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

Authors

Se Eun Park, Eun Roh, Jae Woo Park, Seong Jun Kim, So Yeon Jeong, Chae Beom Park, Hyo Sun Lim, Ji Soo Kim, Mun Gyeom Kim, Myeong Ju Kim, Young In Cho, Wontae Jeong, Gil Myoung Kang, Sang-Yeob Kim, Se Hee Min, Min-Seon Kim

Published in

Aging cell. Volume 25. Issue 11. Pages e70745.

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 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.

PMID:
42902820
Bibliographic data and abstract were imported from PubMed on 22 Oct 2026.

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