Combined Exercise and Insulin-Like Growth Factor-1 Supplementation Induces Neurogenesis in Old Rats, but Do Not Attenuate Age-Associated DNA Damage

Abstract

We have investigated the effects of 2 weeks of insulin-like growth factor-1 (IGF-1) supplementation (5 mg/kg per day) and 6 weeks of exercise training (60% of the maximal oxygen consumption [VO 2 max]) on neurogenesis, DNA damage/repair, and sirtuin content in the hippocampus of young (3 months old) and old (26 months old) rats. Exercise improved the spatial memory of the old group, but IGF-1 supplementation eliminated this effect. An age-associated decrease in neurogenesis was attenuated by exercise and IGF-1 treatment. Aging increased the levels of 8-oxo-7,8-dihydroguanine (8-oxoG) and the protein Ku70, indicating the role of DNA damage in age-related neuropathology. Acetylation of 8-oxoguanine DNA glycosylase (OGG1) was detected in vivo, and this decreased with aging. However, in young animals, exercise and IGF-1 treatment increased acetylated (ac) OGG1 levels. Sirtuin 1 (SIRT1) and SIRT3, as DNA damage-associated lysine deacetylases, were measured, and SIRT1 decreased with aging, resulting in a large increase in acetylated lysine residues in the hippocampus. On the other hand, SIRT3 increased with aging. Exercise-induced neurogenesis might not be a causative factor of increased spatial memory, because IGF-1 plus exercise can induce neurogenesis in the hippocampus of older rats. Data revealed that the age-associated increase in 8-oxoG levels is due to decreased acetylation of OGG1. Age-associated decreases in SIRT1 and the associated increase in lysine acetylation, in the hippocampus, could have significant impact on function and thus, could suggest a therapeutic target.

Effect of high intensity interval training on 8-oxoguanine DNA glycosylase and 8-hydroxy-2-deoxyguanosine contents in the brain and liver of rats

“…In addition, it seems that observed changes in OGG1 and 8-OHdG are simply due to HIIT protocol. While two previous studies have been reported that running (Koltai et al, 2011) and swimming (Ogonovszky et al, 2005b) with low to moderate intensity have no significant influence on OGG1 and 8-OHdG levels in rat's hippocampus, our findings show an increase in OGG1 contents of brain and liver following HIIT. Our findings are supported by a study by Ogonovszky et al (2005), who reported an increase in OGG1 activity and 8-OHdG levels of rat liver following strenuous and overtraining (Ogonovszky et al, 2005a).…”

“…OGG1, as main repair enzyme, expresses in all kinds of tissues with significantly different levels, recognizes and cleaves 8-OHdG from DNA (Ogonovszky et al, 2005a). There is now evidence that age (Radak et al, 2011), smoking (Park et al, 2011, VO 2 max (Loft et al, 1994), physical labor, BMI, inter-individual variation, nutrient (Kasai et al, 2001) and mental state, especially clinical depression (Forlenza et al, 2006), all affect OGG1 levels. Therefore, animal models were used in the present study to control the variables mentioned.…”

“…In contrast, neither insulin-like growth factor-1 (IGF-1) supplementation and nor exercise training with 60% of VO 2 max had not any effect on OGG1 and 8-OHdG levels. However, combination of exercise and IGF-1 Supplementation increased acetylated OGG1 levels in hippocampus of old rats (Koltai et al, 2011).…”

“…Guanine is prone to undergo further oxidation upon exposure to hydroxyl radicals due to its lower redox potential compare to other nucleic acid bases. Therefore, 8-hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most frequently generated oxidative base lesions (Radak et al, 2011). Unrepaired 8-OHdG can lead to transversion of G : C to T:A and cause mutation.…”

“…To cope with such detrimental consequences, cells are equipped with DNA repair system to reduce the effects of these oxidative DNA damages. Major mammalian DNA glycosylase for recognizes and cleaves of oxidized guanine from DNA is 8-oxoguanine DNA glycosylase (OGG1) (Radak et al, , 2011. Many factors influence on OGG1 and 8-OHdG levels including maximum oxygen consumption (VO 2 max) (Loft et al, 1994), body mass index (BMI) (Kasai et al, 2001) and exercise training (Ogonovszky et al, 2005a;Koltai et al, 2011).…”