Dietary restriction (DR), the reduction in nutrient intake without malnutrition, has been well documented as a means to extend lifespan and slow age-related diseases in many systems. We and others have previously demonstrated that lifespan extension by inhibition of the TOR pathway overlaps with the effects of DR in D. melanogaster, S. cerevisiae, and C. elegans. However, other DR response mechanisms exist that remain undiscovered. The overall goal of the Kapahi lab is to understand how an organism responds to nutrient status to influence health and disease.
We utilize worms, flies, and mice as model systems to understand how nutrients influence age-related changes in specific tissues and disease processes. We take creative approaches to develop models for various human diseases that are influenced by nutrient status using invertebrates. We study how various physiological and molecular processes, including fat metabolism, circadian clocks, advanced glycation end products, calcification, and intestinal permeability, are influenced by nutrients to impact organismal health and survival. We collaborate with multiple groups at University of California, San Francisco, and University of California, Berkeley, to undertake interdisciplinary approaches to translate our findings from multiple models to humans.
Why it matters
Our work has relevance to certain age-related human diseases, including diabetes, Alzheimer’s disease, kidney stone formation, intestinal diseases, and obesity. There is an ongoing debate about the limitation of lifespan as a measure of aging and the need to assess healthspan to find the most promising interventions for humans. Through functional measures of different tissue functions and disease models, we are also examining the relationship between healthspan and lifespan.
Our work on aging in simple animals has led to real possibilities of treating human diseases, something I never thought possible when I began my career.
Pankaj Kapahi, PhD
Dr. Kapahi received his PhD from the University of Manchester, where he worked with Tom Kirkwood. He did his postdoctoral work with Seymour Benzer at Caltech and Michael Karin at University of California, San Diego. He joined the Buck Institute as an assistant professor in 2004.
Dr. Kapahi has published more than 80 scientific papers and holds three current patents. He has been recognized for his scientific excellence with many awards, including the Eureka Award from the National Institute on Aging, a New Scholar Award from the Ellison Medical Foundation, a Glenn Award for Research in Biological Mechanisms of Aging, the Nathan Shock Young Investigator Award, and the Breakthrough in Gerontology and Julie Martin Mid-career awards from AFAR. He currently serves on the editorial board of Aging Cell, Aging, and PLOS Genetics. Dr. Kapahi also initiated the first master’s degree course in gerontology at the Buck Institute.
Sudipta Bar Postdoctoral Research Scholar
Dr. Bar joined the Kapahi lab as a postdoctoral research fellow in July 2018. He received his Ph.D. in Biological Sciences from Indian Institute of Science Education and Research Kolkata, India where he studied lysosomal storage disorders using Drosophila and cell culture. At Buck, he utilizes Drosophila genetics, molecular biology, and bioinformatics tools to understand the environmental and genetic factors responsible for neurodegeneration in Alzheimer’s and related diseases. He recently received the Larry L. Hillblom postdoctoral fellowship grant (2019).
Jennifer Beck Lab Manager
Jennifer is an honors graduate of University of California, Davis, and has held positions at various institutions. At University of California, Berkeley, she studied NK cells, T-cells, lymphoma, and type 1 diabetes as well as how to control the innate immune system to better fight autoimmune diseases. At Johns Hopkins University, she studied breast cancer, polycystic kidney disease, and understanding cellular migration via 3D microenvironment and advanced microscopy techniques. At Eastern Connecticut Health Network, she analyzed clinical research regarding opioid prescriptions, physician professionalism, and antibiotic resistance. At the Buck, her studies have focused on genetic variance, circadian rhythm, kidney stones, and diabetes. She is currently researching Alzheimer's and neurodegeneration.
Lukas Fluitt Dominican University Graduate Student
Natalie Hill Dominican University Graduate Student
Natalie Hill is originally from Palos Verdes, CA. She recently graduated from Pomona College with a BA in biology and also participated on the water polo team there. Her hobbies include exploring the outdoors (hiking, backpacking, camping), exercising, and listening to music.
Tyler Hilsabeck PhD Candidate, USC-Buck Biology of Aging Program
Tyler holds a bachelor's degree in physics from Texas Tech University and a master's degree in biology from the University of Texas at San Antonio. His PhD studies in both the Kapahi and Brem labs focus on using computational and biological tools to understand the relationships between metabolites, genes, and aging-related phenotypes in Drosophila melanogaster.
