Regulation of lifespan by neural excitation and REST

Joseph M. Zullo, Derek Drake, Liviu Aron, Patrick O’Hern, Sameer C. Dhamne, Noah Davidsohn, Chai-An Mao, William H. Klein, Alexander Rotenberg, David A. Bennett, George M. Church, Monica P. Colaiácovo and Bruce A. Yankner ()
Additional contact information
Joseph M. Zullo: Harvard Medical School
Derek Drake: Harvard Medical School
Liviu Aron: Harvard Medical School
Patrick O’Hern: Harvard Medical School
Sameer C. Dhamne: Boston Children’s Hospital, Harvard Medical School
Noah Davidsohn: Harvard Medical School
Chai-An Mao: The University of Texas McGovern Medical School
William H. Klein: The University of Texas MD Anderson Cancer Center
Alexander Rotenberg: Boston Children’s Hospital, Harvard Medical School
David A. Bennett: Rush University Medical Center
George M. Church: Harvard Medical School
Monica P. Colaiácovo: Harvard Medical School
Bruce A. Yankner: Harvard Medical School

Nature, 2019, vol. 574, issue 7778, 359-364

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1647-8

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