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Erin Munkcsy E. Sandra Chocron Laura Quintanilla Christi M. Gendron Scott D. Pletcher Andrew M. Pickering 《Aging cell》2019,18(5)
Cognitive function declines with age throughout the animal kingdom, and increasing evidence shows that disruption of the proteasome system contributes to this deterioration. The proteasome has important roles in multiple aspects of the nervous system, including synapse function and plasticity, as well as preventing cell death and senescence. Previous studies have shown neuronal proteasome depletion and inhibition can result in neurodegeneration and cognitive deficits, but it is unclear if this pathway is a driver of neurodegeneration and cognitive decline in aging. We report that overexpression of the proteasome β5 subunit enhances proteasome assembly and function. Significantly, we go on to show that neuronal‐specific proteasome augmentation slows age‐related declines in measures of learning, memory, and circadian rhythmicity. Surprisingly, neuronal‐specific augmentation of proteasome function also produces a robust increase of lifespan in Drosophila melanogaster. Our findings appear specific to the nervous system; ubiquitous proteasome overexpression increases oxidative stress resistance but does not impact lifespan and is detrimental to some healthspan measures. These findings demonstrate a key role of the proteasome system in brain aging. 相似文献
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Kaufmann JA Perez M Zhang W Bickford PC Holmes DB Taglialatela G 《Journal of neurochemistry》2003,87(4):981-994
We have previously reported that Bcl-2 is up-regulated in the CNS of aged F344 rats as a consequence of oxidative stress. In addition to increased levels of expression, we now report that there is a subcellular redistribution of Bcl-2 in the CNS of aged F344 rats. Using western blotting, we found Bcl-2 predominantly located in the cytosol of young rats. However, in aged rats Bcl-2 was found primarily in the nucleus. This distribution, in the hippocampus and cerebellum, was reversed by treatment with the nitrone spin trap N-tert-butyl-alpha-phenylnitrone (PBN). Paradoxically, PBN treatment in young rats had the opposite effect, changing Bcl-2 from predominantly cytosolic to nuclear. We also detected an increase in Bax in aged hippocampal samples (both nuclear and cytosolic), which was reversed by treatment with PBN. The distribution of Bcl-2 and Bax in the cytosol of aged rats dramatically decreased the Bcl-2/Bax ratio, a probable indicator of neuronal vulnerability, which was restored upon treatment with PBN. In order to assess the effect of nuclear association of Bcl-2 we used PC12 cells stably transfected with a Bcl-2 construct to which we added the nuclear localization sequence of the SV40 large T antigen to the N-terminus which resulted in nuclear targeting of Bcl-2. Measurement of cell death using lactate dehydrogenase assays showed that, contrary to wild-type Bcl-2, Bcl-2 localized to the nucleus was not effective in protecting cells from treatment with 250 microm H2O2. These results suggest that nuclear localization of Bcl-2 observed in the aged CNS may not reflect a protective mechanism against oxidative stress, a major component of age-associated CNS impairments. 相似文献
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Yeo Wool Kang Yoon Suk Kim Jun Young Park Ga‐eul Chu Young Chul Yang Byung Young Choi Won Gil Cho 《Cell biology international》2020,44(6):1394-1404
Hypoxia is a condition in which the whole body or a region of the body is deprived of oxygen supply. The brain is very sensitive to the lack of oxygen and cerebral hypoxia can rapidly cause severe brain damage. Astrocytes are essential for the survival and function of neurons. Therefore, protecting astrocytes against cell death is one of the main therapeutic strategies for treating hypoxia. Hence, the mechanism of hypoxia‐induced astrocytic cell death should be fully elucidated. In this study, astrocytes were exposed to hypoxic conditions using a hypoxia work station or the hypoxia mimetic agent cobalt chloride (CoCl2). Both the hypoxic gas mixture (1% O2) and chemical hypoxia‐induced apoptotic cell death in T98G glioblastoma cells and mouse primary astrocytes. Reactive oxygen species were generated in response to the hypoxia‐mediated activation of caspase‐1. Active caspase‐1 induced the classical caspase‐dependent apoptosis of astrocytes. In addition, the microRNA processing enzyme Dicer was cleaved by caspase‐3 during hypoxia. Knockdown of Dicer using antisense oligonucleotides induced apoptosis of T98G cells. Taken together, these results suggest that astrocytic cell death during hypoxia is mediated by the reactive oxygen species/caspase‐1/classical caspase‐dependent apoptotic pathway. In addition, the decrease in Dicer levels by active caspase‐3 amplifies this apoptotic pathway via a positive feedback loop. These findings may provide a new target for therapeutic interventions in cerebral hypoxia. 相似文献
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Lucia Frau Nicola Simola Antonio Plumitallo Micaela Morelli 《Journal of neurochemistry》2013,124(1):69-78
