dCubilin- or dAMN-mediated protein reabsorption in Drosophila nephrocytes modulates longevity

Aging is a multifaceted process regulated by multiple cellular pathways, including the proteostasis network. Pharmacological or genetic enhancement of the intracellular proteostasis network extends lifespan and prevents age-related diseases. However, how proteostasis is regulated in different tissues throughout the aging process remains unclear. Here, we show that Drosophila homologs of Cubilin- and Amnionless (dCubilin and dAMN, respectively)-mediated protein reabsorption (CAMPR) from hemolymph insect blood by nephrocytes modulate longevity through regulating proteostasis in muscle and brain tissues. We find that overexpression of dAMN receptor in nephrocytes extends lifespan, whereas nephrocyte-specific dCubilin or dAMN RNAi knockdown shortens lifespan. We also show that CAMPR in nephrocytes regulates proteostasis in hemolymph and improves healthspan. In addition, we show that enhanced CAMPR in nephrocytes slows down the aging process in muscle and brain by maintaining the proteostasis network in these tissues. Altogether, our work has revealed an inter-organ communication network across nephrocytes and muscle/neuronal tissue that is essential for maintaining proteostasis, and to delay senescence in these organs. These findings provide insight into the role of renal protein reabsorption in the aging process via this tele-proteostasis network.