The genetic variability of H. sapiens mitochondrial DNA (mtDNA) can be either germ-line inherited or somatically acquired, and its effect on aging and longevity as well as on the pathogenesis of complex age-related diseases is a hot topic. Here we illustrate the complexity of such studies, related to the large genetic variability of mtDNA in different populations and the fact that the rate of the aging process is different in different cells, tissues and organs. As far as concern Alzheimer's disease, the accumulation of somatic mutations in several tissues have been investigated, as well as the inherited mtDNA variability. However, the issue is still controversial and further studies are needed to clarify the role of mtDNA variants in Alzheimer's disease. This review is aimed to summarize the most recent advances in this field. By high throughput mtDNA sequencing and the study of large cohorts of ethnically homogeneous subjects/patients, it is now possible to perform high dimensionality studies in order to clarify the genetic associations among several inherited mtDNA variants and longevity or age-associated diseases in humans.
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