DMH $ ^{Ppp1r17} $ neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication. The study identifies a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMH $ ^{Ppp1r17} $ neurons), that regulates aging and longevity in mice. These neurons regulate physical activity and white adipose tissue (WAT) function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation. Within DMH $ ^{Ppp1r17} $ neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function. Both DMH-specific Prkg1-knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMH $ ^{Ppp1r17} $ neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan. These findings demonstrate the importance of inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control. The study also shows that Ppp1r17 regulates synaptic function in DMH $ ^{Ppp1r17} $ neurons, and its nuclear-cytoplasmic translocation during aging is regulated by PKG-dependent phosphorylation. Reversing this translocation by Prkg1-knockdown ameliorates age-associated physiological decline and extends lifespan in mice. Chemogenetic activation of DMH $ ^{Ppp1r17} $ neurons increases wheel-running activity, lipolysis, and circulating eNAMPT and extends lifespan in aged mice. The study concludes that DMH $ ^{Ppp1r17} $ neurons are a key component that controls mammalian aging and longevity, and their function is critical for maintaining the inter-tissue communication between the hypothalamus and WAT. The findings provide critical insights into the systemic regulatory network for mammalian aging and longevity control and the development of more effective anti-aging interventions.DMH $ ^{Ppp1r17} $ neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication. The study identifies a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMH $ ^{Ppp1r17} $ neurons), that regulates aging and longevity in mice. These neurons regulate physical activity and white adipose tissue (WAT) function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation. Within DMH $ ^{Ppp1r17} $ neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function. Both DMH-specific Prkg1-knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMH $ ^{Ppp1r17} $ neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan. These findings demonstrate the importance of inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control. The study also shows that Ppp1r17 regulates synaptic function in DMH $ ^{Ppp1r17} $ neurons, and its nuclear-cytoplasmic translocation during aging is regulated by PKG-dependent phosphorylation. Reversing this translocation by Prkg1-knockdown ameliorates age-associated physiological decline and extends lifespan in mice. Chemogenetic activation of DMH $ ^{Ppp1r17} $ neurons increases wheel-running activity, lipolysis, and circulating eNAMPT and extends lifespan in aged mice. The study concludes that DMH $ ^{Ppp1r17} $ neurons are a key component that controls mammalian aging and longevity, and their function is critical for maintaining the inter-tissue communication between the hypothalamus and WAT. The findings provide critical insights into the systemic regulatory network for mammalian aging and longevity control and the development of more effective anti-aging interventions.