A Cilia-Centered Nicotinamide Adenine Dinucleotide (NAD⁺) Signaling Network Regulates Hypothalamic Lysosomal...

Nicotinamide adenine dinucleotide (NAD⁺) is an essential metabolite that regulates diverse cellular metabolic processes. Primary cilia, hair-like organelles on the cell surface, function as critical signaling hubs. Here, we demonstrate that cellular NAD⁺ levels are key regulators of both primary cilia growth and lysosomal function in hypothalamic neurons. NAD⁺ depletion induces ciliary shortening and diminishes lysosomal activity in a cilia-dependent manner. Mechanistically, the lysosomal repair complex protein CHMP4B translocates from periciliary satellites to lysosomes during lysosomal stress, a process impaired by ciliary dysgenesis. Disrupted lysosomal recruitment of CHMP4B leads to abnormal lysosomal Ca²⁺ signaling and lysosomal dysfunction. Aged mice with hypothalamic NAD⁺ deficiency exhibit shortened cilia and lysosomal stress phenotypes, both of which are restored by calorie restriction (CR). Moreover, CR improves aging-associated metabolic dysfunction, at least in part, through hypothalamic cilia-dependent mechanisms. These findings identify a primary cilium-mediated-NAD⁺ signaling axis that maintains lysosomal homeostasis in hypothalamic neurons, the disruption of which drives metabolic aging.