FOXO protects against age-progressive axonal degeneration.

Abstract:

:Neurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age-progressive axonal degeneration in mammals. FOXO expression progressively increased in aging human and mouse brains. The nervous system-specific deletion of Foxo transcription factors in mice accelerates aging-related axonal tract degeneration, which is followed by motor dysfunction. This accelerated neurodegeneration is accompanied by levels of white matter astrogliosis and microgliosis in middle-aged Foxo knockout mice that are typically only observed in very old wild-type mice and other aged mammals, including humans. Mechanistically, axonal degeneration in nerve-specific Foxo knockout mice is associated with elevated mTORC1 activity and accompanying proteotoxic stress due to decreased Sestrin3 expression. Inhibition of mTORC1 by rapamycin treatment mimics FOXO action and prevented axonal degeneration in Foxo knockout mice with accelerated nervous system aging. Defining this central role for FOXO in neuroprotection during mammalian aging offers an invaluable window into the aging process itself.

journal_name

Aging Cell

journal_title

Aging cell

authors

Hwang I,Oh H,Santo E,Kim DY,Chen JW,Bronson RT,Locasale JW,Na Y,Lee J,Reed S,Toth M,Yu WH,Muller FL,Paik J

doi

10.1111/acel.12701

subject

Has Abstract

pub_date

2018-02-01 00:00:00

issue

1

eissn

1474-9718

issn

1474-9726

journal_volume

17

pub_type

杂志文章
  • Exercise-stimulated interleukin-15 is controlled by AMPK and regulates skin metabolism and aging.

    abstract::Aging is commonly associated with a structural deterioration of skin that compromises its barrier function, healing, and susceptibility to disease. Several lines of evidence show that these changes are driven largely by impaired tissue mitochondrial metabolism. While exercise is associated with numerous health benefit...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12341

    authors: Crane JD,MacNeil LG,Lally JS,Ford RJ,Bujak AL,Brar IK,Kemp BE,Raha S,Steinberg GR,Tarnopolsky MA

    更新日期:2015-08-01 00:00:00

  • Inhibition of histone acetyltransferase GCN5 extends lifespan in both yeast and human cell lines.

    abstract::Histone acetyltransferases (HATs) are important enzymes that transfer acetyl groups onto histones and thereby regulate both gene expression and chromosomal structures. Previous work has shown that the activation of sirtuins, which are histone deacetylases, can extend lifespan. This suggests that inhibiting HATs may ha...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13129

    authors: Huang B,Zhong D,Zhu J,An Y,Gao M,Zhu S,Dang W,Wang X,Yang B,Xie Z

    更新日期:2020-04-01 00:00:00

  • GSK3-ARC/Arg3.1 and GSK3-Wnt signaling axes trigger amyloid-β accumulation and neuroinflammation in middle-aged Shugoshin 1 mice.

    abstract::The cerebral amyloid-β accumulation that begins in middle age is considered the critical triggering event in the pathogenesis of late-onset Alzheimer's disease (LOAD). However, the molecular mechanism remains elusive. The Shugoshin 1 (Sgo1-/+ ) mouse model, a model for mitotic cohesinopathy-genomic instability that is...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13221

    authors: Rao CV,Farooqui M,Madhavaram A,Zhang Y,Asch AS,Yamada HY

    更新日期:2020-10-01 00:00:00

  • Using measures of single-cell physiology and physiological state to understand organismic aging.

    abstract::Genetically identical organisms in homogeneous environments have different lifespans and healthspans. These differences are often attributed to stochastic events, such as mutations and 'epimutations', changes in DNA methylation and chromatin that change gene function and expression. But work in the last 10 years has r...

    journal_title:Aging cell

    pub_type: 杂志文章,评审

    doi:10.1111/acel.12424

    authors: Mendenhall A,Driscoll M,Brent R

    更新日期:2016-02-01 00:00:00

  • Sulforaphane prevents age-associated cardiac and muscular dysfunction through Nrf2 signaling.

