PMID: 15374442Mar 1, 1991Paper

An integrated theory of aging as the result of mitochondrial-DNA mutation in differentiated cells

Archives of Gerontology and Geriatrics
J Miquel

Abstract

We maintain that aging of humans and animals derives from a mutation or inactivation (probably followed by endonuclease digestion) of the mitochondrial genome of differentiated cells. This extranuclear somatic mutation hypothesis of aging is based on the finding that mitochondrial DNA (mtDNA) synthesis takes place at the inner mitochondrial membrane near the sites of formation of highly reactive oxygen species and their products, such as lipoperoxides and malonaldehyde. The mtDNA may be unable to counteract the damage inflicted by those by-products of respiration because, in contrast to the nuclear genome, it lacks histone protection and scission repair. Since the mitochondrial genome controls the synthesis of several hydrophobic proteins of the inner mitochondrial membrane, the postulated mutation, inactivation or loss of mtDNA will prevent the replication of the organelles. Thus deprived of the ability to regenerate their mitochondrial populations, the cells will sustain an irreversible decline in their bioenergetic ability, with concomitant senescent loss of physiological performance and eventual death. The above hypothesis is integrated with the concepts of Minot, Pearl and others in order to offer a more comprehensive view...Continue Reading

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