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  • NLM标题： Aging Cell
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  • 1.

    【2hr】Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin

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    机译 DNA修复蛋白ERCC1的缺乏触发了人类成纤维细胞和小鼠皮肤衰老与凋亡之间的联系
    摘要：ERCC1 (excision repair cross complementing‐group 1) is a mammalian endonuclease that incises the damaged strand of DNA during nucleotide excision repair and interstrand cross‐link repair. mice, carrying one null and one hypomorphic allele, have been widely used to study aging due to accelerated aging phenotypes in numerous organs and their shortened lifespan. mice display combined features of human progeroid and cancer‐prone syndromes. Although several studies report cellular senescence and apoptosis associated with the premature aging of mice, the link between these two processes and their physiological relevance in the phenotypes of mice are incompletely understood. Here, we show that ERCC1 depletion, both in cultured human fibroblasts and the skin of mice, initially induces cellular senescence and, importantly, increased expression of several SASP (senescence‐associated secretory phenotype) factors. Cellular senescence induced by ERCC1 deficiency was dependent on activity of the p53 tumor‐suppressor protein. In turn, TNFα secreted by senescent cells induced apoptosis, not only in neighboring ERCC1‐deficient nonsenescent cells, but also cell autonomously in the senescent cells themselves. In addition, expression of the stem cell markers p63 and Lgr6 was significantly decreased in mouse skin, where the apoptotic cells are localized, compared to age‐matched wild‐type skin, possibly due to the apoptosis of stem cells. These data suggest that ERCC1‐depleted cells become susceptible to apoptosis via TNFα secreted from neighboring senescent cells. We speculate that parts of the premature aging phenotypes and shortened health‐ or lifespan may be due to stem cell depletion through apoptosis promoted by senescent cells.
  • 2.

    【2hr】Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

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    机译 Tenomodulin表达的丧失是与年龄相关的椎间盘退变的危险因素
    摘要：The intervertebral disc (IVD) degeneration is thought to be closely related to ingrowth of new blood vessels. However, the impact of anti‐angiogenic factors in the maintenance of IVD avascularity remains unknown. Tenomodulin ( ) is a tendon/ligament‐specific marker and anti‐angiogenic factor with abundant expression in the IVD. It is still unclear whether Tnmd contributes to the maintenance of IVD homeostasis, acting to inhibit vascular ingrowth into this normally avascular tissue. Herein, we investigated whether IVD degeneration could be induced spontaneously by the absence of . Our results showed that Tnmd was expressed in an age‐dependent manner primarily in the outer annulus fibrous (OAF) and it was downregulated at 6 months of age corresponding to the early IVD degeneration stage in mice. knockout ( ) mice exhibited more rapid progression of age‐related IVD degeneration. These signs include smaller collagen fibril diameter, markedly lower compressive stiffness, reduced multiple IVD‐ and tendon/ligament‐related gene expression, induced angiogenesis, and macrophage infiltration in OAF, as well as more hypertrophic‐like chondrocytes in the nucleus pulposus. In addition, and chondromodulin I ( , the only homologous gene to ) double knockout ( ) mice displayed not only accelerated IVD degeneration, but also ectopic bone formation of IVD. Lastly, the absence of in OAF‐derived cells promoted p65 and matrix metalloproteinases upregulation, and increased migratory capacity of human umbilical vein endothelial cells. In sum, our data provide clear evidences that Tnmd acts as an angiogenic inhibitor in the IVD homeostasis and protects against age‐related IVD degeneration. Targeting Tnmd may represent a novel therapeutic strategy for attenuating age‐related IVD degeneration.
  • 3.

