The neuron-specific IIS/FOXO transcriptome in aged animals reveals regulatory mechanisms of cognitive aging

Yifei Weng, Shiyi Zhou, Katherine Morillo, Rachel Kaletsky, Sarah Lin, Coleen T. Murphy

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Cognitive decline is a significant health concern in our aging society. Here, we used the model organism C. elegans to investigate the impact of the IIS/FOXO pathway on age-related cognitive decline. The daf-2 Insulin/IGF-1 receptor mutant exhibits a significant extension of learning and memory span with age compared to wild-type worms, an effect that is dependent on the DAF-16 transcription factor. To identify possible mechanisms by which aging daf-2 mutants maintain learning and memory with age while wild-type worms lose neuronal function, we carried out neuron-specific transcriptomic analysis in aged animals. We observed downregulation of neuronal genes and upregulation of transcriptional regulation genes in aging wild-type neurons. By contrast, IIS/FOXO pathway mutants exhibit distinct neuronal transcriptomic alterations in response to cognitive aging, including upregulation of stress response genes and downregulation of specific insulin signaling genes. We tested the roles of significantly transcriptionally-changed genes in regulating cognitive functions, identifying novel regulators of learning and memory. In addition to other mechanistic insights, a comparison of the aged vs young daf-2 neuronal transcriptome revealed that a new set of potentially neuroprotective genes is upregulated; instead of simply mimicking a young state, daf-2 may enhance neuronal resilience to accumulation of harm and take a more active approach to combat aging. These findings suggest a potential mechanism for regulating cognitive function with age and offer insights into novel therapeutic targets for age-related cognitive decline.

Original languageEnglish (US)
JournaleLife
Volume13
DOIs
StatePublished - Jun 26 2024

All Science Journal Classification (ASJC) codes

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

Keywords

  • C. elegans
  • FOXO
  • Insulin/IGF-like signaling
  • RNA-sequencing
  • cognitive aging
  • genetics
  • genomics
  • neurons
  • neuroscience
  • stress-resistance

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