in cognitive function largely remain to be elucidated, and we therefore examined possible roles of ACE2 in cognitive function. Male, 10-week-old C57BL6 (wild type, WT) mice and ACE2 knockout (KO) mice were subjected to the Morris water maze task and Y maze test to evaluate cognitive function. ACE2KO mice exhibited significant impairment of cognitive function, compared with that in WT mice. Superoxide anion production increased in ACE2KO mice, with increased mRNA levels of NADPH oxidase subunit, p22phox, p40phox, p67phox, and gp91phox in the hippocampus of ACE2KO mice compared with WT mice. The protein level of SOD3 decreased in ACE2KO mice compared with WT mice. The AT1 receptor mRNA level in the hippocampus was higher in ACE2KO mice compared with WT mice. In contrast, the AT2 receptor mRNA level in the hippocampus did not differ between the two strains. Mas receptor mRNA was highly expressed in the hippocampus compared with the cortex. Brain-derived neurotrophic factor (BDNF) mRNA and protein levels were lower in the hippocampus in ACE2KO mice compared with WT mice. Taken together, ACE2 deficiency resulted in impaired cognitive function, probably at least in part because of enhanced oxidative stress and a decrease in BDNF. Angiotensin-converting enzyme 2 (ACE2), an enzyme that regulates a cellular pathway linked to blood pressure regulation, is found to play an important role in maintaining normal cognitive functions. Masatsugu Horiuchi and his colleagues from the medical school of Ehime University in Japan, using classical behavioral tests, compared the cognitive functions of mice without ACE2 with those of normal mice, and found impaired spatial learning and memory in the former. Among the ACE2-deficient mice, the researchers observed an increased production of free radicals and a decrease of an important learning-related nerve growth factor, which might explain their impaired cognitive functions. The study helps elucidate cognitive effects of the protective arm of the hormone system that regulates blood pressure, with potential applications in the prevention of cognitive decline in diseases such as hypertension and diabetes.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2016-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.24","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lear E Brace, Sarah C Vose, Kristopher Stanya, Rose M Gathungu, Vasant R Marur, Alban Longchamp, Humberto Treviño-Villarreal, Pedro Mejia, Dorathy Vargas, Karen Inouye, Roderick T Bronson, Chih-Hao Lee, Edward Neilan, Bruce S Kristal, James R Mitchell
Accumulation of DNA damage is intricately linked to aging, aging-related diseases and progeroid syndromes such as Cockayne syndrome (CS). Free radicals from endogenous oxidative energy metabolism can damage DNA, however the potential of acute or chronic DNA damage to modulate cellular and/or organismal energy metabolism remains largely unexplored. We modeled chronic endogenous genotoxic stress using a DNA repair-deficient Csa−/−|Xpa−/− mouse model of CS. Exogenous genotoxic stress was modeled in mice in vivo and primary cells in vitro treated with different genotoxins giving rise to diverse spectrums of lesions, including ultraviolet radiation, intrastrand crosslinking agents and ionizing radiation. Both chronic endogenous and acute exogenous genotoxic stress increased mitochondrial fatty acid oxidation (FAO) on the organismal level, manifested by increased oxygen consumption, reduced respiratory exchange ratio, progressive adipose loss and increased FAO in tissues ex vivo. In multiple primary cell types, the metabolic response to different genotoxins manifested as a cell-autonomous increase in oxidative phosphorylation (OXPHOS) subsequent to a transient decline in steady-state NAD+ and ATP levels, and required the DNA damage sensor PARP-1 and energy-sensing kinase AMPK. We conclude that increased FAO/OXPHOS is a general, beneficial, adaptive response to DNA damage on cellular and organismal levels, illustrating a fundamental link between genotoxic stress and energy metabolism driven by the energetic cost of DNA damage. Our study points to therapeutic opportunities to mitigate detrimental effects of DNA damage on primary cells in the context of radio/chemotherapy or progeroid syndromes. A link between DNA damage and cellular metabolism could benefit patients with premature aging disorders and lead to safer cancer treatments. Cells consume considerable energy to repair the destructive effects of chemicals, radiation and aging on the chromosomes. Researchers led by James Mitchell of the Harvard T.H. Chan School of Public Health have found that the damage-induced activation of these pathways accelerates fat metabolism and boosts production of ATP, the cell’s energetic currency. This metabolic shift is beneficial for cellular health, and appears to be an important defense mechanism in premature aging disorders like Cockayne syndrome. The researchers hypothesize that interventions such as dietary restriction could help protect against the side effects of DNA damage from radio- or chemotherapy by switching cellular energy metabolism into a more efficient state.
