Dietary restriction and aging in rodents: a current view on its molecular mechanisms

Abstract

Dietary restriction (DR) is a robust non-genetic intervention that reduces morbidity and mortality in a range of organisms. This suggests the presence of an evolutionary-conserved pathway that regulates aging and lifespan in response to reduced food or energy intake. Recent genetic analyses have shown that single gene mutations could extend the lifespan, even in mammals. Many longevity genes are clustered into nutrient-sensing and metabolic adaptation pathways, which are also thought to be involved in the effect of DR. The responses of these mutant animals to DR in terms of lifespan or other aging phenotypes suggest that proteins encoded by these genes are involved in the effects of DR. This review focuses on the roles of fork head box O (FoxO) transcription factors, AMP-activated protein kinase (AMPK), and sirtuins (particularly SIRT1) in the effects of DR in rodents. FoxO transcription factors are mammalian orthologs of DAF-16, which is required for the lifespan extending effects of reduced insulin-like signaling in nematodes. A recent study in rodents suggested that FoxO1 is involved in the anti-neoplastic effects of DR. Although aak2 in nematodes (mammalian AMPK), Sir2 in yeast and Sir2.1 in nematodes (mammalian SIRT1) were also reported to be essential for lifespan extension by DR, the findings are thought to depend on the genetic backgrounds of the organisms and/or methods used to induce DR. In rodents, AMPK and SIRT1 are implicated in the metabolic regulation by long-term DR. Genetic and molecular dissection of the mechanisms underlying the effects of DR will provide us with knowledge of the basic aging processes, as well as insights into the development of DR mimetics, to extend the healthy lifespan in humans.

Keywords: AMPK; Dietary restriction; FoxO1; Rodents; SIRT1.

Figure 1.

The anti-neoplastic effects of dietary restriction (DR) are mediated through FoxO1 and Nrf2. DR inhibits IGF-1 signaling, which negatively regulates the FoxO1 transcription factor. This enhances the FoxO1 response to oxidative or genotoxic stress and the induction of FoxO1 target genes. Of the known FoxO1 target genes, p21 not only induces cell cycle arrest but also interacts with Nrf2, and facilitates nuclear transportation of Nrf2 to induce its target genes. This sequence protects animals from neoplastic processes. However, the cell cycle arrest and DNA repair processes that are simultaneously activated by p21 and other molecules might promote senescence under DR conditions.

Figure 2.

Conditional survival curves in FoxO1-knockout (+/–; HT) and wild-type (WT) mice. Survival and cause-of-death data are described in more detail in the original report [33]. (A) Conditional survival curves with neoplastic death excluded from the causes of death (i.e., neoplastic death was censored along with random sacrifice of the mice). The statistical analyses used to determine the conditional survival rate are described elsewhere [119]. (B) Conditional survival curves with non-neoplastic death excluded from the causes of death. The number of mice is limited and the survival curves are incomplete. However, HT-DR mice tended to live longer than WT-DR mice if neoplastic death is eliminated, suggesting that non-neoplastic events, and thus senescence, are delayed in HT-DR mice. By contrast, the conditional survival curves for neoplastic death indicate that HT-DR mice seem to die earlier as a result of neoplastic causes than do WT-DR mice.

Figure 3.

Involvement of AMPK and SIRT1 in the metabolic traits of dietary restriction (DR). In the fasted phase of DR feeding, SIRT1 promotes gluconeogenesis and fatty acid (FA) oxidation, but inhibits lipogenesis in the liver. AMPK activity is reduced by DR, and its inhibitory signal to gluconeogenesis is thus attenuated. The net effect is a prompt gluconeogenic response in the fasted phase of DR. AMPK promotes glucose uptake for lipogenesis in fat cells by an insulin-independent mechanism. Lipogenesis, lipolysis and FA oxidation are simultaneously activated in white adipose tissue (WAT). AMPK and SIRT1 seem to counteract lipogenesis activated by signals converging on PPARγ. AMPK inhibits lipolysis, whereas SIRT1 promotes lipolysis. Therefore, both molecules competitively regulate lipolysis. AMPK and SIRT1 activate FA oxidation cooperatively. AMPK and SIRT1 exquisitely regulate energy flux among tissues during DR.

Figure 4.

Regulation of FoxO1 by AMPK and SIRT1 in DR conditions. In the liver, the reduced AMPK activity and up-regulated SIRT1 activity promote transcriptional activity of FoxO1 for gluconeogenesis and stress resistance. In white adipose tissue, AMPK appears to repress FoxO1 activity. However, deacetylation of FoxO1 by SIRT1 could overcome and finally counteract adipogenesis or lipogenesis promoted by PPARγ.