    【2hr】Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

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    机译 小鼠生理和加速衰老过程中衰老细胞积累的组织特异性
    摘要：Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence‐associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. ERCC1‐XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome. Humans or mice with reduced expression of this enzyme age rapidly due to increased levels of spontaneous, genotoxic stress. Here, we asked whether this corresponds to an increased level of senescent cells. and mRNA were increased ~15‐fold in peripheral lymphocytes from 4‐ to 5‐month‐old and 2.5‐year‐old wild‐type (WT) mice, suggesting that these animals exhibit a similar biological age. and mRNA were elevated in 10 of 13 tissues analyzed from 4‐ to 5‐month‐old mice, indicating where endogenous DNA damage drives senescence in vivo. Aged WT mice had similar increases of and mRNA in the same 10 tissues as the mutant mice. Senescence‐associated β–galactosidase activity and p21 protein also were increased in tissues of the progeroid and aged mice, while Lamin B1 mRNA and protein levels were diminished. In mice with a luciferase reporter, bioluminescence rose steadily with age, particularly in lung, thymus, and pancreas. These data illustrate where senescence occurs with natural and accelerated aging in mice and the relative extent of senescence among tissues. Interestingly, senescence was greater in male mice until the end of life. The similarities between and aged WT mice support the conclusion that the DNA repair‐deficient mice accurately model the age‐related accumulation of senescent cells, albeit six‐times faster.
  • 4.

    【2hr】Mitochondrial function in skeletal myofibers is controlled by a TRF2‐SIRT3 axis over lifetime

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    机译 骨骼肌纤维的线粒体功能在整个生命周期中受TRF2-SIRT3轴控制
    摘要：Telomere shortening follows a developmentally regulated process that leads to replicative senescence of dividing cells. However, whether telomere changes are involved in postmitotic cell function and aging remains elusive. In this study, we discovered that the level of the TRF2 protein, a key telomere‐capping protein, declines in human skeletal muscle over lifetime. In cultured human myotubes, TRF2 downregulation did not trigger telomere dysfunction, but suppressed expression of the mitochondrial Sirtuin 3 gene ( ) leading to mitochondrial respiration dysfunction and increased levels of reactive oxygen species. Importantly, restoring the Sirt3 level in TRF2‐compromised myotubes fully rescued mitochondrial functions. Finally, targeted ablation of the gene in mouse skeletal muscle leads to mitochondrial dysfunction and sirt3 downregulation similarly to those of TRF2‐compromised human myotubes. Altogether, these results reveal a TRF2‐SIRT3 axis controlling muscle mitochondrial function. We propose that this axis connects developmentally regulated telomere changes to muscle redox metabolism.
  • 5.

    【2hr】Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

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    机译 帕金森氏病，衰老和成人神经发生：Wnt /β-catenin信号传导是揭开内源性大脑修复之谜的关键
    摘要：A common hallmark of age‐dependent neurodegenerative diseases is an impairment of adult neurogenesis. (WβC) signalling is a vital pathway for dopaminergic (DAergic) neurogenesis and an essential signalling system during embryonic development and aging, the most critical risk factor for Parkinson's disease (PD). To date, there is no known cause or cure for PD. Here we focus on the potential to reawaken the impaired neurogenic niches to rejuvenate and repair the aged PD brain. Specifically, we highlight WβC signalling in the plasticity of the subventricular zone (SVZ), the largest germinal region in the mature brain innervated by nigrostriatal DAergic terminals, and the mesencephalic aqueduct‐periventricular region (Aq‐PVR) Wnt‐sensitive niche, which is in proximity to the SNpc and harbors neural stem progenitor cells (NSCs) with DAergic potential. The hallmark of the WβC pathway is the cytosolic accumulation of β‐catenin, which enters the nucleus and associates with T cell factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors, leading to the transcription of target genes. Here, we underscore the dynamic interplay between DAergic innervation and astroglial‐derived factors regulating WβC‐dependent transcription of key genes orchestrating NSC proliferation, survival, migration and differentiation. Aging, inflammation and oxidative stress synergize with neurotoxin exposure in “turning off” the WβC neurogenic switch via down‐regulation of the nuclear factor erythroid‐2‐related factor 2/Wnt‐regulated signalosome, a key player in the maintenance of antioxidant self‐defense mechanisms and NSC homeostasis. Harnessing WβC‐signalling in the aged PD brain can thus restore neurogenesis, rejuvenate the microenvironment, and promote neurorescue and regeneration.
  • 6.

