Reduced bone morphogenic protein signaling along the gut–neuron axis by heat shock factor promotes longevity

Sonja L.B. Arneaud, Jacob McClendon, Lexus Tatge, Abigail Watterson, Kielen R. Zuurbier, Bhoomi Madhu, Tina L. Gumienny, Peter M. Douglas

Research output: Contribution to journalArticlepeer-review


Aging is a complex and highly regulated process of interwoven signaling mechanisms. As an ancient transcriptional regulator of thermal adaptation and protein homeostasis, the Heat Shock Factor, HSF-1, has evolved functions within the nervous system to control age progression; however, the molecular details and signaling dynamics by which HSF-1 modulates age across tissues remain unclear. Herein, we report a nonautonomous mode of age regulation by HSF-1 in the Caenorhabditis elegans nervous system that works through the bone morphogenic protein, BMP, signaling pathway to modulate membrane trafficking in peripheral tissues. In particular, HSF-1 represses the expression of the neuron-specific BMP ligand, DBL-1, and initiates a complementary negative feedback loop within the intestine. By reducing receipt of DBL-1 in the periphery, the SMAD transcriptional coactivator, SMA-3, represses the expression of critical membrane trafficking regulators including Rab GTPases involved in early (RAB-5), late (RAB-7), and recycling (RAB-11.1) endosomal dynamics and the BMP receptor binding protein, SMA-10. This reduces cell surface residency and steady-state levels of the type I BMP receptor, SMA-6, in the intestine and further dampens signal transmission to the periphery. Thus, the ability of HSF-1 to coordinate BMP signaling along the gut–brain axis is an important determinate in age progression.

Original languageEnglish (US)
Article numbere13693
JournalAging Cell
Issue number9
StatePublished - Sep 2022


  • BMP signaling
  • HSF-1
  • Rab GTPases
  • SMAD
  • TGF-β
  • aging
  • endocytosis
  • gut–neuron axis
  • membrane traffic

ASJC Scopus subject areas

  • Aging
  • Cell Biology


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