A Cilia–Centered Nicotinamide Adenine Dinucleotide ( NAD ⁺ ) Signaling Network Regulates Hypothalamic Lysosomal Homeostasis and Metabolic Aging

ABSTRACT

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 Ca ²⁺ 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.