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AbstractTwenty years have passed since Kadenbach and Müller-Höcker first proposed that the age-related accumulation of mutant mitochondrial DNA is caused by its clonal expansion, rather than by a “vicious cycle” of de novomutational events caused by the disruptive metabolic impact of prior ones. Proof that they were correct emerged rapidly (though recognition of this was much slower); however, the mechanism underlying this selective advantage remained obscure. Numerous hypotheses were advanced during the 1990s, but proved hard to test. A wealth of data has been published very recently that bears on this question. While these reports surely bring us closer to an understanding of this phenomenon, and thus probably to a better understanding of how it might be combated or even reversed, they currently raise more questions than they answer. [ABSTRACT FROM AUTHOR]