    【2hr】LSD1 contributes to programmed oocyte death by regulating the transcription of autophagy adaptor SQSTM1/p62

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    机译 LSD1通过调节自噬衔接子SQSTM1 / p62的转录有助于程序性卵母细胞死亡
    摘要：In female mammals, the size of the initially established primordial follicle (PF) pool within the ovaries determines the reproductive lifespan of females. Interestingly, the establishment of the PF pool is accompanied by a remarkable programmed oocyte loss for unclear reasons. Although apoptosis and autophagy are involved in the process of oocyte loss, the underlying mechanisms require substantial study. Here, we identify a new role of lysine‐specific demethylase 1 (LSD1) in controlling the fate of oocytes in perinatal mice through regulating the level of autophagy. Our results show that the relatively higher level of LSD1 in fetal ovaries sharply reduces from 18.5 postcoitus (dpc). Meanwhile, the level of autophagy increases while oocytes are initiating programmed death. Specific disruption of LSD1 resulted in significantly increased autophagy and obviously decreased oocyte number compared with the control. Conversely, the oocyte number is remarkably increased by the overexpression of in ovaries. We further demonstrated that LSD1 exerts its role by regulating the transcription of and affecting autophagy level through its H3K4me2 demethylase activity. Finally, in physiological conditions, a decrease in LSD1 level leads to an increased level of autophagy in the oocyte when a large number of oocytes are being lost. Collectively, LSD1 may be one of indispensible epigenetic molecules who protects oocytes against preterm death through repressing the autophagy level in a time‐specific manner. And epigenetic modulation contributes to programmed oocyte death by regulating autophagy in mice.
  • 7.

    【2hr】Cellular senescence contributes to age‐dependent changes in circulating extracellular vesicle cargo and function

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    机译 细胞衰老有助于循环中细胞外囊泡货物和功能的年龄依赖性变化
    摘要：Extracellular vesicles (EVs) have emerged as important regulators of inter‐cellular and inter‐organ communication, in part via the transfer of their cargo to recipient cells. Although circulating EVs have been previously studied as biomarkers of aging, how circulating EVs change with age and the underlying mechanisms that contribute to these changes are poorly understood. Here, we demonstrate that aging has a profound effect on the circulating EV pool, as evidenced by changes in concentration, size, and cargo. Aging also alters particle function; treatment of cells with EV fractions isolated from old plasma reduces macrophage responses to lipopolysaccharide, increases phagocytosis, and reduces endothelial cell responses to vascular endothelial growth factor compared to cells treated with young EV fractions. Depletion studies indicate that CD63 particles mediate these effects. Treatment of macrophages with EV‐like particles revealed that old particles increased the expression of EV miRNAs in recipient cells. Transfection of cells with microRNA mimics recapitulated some of the effects seen with old EV‐like particles. Investigation into the underlying mechanisms using bone marrow transplant studies revealed circulating cell age does not substantially affect the expression of aging‐associated circulating EV miRNAs in old mice. Instead, we show that cellular senescence contributes to changes in particle cargo and function. Notably, senolytic treatment of old mice shifted plasma particle cargo and function toward that of a younger phenotype. Collectively, these results demonstrate that senescent cells contribute to changes in plasma EVs with age and suggest a new mechanism by which senescent cells can affect cellular functions throughout the body.
  • 8.

