Neurodegenerative diseases are a growing societal problem as the world’s population ages because, the major factor for developing a neurodegenerative clinical illness, whether sporadic or of genetic origin, is increasing age. Age affects neuron cellular biology, so they become vulnerable to neurodegenerative diseases. With age neuronal mitochondrial function declines, due to recurrent minor damage by their reactive oxygen species metabolites, which leads to oxidative stress and associated oxidation of the proteosome. The ensuing proteostasis alters autophagy so that dysfunctional cytoplasmic molecules accumulate causing neuronal senescence and chronic inflammation. Each stage of neuronal dysfunction is accompanied by increasing loss of calcium regulation, which worsens mitochondrial dysfunction and initiates cell death. This cascade of increasing neuronal vulnerability occurs first in cells with the highest metabolic needs, i.e. large projection neurons which sustain long axons and/or large dendritic trees; which are also the first neurons to be affected in many neurodegenerative diseases.