Several lines of evidence implicate mtDNA in the mechanisms of aging and longevity. The authors examined possible links between mtDNA composition and maximum lifespan of multicellular eukaryotes, including 102 mammals. MLS correlates positively with cytosine and negatively with adenine or thymine content, whereas guanine has no apparent effect. This is especially noted for primates. It appears that an increase in MLS of mammals is associated with thymine-to-cytosine substitution. The results suggest that the MLS may be associated with stability and/or mutability of mtDNA and call for further investigation of the mitochondrial genome as a potential target for lifespan-extending interventions.