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Peer-reviewedCC BYAging cell

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

  • Se Eun Park1
  • Eun Roh2
  • Jae Woo Park1
  • Seong Jun Kim1
  • So Yeon Jeong1
  • Chae Beom Park1
  • Hyo Sun Lim1
  • Ji Soo Kim1
  • Mun Gyeom Kim1
  • Myeong Ju Kim1
  • Young In Cho1
  • Wontae Jeong1
4 more authors
  • Gil Myoung Kang3
  • Sang-Yeob Kim3
  • Se Hee Min4
  • Min-Seon Kim4
4 affiliations
  1. 1Department of Biomedical Science, University of Ulsan College of Medicine, Seoul, Korea.
  2. 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.
  3. 3Asan Institute for Life Science, Asan Medical Center, Seoul, Korea.
  4. 4Division of Endocrinology and Metabolism, Diabetes Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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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.

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Cite

BibTeXRIS
BibTeX
@article{park2026ciliacentered,
  title = {{A Cilia-Centered Nicotinamide Adenine Dinucleotide (NAD⁺) Signaling Network Regulates Hypothalamic Lysosomal Homeostasis and Metabolic Aging.}},
  author = {Se Eun Park and Eun Roh and Jae Woo Park and Seong Jun Kim and So Yeon Jeong and Chae Beom Park and Hyo Sun Lim and Ji Soo Kim and Mun Gyeom Kim and Myeong Ju Kim and Young In Cho and Wontae Jeong and Gil Myoung Kang and Sang-Yeob Kim and Se Hee Min and Min-Seon Kim},
  journal = {Aging cell},
  year = {2026},
  month = oct,
  doi = {10.1111/acel.70745},
  url = {https://europepmc.org/article/MED/42902820},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - A Cilia-Centered Nicotinamide Adenine Dinucleotide (NAD⁺) Signaling Network Regulates Hypothalamic Lysosomal Homeostasis and Metabolic Aging.
AU  - Se Eun Park
AU  - Eun Roh
AU  - Jae Woo Park
AU  - Seong Jun Kim
AU  - So Yeon Jeong
AU  - Chae Beom Park
AU  - Hyo Sun Lim
AU  - Ji Soo Kim
AU  - Mun Gyeom Kim
AU  - Myeong Ju Kim
AU  - Young In Cho
AU  - Wontae Jeong
AU  - Gil Myoung Kang
AU  - Sang-Yeob Kim
AU  - Se Hee Min
AU  - Min-Seon Kim
PY  - 2026
DA  - 2026/10/30
JO  - Aging cell
DO  - 10.1111/acel.70745
UR  - https://europepmc.org/article/MED/42902820
AB  - 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.
SN  - 1474-9718
SN  - 1474-9726
ER  -