The study identifies a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMH^Ppp1r17 neurons), which regulates aging and longevity in mice through inter-tissue communication between the hypothalamus and white adipose tissue (WAT). DMH^Ppp1r17 neurons regulate physical activity and WAT function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), via sympathetic nervous stimulation. The phosphorylation and nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase (PKG), affect gene expression related to synaptic function, causing synaptic transmission dysfunction and impaired WAT function. DMH-specific PKG knockdown, which suppresses age-associated Ppp1r17 translocation, and chemogenetic activation of DMH^Ppp1r17 neurons significantly improve age-associated WAT dysfunction, increase physical activity, and extend lifespan. These findings highlight the importance of inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control.The study identifies a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMH^Ppp1r17 neurons), which regulates aging and longevity in mice through inter-tissue communication between the hypothalamus and white adipose tissue (WAT). DMH^Ppp1r17 neurons regulate physical activity and WAT function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), via sympathetic nervous stimulation. The phosphorylation and nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase (PKG), affect gene expression related to synaptic function, causing synaptic transmission dysfunction and impaired WAT function. DMH-specific PKG knockdown, which suppresses age-associated Ppp1r17 translocation, and chemogenetic activation of DMH^Ppp1r17 neurons significantly improve age-associated WAT dysfunction, increase physical activity, and extend lifespan. These findings highlight the importance of inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control.