Effect of Every Other Day Feeding on Mitochondrial Free Radical Production and Oxidative Stress in Mouse Liver

Abstract

It is known that dietary restriction (DR) increases maximum longevity in rodents, but the mechanisms involved remain unknown. Among the possible mechanisms, several lines of evidence support the idea that decreases in mitochondrial oxidative stress and in insulin signaling are involved but it is not known if they are interconnected. It has been reported that when C57BL/6 mice are maintained on an every other day (EOD) feeding their overall food intake is only slightly decreased and plasma insulin-like growth factor (IGF)-1 is even somewhat increased. In spite of this, their maximum longevity is increased, analogously to what occurs in classic DR. Thus, this model dissociates the increase in longevity from the decrease in IGF-1 observed in classic DR. Based on these facts, we have studied the effect of EOD DR on the rate of mitochondrial reactive oxygen species (ROS) production, oxygen consumption, and the percent free radical leak (FRL) of well-coupled liver mitochondria, the marker of mtDNA oxidative damage 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxodG), the content of complexes I to IV of the respiratory chain, the apoptosis inducing factor (AIF), PGC1-alpha, UCP2, five different markers of oxidative damage to proteins and the full fatty acid composition on C57BL/6 mice liver. It was found that EOD DR decreased ROS production in complex I but not in complex III without changes in oxygen consumption. As a result, FRL was decreased in complex I. Oxidative damage to mtDNA (8-oxodG) and protein oxidation, glycoxidation and lipoxidation were also lower in the EOD restricted group in comparison with the control one while the degree of fatty acid unsaturation was held constant. The EOD group also showed decreases in AIF, PGC1-alpha, and UCP2. These results support the possibility that EOD DR increases maximum life span at least in part through decreases in mitochondrial oxidative stress which are independent from insulin/IGF-1-like signaling.

Caloric restriction

“…The EOD group also showed decreases in apoptosis inducing factor (AIF), PGC1-a, and UCP2. These results support the possibility that EOD increases maximum life span at least in part through decreases in mitochondrial oxidative stress which is independent from insulin/IGF-1-like signaling (Caro et al, 2008b).…”

Metabolic adaptations to short-term every-other-day feeding in long-living Ames dwarf mice

“…This finding holds true for dwarf mice subjected to EOD feeding supporting the protection of mitochondrial function during a metabolic stress such as energy restriction. Others have also observed significant reductions in liver OXPHOS proteins with EOD feeding in mice (Caro et al, 2008). A recent report found that intermittent feeding in rats decreased kidney complex I activity but increased complex IV activities in liver, kidney and heart (Singh et al, 2012).…”

“…There are numerous examples of studies in which DNA, protein and lipid (peroxidation) oxidative damage were reduced following both EOD and DR (Caro et al, 2008; Merry, 2002; 2004; Barja, 2004; Heilbronn et al, 2006; Castello et al, 2005; Chiarpotto et al, 2006; Gredilla and Barja, 2005). These studies among many others conclude that these dietary manipulations reduce cumulative oxidative damage by altering ROS production and protective mechanisms (antioxidative enzymes, repair pathways).…”

“…Rodents, in particular, have been examined using numerous dietary intervention protocols that have varied the age of onset of the restrictive intervention, the length of time restrictive intervention was applied, the level of restriction and the type of nutrient restriction using either a percent reduction in calories or every other day feeding (EOD). In many cases, these variations have resulted in reduced age-related pathologies and life span extension (Ingram and Reynolds, 1987; Weindruch and Walford, 1988; Weindruch et al, 1986; Goodrick et al, 1990; Anson et al, 2003; Shimokawa et al, 2003; Caro et al, 2008; Pearson et al, 2008; Tatsumi et al, 2008; Cleary et al, 2007; Zha et al, 2008; Masoro, 2009). …”

Aging and Mitochondrial DNA

“…The strategy has been proved to be effective grossly in mammals [45]. Even in yeast, CR has been shown to delay aging [46].CR retards oxidative stress-related damage and aging in mammals by lowering mitochondrial ROS-induced oxidative stress [47], and was found to increase maximum life span [48]. However, age-related alterations in energy metabolism are tissue specific, and that CR is unable to attenuate these effects in all types of tissues with equal competence [49].…”