Evidence is accumulating to suggest that 3,4‐methylenedioxymethamphetamine (MDMA) has neurotoxic and neuroinflammatory properties. MDMA is composed of two enantiomers with different biological activities. In this study, we evaluated the in vivo effects of S(+)‐MDMA, R(?)‐MDMA, and S(+)‐MDMA in combination with R(?)‐MDMA on microglial and astroglial activation compared with racemic MDMA, by assessment of complement type 3 receptor (CD11b) and glial fibrillary acidic protein (GFAP) immunoreactivity in the mouse striatum, nucleus accumbens, motor cortex, and substantia nigra. Motor activity and body temperature were also measured, to elucidate the physiological modifications paired with the observed glial changes. Similar to racemic MDMA (4 × 20 mg/kg), S(+)‐MDMA (4 × 10 mg/kg) increased both CD11b and GFAP in the striatum, although to a lower degree, whereas R(?)‐MDMA (4 × 10 mg/kg) did not induce any significant glial activation. Combined administration of S(+) plus R(?)‐MDMA did not induce any further activation compared with S(+)‐MDMA. In all other areas, only racemic MDMA was able to slightly activate the microglia, but not the astroglia, whereas enantiomers had no effect, either alone or in combination. Racemic MDMA and S(+)‐MDMA similarly increased motor activity and raised body temperature, whereas R(?)‐MDMA affected neither body temperature nor motor activity. Interestingly, the increase in body temperature was correlated with glial activation. The results show that no synergism, but only additivity of effects, is caused by the combined administration of S(+)‐ and R(?)‐MDMA, and underline the importance of investigating the biochemical and behavioral properties of the two MDMA enantiomers to understand their relative contribution to the neuroinflammatory and neurotoxic effects of MDMA. 相似文献
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Beatriz Novoa Patricia Pereiro Azucena Lpez‐Muoz Mnica Varela Gabriel Forn‐Cuní Monique Anchelin Sonia Dios Alejandro Romero Alicia Martinez‐Lpez Regla María Medina‐Gali Manuel Collado Julio Coll Amparo Estepa María Luisa Cayuela Victoriano Mulero Antonio Figueras 《Aging cell》2019,18(5)
In mammals, recombination activating gene 1 (RAG1) plays a crucial role in adaptive immunity, generating a vast range of immunoglobulins. Rag1?/? zebrafish (Danio rerio) are viable and reach adulthood without obvious signs of infectious disease in standard nonsterile conditions, suggesting that innate immunity could be enhanced to compensate for the lack of adaptive immunity. By using microarray analysis, we confirmed that the expression of immunity‐ and apoptosis‐related genes was increased in the rag1?/? fish. This tool also allows us to notice alterations of the DNA repair and cell cycle mechanisms in rag1?/? zebrafish. Several senescence and aging markers were analyzed. In addition to the lower lifespan of rag1?/? zebrafish compared to their wild‐type (wt) siblings, rag1?/? showed a higher incidence of cell cycle arrest and apoptosis, a greater amount of phosphorylated histone H2AX, oxidative stress and decline of the antioxidant mechanisms, an upregulated expression and activity of senescence‐related genes and senescence‐associated β‐galactosidase, respectively, diminished telomere length, and abnormal self‐renewal and repair capacities in the retina and liver. Metabolomic analysis also demonstrated clear differences between wt and rag1?/? fish, as was the deficiency of the antioxidant metabolite l ‐acetylcarnitine (ALCAR) in rag1?/? fish. Therefore, Rag1 activity does not seem to be limited to V(D)J recombination but is also involved in senescence and aging. Furthermore, we confirmed the senolytic effect of ABT‐263, a known senolytic compound and, for the first time, the potential in vivo senolytic activity of the antioxidant agent ALCAR, suggesting that this metabolite is essential to avoid premature aging. 相似文献
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PPARβ是配体活化的核转录因子,属核受体超家族成员。PPARβ在哺乳动物体内表达十分丰富,日前对PPARβ的研究比较少,但现有的研究表明PPARβ可能参与了机体多种生理和病理过程。本文将对PPARβ的生物学特征及其在中枢神经系统中的意义作一综述。 相似文献
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Amalia Icreverzi Aida Flor A. de la Cruz David W. Walker Bruce A. Edgar 《Aging cell》2015,14(5):896-906
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The cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging‐associated diseases. 相似文献
