Dietary restriction is a reduction in food intake without reaching levels of malnutrition

Published: 2021-06-26 12:50:04
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Dietary restriction is a reduction in food intake without reaching levels of malnutrition (Fontana and Partridge 2015). Studies have shown that when mice, yeast, worms, fruit flies and rhesus monkeys have a restricted diet, the lifespan of the model organism increases. In addition, studies have shown that humans who are on a strict food restriction without reaching levels of malnutrition have similar metabolic, molecular, and physiological biomarkers correlated with dietary restriction in animals (Fontana and Partridge 2015). These studies have concluded that dietary restriction can prevent numerous age-related diseases such as developing diabetes, cancer, and cardiovascular disease. However, it is difficult to perform long-term studies in humans because it is difficult to maintain a calorie restriction diet. The effect of dietary restriction in all the living organisms that have been tested including humans suggests that there are evolutionarily conserved nutrient-sensing pathways that mediate the extension of longevity under the calorie restriction diet.
One of these nutrient-sensing pathways suggested to play a role in the effect of dietary restriction is mammalian target of rapamycin (mTOR) (Bjedov et al. 2010). mTOR is a highly conserved serine-threonine kinase which consists of 2 multi-protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). One of the roles of mTORC1 is to regulate nutrient levels, cell metabolism, and proliferation by promoting anabolic processes. In addition, the most important role of mTORC1 activation is to promote the utilization of glucose and stimulates glutamine anaplerosis by promoting the activity of glutamate dehydrogenase (gdh) that is special importance for this particular study(Csibi et al 2013). Gdh plays a role in controlling amino acid catabolism. This regulation allows gdh activity to modulate change in energy state and amino acid availability (Stanley 2009).
Studies have shown that the D. melanogaster larvae have a high gdh activity (Nowak and Piechowska 1982). The gdh activity increases with the growth of larvae on the third day of development. However, gdh activity decreases rapidly the seventh day of development. The changes of gdh activity correlate with changes in larval oxygen consumption (Nowak and Piechowska 1982). The oxygen consumption was the highest on the third day of development and lowest on the seventh day of development. These studies imply that the activity of glutamate dehydrogenase is related to changes in the mitochondrial processes of energy production.
A pathway that may control the energy production is mTOR signaling pathway. The mTOR pathway is activated during different cellular processes such as tumor formation, angiogenesis, insulin resistance, adipogenesis, and T-lymphocyte activation (Laplante and Sabatini 2009). Over the last decade, the knowledge of mTOR signaling pathway has progressed which allows researchers to understand the mechanisms of diseases such as cancer, diabetes, and neurodegenerative diseases.
mTOR plays a role in aging in response to nutrients that are obtained from organism’s
diet. The amino acids obtained from the nutrient rich diet result in the upregulation of the TOR
pathway. Studies have shown that a calorie restriction diet suppress the mTOR pathway and
downregulate the aging process (Blagosklonny 2010). This is highlighted by the pro-longevity
and pro-health effects of mTOR inhibitor, rapamycin. Rapamycin treatment extends lifespan in
model organisms such as mice, flies, and yeast when compared to the control
food suggesting that like dietary restriction, rapamycin extends longevity by inhibiting TORC1
(Lamming et al. 2012). Furthermore, rapamycin has been used to treat tumors, organ transplant rejection, coronary restenosis and rheumatoid arthritis (Laplante and Sabatini 2009). Understanding the benefits of rapamycin treatment will advance our understanding of the development of therapeutic treatments to human diseases.
mTOR signaling has been emerged as regulator of cell metabolism by coordinating both
anabolic and catabolic processes (Saxton and Sabatini 2017). In the cell metabolism, cell
respiration provides energy from the nutrients and allows essential cellular processes. The first stage of cellular respiration is glycolysis which takes place in the cytosol (Alberts et al. 2013). During glycolysis, glucose molecules break down into two molecules of pyruvate. Furthermore, glycolysis produces two molecules of NADH as an energy source. The products of glycolysis can either occur in aerobic respiration or anaerobic respiration. At the end of aerobic respiration generates thirty-eight molecules of ATP that are accounted for when oxygen is presented. In addition, pyruvate is converted to acetyl-COA by releasing carbon dioxide . This is achieved by the pyruvate dehydrogenase complex which consists of three enzymes located in the mitochondrial matrix and connects glycolysis to kreb cycle.
