Skeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism-modifying functions in targeted tissues, including the CNS. Here we report the generation of a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of TFEB. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity, reduce neuroinflammation and promotes transcriptional remodeling of the aging CNS, preserving cognition/memory in aging mice. Enhancing skeletal muscle proteostasis also reduced neuroinflammation and accumulation of tau-associated pathological hallmarks in a mouse model of tau pathology and was accompanied by increased secretion of CNS-targeting circulating factors from skeletal muscle. Our results implicate maintenance of skeletal muscle proteostasis throughout aging to direct regulations of the aging CNS metabolism and function, and suggest that skeletal-muscle originating factors may act as novel therapeutic targets against age-associated neurodegenerative diseases.