Understanding how cellular metabolism interacts with the genes and pathways that regulate aging has led to many of the potential interventions now being investigated to promote healthspan. Exercise, fasting, and dietary restriction all work to promote health by activating specific cellular signaling pathways. Many of these signaling pathways involve ordinary cellular metabolites like acetyl-CoA and NAD, which have “secret” lives regulating enzymes and genes. The Newman lab focuses on an emerging signaling metabolite, the ketone body beta-hydroxybutyrate, and the roles it may have in responding to stressors and regulating healthspan.
Ketone bodies are the energy currency that allows the body’s cells to utilize fats for fuel. They are made normally in the liver from fats whenever carbohydrates are scarce, as when fasting or exercising. Ketone bodies are to fats what glucose is to carbohydrates. But beta-hydroxybutyrate has signaling activities as well, including regulating gene expression, modulating inflammation, and controlling metabolism by inhibiting enzymes, binding to proteins, and activating receptors. We have found that long-term exposure to ketone bodies using a ketogenic diet can extend the healthy lifespan of normal mice and, in particular, protect the aging brain. We seek a mechanistic understanding of how ketone bodies might work in an aging mammal to promote health, particularly in age-related memory decline and Alzheimer’s disease. Our goal is to develop targeted therapies that might enhance the resilience of older adults to diseases like Alzheimer’s and stresses like hospitalization.
Why it matters
The translation of geroscience into clinical practice has great potential to improve the lives of older adults. We already know that the best way to treat the complex medical problems of older adults is through the systematic, individualized geriatric medicine approach of comprehensive assessments and multidomain interventions. Interventions developed from geroscience usually act on multiple aging-related cellular pathways, like how the signaling activities of ketone bodies affect gene expression, inflammation, and metabolism. These interventions may hold great promise for treating complex geriatric syndromes like frailty, multimorbidity, and delirium that affect the health and independence of millions of older adults.
As a physician-scientist, working on interventions that act on multiple age-related cellular pathways is particularly rewarding. This may be the best way to address the complex geriatric syndromes that affect patients.
John Newman, MD, PhD
John Newman, MD, PhD, is an assistant professor at the Buck Institute for Research on Aging and in the Division of Geriatrics at University of California San Francisco (UCSF). His career goal is to translate our expanding understanding of aging biology to improve the care and help maintain the independence of older adults. His research at the Buck Institute studies the molecular details of how diet and fasting regulate the genes and pathways that in turn control aging, focusing on the ketone body beta-hydroxybutyrate and how its molecular signaling activities involving epigenetics and inflammation regulate aging and memory in mice.
Dr. Newman is also a geriatrician who cares for hospitalized older adults at UCSF and the San Francisco VA Medical Center, focusing on preserving mobility and preventing delirium. His undergraduate education was at Yale University, with a BS/MS in molecular biophysics and biochemistry that included studying growth factor signaling in the roundworm C. elegans. He completed an MD/PhD at the University of Washington, where his graduate work studies focused on the progeroid Cockayne syndrome with Dr. Alan Weiner. While at UW, he developed new bioinformatics tools for the analysis of patterns in gene expression data. He then completed a residency in internal medicine and fellowship training in geriatric medicine at UCSF. He is an National Institute on Aging Beeson Scholar.
Dr. Newman is a native of Long Island, New York, and a lifelong Mets fan. He has lived in San Francisco since 2008. He enjoys playing volleyball, watching baseball, exploring the natural beauty of the Bay Area, and having fun food experiences.
Thelma Y. García, PhD Lab Research and Administrative Manager
Dr. Thelma Garcia is the Newman Lab Research and Administrative Manager. Her current research project involves maintaining a comprehensive database of ketone body science. Her main focus is in glucose and insulin sensitivity, energy expenditure, mitochondrial function, lipid metabolism and other effects of BHB and other related compounds. She also enjoys and takes big pride in training, supervising and mentoring interns who work in vitro assays of assays of BHB function and enzyme activity.
She also serves as a hands-on research project manager. She assists scientists plan and troubleshoot experiments and promotes awareness and communication in the lab. As a safety lab officer ensures renewal, update, and modification of Biological User Authorizations (BUA, BSL-2), IACUC, and any other permits for all projects. As an administrator, she provides requested input on capital budgets, resource requirements, and financial budgets and analysis, as well as grant support.
She proactively assess the needs of the scientists and develop processes and methods to enable efficient functioning of the lab. Partner with relevant functions to ensure the needs of the scientists are met and be the main point of contact for scientific community. Responsible for generating and managing purchase orders for equipment and collaborations. She trains and leads in specialty lab equipment.
