This application for the Paul B. Beeson Clinical Scientist Development Award in Aging (K08) describes the five-year career development plan of Dr. John Newman, a geriatrician and young physician-scientist in the Division of Geriatrics at the University of California, San Francisco. Dr. Newman's long-term career goal is to elucidate the mechanisms of pathways that broadly regulate healthspan and longevity in mammals, and translate these advances into therapies targeted at elders at high risk for frailty, cognitive decline, and functional dependence. The specific career development goals outlined in this application include developing expertise in the study of mitochondrial and cellular metabolism, deacetylases and histone modifications; the assessment of metabolic health and behavioral function in mouse model systems; and the translational application of aging biology. The primary mentor for accomplishing these career development goals is Dr. Eric Verdin, Professor of Medicine at UCSF and Senior Investigator at the Gladstone Institutes, a world-renowned expert on cellular metabolism, protein acylation, and the biology of aging. Dr. Verdin will be assisted by co-mentor Dr. Michael Steinman, Associate Professor, Director of Research Training, and Co-Director of Research in the UCSF Division of Geriatrics, and an accomplished physician-scientist. The career development plan of Dr. Newman includes individualized mentorship with his mentorship team, formal coursework, and a research program that builds upon Dr. Newman's prior experience in geriatrics, molecular biology, and bioinformatics with thorough training in metabolism, protein biochemistry, and mouse behavioral analysis. The overall objective of the research plan is to elucidate the biological effects of histone deacetylas inhibition by -hydroxybutyrate (BOHB), the major ketone body in humans. BOHB is produced from stored fat during fasting or strenuous exercise. Work in Dr. Verdin's laboratory recently found that BOHB inhibits deacetylases in vitro and in vivo and causes up-regulation of oxidative stress-response genes in the mouse kidney. The central hypothesis of this project is that BOHB is an endogenous epigenetic mediator of some of the health and longevity benefits of calorie restriction.
The specific aims of the project include systematically mapping changes in gene expression and histone modifications caused by BOHB in various mouse organs; testing the hypothesis that BOHB improves metabolic, cognitive, or neuromuscular health in middle-aged mice; and assessing longevity in mice consistently exposed to BOHB.
These aims will permit detailed mechanistic follow-on studies of links between BOHB -regulated genes and phenotypes in specific tissues, with identification of targets that are downstream of BOHB for drug discovery. The application is relevant to NIH and NIA because Dr. Newman's career goal is to leverage an understanding of the multifactorial pathways that regulate aging and longevity to provide translational therapies for the multifactorial geriatric syndromes.

Public Health Relevance

The proposed research is relevant to public health because the geriatric syndromes, such as frailty and cognitive decline, are a major reason why elders lose the ability to live independently, and result in large individual, family and societal costs fr personal and custodial care of dependent elders. The proposed project seeks new treatments for ameliorating the geriatric syndromes, and preserving elder independence, based on molecular mechanisms that regulate longevity and diseases of aging. The project will explore one such molecular mechanism, ketone bodies, in deep detail, and attempt to understand how ketone bodies affect specific geriatric syndromes and diseases of aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZAG1)
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Guo, Max
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Buck Institute for Age Research
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Newman, John C; Covarrubias, Anthony J; Zhao, Minghao et al. (2017) Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice. Cell Metab 26:547-557.e8
Newman, John C; Verdin, Eric (2017) ?-Hydroxybutyrate: A Signaling Metabolite. Annu Rev Nutr 37:51-76
Newman, John C; Milman, Sofiya; Hashmi, Shahrukh K et al. (2016) Strategies and Challenges in Clinical Trials Targeting Human Aging. J Gerontol A Biol Sci Med Sci 71:1424-1434
Justice, Jamie; Miller, Jordan D; Newman, John C et al. (2016) Frameworks for Proof-of-Concept Clinical Trials of Interventions That Target Fundamental Aging Processes. J Gerontol A Biol Sci Med Sci 71:1415-1423
Newman, John C (2015) Copyright and Bedside Cognitive Testing: Why We Need Alternatives to the Mini-Mental State Examination. JAMA Intern Med 175:1459-60
Newman, John C; Verdin, Eric (2014) ?-hydroxybutyrate: much more than a metabolite. Diabetes Res Clin Pract 106:173-81
Newman, John C; Verdin, Eric (2014) Ketone bodies as signaling metabolites. Trends Endocrinol Metab 25:42-52