Aging is the major known risk factor for the onset of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Mitochondria play a central role in aging as mitochondrial dysfunction increases with age and produces harmful levels of reactive oxygen species which leads to cellular oxidative stress (free-radical theory of aging). Oxidative stress is highly damaging to cellular macromolecules and is also a major cause of the loss and impairment of neurons in neurodegenerative disorders. A growing body of evidence suggests that modulation of sirtuin activity and restricting calorie intake has a strong neuroprotective effect. SIRT1 induction by the use of pharmacological activators or by calorie restriction (CR) diet regimen has been shown to protect against neuronal loss and impairment in the cellular and animal models of AD and PD. Here, we review the current knowledge and recent data related to the role of sirtuins and CR in neurodegeneration and discuss the potential underlying signaling pathways of neuroprotection that might serve as attractive targets for the future therapeutic intervention of these age-related neurodegenerative diseases.