Motor function declines with aging resulting in impaired mobility, loss of independence and increased susceptibility to injury and diseases. Many studies have sought to determine the cellular and molecular factors that contribute to aging of the neuromuscular system. Recent findings strongly suggest that structural and molecular alterations at neuromuscular junctions occur before motor neurons and skeletal muscle fibers exhibit obvious age-related pathological changes. Thus, deleterious changes at the neuromuscular junction may trigger the slow but consistent loss of motor function during aging. While it is known that muscle-derived factors are required to maintain and repair the neuromuscular junction, the identity of such factors has remained elusive. To this end, we have taken varied, yet complementary, approaches to identify muscle- derived factors that function to maintain the structural and functional integrity of neuromuscular junctions from the ravages of aging. In this regard, we have gathered preliminary data suggesting that three members of the fibroblast growth factor (FGF) signaling pathway, FGF-7/10/22, and a FGF-binding protein (FGFBP1) are promising candidate molecules for protecting neuromuscular junctions from insults emanating from normal aging, ALS-causing mutations and injury to peripheral nerves. In mice, deletion of FGF-22 results in premature aging of the neuromuscular junction. It also delays reinnervation of skeletal muscles after injury. Similarly, a reduction in FGFBP1 accelerates age-associated changes at neuromuscular junctions and compromises motor function in young adult mice. Importantly, introducing FGFBP1 and FGF-22 into denervated muscles accelerates their reinnervation, further indicating that FGF-22 and FGFBP1 function to repair the neuromuscular junction. We strongly believe that the proposed experiments could lead to new molecular targets for developing therapeutic interventions to protect and repair the neuromuscular junction, and thus slow, prevent or even reverse aging of the motor system.