p300 nucleocytoplasmic shuttling regulates mTORC1 activity in response to amino acid and glucose levels. Depletion of these nutrients causes cytoplasm-to-nucleus relocalization of p300, decreasing raptor acetylation and reducing mTORC1 activity, which activates autophagy. This is mediated by AMPK-dependent phosphorylation of p300 at serine 89. Nutrient addition to starved cells results in PP2A-dependent dephosphorylation of nuclear p300, enabling its CRM1-dependent export to the cytoplasm to mediate mTORC1 reactivation. p300 shuttling regulates mTORC1 in most cell types and occurs in response to altered nutrients in diverse mouse tissues. In Hutchinson–Gilford progeria syndrome (HGPS), p300 mislocalization by progerin activates mTORC1 and inhibits autophagy, phenotypes that are normalized by modulating p300 shuttling. These results reveal how nutrients regulate mTORC1, a cytoplasmic complex, by shuttling its positive regulator p300 in and out of the nucleus, and how this pathway is misregulated in HGPS, causing mTORC1 hyperactivation and defective autophagy. The study shows that p300 shuttling is essential for mTORC1 regulation in response to nutrient status, with AMPK and PP2A playing key roles in its nuclear import and export. In HGPS, altered p300 shuttling leads to mTORC1 hyperactivation and autophagy inhibition. Modulating p300 shuttling can normalize HGPS phenotypes by restoring autophagy and progerin degradation. The findings highlight the importance of p300 nucleocytoplasmic shuttling in regulating mTORC1 and autophagy, and its disruption in HGPS.p300 nucleocytoplasmic shuttling regulates mTORC1 activity in response to amino acid and glucose levels. Depletion of these nutrients causes cytoplasm-to-nucleus relocalization of p300, decreasing raptor acetylation and reducing mTORC1 activity, which activates autophagy. This is mediated by AMPK-dependent phosphorylation of p300 at serine 89. Nutrient addition to starved cells results in PP2A-dependent dephosphorylation of nuclear p300, enabling its CRM1-dependent export to the cytoplasm to mediate mTORC1 reactivation. p300 shuttling regulates mTORC1 in most cell types and occurs in response to altered nutrients in diverse mouse tissues. In Hutchinson–Gilford progeria syndrome (HGPS), p300 mislocalization by progerin activates mTORC1 and inhibits autophagy, phenotypes that are normalized by modulating p300 shuttling. These results reveal how nutrients regulate mTORC1, a cytoplasmic complex, by shuttling its positive regulator p300 in and out of the nucleus, and how this pathway is misregulated in HGPS, causing mTORC1 hyperactivation and defective autophagy. The study shows that p300 shuttling is essential for mTORC1 regulation in response to nutrient status, with AMPK and PP2A playing key roles in its nuclear import and export. In HGPS, altered p300 shuttling leads to mTORC1 hyperactivation and autophagy inhibition. Modulating p300 shuttling can normalize HGPS phenotypes by restoring autophagy and progerin degradation. The findings highlight the importance of p300 nucleocytoplasmic shuttling in regulating mTORC1 and autophagy, and its disruption in HGPS.