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Mitochondrial polymorphisms are associated both with increased and decreased longevity.

ABSTRACT: Previous work compared frequency of longevity-associated polymorphisms (LAPS) in long-lived individuals and in controls from the general population (primarily in Europe and Japan), suggesting the polymorphisms are responsible for unusual longevity. However, individuals from the general population are not the control group for long-lived subjects because both were born in different periods. We report results of a project which collected mtDNA from living subjects in Costa Rica, and traced back their maternal genealogy. Since mtDNA does not recombine and its probability of mutation is low, we can assume that the maternal ancestors had the same mtDNA of their descendants. We compared the longevity of individuals with LAPS with the longevity of controls born in the same time period. We did not confirm previous associations for several markers, but found that the 5178A mutation in haplogroup D is associated with decreased longevity, whereas the 150T mutation is associated with increased longevity. These associations however, are not significant for all time periods under study. While our data confirm that mtDNA make up affects longevity, they also indicate that the time period in which a person was born had a much greater impact on longevity than presence or absence of a marker.

SUBMITTER: Castri L

PROVIDER: S-EPMC2868917 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The nuo-6 and isp-1 genes of C. elegans encode, respectively, subunits of complex I and III of the mitochondrial respiratory chain. Partial loss-of-function mutations in these genes decrease electron transport and greatly increase the longevity of C. elegans by a mechanism that is distinct from that induced by reducing their level of expression by RNAi. Electron transport is a major source of the superoxide anion (O(?) (-)), which in turn generates several types of toxic reactive oxygen species (ROS), and aging is accompanied by increased oxidative stress, which is an imbalance between the generation and detoxification of ROS. These observations have suggested that the longevity of such mitochondrial mutants might result from a reduction in ROS generation, which would be consistent with the mitochondrial oxidative stress theory of aging. It is difficult to measure ROS directly in living animals, and this has held back progress in determining their function in aging. Here we have adapted a technique of flow cytometry to directly measure ROS levels in isolated mitochondria to show that the generation of superoxide is elevated in the nuo-6 and isp-1 mitochondrial mutants, although overall ROS levels are not, and oxidative stress is low. Furthermore, we show that this elevation is necessary and sufficient to increase longevity, as it is abolished by the antioxidants NAC and vitamin C, and phenocopied by mild treatment with the prooxidant paraquat. Furthermore, the absence of effect of NAC and the additivity of the effect of paraquat on a variety of long- and short-lived mutants suggest that the pathway triggered by mitochondrial superoxide is distinct from previously studied mechanisms, including insulin signaling, dietary restriction, ubiquinone deficiency, the hypoxic response, and hormesis. These findings are not consistent with the mitochondrial oxidative stress theory of aging. Instead they show that increased superoxide generation acts as a signal in young mutant animals to trigger changes of gene expression that prevent or attenuate the effects of subsequent aging. We propose that superoxide is generated as a protective signal in response to molecular damage sustained during wild-type aging as well. This model provides a new explanation for the well-documented correlation between ROS and the aged phenotype as a gradual increase of molecular damage during aging would trigger a gradually stronger ROS response.

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Mitochondrial polymorphisms are associated both with increased and decreased longevity.

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