Regulation of lifespan by neural excitation and REST
| Autor: | Monica P. Colaiácovo, Bruce A. Yankner, Joseph M. Zullo, David A. Bennett, William H. Klein, Derek Drake, Patrick O’Hern, Noah Davidsohn, Sameer C. Dhamne, Liviu Aron, Chai An Mao, George M. Church, Alexander Rotenberg |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Aging Mice 129 Strain media_common.quotation_subject Longevity Mice Transgenic FOXO1 Article Transcriptome Mice 03 medical and health sciences 0302 clinical medicine Biological neural network medicine Animals Humans Caenorhabditis elegans Caenorhabditis elegans Proteins Transcription factor media_common Mice Knockout Neurons Regulation of gene expression Multidisciplinary biology Brain RNA-Binding Proteins Forkhead Transcription Factors biology.organism_classification Cell biology DNA-Binding Proteins Mice Inbred C57BL Repressor Proteins 030104 developmental biology medicine.anatomical_structure Cerebral cortex RNA Interference 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | The mechanisms that extend lifespan in humans are poorly understood. Here we show that extended longevity in humans is associated with a distinct transcriptome signature in the cerebral cortex that is characterized by downregulation of genes related to neural excitation and synaptic function. In Caenorhabditis elegans, neural excitation increases with age and inhibition of excitation globally, or in glutamatergic or cholinergic neurons, increases longevity. Furthermore, longevity is dynamically regulated by the excitatory–inhibitory balance of neural circuits. The transcription factor REST is upregulated in humans with extended longevity and represses excitation-related genes. Notably, REST-deficient mice exhibit increased cortical activity and neuronal excitability during ageing. Similarly, loss-of-function mutations in the C. elegans REST orthologue genes spr-3 and spr-4 elevate neural excitation and reduce the lifespan of long-lived daf-2 mutants. In wild-type worms, overexpression of spr-4 suppresses excitation and extends lifespan. REST, SPR-3, SPR-4 and reduced excitation activate the longevity-associated transcription factors FOXO1 and DAF-16 in mammals and worms, respectively. These findings reveal a conserved mechanism of ageing that is mediated by neural circuit activity and regulated by REST. Studies of humans, mice and nematodes reveal a conserved role of neural activity and the transcription factor REST in extended longevity. |
| Databáze: | OpenAIRE |
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