DNA 损伤的累积与衰老、衰老相关疾病和类早衰综合征（如科凯恩综合征（Cockayne Syndrome，CS））密切相关。内源性氧化能量代谢产生的自由基可损伤DNA，但急性或慢性DNA损伤调节细胞和/或机体能量代谢的潜力在很大程度上仍未得到探索。我们利用DNA修复缺陷的Csa-/-|Xpa-/-小鼠CS模型来模拟慢性内源性基因毒性应激。外源性基因毒性应激模型是在小鼠体内和原代细胞体外用不同的基因毒性物质（包括紫外线辐射、链内交联剂和电离辐射）处理后产生的。慢性内源性和急性外源性基因毒性应激都会在机体水平上增加线粒体脂肪酸氧化（FAO），表现为耗氧量增加、呼吸交换比降低、脂肪逐渐流失以及体外组织中的 FAO 增加。在多种原代细胞类型中，对不同基因毒素的新陈代谢反应表现为细胞自主的氧化磷酸化（OXPHOS）增加，随后稳态 NAD+ 和 ATP 水平短暂下降，并且需要 DNA 损伤传感器 PARP-1 和能量感应激酶 AMPK。我们的结论是，FAO/OXPHOS 的增加是细胞和机体对 DNA 损伤的一种普遍、有益的适应性反应，说明了 DNA 损伤的能量成本所驱动的基因毒性应激与能量代谢之间的基本联系。我们的研究为减轻 DNA 损伤对放疗/化疗或类风湿综合征原代细胞的有害影响提供了治疗机会。DNA损伤与细胞新陈代谢之间的联系可使早衰症患者受益，并带来更安全的癌症治疗方法。细胞需要消耗大量能量来修复化学物质、辐射和衰老对染色体造成的破坏性影响。哈佛大学陈德熙公共卫生学院的詹姆斯-米切尔领导的研究人员发现，这些通路的损伤诱导激活会加速脂肪代谢，促进细胞的能量货币--ATP 的产生。这种新陈代谢的转变有利于细胞健康，似乎也是科凯恩综合征等早衰疾病的重要防御机制。研究人员推测，通过将细胞能量代谢转换到更有效的状态，饮食限制等干预措施有助于防止放疗或化疗造成的 DNA 损伤的副作用。
{"title":"Increased oxidative phosphorylation in response to acute and chronic DNA damage","authors":"Lear E Brace, Sarah C Vose, Kristopher Stanya, Rose M Gathungu, Vasant R Marur, Alban Longchamp, Humberto Treviño-Villarreal, Pedro Mejia, Dorathy Vargas, Karen Inouye, Roderick T Bronson, Chih-Hao Lee, Edward Neilan, Bruce S Kristal, James R Mitchell","doi":"10.1038/npjamd.2016.22","DOIUrl":"10.1038/npjamd.2016.22","url":null,"abstract":"Accumulation of DNA damage is intricately linked to aging, aging-related diseases and progeroid syndromes such as Cockayne syndrome (CS). Free radicals from endogenous oxidative energy metabolism can damage DNA, however the potential of acute or chronic DNA damage to modulate cellular and/or organismal energy metabolism remains largely unexplored. We modeled chronic endogenous genotoxic stress using a DNA repair-deficient Csa−/−|Xpa−/− mouse model of CS. Exogenous genotoxic stress was modeled in mice in vivo and primary cells in vitro treated with different genotoxins giving rise to diverse spectrums of lesions, including ultraviolet radiation, intrastrand crosslinking agents and ionizing radiation. Both chronic endogenous and acute exogenous genotoxic stress increased mitochondrial fatty acid oxidation (FAO) on the organismal level, manifested by increased oxygen consumption, reduced respiratory exchange ratio, progressive adipose loss and increased FAO in tissues ex vivo. In multiple primary cell types, the metabolic response to different genotoxins manifested as a cell-autonomous increase in oxidative phosphorylation (OXPHOS) subsequent to a transient decline in steady-state NAD+ and ATP levels, and required the DNA damage sensor PARP-1 and energy-sensing kinase AMPK. We conclude that increased FAO/OXPHOS is a general, beneficial, adaptive response to DNA damage on cellular and organismal levels, illustrating a fundamental link between genotoxic stress and energy metabolism driven by the energetic cost of DNA damage. Our study points to therapeutic opportunities to mitigate detrimental effects of DNA damage on primary cells in the context of radio/chemotherapy or progeroid syndromes. A link between DNA damage and cellular metabolism could benefit patients with premature aging disorders and lead to safer cancer