The balance between oxidative damage and adaptive responses to oxidative damage appears important in the way in which the operation of metabolism determines natural variations in longevity. Not as important as the factors that determine order of magnitude differences in life spans between species, but important enough to cause 10-20% changes in life expectancy in mice when manipulated, for example. That is the case in this study, in which researchers assess what appeared to be a damaging genetic alteration, a knockout of the NOXO1 gene associated with production of reactive oxygen species that has detrimental effects on intestinal function, and found that mice lived 20% longer or so as a result.
There have been a lot of surprising results in the manipulation of oxidative metabolism. It is a very complex system. Oxidative molecules are generated by mitochondria or during inflammation, and they both damage cellular components and act as signals to provoke greater cellular maintenance activities, or other tissue functions such as the adaptive growth of muscle in response to exercise. Too much oxidative damage to the point of overloading antioxidant and repair systems is directly harmful. Too little oxidative damage can also be harmful in the long term because too little cellular maintenance takes place. It is hard to predict how a reactive biological system of countless interacting component parts will behave when one part is broken or enhanced.
This particularly study may also be an example of the point that the effects of calorie restriction are large in comparison to most other studied mechanisms. Because NOXO1 knockout degrades intestinal function, these mice weigh less, and may thus be benefiting more from a reduced calorie intake than they lose from a suboptimal oxidative biochemistry. Though the usual signs of the calorie restriction response appear absent - the researchers did do some digging on this topic. All in all, investigating the complexities of metabolism is a challenging business; given the modest size of the effect observed here, this particularly line of work is unlikely to be worth the effort from anything other than the purely knowledge-driven perspective.
According to the free radical theory of aging, reactive oxygen species (ROS) have been proposed to be a major cause of aging for a long time. Meanwhile, it became clear that ROS have diverse functions in a healthy organism. They act as second messengers, and as transient inhibitors of phosphatases and others. In fact, their detrimental role is highly dependent on the context of their production. NADPH oxidases (Nox) have been discovered as a controllable source of ROS. NoxO1 enables constitutive ROS formation by Nox1 by acting as a constitutively active cytosolic subunit of the complex. We previously found that both Nox1 and NoxO1 were highly expressed in the colon, and that NoxO1-/- deficiency reduces colon health. We hypothesized that a healthy colon potentially contributes to longevity and NoxO1 deficiency would reduce lifetime, at least in mouse.
In contrast, here we provide evidence that the knockout of NoxO1 results in an elongated life expectancy of mice. No better endothelial function, nor an improved expression of genes related to longevity, such as Sirt1, were found, and therefore may not serve as an explanation for a longer life in NoxO1 deficiency. Rather minor systemic differences, such as lower body weight occur. One effect of low body weight might be the expression and activity of Sirt1 and PGC1α, which are upregulated in response to caloric restriction. However, neither Sirt1 nor PGC1α was upregulated in NoxO1 deficient organs. Accordingly, the Sirt1 downstream target eNOS was not differentially activated in NoxO1-/- mice. We conclude that Sirt1 is not the preliminary effector to prolong the lifespan of NoxO1-/- mice, when compared to wildtypes. Although not significantly different from wildtype mice, low body weight in NoxO1 mice may have other beneficial effects.
As a potential reason for longer life, we suggest better DNA repair capacity in NoxO1 deficient mice. Although final fatal DNA damage appears similar between wildtype and NoxO1 knockout animals, we identified less intermediate DNA damage in colon cells of NoxO1-/- mice, while the number of cells with intact DNA is elevated in NoxO1-/- colons. We conclude that NoxO1 deficiency prolongs lifetime of mice, which correlates with less intermediate and potentially fixable DNA damage at least in colon cells.