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.
Asish Chaudhuri, PhD Staff Scientist
D. D.Diego Diaz Lab 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