The kreb cycle is also known as tricarboxylic acid (TCA) or citric acid cycle. Tricarboxylic acid cycle serves as a catabolic and anabolic pathway in all living organisms (Plaitakis et al. 2017). This metabolic pathway consists of eight distinct enzymes that are located in the mitochondrial matrix (Alberts et al 2013). One of the intermediates in the kreb cycle that is special importance for this research is alpha-ketoglutarate (a-ketoglutarate). The a-ketoglutarate is the fifth carbon compound in the kreb cycle before succincyl COA and after isocitrate. The process of replenishing a-ketoglutarate through two deamination processes is called glutamine anaplerosis (Csibi et. al 2013). The first reaction requires glutaminase to generate glutamate. The second reaction uses gdh that plays a role in glutamine catabolism and cellular proliferation. Gdh converts glutamate into alpha-ketoglutarate. Alpha-ketoglutarate loses a carbon dioxide molecule and further oxidized to form the high-energy thioester succinyl-coenzyme A (CoA) (Alberts et. al 2013). In addition, electrons are transferred to NAD+ ( nicotine adenine dinucleotide) to produce NADH. The enzyme that catalyzes this reaction is alpha-ketoglutarate dehydrogenase complex which regulates the metabolic flux.
Thus far, we have discussed only one of the activated carriers that were produced by the
citric acid cycle, NADH. In addition to NADH, FADH2 (reduced flavin adenine dinucleotide) is produced from FAD which is located in the inner mitochondrial membrane. NADH and FADH2 are carriers of high energy electrons and hydrogen (Alberts et. al 2013). Each turn of the cycle forms three NADH molecules and one FADH2 molecule. NADH and FADH2 connects the last part of aerobic respiration. The oxidation of NADH and FADH releases electrons to electron transport chain.
The electron transport chain is the most complex and important mitochondrial pathway. In the mitochondria, electrons are transferred along an electron transport chain which is composed of complexes I, II, III, and IV. After complex IV, electrons are transferred to oxygen to make water (Correa et al. 2015). As the electrons move from one complex to another, protons are pumped across the membrane which generates a proton gradient and a membrane potential. The proton gradient phosphorylates ADP and turns it into ATP by the ATP synthase. This process is called oxidative phosphorylation because oxygen is not consumed unless ADP is available (Correa et al. 2015). Therefore, oxygen consumption is the representative of the basal metabolic rate in the living organism which is the amount of energy produced by an organism at rest (Niven and Scharlemann 2005).
Oxygen consumption is recognized as a fundamental indicator of mitochondrial function (Schieke et. al 2006). Mitochondria are crucial for maintaining organism’s homeostasis. Previous studies used rapamycin to understand the role of mTOR pathway in mitochondria. In D. melanogaster isolated mitochondria from strains treated with rapamycin had a higher rate of oxygen consumption than isolated mitochondria from D. melanogaster strains on the control treatment Villa- Cuesta et al. 2014). The modulation of oxygen consumption in vitro suggest that rapamycin has been implicated to alter mitochondrial performance. However, little is know about the effect of rapamycin on basal metabolic rate by measuring in vivo oxygen consumption of D.melanogaster.The metabolic rate of D.melanogaster treated with rapamycin decreased when compared to the metabolic rate of D. melanogaster under the control treatment (Figure 1). In addition, the oxygen consumption of flies under rapamycin treatment was similar to those on starvation diet. During starvation, the cell will reuse its organelles by autophagy to produce substrates for energy (Soliman 2013). This will provide the amino acids to activate mTOR which promote energy production.
Recent studies show that the activation of mTORC1 modulates glutamine metabolism by regulating glutamate dehydrogenase and suppressing the transcription of SIRT4 (Csibi et. al 2013). SIRT4 is a mitochondrial protein of the sirtuin family that ribosylates and inhibits gdh. It is proposed that SIRT4 plays a role as a regulator of metabolism and age-related diseases such as cancer and metabolic syndromes (Zhu et al.2014). Furthermore, SIRT4 promotes longevity in fruit flies and energy homeostasis. In particular, SIRT4 modulates metabolic pathways such as glycolysis, TCA cycle, and oxidative phosphorylation in regards to environmental and nutrient conditions (Wood et al. 2018). Preliminary results obtained by an graduate student in our laboratory compared the oxygen consumption of SIRT4 mutants of D. melanogaster and wild-type flies under rapamycin and control treatment. In particular, the oxygen consumption of SIRT4 mutants of D.melanogaster in rapamycin treatment was decreased but significantly less than in wild-type flies under rapamycin treatment. The SIRT4 mutants of D. melanogaster in rapamycin treatment had less effect on the oxygen consumption than the control treatment. The results suggested that SIRT4 is not necessary for rapamycin to decrease oxygen consumption, but at least some of the effect of rapamycin on metabolic rate seems to require SIRT4. Since SIRT4 regulates gdh, rapamycin might be involved in the inhibition of glutamine catabolism.
Recent studies showed glutamine is downregulated after rapamycin treatment in the mitochondria of wild-type flies (Villa-Cuesta et. al 2014). In addition, rapamycin increases levels of glutamate in wild-type flies. The results suggest that glutamate dehydrogenase modulates rapamycin effect on metabolic rate.
Since SIRT4 regulates glutamate dehydrogenase activity and the effect of rapamycin on metabolic rate is partially dependent on SIRT4, in my thesis, I will test the hypothesis that rapamycin does not influence oxygen consumption of glutamate dehydrogenase mutant flies.

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