Regulation of Metabolic Homeostasis
The function of metabolic homeostasis is to ensure an adequate supply of energy and precursors for macromolecules under variable conditions. We know most of the reactions and enzymes that make up human metabolic pathways. However, we know surprisingly little about the specific mechanisms that achieve metabolic homeostasis. For example, skeletal and heart muscle can maintain near-constant ATP concentration in response to >10-fold change in ATP demand. The latter is especially impressive given the ~1-10 seconds half-life of intracellular ATP. Our lab uses mathematical modeling in combination with experiments in live cells and in vitro reconstituted metabolic pathways to understand the regulation of metabolic homeostasis. We are working on addressing the following unanswered questions: What are the specific functions of allosteric regulation of metabolic pathways? How do cells maintain ATP homeostasis? What is the mechanism and logic of Warburg, Crabtree and Pasteur effects? How do cells coordinate conflicting demands of energy production and biosynthesis? A better understanding of metabolic homeostasis is urgently needed as dysregulation of metabolism collectively referred to as metabolic syndrome contributes to several common disorders, including diabetes, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD).
Mechanism of Lifespan Extension by Caloric Restriction
Caloric restriction (CR) extends the lifespan of evolutionarily diverse animals by up to two-fold including, yeast, worms, flies, spiders, mice, rats, and monkeys. In humans, increased body mass index, a correlate of calorie intake, is associated with increased mortality from cancer, heart disease, stroke, diabetes, and infectious disease. Estimates show that one in five deaths in the US are due to high body mass index. Our lab is interested in elucidating the mechanism of CR-mediated lifespan extension and in developing approaches to identify the diet that will maximize the lifespan of an animal. We are using a powerful model organism C. elegans to uncover the specific molecular mechanism that lead to lifespan extension in response to CR. To facilitate these studies, we have setup an automated lifespan imaging machine that allows us to automatically measure the lifespan and motility of > 5,000 worms simultaneously. Our long-term goal is to apply the insights from model organisms towards developing science-based nutrition recommendations that will delay the onset of age-associated diseases in humans.
Genetically Encoded tools for Manipulation of Metabolism (GEMMs)
At a cellular level, the key response to dietary manipulations and exercise involves changes in intracellular bioenergetic parameters such as ATP/ADP, NADH/NAD+, NADPH/NADP+, GSH/GSSG ratios, and mitochondrial membrane potential (ΔΨm). The causal relationship between changes in these crucial parameters and downstream effects of diet and exercise is currently unknown. A key bottleneck in understanding the role of intracellular bioenergetic parameters in regulation of metabolism has been the lack of methods for direct manipulation of these parameters in vivo. To fill this methodological gap, we have introduced two genetically encoded tools – LbNOX and TPNOX – for manipulation of NADH/NAD+ and NADPH/NADP+ ratios in living cells. We are currently working on expanding this toolkit to other metabolic parameters, which will allow us to mimic metabolic changes induced by exercise and dietary changes in cell culture and model organisms.