treatments. Cells consume considerable energy to repair the destructive effects of chemicals, radiation and aging on the chromosomes. Researchers led by James Mitchell of the Harvard T.H. Chan School of Public Health have found that the damage-induced activation of these pathways accelerates fat metabolism and boosts production of ATP, the cell’s energetic currency. This metabolic shift is beneficial for cellular health, and appears to be an important defense mechanism in premature aging disorders like Cockayne syndrome. The researchers hypothesize that interventions such as dietary restriction could help protect against the side effects of DNA damage from radio- or chemotherapy by switching cellular energy metabolism into a more efficient state.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2016-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.22","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Erez Eitan, Emmette R Hutchison, Krisztina Marosi, James Comotto, Maja Mustapic, Saket M Nigam, Caitlin Suire, Chinmoyee Maharana, Gregory A Jicha, Dong Liu, Vasiliki Machairaki, Kenneth W Witwer, Dimitrios Kapogiannis, Mark P Mattson
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates in the brain. Extracellular vesicles (EVs), including exosomes, are small 50–150 nm membrane vesicles that have recently been implicated in the prion-like spread of self-aggregating proteins. Here we report that EVs isolated from AD patient cerebrospinal fluid and plasma, from the plasma of two AD mouse models, and from the medium of neural cells expressing familial AD presenilin 1 mutations, destabilize neuronal Ca2+ homeostasis, impair mitochondrial function, and sensitize neurons to excitotoxicity. EVs contain a relatively low amount of Aβ but have an increased Aβ42/ Aβ40 ratio; the majority of Aβ is located on the surface of the EVs. Impairment of lysosome function results in increased generation of EVs with elevated Aβ42 levels. EVs may mediate transcellular spread of pathogenic Aβ species that impair neuronal Ca2+ handling and mitochondrial function, and may thereby render neurons vulnerable to excitotoxicity. A deadly game of cellular ‘tag’ might underlie the degenerative spread of damage between brain cells in Alzheimer’s patients. Mark Mattson from the National Institute on Aging in Maryland and colleagues investigated a hallmark of Alzheimer’s disease: the proliferation of tangled amyloid β protein clusters between brain cells. They found that small pouches of the outer membrane of brain cells—called extracellular vesicles-shuttled a particularly damaging form of amyloid β between cells. Extracellular vesicles were isolated from the fluid surrounding the brain in Alzheimer’s patients; when normal brain cells were exposed to these vesicles, cellular function in the exposed brain cells turned aberrant, occasionally leading to cell death. Understanding the propagation of Alzheimer’s disease pathology within the brain might uncover markers for detecting the disease earlier, and perhaps a window to intervene and halt the damage.
