NoxO1 Knockout Promotes Longevity in Mice

Abstract

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. 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.

Deletion of NoxO1 limits atherosclerosis development in female mice

“…Comparison of the cytokine array with the RNAseq data also points towards the possibility that hepatic or myeloid but not vascular NoxO1 might be of relevance for the present study. This appears possible as a global knockout mouse was used in the present study, of which we know that the lifespan is expanded [ 53 ] and that inflammatory burden is reduced [ 11 ]. Moreover, it has been shown that NoxO1, potentially through Nox1, promotes peroxynitrite formation, which contributes to the development of degenerative diseases like COPD [ 54 ].…”

Oxidative Stress, Neuroinflammation, and NADPH Oxidase: Implications in the Pathogenesis and Treatment of Alzheimer’s Disease

“…Both mitochondrial- and NOX-derived ROS at moderate levels are involved in actually increasing the longevity of these organisms by redox-signalling pathways, while presumably at higher levels of ROS, both oxidative damage and shortening of life span occur [ 59 , 62 – 64 ]. However, the results of such life span alteration experiments on mammals by knocking out antioxidant enzyme genes or NOX have remained controversial, failing to show clearly the link between oxidative stress and longevity [ 65 – 68 ]. The redox-signalling pathways comprised of various redox-sensitive transcription factors and cell signalling kinases and their downstream components have also been identified and explored in detail in mammalian cells, but their precise role in mammalian aging at the organismal level has not been elucidated yet [ 10 , 49 , 69 ].…”

Downregulation of DUOX1 function contributes to aging-related impairment of innate airway injury responses and accelerated senile emphysema

“…For example, lung tissue NOX4 levels appear to increase with age (25,26), but NOX4 does not affect longevity in mice (27). Recently, NADPH oxidase organizer 1 (NOXO1), a component of functional NOX1, was found to negatively affect life span in mice (28). Conversely, studies in Caenorhabditia elegans suggest that its major NOX homolog Duox1/BLI3 actually prolongs longevity, related to its contribution to adaptive responses to environmental stress (29,30).…”