Accumulating evidence suggest that degeneration of axons is an early event in several neurodegenerative conditions, including Alzheimer’s disease, Amyotrophic lateral sclerosis, and Parkinson’s disease. Interestingly, axonal degeneration also takes place as a consequence of healthy aging, and studies in animal models suggest that this degenerative process contributes to the loss of cognitive functions during ageing. Axonal degeneration involves destruction programs that are independent of the survival of the cell soma, and is associated to NAD+ depletion and mitochondrial dysfunction in the axonal compartment. Recently, we have demonstrated that necroptosis, a programmed cell death process, is involved in axonal degeneration after diverse stimuli as well as in models of neurodegenerative conditions, including Parkinson and Alzheimer disease. Importantly, necroptosis activation and axonal degeneration are dependent on several parameters associated to the ageing process, including a decrease in NAD+ levels in the brain, mitochondrial dysfunction and ROS production, inflammation and pathogen ligands. We propose that an age-dependent increase in the susceptibility to activation of the necroptosis machinery in neurons is associated to progressive axonal degeneration during healthy ageing, a process that can be accelerated by diverse stimuli with pathological consequences.