阿尔茨海默病（AD）是一种与年龄有关的神经退行性疾病，在这种疾病中，易聚集的神经毒性淀粉样β肽（Aβ）会在大脑中积累。细胞外囊泡（EVs），包括外泌体（exosomes），是一种 50-150 nm 的小膜囊泡，最近被认为与自聚集蛋白的朊病毒样扩散有关。我们在此报告说，从 AD 患者脑脊液和血浆、两种 AD 小鼠模型的血浆以及表达家族性 AD presenilin 1 突变的神经细胞培养基中分离出的 EVs 破坏了神经元的 Ca2+ 稳态，损害了线粒体功能，并使神经元对兴奋毒性敏感。EVs中Aβ的含量相对较低，但Aβ42/ Aβ40的比例却有所增加；大部分Aβ位于EVs的表面。溶酶体功能受损会导致产生更多 Aβ42 水平升高的 EVs。EVs可能会介导致病Aβ物种的跨细胞传播，损害神经元的Ca2+处理和线粒体功能，从而使神经元易受兴奋性毒性的影响。阿尔茨海默氏症患者脑细胞间损害的变性扩散可能是一种致命的细胞 "捉迷藏 "游戏。马里兰州国家老龄化研究所的马克-马特森及其同事研究了阿尔茨海默氏症的一个特征：脑细胞间纠结的淀粉样β蛋白团扩散。他们发现，脑细胞外膜上的小囊泡--细胞外囊泡--在细胞之间装载了一种破坏性特别强的淀粉样β。研究人员从阿尔茨海默氏症患者大脑周围的液体中分离出了细胞外囊泡；当正常脑细胞暴露在这些囊泡中时，暴露的脑细胞的细胞功能会发生异常，有时会导致细胞死亡。了解阿尔茨海默氏症病理在大脑中的传播过程，也许能发现更早地发现这种疾病的标志物，也许还能找到干预和阻止损害的窗口。
{"title":"Extracellular vesicle-associated Aβ mediates trans-neuronal bioenergetic and Ca2+-handling deficits in Alzheimer’s disease models","authors":"Erez Eitan, Emmette R Hutchison, Krisztina Marosi, James Comotto, Maja Mustapic, Saket M Nigam, Caitlin Suire, Chinmoyee Maharana, Gregory A Jicha, Dong Liu, Vasiliki Machairaki, Kenneth W Witwer, Dimitrios Kapogiannis, Mark P Mattson","doi":"10.1038/npjamd.2016.19","DOIUrl":"10.1038/npjamd.2016.19","url":null,"abstract":"Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates in the brain. Extracellular vesicles (EVs), including exosomes, are small 50–150 nm membrane vesicles that have recently been implicated in the prion-like spread of self-aggregating proteins. Here we report that EVs isolated from AD patient cerebrospinal fluid and plasma, from the plasma of two AD mouse models, and from the medium of neural cells expressing familial AD presenilin 1 mutations, destabilize neuronal Ca2+ homeostasis, impair mitochondrial function, and sensitize neurons to excitotoxicity. EVs contain a relatively low amount of Aβ but have an increased Aβ42/ Aβ40 ratio; the majority of Aβ is located on the surface of the EVs. Impairment of lysosome function results in increased generation of EVs with elevated Aβ42 levels. EVs may mediate transcellular spread of pathogenic Aβ species that impair neuronal Ca2+ handling and mitochondrial function, and may thereby render neurons vulnerable to excitotoxicity. A deadly game of cellular ‘tag’ might underlie the degenerative spread of damage between brain cells in Alzheimer’s patients. Mark Mattson from the National Institute on Aging in Maryland and colleagues investigated a hallmark of Alzheimer’s disease: the proliferation of tangled amyloid β protein clusters between brain cells. They found that small pouches of the outer membrane of brain cells—called extracellular vesicles-shuttled a particularly damaging form of amyloid β between cells. Extracellular vesicles were isolated from the fluid surrounding the brain in Alzheimer’s patients; when normal brain cells were exposed to these vesicles, cellular function in the exposed brain cells turned aberrant, occasionally leading to cell death. Understanding the propagation of Alzheimer’s disease pathology within the brain might uncover markers for detecting the disease earlier, and perhaps a window to intervene and halt the damage.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2016-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.19","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"57528193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Time perception is an essential function of the human brain, which is compromised in Alzheimer’s disease (AD). Here, we review empirical findings on time distortions in AD and provide a theoretical framework that integrates time and memory distortions in AD and explains their bidirectional modulation. The review was based on a literature survey performed on the PubMed and PsycInfo databases. According to our theoretical framework, time distortions may induce decline in the ability to mentally project