Senescence-accelerated mice (SAM) represent an aging model establish by selective inbreeding of the AKR/J strain. SAMP8 is a suitable model to study the genetics or proteics fundamental mechanisms of aging, in physiological or pathological conditions, because SAMP8 develop neuropathological markers also found in neurodegenerative diseases like Alzheimer. Melatonin is known as sleep hormone because its action controlling the sleep/awake circadian rhythm. Moreover, melatonin has antioxidant properties and may have an important anti-aging role. The chronic treatment with melatonin in the SAMP8 model was able to reduce oxidative stress and the neurodegenerative calpain/Cdk5 pathway and primed phosphorylation of GSK3beta and tau hiperphosphorylation markers of cerebral aging and neurodegeneration in SAMP8 brains, indicating the neuroprotective and anti-aging effect of melatonin.