When a theory of aging ages badly - PubMed (original) (raw)

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When a theory of aging ages badly

Jérôme Lapointe et al. Cell Mol Life Sci. 2010 Jan.

Abstract

According to the widely acknowledged mitochondrial free radical theory of aging (MFRTA), the macromolecular damage that results from the production of toxic reactive oxygen species (ROS) during cellular respiration is the cause of aging. However, although it is clear that oxidative damage increases during aging, the fundamental question regarding whether mitochondrial oxidative stress is in any way causal to the aging process remains unresolved. An increasing number of studies on long-lived vertebrate species, mutants and transgenic animals have seriously challenged the pervasive MFRTA. Here, we describe some of these new results, including those pertaining to the phenotype of the long-lived Mclk1(-/-) mice, which appear irreconcilable with the MFRTA. Thus, we believe that it is reasonable to now consider the MFRTA as refuted and that it is time to use the insight gained by many years of testing this theory to develop new views as to the physiological causes of aging.

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Figures

Fig. 1

Fig. 1

Schematic representation of the core statement and the associated hypotheses of the MFRTA, which have been tested by multiple studies in mammals. Taken together, the findings of these analyses have led to the conclusions that the core statement of the theory can now be considered as falsified in contrast to the associated hypotheses that have been verified by a variety of measures

Fig. 2

Fig. 2

Regulation of mitochondrial function by MCLK1 determines the rate of aging in a manner that is irreconcilable with the MFRTA. Reduction of MCLK1 levels in Mclk1 +/− mutants strongly affects mitochondrial function. The reduced mitochondrial function is linked to a reduction in the rate of electron transport, a decrease in energy production as well as to an increase in intra-mitochondrial oxidative stress. Mclk1 +/− mutant animals also display a decrease in cytosolic and global ROS damage as well as in the rate of aging

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