Calorie restriction and the exercise of chromatin

Abstract

Since the earliest stages of evolution, organisms have faced the challenge of sensing and adapting to environmental changes for their survival under compromising conditions such as food depletion or stress. Implicit in these responses are mechanisms developed during evolution that include the targeting of chromatin to allow or prevent expression of fundamental genes and to protect genome integrity. Among the different approaches to study these mechanisms, the analysis of the response to a moderate reduction of energy intake, also known as calorie restriction (CR), has become one of the best sources of information regarding the factors and pathways involved in metabolic adaptation from lower to higher eukaryotes. Furthermore, responses to CR are involved in life span regulation-conserved from yeast to mammals-and therefore have garnered major research interest. Herein we review current knowledge of responses to CR at the molecular level and their functional link to chromatin.

Figure 1.

Main pathways associated with response to CR. Metabolic fluctuations signal through a nutrient and energy level. A decrease in the nutrient levels down-regulates the IIS pathway and the nutrient-dependent kinases TOR, PKA, and AKT, which in turn up-regulate stress response organizers such as the transcription factors NF-κB and FOXOs. In parallel, the cell's energetic imbalance produced by CR up-regulates the NAD⁺-dependent family of Sirtuins and the nutrient-dependent kinase AMPK, which in turn activate and modulate the stress response. Sirtuins are also involved in the activation of the LKB1 kinase. Overall, as is shown in the bottom part of the figure, survival and life span increase is activated through the activation of several processes (in blue) and inhibition of others (in green).

Figure 2.

CR response on chromatin. CR has an effect on chromatin at three different levels—chromatin structure, gene expression (up-regulation of certain genes and down-regulation of others as indicated by the arrows), and DNA repair—which in general produce an increase in genome stability and can explain, at least partially, the life span increase effect of CR (see the text).

Figure 3.

CR signaling mediators to chromatin. CR induces an energetic imbalance through changes in the NAD⁺/NADH ratio that activates Sirtuins and down-regulates PARPs. Because of their capacity to respond to changes in the NAD⁺/NADH ratio, CtBP and GAPDH (and other metabolic enzymes such as LDH) are likely to be activated by CR response (gray arrows), but the link between their activity and CR has not been formally demonstrated yet. Interestingly, the inhibition of the TOR pathway by CR has dramatic effects on chromatin nucleolar structure and expression (see the text). In blue boxes are represented the roles that these mediators perform or are likely to perform (indicated by ?) in chromatin.

Figure 4.

SirT1 regulates multiple processes through coordination of heterochromatin formation. To perform its specific functions, SirT1 interacts with a wide variety of factors that seem to provide specificity and localization to specific targets (in blue boxes). However, SirT1 is involved in other functions such as DNA repair signaling of DSBs, gene activation, or cell cycle regulation that have not been shown to be due to a direct effect of this sirtuin on chromatin.