Nutrition is one of the biggest modifiable drivers of age-associated diseases in humans. Decrease in food intake extends the lifespan of evolutionary 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 food intake, is associated with increased mortality from cancer, heart disease, stroke, diabetes, and infectious disease. These effects are dramatic. Estimates show that one in five deaths in the US are due to high body mass index. CDC estimates that eliminating cancer or heart disease would increase human lifespan by 3-5%, while diet can increase the lifespan of animals by up to 100%. Therefore, leveraging nutrition to control age-associated diseases will have a major impact on human health, comparable to eliminating cancer or heart disease. Molecular mechanisms driving the effect of nutrition on age-associated diseases are largely unknown.
The long-term goal of our laboratory is to uncover the molecular mechanism(s) driving the effect of nutrition on aging and age-associated diseases. We are interested in the following broad questions: How does diet extend lifespan and delay onset of age-associated diseases? How can we develop mathematical models of metabolism that will accurately predict experimental results? How can we predict the diet that will increase the lifespan of an individual animal?
CURRENT RESEARCH IN OUR LAB IS FOCUSED ON THE FOLLOWING THREE DIRECTIONS:
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.
Mechanism of Lifespan Extension by Calorie Restriction
Calorie restriction (CR) extends the lifespan of evolutionary 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. CR induces dramatic changes in energy metabolism and gene expression but it remains unclear which specific changes in metabolism and/or gene expression are responsible for mediating the beneficial effects of calorie restriction. We’re using GEMMs to mimic the effect of CR on energy metabolism pathways of C. elegans to uncover the specific metabolic changes that are necessary and sufficient for CR-mediated extension of lifespan. To facilitate these studies, we have setup a lifespan imaging machine that allows us to automatically measure the lifespan and motility of thousands of worms. 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.
Mathematical Models of Metabolism
The ultimate test of our understanding of a natural process lies in our ability to build a mechanistic model that predicts the behavior of the process from basic assumptions. Thus, the ultimate goal of metabolism research is to build a mechanistic model that quantitatively predicts outcomes of all experiments similar to how Newtonian mechanics quantitatively predicts movement of objects on Earth and beyond. To be generally applicable, such a mechanistic model should be based on chemical and physical laws and not be a fit of arbitrary equations to data. Our lab is working on developing mechanistic models of metabolism. We are using the insight from mechanistic models together with experiments to address several unanswered questions about the regulation of metabolism pathways: Which regulatory mechanisms are necessary and sufficient to recapitulate in vivo regulation of metabolism? What is the mechanism and logic of Warburg, Crabtree and Pasteur effects? How can we manipulate metabolic pathways to mimic the beneficial effects of nutrition?