The role of mitochondria in aging
Ana Bratic, Nils-Göran Larsson
Ana Bratic, Nils-Göran Larsson
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The role of mitochondria in aging

Abstract

Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and major phenotypes associated with aging. Somatic mitochondrial DNA (mtDNA) mutations and respiratory chain dysfunction accompany normal aging, but the first direct experimental evidence that increased mtDNA mutation levels contribute to progeroid phenotypes came from the mtDNA mutator mouse. Recent evidence suggests that increases in aging-associated mtDNA mutations are not caused by damage accumulation, but rather are due to clonal expansion of mtDNA replication errors that occur during development. Here we discuss the caveats of the traditional mitochondrial free radical theory of aging and highlight other possible mechanisms, including insulin/IGF-1 signaling (IIS) and the target of rapamycin pathways, that underlie the central role of mitochondria in the aging process.

Authors

Ana Bratic, Nils-Göran Larsson

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Figure 3

Model for the effects of impaired IIS and CR on mitochondrial function and aging.

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Model for the effects of impaired IIS and CR on mitochondrial function a...
Mitochondrial metabolism plays an important role in mediating longevity promoted by nutrient-sensing pathways like the IIS, the TOR pathway, and CR. Impaired IIS leads to reduced availability of intracellular glucose and consequently to an elevated cellular AMP/ATP ratio that activates AMPK. In its turn, AMPK activates PGC-1α and increases mitochondrial metabolism and respiration rate, which consequently results in transient ROS production. The transient increase in ROS levels activates the expression of scavenging enzymes, e.g., SOD and catalase, resulting in decreased ROS levels, increased stress resistance, and extended life span. Furthermore, current findings suggest that the beneficial effect of CR on longevity is at least partly mediated by improved mitochondrial function mediated through activation of SIRT1 and PGC-1α. The activity of PGC-1α is tightly controlled via glycogen synthase kinase-3β (GSK3β), which acts via phosphorylation to prime PGC-1α for ubiquitinylation and degradation.