Brian Hodge, PhD Postdoctoral Research Fellow
Dr. Hodge joined the Kapahi lab as a postdoctoral research fellow in the summer of 2016. He received his PhD in physiology from the University of Kentucky and completed a short postdoc at the University of Florida prior to starting at the Buck. His research is focused on understanding how environmental factors such as nutrients and light influence circadian gene expression and the processes of aging. He utilizes Drosophila genetics and bioinformatic (RNA-Seq, ChIP-Seq) and molecular genetic approaches to identify transcriptional regulators of circadian clocks and longevity. Brian also serves as vice president of the Postdoctoral Association at the Buck.
Charles Lau Dominican University Graduate Student
Charles Lau earned his degree in molecular cell biology at Dominican University of California in the Spring of 2019. Charles has a great passion for discovery and aspires to reach great heights in his research and studies. He is currently studying as a graduate student at the Buck Institute, where he is working in the Kapahi lab researching ocular degeneration and how it is link to aging in fruit flies. He hopes to one day further expand his knowledge on stem cells and its benefits for humanity.
Kristeen Pareja, PhD Postdoctoral Research Scholar
Dr. Pareja is originally from Los Baños Laguna, Philippines. She earned her BS degree in Biochemistry and Molecular Biology from UC Davis and her PhD in Pharmacology from Cornell University. Prior to attending graduate school, she worked in several labs including Lawrence Berkeley National Laboratory, Novozymes and Touro University. As a graduate student in the Sevier lab, she studied chaperone proteins involved in ER oxidative stress signaling. She joined the Kapahi lab in July 2018 where she is currently investigating the role of advanced glycation end products in aging and neurodegenerative diseases.
Harshani Peiris, PhD Postdoctoral Research Fellow
Harshani Peiris received her Bachelor’s degree from Ramapo College of NJ in biology and bioinformatics, the post baccalaureate degree from University of Pennsylvania and PhD in quantitative systems biology from University of California, Merced. She joined Buck Institute as a postdoctoral scientist in 2015 and is a Hillblom post-doctoral fellow grantee since 2017. She is a molecular biologist trained in in-vitro cell culture model systems and in- vivo vertebrate (mouse, rat) and invertebrate (planarian/ Schmidtea mediterranea, C. elegans) systems. Her goal is to understand how different systems maintain systemic homeostasis and how disruption of the systemic balance leads towards aging and pathologies. Further, Harshani is investigating how signaling pathways govern metabolic and proliferative homeostasis, and how we can tune these pathways to achieve homeostasis and longevity.
Muniesh Muthaiyan Shanmugam , PhD Postdoctoral Research Fellow
Kenneth Wilson PhD Candidate, USC-Buck Biology of Aging Program
Kenneth received his bachelor’s degree in molecular and cell biology from University of California Berkeley and his master’s degree in biological sciences from Dominican University of California. His current research focuses on understanding how natural genetic variation can influence response to diet to affect longevity and health.
- Investigating the Role of Advanced Glycation End (AGE) products in aging, diabetes, and neurodegeneration
Diabetes is a metabolic disease resulting from elevated glucose over a prolonged period. In the United States, 11.3 percent of all adults 20 or over have diabetes. Diabetes overall at least doubles the risk of death. Diabetes leads to various complications and organ failure, including cardiovascular diseases, kidney failure, diabetic retinopathy in the United States in 2010. Diabetes also more than doubles the risk of Alzheimer’s and Parkinson’s disease. However, the mechanisms by which diabetes causes these pathologies remain poorly understood
Our working hypothesis is that prolonged elevation of glucose leads to glycation of macromolecules like protein and lipids, by forming Advanced Glycation End-products (AGEs). Methylglyoxal (MGO) and other glyoxals, which are unavoidable byproducts of anaerobic glycolysis and lipid peroxidation, react indiscriminately with proteins, lipids, and DNA to yield a heterogeneous array of molecules collectively called AGEs The formation of AGEs damages cellular macromolecules and has been associated with the complications of diabetes and other diseases. We have developed a model to study various pathologies including diabetic neuropathy, neurotoxicity, and accelerated aging using C. elegans within a two-week timeframe. We have established a C. elegans model, based on impaired glyoxalases (GLO1 or DJ-1), to broadly study MGO related stress. We show that, in comparison to wild-type animal, the mutants rapidly exhibit several pathogenic phenotypes, including hyperesthesia, neuronal damage, reduced motility, and early mortality. We further demonstrate TRPA-1/TRPA1 as a sensor for a-DCs, conserved between worms and mammals. Moreover, TRPA-1 activates SKN-1/Nrf via calcium-modulated kinase signaling, ultimately regulating the glutathione-dependent (GLO1) and co-factor-independent (DJ1) glyoxalases to detoxify a-DCs. Using our model, we are uncovering genetic and pharmacological targets that modulate the onset of AGEs pathology in our worm model at different steps shown in Figure 1. We are currently pursuing these targets in various models of neurodegenerative diseases using worms, mice, and induced pluripotent stem cells.