    【2hr】A high‐fat diet reverses metabolic disorders and premature aging by modulating insulin and IGF1 signaling in SIRT6 knockout mice

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    机译 高脂饮食通过调节SIRT6基因敲除小鼠的胰岛素和IGF1信号传导来逆转代谢紊乱和过早衰老
    摘要：Mammalian sirtuin 6 (SIRT6) is involved in the regulation of many essential processes, especially metabolic homeostasis. SIRT6 knockout mice undergo premature aging and die at age ~4 weeks. Severe glycometabolic disorders have been found in SIRT6 knockout mice, and whether a dietary intervention can rescue SIRT6 knockout mice remains unknown. In our study, we found that at the same calorie intake, a high‐fat diet dramatically increased the lifespan of SIRT6 knockout mice to 26 weeks (males) and 37 weeks (females), reversed multi‐organ atrophy, and reduced body weight, hypoglycemia, and premature aging. Furthermore, the high‐fat diet partially but significantly normalized the global gene expression profile in SIRT6 knockout mice. Regarding the mechanism, excessive glucose uptake and glycolysis induced by the SIRT6 deficiency were attenuated in skeletal muscle through inhibition of insulin and IGF1 signaling by the high‐fat diet. Similarly, fatty acids but not ketone bodies inhibited glucose uptake, glycolysis, and senescence in SIRT6 knockout fibroblasts, whereas PI3K inhibition antagonized the effects of a high‐fatty‐acid medium in vitro. Overall, the high‐fat diet dramatically reverses numerous consequences of SIRT6 deficiency through modulation of insulin and IGF1 signaling, providing a new basis for elucidation of SIRT6 and fatty‐acid functions and supporting novel therapeutic approaches against metabolic disorders and aging‐related diseases.
  • 9.

    【2hr】Physical fitness in community‐dwelling older adults is linked to dietary intake, gut microbiota, and metabolomic signatures

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    机译 社区居民中老年人的身体健康与饮食摄入，肠道菌群和代谢组学特征有关
    摘要：When humans age, changes in body composition arise along with lifestyle‐associated disorders influencing fitness and physical decline. Here we provide a comprehensive view of dietary intake, physical activity, gut microbiota (GM), and host metabolome in relation to physical fitness of 207 community‐dwelling subjects aged +65 years. Stratification on anthropometric/body composition/physical performance measurements (ABPm) variables identified two phenotypes (high/low‐fitness) clearly linked to dietary intake, physical activity, GM, and host metabolome patterns. Strikingly, despite a higher energy intake high‐fitness subjects were characterized by leaner bodies and lower fasting proinsulin‐C‐peptide/blood glucose levels in a mechanism likely driven by higher dietary fiber intake, physical activity and increased abundance of Bifidobacteriales and Clostridiales species in GM and associated metabolites (i.e., enterolactone). These factors explained 50.1% of the individual variation in physical fitness. We propose that targeting dietary strategies for modulation of GM and host metabolome interactions may allow establishing therapeutic approaches to delay and possibly revert comorbidities of aging.
  • 10.

    【2hr】Transplanting cells from old but not young donors causes physical dysfunction in older recipients

    包量

    机译 从旧的而不是年轻的供体中移植细胞会导致老年人的身体功能障碍
    摘要：Adipose‐derived mesenchymal stem cell (ADSC)‐based regenerative therapies have shown potential for use in many chronic diseases. Aging diminishes stem cell regenerative potential, yet it is unknown whether stem cells from aged donors cause adverse effects in recipients. ADSCs can be obtained using minimally invasive approaches and possess low immunogenicity. Nevertheless, we found that transplanting ADSCs from old donors, but not those from young donors, induces physical dysfunction in older recipient mice. Using single‐cell transcriptomic analysis, we identified a naturally occurring senescent cell‐like population in ADSCs primarily from old donors that resembles in vitro‐generated senescent cells with regard to a number of key pathways. Our study reveals a previously unrecognized health concern due to ADSCs from old donors and lays the foundation for a new avenue of research to devise interventions to reduce harmful effects of ADSCs from old donors.
  • 11.

