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

Abstract

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 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.

Growth hormone signaling is necessary for lifespan extension by dietary methionine

“…We showed that with alternate day feeding, methionine recycling was enhanced in wild-type and dwarf mice, while transsulfuration was significantly decreased similar to that reported in mice fed low MET and in rats fed high fat (Finkelstein et al ., 1988; Tang et al ., 2010; Brown-Borg & Rakoczy, 2013; Dahlhoff et al ., 2013), effectively decreasing transsulfuration to conserve MET. A potential link between these observations involves the peroxisome proliferator-activated receptor (PPAR) gene family.…”

Diminished mTOR signaling: a common mode of action for endocrine longevity factors

“…GH may also promote PI3K/Akt/mTOR signaling through IGF-1 independent pathways. For example, GH has profound effects on methionine metabolism (Brown-Borg and Rakoczy 2013 ), and amino acids regulate mTORC1 via the Rag family of GTPases (Bar-Peled and Sabatini 2014 ). GH directly modulates glucose uptake by skeletal muscle (Yakar et al 2004 ), and glucose regulates mTORC1 signaling directly via the Rag family of GTPases (Efeyan et al 2013 ).…”

Promoting Health and Longevity through Diet: From Model Organisms to Humans

“…Treatment of cells and mice with βOHB, an endogenous histone deacetylase inhibitor powerfully induced by fasting, protects against oxidative stress (Shimazu et al, 2013). Fasting improves mitochondrial function, stimulates the production of chaperones such as HSP-70 and GRP-78, and by inhibiting the AKT/mTOR pathway, triggers autophagy and DNA repair pathways in multiple cells types (Brown-Borg HM, Rakoczy S. 2013; Mattson et al, 2014). Moreover, in mice, multiple cycles of fasting modulate hematopoietic stem cell protection, self-renewal, and regeneration via IGF-1 or PKA inhibition (Cheng et al 2014).…”