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Peer-reviewedCC BY 4.0eLife

The hypoxic response extends lifespan through a bioaminergic and peptidergic neural circuit

  • Elizabeth S Kitto1
  • Shijiao Huang2
  • Mira Bhandari1
  • Cassie Tian1
  • Rebecca L Cox1
  • Safa Beydoun1
  • Emily Wang3
  • Danielle Shave1
  • Hillary Miller4
  • Sarah A Easow1
  • Ella Henry1
  • Eugene Chung1
2 more authors
  • Megan L Schaller1
  • Scott F Leiser1,5
5 affiliations
  1. 1Molecular and Integrative Physiology Department; University of Michigan, Ann Arbor, United States
  2. 2Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, United States
  3. 3Department of Cellular and Developmental Biology; University of Michigan, Ann Arbor, United States
  4. 4Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States
  5. 5Department of Internal Medicine; University of Michigan, Ann Arbor, United States
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Abstract

A coordinated response to stress is crucial for promoting the short- and long-term health of an organism. The perception of stress, frequently through the nervous system, can lead to physiological changes that are fundamental to maintaining homeostasis. Activating the response to low oxygen, or hypoxia, extends healthspan and lifespan in Caenorhabditis elegans. However, despite some positive impacts, negative effects of the hypoxic response in specific tissues prevent translation of their benefits in mammals. Thus, it is imperative to identify which components of this response promote longevity. Here, we interrogate the cell-nonautonomous signaling pathway downstream of genetic activation of the hypoxic response. We find that HIF-1-mediated signaling in ADF serotonergic neurons is both necessary and sufficient for lifespan extension. Signaling through the serotonin receptor SER-7 in the GABAergic RIS interneurons is necessary in this process. Our findings also highlight the involvement of additional neural signaling molecules, including the neurotransmitters tyramine and GABA, and the neuropeptide NLP-17, in mediating longevity effects. Finally, we demonstrate that oxygen- and carbon-dioxide-sensing neurons act downstream of HIF-1 in this circuit. Together, these insights demonstrate a circuit for how genetic induction of the hypoxic response cell-nonautonomously modifies aging and suggests valuable targets for modulating aging in mammals.

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Cite

BibTeXRIS
BibTeX
@article{kitto2026hypoxic,
  title = {{The hypoxic response extends lifespan through a bioaminergic and peptidergic neural circuit}},
  author = {Elizabeth S Kitto and Shijiao Huang and Mira Bhandari and Cassie Tian and Rebecca L Cox and Safa Beydoun and Emily Wang and Danielle Shave and Hillary Miller and Sarah A Easow and Ella Henry and Eugene Chung and Megan L Schaller and Scott F Leiser},
  journal = {eLife},
  year = {2026},
  month = nov,
  doi = {10.7554/elife.107651},
  url = {https://elifesciences.org/articles/107651},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - The hypoxic response extends lifespan through a bioaminergic and peptidergic neural circuit
AU  - Elizabeth S Kitto
AU  - Shijiao Huang
AU  - Mira Bhandari
AU  - Cassie Tian
AU  - Rebecca L Cox
AU  - Safa Beydoun
AU  - Emily Wang
AU  - Danielle Shave
AU  - Hillary Miller
AU  - Sarah A Easow
AU  - Ella Henry
AU  - Eugene Chung
AU  - Megan L Schaller
AU  - Scott F Leiser
PY  - 2026
DA  - 2026/11/06
JO  - eLife
DO  - 10.7554/elife.107651
UR  - https://elifesciences.org/articles/107651
AB  - A coordinated response to stress is crucial for promoting the short- and long-term health of an organism. The perception of stress, frequently through the nervous system, can lead to physiological changes that are fundamental to maintaining homeostasis. Activating the response to low oxygen, or hypoxia, extends healthspan and lifespan in Caenorhabditis elegans. However, despite some positive impacts, negative effects of the hypoxic response in specific tissues prevent translation of their benefits in mammals. Thus, it is imperative to identify which components of this response promote longevity. Here, we interrogate the cell-nonautonomous signaling pathway downstream of genetic activation of the hypoxic response. We find that HIF-1-mediated signaling in ADF serotonergic neurons is both necessary and sufficient for lifespan extension. Signaling through the serotonin receptor SER-7 in the GABAergic RIS interneurons is necessary in this process. Our findings also highlight the involvement of additional neural signaling molecules, including the neurotransmitters tyramine and GABA, and the neuropeptide NLP-17, in mediating longevity effects. Finally, we demonstrate that oxygen- and carbon-dioxide-sensing neurons act downstream of HIF-1 in this circuit. Together, these insights demonstrate a circuit for how genetic induction of the hypoxic response cell-nonautonomously modifies aging and suggests valuable targets for modulating aging in mammals.
SN  - 2050-084X
ER  -