Recent trends in biomedical research have highlighted the potential for effecting significant extensions in longevity with enhanced quality of life in aging human populations. Within this context, any proposed method to achieve enhanced life extension must include therapeutic approaches that draw upon essential biochemical and molecular regulatory processes found in relatively simple single cell organisms that are evolutionarily conserved within complex organ systems of higher animals. Current critical thinking has established the primacy of mitochondrial function in maintaining good health throughout plant and animal phyla. The mitochondrion represents an existentially defined endosymbiotic model of complex organelle development driven by evolutionary modification of a permanently enslaved primordial bacterium. Cellular mitochondria are biochemically and morphologically tailored to provide exponentially enhanced ATP-dependent energy production accordingly to tissue- and organ-specific physiological demands. Thus, individual variations in longevity may then be effectively sorted according to age-dependent losses of single-cell metabolic integrity functionally linked to impaired mitochondrial bioenergetics within an aggregate presentation of compromised complex organ systems. Recent empirical studies have focused on the functional role of mitochondrial heteroplasmy in the regulation of normative cellular processes and the initiation and persistence of pathophysiological states. Accordingly, elucidation of the multifaceted functional roles of mitochondrial heteroplasmy in normal aging and enhanced longevity will provide both a compelling genetic basis and potential targets for therapeutic intervention to effect meaningful life extension in human populations.