oneself in time (i.e., mental time travel), and consequently may contribute to an episodic memory compromise in AD. Conversely, episodic memory compromise in AD may result in a loss of the ability to retrieve information about time and/or the ability to project oneself in subjective time. The relationship between time distortions and memory decline in AD can be jointly attributed to hippocampus involvement, as this brain area supports both time perception and memory and is preferentially targeted by the neuropathological processes of AD. Clinical implications of time distortions are discussed and directions for future research are suggested.
{"title":"Time distortions in Alzheimer’s disease: a systematic review and theoretical integration","authors":"Mohamad El Haj, Dimitrios Kapogiannis","doi":"10.1038/npjamd.2016.16","DOIUrl":"10.1038/npjamd.2016.16","url":null,"abstract":"Time perception is an essential function of the human brain, which is compromised in Alzheimer’s disease (AD). Here, we review empirical findings on time distortions in AD and provide a theoretical framework that integrates time and memory distortions in AD and explains their bidirectional modulation. The review was based on a literature survey performed on the PubMed and PsycInfo databases. According to our theoretical framework, time distortions may induce decline in the ability to mentally project oneself in time (i.e., mental time travel), and consequently may contribute to an episodic memory compromise in AD. Conversely, episodic memory compromise in AD may result in a loss of the ability to retrieve information about time and/or the ability to project oneself in subjective time. The relationship between time distortions and memory decline in AD can be jointly attributed to hippocampus involvement, as this brain area supports both time perception and memory and is preferentially targeted by the neuropathological processes of AD. Clinical implications of time distortions are discussed and directions for future research are suggested.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-5"},"PeriodicalIF":0.0,"publicationDate":"2016-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.16","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The coupling of nicotinamide adenine dinucleotide (NAD+) breakdown and protein deacylation is a unique feature of the family of proteins called ‘sirtuins.’ This intimate connection between NAD+ and sirtuins has an ancient origin and provides a mechanistic foundation that translates the regulation of energy metabolism into aging and longevity control in diverse organisms. Although the field of sirtuin research went through intensive controversies, an increasing number of recent studies have put those controversies to rest and fully established the significance of sirtuins as an evolutionarily conserved aging/longevity regulator. The tight connection between NAD+ and sirtuins is regulated at several different levels, adding further complexity to their coordination in metabolic and aging/longevity control. Interestingly, it has been demonstrated that NAD+ availability decreases over age, reducing sirtuin activities and affecting the communication between the nucleus and mitochondria at a cellular level and also between the hypothalamus and adipose tissue at a systemic level. These dynamic cellular and systemic processes likely contribute to the development of age-associated functional decline and the pathogenesis of diseases of aging. To mitigate these age-associated problems, supplementation of key NAD+ intermediates is currently drawing significant attention. In this review article, we will summarize these important aspects of the intimate connection between NAD+ and sirtuins in aging/longevity control.
