A Cilia-Based NAD+ Signaling System Controls Lysosome Balance in the Hypothalamus and Metabolic Aging

Cellular NAD⁺ levels are key regulators of primary cilia growth and lysosomal function in hypothalamic neurons.

• NAD⁺ depletion leads to shorter primary cilia and reduced lysosomal activity.
• The protein CHMP4B moves from nearby structures to lysosomes during lysosomal stress, a process hindered by ciliary dysfunction.
• Impaired recruitment of CHMP4B causes abnormal calcium signaling and lysosomal dysfunction.
• Aged mice with NAD⁺ deficiency show similar ciliary shortening and lysosomal stress, which can be reversed by calorie restriction.
• Calorie restriction may improve age-related metabolic issues through mechanisms dependent on primary cilia in the hypothalamus.

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