    abstract::Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13261

    authors: Bose C,Alves I,Singh P,Palade PT,Carvalho E,Børsheim E,Jun SR,Cheema A,Boerma M,Awasthi S,Singh SP

    更新日期:2020-11-01 00:00:00

  • Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction.

    abstract::Caloric restriction (CR) can delay onset of several age-related pathophysiologies and extend lifespan in various species, including rodents. CR also induces metabolic remodeling involved in activation of lipid metabolism, enhancement of mitochondrial biogenesis, and reduction of oxidative stress in white adipose tissu...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12576

    authors: Fujii N,Narita T,Okita N,Kobayashi M,Furuta Y,Chujo Y,Sakai M,Yamada A,Takeda K,Konishi T,Sudo Y,Shimokawa I,Higami Y

    更新日期:2017-06-01 00:00:00

  • Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection.

    abstract::Recent studies demonstrate that aging exacerbates hypertension-induced cognitive decline, but the specific age-related mechanisms remain elusive. Cerebral microhemorrhages (CMHs) are associated with rupture of small intracerebral vessels and are thought to progressively impair neuronal function. To determine whether a...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12315

    authors: Toth P,Tarantini S,Springo Z,Tucsek Z,Gautam T,Giles CB,Wren JD,Koller A,Sonntag WE,Csiszar A,Ungvari Z

    更新日期:2015-06-01 00:00:00

  • Loss of HDAC3 contributes to meiotic defects in aged oocytes.

    abstract::Maternal age-related decline in oocyte quality is associated with meiotic defects, but the underlying mechanisms remain to be explored. Histone deacetylase 3 (HDAC3) has been shown to govern multiple cellular events via deacetylating diverse substrates. We previously found that HDAC3 could promote meiotic apparatus as...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13036

    authors: He Y,Li X,Gao M,Liu H,Gu L

    更新日期:2019-12-01 00:00:00

  • Dysfunction of the unfolded protein response increases neurodegeneration in aged rat hippocampus following proteasome inhibition.

    abstract::Dysfunctions of the ubiquitin proteasome system (UPS) have been proposed to be involved in the aetiology and/or progression of several age-related neurodegenerative disorders. However, the mechanisms linking proteasome dysfunction to cell degeneration are poorly understood. We examined in young and aged rat hippocampu...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2009.00519.x

    authors: Gavilán MP,Pintado C,Gavilán E,Jiménez S,Ríos RM,Vitorica J,Castaño A,Ruano D

    更新日期:2009-12-01 00:00:00

  • Neuronal control of lipid metabolism by STR-2 G protein-coupled receptor promotes longevity in Caenorhabditis elegans.

    abstract::The G protein-coupled receptor (GPCR) encoding family of genes constitutes more than 6% of genes in Caenorhabditis elegans genome. GPCRs control behavior, innate immunity, chemotaxis, and food search behavior. Here, we show that C. elegans longevity is regulated by a chemosensory GPCR STR-2, expressed in AWC and ASI a...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13160

    authors: Dixit A,Sandhu A,Modi S,Shashikanth M,Koushika SP,Watts JL,Singh V

    更新日期:2020-06-01 00:00:00

  • Reversal of aging-associated hippocampal synaptic plasticity deficits by reductants via regulation of thiol redox and NMDA receptor function.

    abstract::Deficits in learning and memory accompanied by age-related neurodegenerative diseases are closely related to the impairment of synaptic plasticity. In this study, we investigated the role of thiol redox status in the modulation of the N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) in CA1 ...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2010.00595.x

    authors: Yang YJ,Wu PF,Long LH,Yu DF,Wu WN,Hu ZL,Fu H,Xie N,Jin Y,Ni L,Wang JZ,Wang F,Chen JG

    更新日期:2010-10-01 00:00:00

  • Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age-related insulin resistance.

