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Review
. 2011 Oct;21(10):569-76.
doi: 10.1016/j.tcb.2011.06.008. Epub 2011 Aug 6.

Taking a "good" look at free radicals in the aging process

Siegfried Hekimi  1 , Jérôme Lapointe, Yang Wen
Affiliations
Review

Taking a "good" look at free radicals in the aging process

Siegfried Hekimi et al. Trends Cell Biol. 2011 Oct.

Abstract

The mitochondrial free radical theory of aging (MFRTA) proposes that aging is caused by damage to macromolecules by mitochondrial reactive oxygen species (ROS). This is based on the observed association of the rate of aging and the aged phenotype with the generation of ROS and oxidative damage. However, recent findings, in particular in Caenorhabditis elegans but also in rodents, suggest that ROS generation is not the primary or initial cause of aging. Here, we propose that ROS are tightly associated with aging because they play a role in mediating a stress response to age-dependent damage. This could generate the observed correlation between aging and ROS without implying that ROS damage is the earliest trigger or main cause of aging.

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Figures

Figure 1
Figure 1. Sources and targets of reactive oxygen species (ROS)
A variety of exogenous and endogenous factors can stimulate ROS production from the mitochondria and other compartments. Cellular ROS levels are controlled by a complex network of antioxidant activities. The reaction of ROS with macromolecules can produce two diametrically opposed outcomes: ROS can act as modulators in several signaling pathways implicated in stress-responses and other functions, but ROS can also inflict damage to lipids, nucleic acids, and proteins.
Figure 2
Figure 2. High ROS phenotypes that affects aging and lifespan positively
The C. elegans nuo-6 mutants produce more mitochondrial superoxide, yet display an increased lifespan that, furthermore, can be suppressed by the antioxidant NAC[43]. Mclk1+/− mice sustain high mitochondrial oxidative stress but live longer than their wild type siblings [48, 50]. High levels of oxidative damage have been observed in several tissues of very long-lived naked mole rats (NMRs) [56].
Figure 3
Figure 3. The gradual ROS response hypothesis
Cellular constituents sustain a variety of age-dependent damage that trigger ROS-dependent, protective, stress-response pathways. The ROS generation that is triggered by these mechanisms is well handled by the cellular detoxification systems and is therefore not deleterious (left side of the figure). These protective mechanisms appear unable to fully prevent the gradual accumulation of age-related damage. Thus the gradual increase in damage induces an ever greater stimulation of ROS production as the cell attempts to enhance its stress response. As aging progresses, ROS generation partially escapes control by the antioxidant systems and ROS toxicity starts to participate in causing the very damage that the ROS-dependent stress pathways are meant to neutralize (right side of the figure). This could trigger a toxic runaway process that might form the basis of the involvement of ROS in age-dependent diseases, which tend to develop only in the second half of lifespan.
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