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




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

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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.

Abbreviations: BMP, Bone morphogenic protein; EV, Empty vector; FUdR, 5-fluorouracil- 2'- deoxyribose; GFP, Green fluorescent protein; HSF, Heat shock factor; LRIG, Leucine rich and immunoglobulin domains; NGM, Nematode growth medium; qPCR, Quantitative reverse-transcriptase PCR; TB, Terrific broth; TGF, Transforming growth factor; WT, wild-type.


Article originally published in Aging Cell, 21(9). English. Published online 2023.


Aging, BMP signaling, Endocytosis, Gut–neuron axis, HSF-1, Membrane traffic, Rab GTPases, SMAD, TGF-β


This is a published version of an article that is available at: Recommended citation: Arneaud, S. L., McClendon, J., Tatge, L., Watterson, A., Zuurbier, K. R., Madhu, B., Gumienny, T. L., & Douglas, P. M. (2022). Reduced bone morphogenic protein signaling along the gut–neuron axis by heat shock factor promotes longevity. Aging Cell, 21(9). This item has been deposited in accordance with publisher copyright and licensing terms and with the author’s permission.