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Investigating the molecular basis of aging has been difficult, primarily owing to the pleiotropic and segmental nature of the aging phenotype. There are many often interacting symptoms of aging, some of which are obvious and appear to be common to every aged individual, whereas others affect only a subset of the elderly population. Although at first sight this would suggest multiple molecular mechanisms of aging, there now appears to be almost universal consensus that aging is ultimately the result of the accumulation of somatic damage in cellular macromolecules, with reactive oxygen species likely to be the main damage-inducing agent. What remains significant is unravelling how such damage can give rise to the large variety of aging symptoms and how these can be controlled. Although humans, with over a century of clinical observations, remain the obvious target of study, the mouse, with a relatively short lifespan, easy genetic accessibility and close relatedness to humans, is the tool par excellence to model aging-related phenotypes and test strategies of intervention. Here we present the argument that mouse models with engineered defects in genome maintenance systems are especially important because they often exhibit a premature appearance of aging symptoms. Confirming studies on human segmental progeroid syndromes, most of which are based on heritable mutations in genes involved in genome maintenance, the results thus far obtained with mouse models strongly suggest that lifespan and onset of aging are directly related to the quality of DNA metabolism. This may be in keeping with the recent discovery of a possible 'universal survival' pathway that improves antioxidant defence and genome maintenance and simultaneously extends lifespan in the mouse and several invertebrate species. 相似文献
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Lisa A. Lesniewski Ashley E. Walker Grant D. Henson Mark W. Blimline Daniel W. Trott Gary C. Bosshardt Thomas J. LaRocca Brooke R. Lawson Melanie C. Zigler Anthony J. Donato 《Aging cell》2017,16(1):17-26
Inhibition of mammalian target of rapamycin, mTOR, extends lifespan and reduces age‐related disease. It is not known what role mTOR plays in the arterial aging phenotype or if mTOR inhibition by dietary rapamycin ameliorates age‐related arterial dysfunction. To explore this, young (3.8 ± 0.6 months) and old (30.3 ± 0.2 months) male B6D2F1 mice were fed a rapamycin supplemented or control diet for 6–8 weeks. Although there were few other notable changes in animal characteristics after rapamycin treatment, we found that glucose tolerance improved in old mice, but was impaired in young mice, after rapamycin supplementation (both P < 0.05). Aging increased mTOR activation in arteries evidenced by elevated S6K phosphorylation (P < 0.01), and this was reversed after rapamycin treatment in old mice (P < 0.05). Aging was also associated with impaired endothelium‐dependent dilation (EDD) in the carotid artery (P < 0.05). Rapamycin improved EDD in old mice (P < 0.05). Superoxide production and NADPH oxidase expression were higher in arteries from old compared to young mice (P < 0.05), and rapamycin normalized these (P < 0.05) to levels not different from young mice. Scavenging superoxide improved carotid artery EDD in untreated (P < 0.05), but not rapamycin‐treated, old mice. While aging increased large artery stiffness evidenced by increased aortic pulse‐wave velocity (PWV) (P < 0.01), rapamycin treatment reduced aortic PWV (P < 0.05) and collagen content (P < 0.05) in old mice. Aortic adenosine monophosphate‐activated protein kinase (AMPK) phosphorylation and expression of the cell cycle‐related proteins PTEN and p27kip were increased with rapamycin treatment in old mice (all P < 0.05). Lastly, aging resulted in augmentation of the arterial senescence marker, p19 (P < 0.05), and this was ameliorated by rapamycin treatment (P < 0.05). These results demonstrate beneficial effects of rapamycin treatment on arterial function in old mice and suggest these improvements are associated with reduced oxidative stress, AMPK activation and increased expression of proteins involved in the control of the cell cycle. 相似文献
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Redox regulation of SUMO enzymes is required for ATM activity and survival in oxidative stress 
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下载免费PDF全文 Nicolas Stankovic‐Valentin Katarzyna Drzewicka Cornelia König Elmar Schiebel Frauke Melchior 《The EMBO journal》2016,35(12):1312-1329
To sense and defend against oxidative stress, cells depend on signal transduction cascades involving redox‐sensitive proteins. We previously identified SUMO (small ubiquitin‐related modifier) enzymes as downstream effectors of reactive oxygen species (ROS). Hydrogen peroxide transiently inactivates SUMO E1 and E2 enzymes by inducing a disulfide bond between their catalytic cysteines. How important their oxidation is in light of many other redox‐regulated proteins has however been unclear. To selectively disrupt this redox switch, we identified a catalytically fully active SUMO E2 enzyme variant (Ubc9 D100A) with strongly reduced propensity to maintain a disulfide with the E1 enzyme in vitro and in cells. Replacement of Ubc9 by this variant impairs cell survival both under acute and mild chronic oxidative stresses. Intriguingly, Ubc9 D100A cells fail to maintain activity of the ATM–Chk2 DNA damage response pathway that is induced by hydrogen peroxide. In line with this, these cells are also more sensitive to the ROS‐producing chemotherapeutic drugs etoposide/Vp16 and Ara‐C. These findings reveal that SUMO E1~E2 oxidation is an essential redox switch in oxidative stress. 相似文献