{"title":"It takes two to tango: NAD+ and sirtuins in aging/longevity control","authors":"Shin-ichiro Imai, Leonard Guarente","doi":"10.1038/npjamd.2016.17","DOIUrl":"10.1038/npjamd.2016.17","url":null,"abstract":"The coupling of nicotinamide adenine dinucleotide (NAD+) breakdown and protein deacylation is a unique feature of the family of proteins called ‘sirtuins.’ This intimate connection between NAD+ and sirtuins has an ancient origin and provides a mechanistic foundation that translates the regulation of energy metabolism into aging and longevity control in diverse organisms. Although the field of sirtuin research went through intensive controversies, an increasing number of recent studies have put those controversies to rest and fully established the significance of sirtuins as an evolutionarily conserved aging/longevity regulator. The tight connection between NAD+ and sirtuins is regulated at several different levels, adding further complexity to their coordination in metabolic and aging/longevity control. Interestingly, it has been demonstrated that NAD+ availability decreases over age, reducing sirtuin activities and affecting the communication between the nucleus and mitochondria at a cellular level and also between the hypothalamus and adipose tissue at a systemic level. These dynamic cellular and systemic processes likely contribute to the development of age-associated functional decline and the pathogenesis of diseases of aging. To mitigate these age-associated problems, supplementation of key NAD+ intermediates is currently drawing significant attention. In this review article, we will summarize these important aspects of the intimate connection between NAD+ and sirtuins in aging/longevity control.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2016-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic inflammation is the common pathological basis for such age-associated diseases as cardiovascular disease, diabetes, cancer and Alzheimer’s disease. A multitude of bodily changes occur with aging that contribute to the initiation and development of inflammation. In particular, the immune system of elderly individuals often exhibits diminished efficiency and fidelity, termed immunosenescence. But, although immune responses to new pathogens and vaccines are impaired, immunosenescence is also characterized by a basal systemic inflammatory state. This alteration in immune system function likely promotes chronic inflammation. Changes in the tissue microenvironment, such as the accumulation of cell debris, and systemic changes in metabolic and hormonal signals, also likely contribute to the development of chronic inflammation. Monocyte/macrophage lineage cells are crucial to these age-associated changes, which culminate in the development of chronic inflammatory diseases. In this review, we will summarize the diverse physiological and pathological roles of macrophages in the chronic inflammation underlying age-associated diseases.
{"title":"Macrophages in age-related chronic inflammatory diseases","authors":"Yumiko Oishi, Ichiro Manabe","doi":"10.1038/npjamd.2016.18","DOIUrl":"10.1038/npjamd.2016.18","url":null,"abstract":"Chronic inflammation is the common pathological basis for such age-associated diseases as cardiovascular disease, diabetes, cancer and Alzheimer’s disease. A multitude of bodily changes occur with aging that contribute to the initiation and development of inflammation. In particular, the immune system of elderly individuals often exhibits diminished efficiency and fidelity, termed immunosenescence. But, although immune responses to new pathogens and vaccines are impaired, immunosenescence is also characterized by a basal systemic inflammatory state. This alteration in immune system function likely promotes chronic inflammation. Changes in the tissue microenvironment, such as the accumulation of cell debris, and systemic changes in metabolic and hormonal signals, also likely contribute to the development of chronic inflammation. Monocyte/macrophage lineage cells are crucial to these age-associated changes, which culminate in the development of chronic inflammatory diseases. In this review, we will summarize the diverse physiological and pathological roles of macrophages in the chronic inflammation underlying age-associated diseases.