- The role of diet and circadian clocks in aging and neurodegeneration
Dietary Restriction (DR) is the reduction of particular or total nutrient intake without causing malnutrition. DR extends lifespan and delays the onset of age-related neurodegeneration in models of neurodegenerative disease in diverse organisms, including yeast, flies, and rodents. Several studies in mice have documented that caloric restriction or time-restricted feeding slow age-related neurological decline in both normal aging and models of AD. However, the molecular mechanisms through which nutrient restriction protects the brain and other tissues during normal aging and AD are just beginning to be elucidated.
We propose to use the fly to study this question as it is a well-established and expedient model to study aging, dietary changes, and neurodegenerative diseases. We are also studying the cross-talk between nutrient-sensing pathways and circadian clocks to modulate aging and neurodegeneration. Our interdisciplinary studies involve the use of genetics, proteomics, bioinformatics to define the nutrient responsive pathways that modulate aging and neurodegenration. Furthermore, we are using flies, mice and induced pluripotent stem cells to study pathways that influence aging and neurodegeneration.
- Jyotiska Chaudhuri, Yasmin Bains, Sanjib Guha, Arnold Kahn,David Hall, Neelanjan Bose, Alejandro Gugliucci, Pankaj Kapahi, The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality, Cell Metabolism, Volume 28, Issue 3, 4 September 2018, Pages 337-352
- Zee, T., Bose, N., Stoller, M., Kapahi, P. Alpha-lipoic acid ameliorates stone formation in a mouse model of cystinuria. (Accepted at Nature Medicine).
- Luis, N. M., Wang, L., Ortega, M., Deng, H., Katewa, S. D., Li, P. W., Karpac, J., Jasper, H., Kapahi, P. Intestinal IRE1 is required for increased triglyceride metabolism and longer lifespan under dietary restriction. Cell Rep, 25, 17(5), 1207–1216.
- Chaudhuri, J., Bose, N., Gong, J., Hall, D., Rifkind, A., Bhaumik, D., Peiris, T. H., Chamoli, M., Le, C. H., Liu, J., Lithgow, G. J., Ramanathan, A., Xu, X. Z., Kapahi, P. (2016 Nov 21). A Caenorhabditis elegans model elucidates a conserved role for TRPA1-Nrf signaling in reactive α-Dicarbonyl detoxification. Curr Biol, 26(22), 3014–25.
- Katewa, S. D., Akagi, K., Bose, N., Rakshit, K., Camarella, T., Zheng, X., Hall, D., Davis, S., Nelson, C. S., Brem, R. B., Ramanathan, A., Sehgal, A., Giebultowicz, J. M., Kapahi, P. (2016 Jan 12). Peripheral clocks modulate lifespan and fat metabolism upon dietary restriction. Cell Metab, 23(1), 143-54. doi: 10.1016/j.cmet.2015.10.014. Epub 2015 Nov 25.
- Chen, D., Li, P. W., Goldstein, B. A., Cai, W., Thomas, E. L., Chen, F., Hubbard, A. E., Melov, S., Kapahi, P. (2013). Germline signaling mediates the synergistically prolonged longevity produced by double mutations in daf-2 and rsks-1 in C. elegans. Cell Rep, 5, 1600–10.
- Katewa, D., Demontis, F., Kolipinski, M., Hubbard, A., Gill, M., Perrimon, N., Melov, S., Kapahi, P. (2012). Intra-myocellular triglyceride turnover plays a critical role in mediating responses to dietary restriction in Drosophila melanogaster. Cell Metab, 16, 97–103.
- Zid, B. M., Rogers, A. N., Katewa, S. D., Vargas M. A., Kolipinski, M. C., Lu, T. A., Kapahi, P. (2009). 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell, 139, 149–60.
- Pan, K. Z., Palter, J. E., Rogers, A. N., Olsen, A., Chen, D., Lithgow, G. J., Kapahi, P. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell, 6(1), 111–9. PMID: 17266680.
- Kapahi, P., Zid, B. M., Harper, T., Koslover, D., Sapin, V., Benzer, S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol, 14, 885–90.
- Rossi, A., Kapahi, P., Natoli, G., Takahashi, T., Chen, Y., Karin, M. (2000). Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature, 403(6765), 103–8.