Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging

Abstract

Mice heterozygous for the Sod2 gene (Sod2+/- mice) have been used to study the phenotype of life-long reduced Mn-superoxide dismutase (MnSOD) activity. The Sod2+/- mice have reduced MnSOD activity (50%) in all tissues throughout life. The Sod2+/- mice have increased oxidative damage as demonstrated by significantly elevated levels of 8-oxo-2-deoxyguanosine (8oxodG) in nuclear DNA in all tissues of Sod2+/- mice studied. The levels of 8oxodG in nuclear DNA increased with age in all tissues of Sod2+/- and wild-type (WT) mice, and at 26 mo of age, the levels of 8oxodG in nuclear DNA were significantly higher (from 15% in heart to over 60% in liver) in the Sod2+/- mice compared with WT mice. The level of 8oxodG was also higher in mitochondrial DNA isolated from liver and brain in Sod2+/- mice compared with WT mice. The increased oxidative damage to DNA in the Sod2+/- mice is associated with a 100% increase in tumor incidence (the number of mice with tumors) in old Sod2+/- mice compared with the old WT mice. However, the life spans (mean and maximum survival) of the Sod2+/- and WT mice were identical. In addition, biomarkers of aging, such as cataract formation, immune response, and formation of glycoxidation products carboxymethyl lysine and pentosidine in skin collagen changed with age to the same extent in both WT and Sod2+/- mice. Thus life-long reduction of MnSOD activity leads to increased levels of oxidative damage to DNA and increased cancer incidence but does not appear to affect aging.

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice

“…Although oxidative damage has been shown to play important roles in carcinogenesis [40], our results show that reduced oxidative damage in the cells/tissues appeared to have little influence on spontaneous tumor formation in old mice. Furthermore, our results also show that reduced oxidative stress had little effects on lifespan.…”

“…These observations were consistent with our previous studies that also demonstrated that the interventions (genetic, dietary, and others), which change the incidence/development of one disease (e.g., cancer), did not change the lifespan in rodents. For example: 1) MnSOD heterozygous KO mice had an increased incidence of tumors, however, these mice had a similar lifespan compared to WT mice [40]; 2) single housed calorie restricted (CR) male C57BL/6 mice had less fatal tumors, but the lifespan was similar to multiple housed CR mice [29]; and 3) CR with exercise reduced the fatal tumor incidence in F344 rats, but the maximum lifespan was similar to sedentary CR rats [41]. Therefore, changes in one disease does not always have a maximum impact on lifespan.…”

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

“…GPX1 −/− ,28, 252 SOD2 +/− ,240 extracellular SOD −/− 255, 256 and MSRB −/− 257 knockout murine models show no effect on lifespan. Similarly, transgenic animal models overexpressing RONS protective enzymes including SOD1 Tg ,26 SOD2 Tg ,24 MSRA Tg ,258 mice overexpressing human CAT in nuclei (nCAT Tg )259 and peroxisomal targeted CAT (pCAT Tg ) (the natural site of CAT)260 have failed to provide evidence of increased lifespan, indicating that RONS are not the fundamental determinants of lifespan.…”

“…The impact of altered redox homeostasis in loss of neuromuscular integrity and function with ageing has been investigated in several murine models, which have undergone genetic modifications of redox signalling/homeostasis components 19, 23, 25, 29, 30, 31, 32, 33, 34, 240, 241, 242. Transgenic murine models have provided insight into the importance of RONS regulatory systems in lifespan and neuromuscular ageing, and it has been reported that SOD2 −/− ,243 GRX3 −/− ,244 GPX4 −/− ,245 TRX1 −/− ,246 TRX2 −/− ,247 TR1 −/− 248 and TR2 −/− 249 murine models are embryonically lethal.…”

Lifelong reduction in complex IV induces tissue‐specific metabolic effects but does not reduce lifespan or healthspan in mice

“…While this is a reasonable assumption, the data to support a universal direct link between reduced mitochondrial function and lifespan surprisingly do not exist. For example, we have previously shown that heterozygous ( Sod2 +/− ) mice with reduced levels of MnSOD, a mitochondrial antioxidant enzyme, have compromised mitochondrial function but no reduction in lifespan (Mansouri et al., 2006; Van Remmen et al., 2003; Williams et al., 1998). In contrast, a study by Dell'agnello et al.…”