Calorie Restriction and Alternate Day Fasting in Ames Dwarf and GHRKO Mice

There has been an injection of greater rigor into mainstream mouse studies of longevity in recent years, possibly prompted by a growing realization that many studies of past decades were fatally undermined by a failure to consider the possibility of inadvertent calorie restriction, among other issues. So even well-trafficked areas such as the biology of long-lived lineages like Ames dwarf and growth hormone receptor knockout (GHRKO) mice presently see a steady progression of new and ever more careful studies of the basics. Not that there is any shortage of new ground to cover in something as complex as the biology of a mammal. There are unknowns enough to last for decades at the present pace of discovery.

These two papers take a new look at how some of the long-lived mouse breeds react to calorie restriction and the similar method of alternate day fasting, both of which are shown to extend life in ordinary non-engineered laboratory mice. There is far more evidence for the benefits of calorie restriction than there is for forms of intermittent fasting, as it has been studied for longer and by more research groups. Interestingly, some studies have shown alternative day fasting to extend life to some degree even when the overall level of calories consumed is not reduced. Other studies show that calorie restriction and alternate day fasting produce notably different patterns of gene expression - sets of overlapping but different changes.

The end goal behind this sort of work is to pin down the shared mechanisms by which life is extended, and thereby do a better job of identifying exactly what they are and how they work. If you find two methods of life extension that don't stack - as appears to be the case for GHRKO and calorie restriction - then that's a good place to start looking for these shared root causes.

Metabolic Alterations Due to Caloric Restriction and Every Other Day Feeding in Normal and Growth Hormone Receptor Knockout Mice

Mutations causing decreased somatotrophic signaling are known to increase insulin sensitivity and extend life span in mammals. Caloric restriction and every other day (EOD) dietary regimens are associated with similar improvements to insulin signaling and longevity in normal mice; however, these interventions fail to increase insulin sensitivity or life span in growth hormone receptor knockout (GHRKO) mice.

To investigate the interactions of the GHRKO mutation with caloric restriction and EOD dietary interventions, we measured changes in the metabolic parameters oxygen consumption (VO2) and respiratory quotient produced by either long-term caloric restriction or EOD in male GHRKO and normal mice.

GHRKO mice had increased VO2, which was unaltered by diet. In normal mice, EOD diet caused a significant reduction in VO2 compared with ad libitum (AL) mice during fed and fasted conditions. In normal mice, caloric restriction increased both the range of VO2 and the difference in minimum VO2 between fed and fasted states, whereas EOD diet caused a relatively static VO2 pattern under fed and fasted states. No diet significantly altered the range of VO2 of GHRKO mice under fed conditions. This provides further evidence that longevity-conferring diets cause major metabolic changes in normal mice, but not in GHRKO mice.

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

Restrictive dietary interventions exert significant beneficial physiological effects in terms of aging and age-related disease in many species. Every other day feeding (EOD) has been utilized in aging research and shown to mimic many of the positive outcomes consequent with dietary restriction. This study employed long living Ames dwarf mice subjected to EOD feeding to examine the adaptations of the oxidative phosphorylation (OXPHOS) and antioxidative defense systems to this feeding regimen.

Every other day feeding lowered liver glutathione (GSH) concentrations in dwarf and wild type (WT) mice but altered GSH biosynthesis and degradation in WT mice only. The activities of liver OXPHOS enzymes and corresponding proteins declined in WT mice fed EOD while in dwarf animals, the levels were maintained or increased with this feeding regimen. Antioxidative enzymes were differentially affected depending on the tissue, whether proliferative or post-mitotic. Gene expression of components of liver methionine metabolism remained elevated in dwarf mice when compared to WT mice as previously reported however, enzymes responsible for recycling homocysteine to methionine were elevated in both genotypes in response to EOD feeding.

The data suggest that the differences in anabolic hormone levels likely affect the sensitivity of long living and control mice to this dietary regimen, with dwarf mice exhibiting fewer responses in comparison to WT mice. These results provide further evidence that dwarf mice may be better protected against metabolic and environmental perturbations which may in turn, contribute to their extended longevity.

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