Dr. Garcia is originally from Mexico and loves nature and food. She has lived in the bay area for over 22 years. She attended SRJC, SSU, and later completed doctoral studies in Chemistry at UC Davis. As a CDC-APHL postdoctoral fellow her focus was in biochemistry/toxicology
Thanh Blade Laboratory Technician
Thanh Blade is a lab assistant in the Newman Lab at the Buck Institute. She obtained a Bachelor of Science in Biochemistry from Sonoma State University. Her most recent research interest are in metabolism, especially ketogenic diet metabolism. Her goal in life is to love what she does and to do what she loves.
Asish Chaudhuri, PhD Staff Scientist
Asish Chaudhuri, Ph.D. is a Staff Scientist in John Newman’s laboratory at the Buck Institute for Research on Aging. His primary research interest is to understand how impaired protein homeostasis contributes to aging and age-related diseases like sarcopenia, Alzheimer’s, ALS and diabetes. To address this question, he has developed various fluorescence-based technologies and applied to short-/ long-lived animals and disease mouse models (e.g., ALS, diabetic models) to test the working hypothesis that “accumulation of oxidized proteins as misfolded aggregates is the critical determinant for the onset and progression of aging and age-related diseases”. In November, 2017, he and his colleagues got a patent on the discovery of novel function of an FDA approved drug, hydralazine, generally used for hyper-tension. They showed that hydralazine possesses anti-aging property. He received 13 grants as a Principal or as co-investigator and published 47 peer reviewed papers including top peer review journals like Nature Communication, PNAS, Aging cell, FASEB J., Methods in Enzymology, Biochemistry, Journal of Molecular Biology, Journal of Biological chemistry.
In Newman’s laboratory, he will be focusing on three important aspects; (i) development of high throughput techniques for screening various beta hydroxybutyrate derivatives and other molecules, (ii) development of disaggregation assay to screen molecules, and (iii) development of strategy to find the target proteins for beta hydroxy butyrate and its derivatives.
Dr. Asish Chaudhuri is from Kolkata (formerly called Calcutta), India. He lived 25 years in Texas, (mainly in San Antonio and Dallas) before he moved to California. He loves to play tennis, writing poetry, reading books and hanging out with friends. He enjoys food of different countries.
Brenda Eap USC/Buck Institute Biology of Aging PhD Program
Brenda completed her B.S. in Biochemistry with a minor in Forensic Science at California State University, Los Angeles in 2017. Her PhD work in the Newman lab involves investigating beta-hydroxybutyrate (BHB) and other ketone esters as epigenetic regulators and important metabolites of aging.
During her spare time, she likes bringing friends together and having a good time over board games and food. She also likes to travel and immerse herself in different cultures when she has the time and money.
Wyatt Gray Laboratory Technician
Wyatt Gray started in the Newman Lab as an intern in 2018. In 2019, he was hired as a lab technician. He completed an associates degree from the Santa Rosa Junior College in biology and natural sciences. His work in the Newman lab involves carefully performing different assays . He also assists with rodent research and maintenance. He is currently involved in mice gavage. In his spare time he enjoys adventure in the outdoor, traveling cooking delicious food, and being the president of the Chemistry club at SRJC.
Sidharth S. Madhavan USC/Buck Institute Biology of Aging PhD Program
Sid is a USC-Buck Ph.D. fellow in the Newman Lab. In 2019, he completed a B.S. in Clinical Neuroscience with honors at Virginia Tech. As an undergraduate, he researched structural and biochemical properties of tau proteins, specifically relating to clinical mutations affecting aggregation. As a Ph.D. fellow in the Newman Lab, he will build on his background, investigating the propensity for small energetic metabolites to modulate proteostasis in Alzheimer’s disease. When he isn’t at the bench, Sid loves being outdoors. He has hiked most of the Appalachian Trail in southwest Virginia and enjoys the accessibility to backcountry hiking out west. Sid also enjoys running, cooking new recipes, falling asleep in his hammock, and teaching himself bluegrass flatpicking.
Mitsunori Nomura, PhD Postdoctoral Research Fellow
Dr. Mitsunori Nomura is a Postdoctoral Research Fellow in the Newman lab. His project involves studying how the ketone body beta-hydroxybutyrate (BHB), which is made in the liver by the fatty acid oxidation (FAO) during fasting, ketogenic diet feeding, and exercise, affects the aging brain and age-related diseases. He will use ketone body compounds (BHB derivatives), diet interventions, and genetic modifications in both cells and rodent models to understand the mechanistic effects of ketone bodies on memory and other phenotypes in normal aging and Alzheimer’s disease models. In particular, Dr. Nomura’s research will focus on the role of BHB in metabolic regulation of immune cells, such as macrophages and microglia, resident macrophages in brain.
Dr. Nomura’s doctoral studies at the École polytechnique fédérale de Lausanne (EPFL) focused on studies of how the bile acid signaling shapes macrophage function in metabolic diseases. As a postdoctoral fellow at the National Institutes of Health (NIH), his focus was on understanding the role of macrophage FAO in metabolism.