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2016-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.18","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Different cell types within the body exhibit substantial variation in the average time they live, ranging from days to the lifetime of the organism. The underlying mechanisms governing the diverse lifespan of different cell types are not well understood. To examine gene expression strategies that support the lifespan of different cell types within the human body, we obtained publicly available RNA-seq data sets and interrogated transcriptomes of 21 somatic cell types and tissues with reported cellular turnover, a bona fide estimate of lifespan, ranging from 2 days (monocytes) to a lifetime (neurons). Exceptionally long-lived neurons presented a gene expression profile of reduced protein metabolism, consistent with neuronal survival and similar to expression patterns induced by longevity interventions such as dietary restriction. Across different cell lineages, we identified a gene expression signature of human cell and tissue turnover. In particular, turnover showed a negative correlation with the energetically costly cell cycle and factors supporting genome stability, concomitant risk factors for aging-associated pathologies. In addition, the expression of p53 was negatively correlated with cellular turnover, suggesting that low p53 activity supports the longevity of post-mitotic cells with inherently low risk of developing cancer. Our results demonstrate the utility of comparative approaches in unveiling gene expression differences among cell lineages with diverse cell turnover within the same organism, providing insights into mechanisms that could regulate cell longevity. Human tissue and cell types exhibit different gene signatures based on their cellular lifespans. Vadim Gladyshev and colleagues from Brigham and Women’s Hospital, Harvard Medical School, analyzed the gene expression patterns of 21 different cell types with cellular turnover times ranging from 2 days (white blood cells) to a lifetime (neurons). This turnover–defined as the balance between cell proliferation and death–has been shown to be a good estimate of cellular lifespan. The authors found that long-lived cell lineages, including those of the muscle and the brain, showed lower expression of genes involved in promoting cell division and maintaining genomic fidelity, consistent with a molecular path toward longevity. The finding that cells use lineage-specific strategies to alter their lifespans lays the groundwork for future therapies that promote human longevity by modifying gene expression profiles.
{"title":"Gene expression signatures of human cell and tissue longevity","authors":"Inge Seim, Siming Ma, Vadim N Gladyshev","doi":"10.1038/npjamd.2016.14","DOIUrl":"10.1038/npjamd.2016.14","url":null,"abstract":"Different cell types within the body exhibit substantial variation in the average time they live, ranging from days to the lifetime of the organism. The underlying mechanisms governing the diverse lifespan of different cell types are not well understood. To examine gene expression strategies that support the lifespan of different cell types within the human body, we obtained publicly available RNA-seq data sets and interrogated transcriptomes of 21 somatic cell types and tissues with reported cellular turnover, a bona fide estimate of lifespan, ranging from 2 days (monocytes) to a lifetime (neurons). Exceptionally long-lived neurons presented a gene expression profile of reduced protein metabolism, consistent with neuronal survival and similar to expression patterns induced by longevity interventions such as dietary restriction. Across different cell lineages, we identified a gene expression signature of human cell and tissue turnover. In particular, turnover showed a negative correlation with the energetically costly cell cycle and factors supporting genome stability, concomitant risk factors for aging-associated pathologies. In addition, the expression of p53 was negatively correlated with cellular turnover, suggesting that low p53 activity supports the longevity of post-mitotic cells with inherently low risk of developing cancer. Our results demonstrate the utility of comparative approaches in unveiling gene expression differences among cell lineages with diverse cell turnover within the same organism, providing insights into mechanisms that could regulate cell longevity. Human tissue and cell types exhibit different gene signatures based on their cellular lifespans. Vadim Gladyshev and colleagues from Brigham and Women’s Hospital, Harvard Medical School, analyzed the gene expression patterns of 21 different cell types with cellular turnover times ranging from 2 days (white blood cells) to a lifetime (neurons). This turnover–defined as the balance between cell proliferation and death–has been shown to be a good estimate of cellular lifespan. The authors found that long-lived cell lineages, including those of the muscle and the brain, showed lower expression of genes involved in promoting cell division and maintaining genomic fidelity, consistent with a molecular path toward longevity. The finding that cells use lineage-specific strategies to alter their lifespans lays the groundwork for future therapies that promote human longevity by modifying gene expression profiles.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2016-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.14","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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