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.
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.
W. G.Wyatt Gray Laboratory Technician
Scott Mills Research Associate
Scott Mills has over eighteen years of experience working in the technical and scientific end of in vivo pharmacology. Starting at UCSF in the neurodegenerative facilities moving on to Southern California to Corporate research in inflammation and oncology. In San Diego, he found himself working with every species he could imagine in the lab and on the farm! He never imagined that his career would be so expansive! Scott then headed back to the San Francisco bay area, his home town, to work in discovery research and cardiovascular, lipid research with mice and rats then onto more and pathology/histology as well. Later, He moved onto hematology platelets in vivo in rodents and designing his own studies. After that the military called upon Scott to perform some research work related to soldiers affected by IED explosives in duty in animal models. Stem cell research. A two years contract for bone and muscle regeneration. Next stop, the California Food Safety Lab doing animal necropsies and various large and small animals for public safety. So, here he is very happy to be with us!
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.
L. S.Lexi Straube Laboratory Technician
- 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