Dr. Nomura is originally from Japan and loves physical exercise. If you see a man running around the Buck hill, the guy may be him.
Stepahanie Roa Diaz Laboratory Technician
Stephanie joined the Newman lab as an intern in December 2019. Since then, she has completed her B.S. in Biochemistry at Sonoma State University. While at Sonoma State she studied the binding interactions of an RNA aptamer, as a potential therapeutic agent for Non-Hodgkin’s Lymphoma. She joined the Newman lab as a lab technician in September of 2020. Her current research interests are the aging metabolism and Beta-hydroxybutyrate, BHB, and its role in aging diseases. She hopes to gain insight on ketone body mechanisms to benefit the general public through research. In her free time, Stephanie enjoys being outdoors and spending time with friends and family.
Lexi Straube Laboratory Technician
Lexi began in the Newman Lab as an intern in 2018. After one year of rigorous apprentice work she was hired as a lab technician. She completed an associates degree from the Santa Rosa Junior College in biology and natural sciences and currently continues her education in hopes of becoming a medical doctor. Her work in the Newman lab involves exploring the potential of beta-hydroxybutyrate (BHB) and other ketone esters as signaling metabolites as well as conducting rodent research and maintenance. In her spare time she enjoys outdoor endeavors, traveling, burying her head into textbooks, and playing board games with friends and family.
- Models and Studies of Aging: Executive Summary of a Report from the U13 Conference Series. Hurria A, Carpenter CR, McFarland F, Lundebjerg NE, de Cabo R, Ferrucci L, Studenski SA, Barzilai N, Briggs JP, Ix JH, Kitzman DW, Kuchel GA, Musi N, Newman JC, Rando TA, Smith AK, Walston JD, Kirkland JL, Yung R. Journal of the American Geriatrics Society. 2019; 67(3):428-433. NIHMSID: NIHMS1013523 PubMed [journal]PMID: 30693953 PMCID: PMC6403012
- Newman, J. C., Covarrubias, A. J., Zhao, M., Yu, X., Gut, P., Ng, C. P., Huang, Y., Haldar, S., Verdin, E. (2017). Ketogenic diet reduces mid-life mortality and improves memory in aging mice. Cell Metab, 26(3), 547–57, e8.
- Tognini, P., Murakami, M., Liu, Y., Eckle-Mahan, K. L., Newman, J. C., Verdin, E., Baldi, P., Sassone-Corsi, P. (2017). Distinct circadian signatures in liver and gut clocks revealed by ketogenic diet. Cell Metab, 26(3), 523–538, e5.
- Newman, J. C., Verdin, E. (2017). Beta-hydroxybutyrate: A signaling molecule. Ann Rev Nutr, 37, 51–76.
- Newman, J. C., Kroll, F., Ulrich, S., Palop, J. J., Verdin, E. (2017 May 9).Ketogenic diet or BHB improves epileptiform spikes, memory, survival in Alzheimer’s model. bioRxiv, 136226. DOI: https://doi.org/10.1101/136226
- Newman, J. C., Verdin, E. Ketone bodies as signaling metabolites. (2014). Trends Endocrinol Metab, 25(1), 42–52.
- Shimazu ,T., Hirschey, M. D., Newman, J., He, W., Shirakawa, K., Le Moan, N., Grueter, C. A., Lim, H., Saunders, L. R., Stevens R. D., Newgard, C. B., Farese, R. V., de Cabo, R., Ulrich, S., Akassoglou, K., Verdin, E. (2013). Suppression of oxidative stress by b-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science, 339(6116), 211–4.
- Newman, J. C.*, Justice, J.*, Miller, J. D.*, Hashmi, S. K., Halter, J., Austad, S. N., Barzilai, N., Kirkland, J. L. (2016). Frameworks for proof-of-concept clinical trials of interventions that target fundamental aging processes. J Gerontol A Biol Sci Med Sci, 71(11), 1415-1423.
- Newman, J. C.*, Milman, S.*, Hashmi, S. K., Austad, S. N., Kirkland, J. L., Halter, J. B., Barzilai, N. (2016). Strategies and challenges in clinical trials targeting human aging. J Gerontol A Biol Sci Med Sci, 71(11), 1424–1434.
- Newman, J. C. (2015). Copyright and bedside cognitive testing: Why we need alternatives to the Mini-Mental State Examination. JAMA Intern Med, 175(9), 1459–60.
- Feldman, R., Newman, J. (2013). Copyright at the bedside: Should we stop the spread? Stan Tech L Rev, 16, 623.
- Newman, J. C., Feldman, R. (2011). Copyright and open access at the bedside. New Eng J Med, 365(26), 2447–9.
Dr. Newman’s Pubmed link