    【2hr】Heterochromatin loss as a determinant of progerin‐induced DNA damage in Hutchinson–Gilford Progeria

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    机译 异染色质的损失决定了哈钦森–吉尔福德早衰症中早老素诱导的DNA损伤的决定因素
    摘要：Hutchinson–Gilford progeria is a premature aging syndrome caused by a truncated form of lamin A called progerin. Progerin expression results in a variety of cellular defects including heterochromatin loss, DNA damage, impaired proliferation and premature senescence. It remains unclear how these different progerin‐induced phenotypes are temporally and mechanistically linked. To address these questions, we use a doxycycline‐inducible system to restrict progerin expression to different stages of the cell cycle. We find that progerin expression leads to rapid and widespread loss of heterochromatin in G1‐arrested cells, without causing DNA damage. In contrast, progerin triggers DNA damage exclusively during late stages of DNA replication, when heterochromatin is normally replicated, and preferentially in cells that have lost heterochromatin. Importantly, removal of progerin from G1‐arrested cells restores heterochromatin levels and results in no permanent proliferative impediment. Taken together, these results delineate the chain of events that starts with progerin expression and ultimately results in premature senescence. Moreover, they provide a proof of principle that removal of progerin from quiescent cells restores heterochromatin levels and their proliferative capacity to normal levels.
  • 12.

    【2hr】“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

    包量

    机译 作为预防和/或治疗阿尔茨海默氏病的靶标，“淀粉样β积累周期”
    摘要：The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting.
  • 13.

    【2hr】Mobilization‐based transplantation of young‐donor hematopoietic stem cells extends lifespan in mice

    包量

    机译 基于动员的年轻供体造血干细胞移植延长了小鼠的寿命
    摘要：Mammalian aging is associated with reduced tissue regeneration and loss of physiological integrity. With age, stem cells diminish in their ability to regenerate adult tissues, likely contributing to age‐related morbidity. Thus, we replaced aged hematopoietic stem cells (HSCs) with young‐donor HSCs using a novel mobilization‐enabled hematopoietic stem cell transplantation (HSCT) technology as an alternative to the highly toxic conditioning regimens used in conventional HSCT. Using this approach, we are the first to report an increase in median lifespan (12%) and a decrease in overall mortality hazard (HR: 0.42, CI: 0.273–0.638) in aged mice following transplantation of young‐donor HSCs. The increase in longevity was accompanied by reductions of frailty measures and increases in food intake and body weight of aged recipients. Young‐donor HSCs not only preserved youthful function within the aged bone marrow stroma, but also at least partially ameliorated dysfunctional hematopoietic phenotypes of aged recipients. This compelling evidence that mammalian health and lifespan can be extended through stem cell therapy adds a new category to the very limited list of successful anti‐aging/life‐extending interventions. Our findings have implications for further development of stem cell therapies for increasing health and lifespan.
  • 14.

    【2hr】Melatonin suppresses senescence‐derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L–mitophagy pathway

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    机译 褪黑素通过HSPA1L-线粒体途径抑制间充质干细胞中的衰老源性线粒体功能障碍
    摘要：Mesenchymal stem cells (MSCs) are a popular cell source for stem cell‐based therapy. However, continuous ex vivo expansion to acquire large amounts of MSCs for clinical study induces replicative senescence, causing decreased therapeutic efficacy in MSCs. To address this issue, we investigated the effect of melatonin on replicative senescence in MSCs. In senescent MSCs (late passage), replicative senescence decreased mitophagy by inhibiting mitofission, resulting in the augmentation of mitochondrial dysfunction. Treatment with melatonin rescued replicative senescence by enhancing mitophagy and mitochondrial function through upregulation of heat shock 70 kDa protein 1L (HSPA1L). More specifically, we found that melatonin‐induced HSPA1L binds to cellular prion protein (PrP ), resulting in the recruitment of PrP into the mitochondria. The HSPA1L‐PrP complex then binds to COX4IA, which is a mitochondrial complex IV protein, leading to an increase in mitochondrial membrane potential and anti‐oxidant enzyme activity. These protective effects were blocked by knockdown of HSPA1L. In a murine hindlimb ischemia model, melatonin‐treated senescent MSCs enhanced functional recovery by increasing blood flow perfusion, limb salvage, and neovascularization. This study, for the first time, suggests that melatonin protects MSCs against replicative senescence during ex vivo expansion for clinical application via mitochondrial quality control.
  • 15.