    abstract::While age-related insulin resistance and hyperinsulinemia are usually considered to be secondary to changes in muscle, the liver also plays a key role in whole-body insulin handling and its role in age-related changes in insulin homeostasis is largely unknown. Here, we show that patent pores called 'fenestrations' are...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12481

    authors: Mohamad M,Mitchell SJ,Wu LE,White MY,Cordwell SJ,Mach J,Solon-Biet SM,Boyer D,Nines D,Das A,Catherine Li SY,Warren A,Hilmer SN,Fraser R,Sinclair DA,Simpson SJ,de Cabo R,Le Couteur DG,Cogger VC

    更新日期:2016-08-01 00:00:00

  • Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice.

    abstract::Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age-related disease. The molecula...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13159

    authors: Roh JD,Houstis N,Yu A,Chang B,Yeri A,Li H,Hobson R,Lerchenmüller C,Vujic A,Chaudhari V,Damilano F,Platt C,Zlotoff D,Lee RT,Shah R,Jerosch-Herold M,Rosenzweig A

    更新日期:2020-06-01 00:00:00

  • The true face of JNK activation in apoptosis.

    abstract::Age-associated changes in apoptotic rates have been observed in a number of different tissues. While the implications of these findings remain unclear, a better understanding of how apoptosis is regulated may further our understanding of the aging process. The role of the JNK pathway in apoptosis has been highly contr...

    journal_title:Aging cell

    pub_type: 杂志文章,评审

    doi:10.1046/j.1474-9728.2002.00014.x

    authors: Lin A,Dibling B

    更新日期:2002-12-01 00:00:00

  • Rifampicin reduces advanced glycation end products and activates DAF-16 to increase lifespan in Caenorhabditis elegans.

    abstract::Advanced glycation end products (AGEs) are formed when glucose reacts nonenzymatically with proteins; these modifications are implicated in aging and pathogenesis of many age-related diseases including type II diabetes, atherosclerosis, and neurodegenerative disorders. Thus, pharmaceutical interventions that can reduc...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12327

    authors: Golegaonkar S,Tabrez SS,Pandit A,Sethurathinam S,Jagadeeshaprasad MG,Bansode S,Sampathkumar SG,Kulkarni MJ,Mukhopadhyay A

    更新日期:2015-06-01 00:00:00

  • JNK modifies neuronal metabolism to promote proteostasis and longevity.

    abstract::Aging is associated with a progressive loss of tissue and metabolic homeostasis. This loss can be delayed by single-gene perturbations, increasing lifespan. How such perturbations affect metabolic and proteostatic networks to extend lifespan remains unclear. Here, we address this question by comprehensively characteri...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12849

    authors: Wang L,Davis SS,Borch Jensen M,Rodriguez-Fernandez IA,Apaydin C,Juhasz G,Gibson BW,Schilling B,Ramanathan A,Ghaemmaghami S,Jasper H

    更新日期:2019-06-01 00:00:00

  • High-fat diet protects the blood-brain barrier in an Alzheimer's disease mouse model.

    abstract::Type 2 diabetes (T2D) is associated with increased risk of Alzheimer's disease (AD). There is evidence for impaired blood-brain barrier (BBB) in both diseases, but its role in the interplay between them is not clear. Here, we investigated the effects of high-fat diet (HFD), a model for T2D, on the Tg2576 mouse model o...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12818

    authors: Elhaik Goldman S,Goez D,Last D,Naor S,Liraz Zaltsman S,Sharvit-Ginon I,Atrakchi-Baranes D,Shemesh C,Twitto-Greenberg R,Tsach S,Lotan R,Leikin-Frenkel A,Shish A,Mardor Y,Schnaider Beeri M,Cooper I

    更新日期:2018-10-01 00:00:00

  • Hsp90β interacts with MDM2 to suppress p53-dependent senescence during skeletal muscle regeneration.

