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

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.