    【2hr】Age‐related changes to macrophages are detrimental to fracture healing in mice

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    机译 年龄相关性巨噬细胞变化不利于小鼠骨折愈合
    摘要：The elderly population suffers from higher rates of complications during fracture healing that result in increased morbidity and mortality. Inflammatory dysregulation is associated with increased age and is a contributing factor to the myriad of age‐related diseases. Therefore, we investigated age‐related changes to an important cellular regulator of inflammation, the macrophage, and the impact on fracture healing outcomes. We demonstrated that old mice (24 months) have delayed fracture healing with significantly less bone and more cartilage compared to young mice (3 months). The quantity of infiltrating macrophages into the fracture callus was similar in old and young mice. However, RNA‐seq analysis demonstrated distinct differences in the transcriptomes of macrophages derived from the fracture callus of old and young mice, with an up‐regulation of M1/pro‐inflammatory genes in macrophages from old mice as well as dysregulation of other immune‐related genes. Preventing infiltration of the fracture site by macrophages in old mice improved healing outcomes, with significantly more bone in the calluses of treated mice compared to age‐matched controls. After preventing infiltration by macrophages, the macrophages remaining within the fracture callus were collected and examined via RNA‐seq analysis, and their transcriptome resembled macrophages from young calluses. Taken together, infiltrating macrophages from old mice demonstrate detrimental age‐related changes, and depleting infiltrating macrophages can improve fracture healing in old mice.
  • 16.

    【2hr】TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer’s disease

    包量

    机译 TRPV1激活通过抑制阿尔茨海默病APP23 / PS45小鼠模型中的AMPAR内吞作用减轻认知和突触可塑性损伤
    摘要：Alzheimer's disease (AD) is one of the most common causes of neurodegenerative diseases in the elderly. The accumulation of amyloid‐β (Aβ) peptides is one of the pathological hallmarks of AD and leads to the impairments of synaptic plasticity and cognitive function. The transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel, is involved in synaptic plasticity and memory. However, the role of TRPV1 in AD pathogenesis remains largely elusive. Here, we reported that the expression of TRPV1 was decreased in the brain of APP23/PS45 double transgenic AD model mice. Genetic upregulation of TRPV1 by adeno‐associated virus (AAV) inhibited the APP processing and Aβ deposition in AD model mice. Meanwhile, upregulation of TRPV1 ameliorated the deficits of hippocampal CA1 long‐term potentiation (LTP) and spatial learning and memory through inhibiting GluA2‐containing α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) endocytosis. Furthermore, pharmacological activation of TRPV1 by capsaicin (1 mg/kg, i.p.), an agonist of TRPV1, dramatically reversed the impairments of hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, these results indicate that TRPV1 activation effectively ameliorates cognitive and synaptic functions through inhibiting AMPAR endocytosis in AD model mice and could be a novel molecule for AD treatment.
  • 17.

    【2hr】A lncRNA survey finds increases in neuroprotective LINC‐PINT in Parkinson’s disease substantia nigra

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    机译 lncRNA调查发现帕金森氏病黑质中神经保护性LINC-PINT增加
    摘要：Recent reports highlight regulatory functions of long noncoding RNAs (lncRNAs) in neurodegeneration and aging, but biomedical implications remain limited. Here, we report an rRNA‐depletion‐based long RNA‐Sequencing Resource of 65 substantia nigra, amygdala, and medial temporal gyrus samples from Parkinson's disease (PD) and matched control brains. Using a lncRNA‐focused analysis approach to identify functionally important transcripts, we discovered and prioritized many lncRNAs dysregulated in PD. Those included pronounced elevation of the P53‐induced noncoding transcript LINC‐PINT in the substantia nigra of PD patients, as well as in additional models of oxidative stress and PD. Intriguingly, we found that LINC‐PINT is a primarily neuronal transcript which showed conspicuous increases in maturing primary culture neurons. LINC‐PINT also accumulated in several brain regions of Alzheimer's and Huntington's disease patients and decreased with healthy brain aging, suggesting a general role in aging and neurodegeneration for this lncRNA. RNAi‐mediated depletion of LINC‐PINT exacerbated the death of cultured N2A and SH‐SY5Y cells exposed to oxidative stress, highlighting a previously undiscovered neuroprotective role for this tumor‐inducible lncRNA in the brains of patients with neurodegenerative disorders.
  • 18.

