ArticleNature2019
Regulation of lifespan by neural excitation and REST.
Article in Nature, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 138 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
138 citing papers in PubMed, 1 synthesis or guideline pooled it, 242 citations in OpenAlex.
- C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.CNS neuroscience & therapeutics · 2024Pooled it
- Oligodendrocyte dysfunction in human age-related cognitive decline.Nature medicine · 2026Article
- Molecular Networks and Key Regulators Underlying Resilience of the Human Brain to Aging and Dementia.Biomolecules · 2026Article
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- Phosphatidylinositol transfer protein-1 integrates insulin/IGF-1 and TOR signaling to negatively regulate lifespan and healthspan in Caenorhabditis elegans.Journal of biomedical science · 2026Article
- Reconstructing mammalian lifespan evolution reveals strong phylogenetic effects and lifespan-associated genes.BMC biology · 2026Article
- Loss of REST associated with Alzheimer's disease pathology is ameliorated by NAD.Brain : a journal of neurology · 2026Article
- Mutual regulation of spermatogenesis-specific Argonaute proteins and Insulin/IGF-1 signaling in aging control.EMBO reports · 2026Article
- Fn14 is an activity-dependent, Bmal1-regulated cytokine receptor that induces rod-like microglia and restricts neuronal activity in vivo.Cell reports · 2026Article
- Proliferation of activated hepatic stellate cells requires REST.Molecular medicine (Cambridge, Mass.) · 2026Article
- Unlocking neuronal health: leveraging C. elegans for drug repurposing studies.Cell communication and signaling : CCS · 2026Review
- Organ-Specific Regulation of Systemic Aging: Focus on the Brain, Skeletal Muscle, and Gut.Cells · 2026Review
- Reserpine prolongs lifespan but compromises locomotion and heat-stress resilience in Drosophila melanogaster.npj aging · 2026Article
- Multilayered regulation of longevity in Caenorhabditis elegans.Molecules and cells · 2026Review
- From mice to clinical relevance: humanizing neuroscience with human-based model systems.Frontiers in cellular neuroscience · 2026Review
- Synergistic effects of 3-O-methylquercetin and polyphenols on longevity, healthspan, and neuroprotection via FOXO/Nrf2.Biogerontology · 2025Article
- Gastrodin extends the lifespan of Caenorhabditis elegans via the DAF-16/FOXO signaling pathway and autophagy.Functional & integrative genomics · 2025Article
- The cell autonomous and non-autonomous functions of Rab27 in longevity and neuroprotection inAutophagy · 2025Article
- CoREST3 exhibits isoform specific expression in Alzheimer's disease and regulation of HDAC2.BMC biology · 2025Article
- Pelota-mediated ribosome-associated quality control counteracts aging and age-associated pathologies across species.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
78 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.