In the hypothalamus, specifically in the DMH and LH, Sirt1 upregulates Ox2r expression and neural activation by interacting with and deacetylating Nkx2-1. Enhanced neural activity in the DMH and LH stimulates the sympathetic nervous system and maintains skeletal muscle mitochondrial morphology and function, physical activity, body temperature, and oxygen consumption during aging. This neural activation by Sirt1/Nkx2-1/Ox2r is also critical to preserve quality of sleep during aging. These functional benefits contribute to the maintenance of youthful physiology and promote longevity.