    【2hr】Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

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    机译 抑制USP7活性部分地通过恢复p53活性来选择性消除衰老细胞
    摘要：The accumulation of senescent cells (SnCs) is a causal factor of various age‐related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin‐specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin–proteasome system. This degradation increases the levels of p53, which in turn induces the pro‐apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL‐XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence‐associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy‐induced toxicities and treat age‐related diseases.
  • 19.

    【2hr】miR‐181a negatively modulates synaptic plasticity in hippocampal cultures and its inhibition rescues memory deficits in a mouse model of Alzheimer’s disease

    包量

    机译 miR-181a负调节海马培养物中的突触可塑性，其抑制作用可挽救阿尔茨海默氏病小鼠模型中的记忆缺陷
    摘要：MicroRNAs play a pivotal role in rapid, dynamic, and spatiotemporal modulation of synaptic functions. Among them, recent emerging evidence highlights that microRNA‐181a (miR‐181a) is particularly abundant in hippocampal neurons and controls the expression of key plasticity‐related proteins at synapses. We have previously demonstrated that miR‐181a was upregulated in the hippocampus of a mouse model of Alzheimer's disease (AD) and correlated with reduced levels of plasticity‐related proteins. Here, we further investigated the underlying mechanisms by which miR‐181a negatively modulated synaptic plasticity and memory. In primary hippocampal cultures, we found that an activity‐dependent upregulation of the microRNA‐regulating protein, translin, correlated with reduction of miR‐181a upon chemical long‐term potentiation (cLTP), which induced upregulation of GluA2, a predicted target for miR‐181a, and other plasticity‐related proteins. Additionally, Aβ treatment inhibited cLTP‐dependent induction of translin and subsequent reduction of miR‐181a, and cotreatment with miR‐181a antagomir effectively reversed the effects elicited by Aβ but did not rescue translin levels, suggesting that the activity‐dependent upregulation of translin was upstream of miR‐181a. In mice, a learning episode markedly decreased miR‐181a in the hippocampus and raised the protein levels of GluA2. Lastly, we observed that inhibition of miR‐181a alleviated memory deficits and increased GluA2 and GluA1 levels, without restoring translin, in the 3xTg‐AD model. Taken together, our results indicate that miR‐181a is a major negative regulator of the cellular events that underlie synaptic plasticity and memory through AMPA receptors, and importantly, Aβ disrupts this process by suppressing translin and leads to synaptic dysfunction and memory impairments in AD.
  • 20.

    【2hr】Sexual dimorphism in the nutritional requirement for adult lifespan in Drosophila melanogaster

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    机译 果蝇的成年寿命营养需求中的性二态性
    摘要：The nutritional requirements of have mostly been studied for development and reproduction, but the minimal requirements for adult male and female flies for lifespan have not been established. Following development on a complete diet, we find substantial sex difference in the basic nutritional requirement of adult flies for full length of life. Relative to females, males require less of each nutrient, and for some nutrients that are essential for development, adult males have no requirement at all for lifespan. The most extreme (and surprising) sex differences were that chronic cholesterol and vitamin deficiencies had no effect on the lifespan of adult males, but they greatly decreased lifespan in females. Female oogenesis rather than chromosomal karyotype and mating status is the key cause of this gender difference in life‐sustaining nutritional requirements. These data are important to the way we understand the mechanisms by which diet modifies lifespan.
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