    abstract::Cellular senescence plays both beneficial and detrimental roles in embryonic development and tissue regeneration, while the underlying mechanism remains elusive. Recent studies disclosed the emerging roles of heat-shock proteins in regulating muscle regeneration and homeostasis. Here, we found that Hsp90β, but not Hsp...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13003

    authors: He MY,Xu SB,Qu ZH,Guo YM,Liu XC,Cong XX,Wang JF,Low BC,Li L,Wu Q,Lin P,Yan SG,Bao Z,Zhou YT,Zheng LL

    更新日期:2019-10-01 00:00:00

  • MiR-103-3p targets the m6 A methyltransferase METTL14 to inhibit osteoblastic bone formation.

    abstract::Impaired osteoblast function is involved in osteoporosis, and microRNA (miRNA) dysregulation may cause abnormal osteoblast osteogenic activity. However, the influence of miRNA on osteoblast activity and the underlying mechanisms remain elusive. In this study, miR-103-3p was found to be negatively correlated with bone ...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13298

    authors: Sun Z,Wang H,Wang Y,Yuan G,Yu X,Jiang H,Wu Q,Yang B,Hu Z,Shi F,Cao X,Zhang S,Guo T,Zhao J

    更新日期:2021-01-13 00:00:00

  • Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice.

    abstract::Dietary restriction (DR) and rapamycin extend healthspan and life span across multiple species. We have recently shown that DR in progeroid DNA repair-deficient mice dramatically extended healthspan and trippled life span. Here, we show that rapamycin, while significantly lowering mTOR signaling, failed to improve lif...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13302

    authors: Birkisdóttir MB,Jaarsma D,Brandt RMC,Barnhoorn S,van Vliet N,Imholz S,van Oostrom CT,Nagarajah B,Portilla Fernández E,Roks AJM,Elgersma Y,van Steeg H,Ferreira JA,Pennings JLA,Hoeijmakers JHJ,Vermeij WP,Dollé MET

    更新日期:2021-01-23 00:00:00

  • How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes.

    abstract::A huge amount of evidence has implicated amyloid beta (A beta) peptides and other derivatives of the amyloid precursor protein (beta APP) as central to the pathogenesis of Alzheimer's disease (AD). It is also widely recognized that age is the most important risk factor for AD and that the innate immune system plays a ...

    journal_title:Aging cell

    pub_type: 杂志文章,评审

    doi:10.1111/j.1474-9728.2004.00101.x

    authors: Blasko I,Stampfer-Kountchev M,Robatscher P,Veerhuis R,Eikelenboom P,Grubeck-Loebenstein B

    更新日期:2004-08-01 00:00:00

  • Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation.

    abstract::Pre-lamin A and progerin have been implicated in normal aging, and the pathogenesis of age-related degenerative diseases is termed 'laminopathies'. Here, we show that mature lamin A has an essential role in cellular fitness and that oxidative damage to lamin A is involved in cellular senescence. Primary human dermal f...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2011.00750.x

    authors: Pekovic V,Gibbs-Seymour I,Markiewicz E,Alzoghaibi F,Benham AM,Edwards R,Wenhert M,von Zglinicki T,Hutchison CJ

    更新日期:2011-12-01 00:00:00

  • Ventriculomegaly associated with ependymal gliosis and declines in barrier integrity in the aging human and mouse brain.

    abstract::Age-associated ventriculomegaly is typically attributed to neurodegeneration; however, additional factors might initiate or contribute to progressive ventricular expansion. By directly linking postmortem human MRI sequences with histological features of periventricular tissue, we show that substantial lateral ventricl...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12184

    authors: Shook BA,Lennington JB,Acabchuk RL,Halling M,Sun Y,Peters J,Wu Q,Mahajan A,Fellows DW,Conover JC

    更新日期:2014-04-01 00:00:00

  • Suppression of IGF-I signals in neural stem cells enhances neurogenesis and olfactory function during aging.

