ABSTRACT In humans, an age-related decline in neuromuscular function is associated with loss of muscle mass (sarcopenia), increased frailty and a degradation of both health and quality of life. The only known treatments are life-style based, including exercise and diet. Rodent models have been used to demonstrate age-related changes at the neuromuscular junction (NMJ) including the fragmentation, remodeling and eventual denervation of muscle. As eloquently stated by Joshua Sanes and Jeff Lichtman, “A key feature of the adult NMJ is that it is remarkably stable under ordinary circumstances yet capable of remodeling” when perturbed by injury or age. “This combination of stability and malleability implies that synaptic maintenance is controlled actively, yet little is known about the underlying molecular mechanisms”. This is where we have recently advanced the field. In a recently published paper we demonstrate the power of homeostatic plasticity to preserve neuromuscular anatomy and function with dramatic effects on organismal health, behavior and lifespan. We refer to this as “Homeostatic Neuroprotection”. We propose to determine whether homeostatic neuroprotection counteracts the insidious effects of age-related neuromuscular decline over the normal lifespan of mice. This will be achieved by characterizing three independent mouse strains across the lifespan. We provide strong preliminary data supporting an evolutionarily conserved role for all three genes in the mechanisms of presynaptic homeostatic plasticity and accelerated aging in the mouse neuromuscular system. Age is one of the most important risk factors for nearly all neurodegenerative disorders. This line of research may underscore the general relevance of homeostatic neuroprotection as a future therapeutic avenue to ameliorate the adverse effects of age and neurological disease.