    abstract::Downregulation of insulin-like growth factor (IGF) pathways prolongs lifespan in various species, including mammals. Still, the cellular mechanisms by which IGF signaling controls the aging trajectory of individual organs are largely unknown. Here, we asked whether suppression of IGF-I receptor (IGF-1R) in adult stem ...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12365

    authors: Chaker Z,Aïd S,Berry H,Holzenberger M

    更新日期:2015-10-01 00:00:00

  • Age-related changes in regional brain mitochondria from Fischer 344 rats.

    abstract::Brain mitochondrial function has been posited to decline with aging. In order to test this hypothesis, cortical and striatal mitochondria were isolated from Fischer 344 rats at 2, 5, 11, 24 and 33 months of age. Mitochondrial membrane potential remained stable through 24 months, declining slightly in mitochondria from...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2005.00156.x

    authors: LaFrance R,Brustovetsky N,Sherburne C,Delong D,Dubinsky JM

    更新日期:2005-06-01 00:00:00

  • The chronological life span of Saccharomyces cerevisiae.

    abstract::Simple model systems have played an important role in the discovery of fundamental mechanisms of aging. Studies in yeast, worms and fruit flies have resulted in the identification of proteins and signalling pathways that regulate stress resistance and longevity. New findings indicate that these pathways may have evolv...

    journal_title:Aging cell

    pub_type: 杂志文章,评审

    doi:10.1046/j.1474-9728.2003.00033.x

    authors: Fabrizio P,Longo VD

    更新日期:2003-04-01 00:00:00

  • Endoplasmic reticulum stress occurs downstream of GluN2B subunit of N-methyl-d-aspartate receptor in mature hippocampal cultures treated with amyloid-β oligomers.

    abstract::Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting both the hippocampus and the cerebral cortex. Reduced synaptic density that occurs early in the disease process seems to be partially due to the overactivation of N-methyl-d-aspartate receptors (NMDARs) leading to excitotoxicity. Recently, ...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2012.00848.x

    authors: Costa RO,Lacor PN,Ferreira IL,Resende R,Auberson YP,Klein WL,Oliveira CR,Rego AC,Pereira CM

    更新日期:2012-10-01 00:00:00

  • ING1a expression increases during replicative senescence and induces a senescent phenotype.

    abstract::The ING family of tumor suppressor proteins affects cell growth, apoptosis and response to DNA damage by modulating chromatin structure through association with different HAT and HDAC complexes. The major splicing isoforms of the ING1 locus are ING1a and INGlb. While INGlb plays a role in inducing apoptosis, the funct...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2008.00427.x

    authors: Soliman MA,Berardi P,Pastyryeva S,Bonnefin P,Feng X,Colina A,Young D,Riabowol K

    更新日期:2008-12-01 00:00:00

  • Age-related sensitivity to endotoxin-induced liver inflammation: Implication of inflammasome/IL-1β for steatohepatitis.

    abstract::Aging is associated with increased vulnerability to inflammatory challenge. However, the effects of altered inflammatory response on the metabolic status of tissues or organs are not well documented. In this study, we present evidence demonstrating that lipopolysaccharide (LPS)-induced upregulation of the inflammasome...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12305

    authors: Chung KW,Lee EK,Kim DH,An HJ,Kim ND,Im DS,Lee J,Yu BP,Chung HY

    更新日期:2015-08-01 00:00:00

  • miR-370 and miR-373 regulate the pathogenesis of osteoarthritis by modulating one-carbon metabolism via SHMT-2 and MECP-2, respectively.

    abstract::The aim of this study was to determine the mechanism underlying the association between one-carbon metabolism and DNA methylation during chronic degenerative joint disorder, osteoarthritis (OA). Articular chondrocytes were isolated from human OA cartilage and normal cartilage biopsied, and the degree of cartilage degr...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12363

    authors: Song J,Kim D,Chun CH,Jin EJ

    更新日期:2015-10-01 00:00:00