John C. Newman, MD, PhD - US grants

DESCRIPTION (provided by applicant): 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.

PROJECT SUMMARY Signaling metabolites are small molecules with routine functions in cellular energy metabolism that also act as signals to regulate diverse cellular pathways in response to a changing energy state. Signaling metabolites link nutrition to aging. Many of the emerging geroscience therapies that target mechanisms of aging have come from the discovery and understanding of signaling metabolites. The ketone body ?-hydroxybutyrate (BHB) is a new signaling metabolite. It is produced during fasting, dietary restriction, exercise, or carbohydrate restriction to keep the body's tissues supplied with energy when glucose is scarce. We now have growing evidence that it also functions as a signal, by inhibiting enzymes, binding directly to proteins as a post-translational modification, and activating receptors. Through its signaling activities, BHB regulates gene expression, inflammation, metabolism, senescence, and other cellular activities important to both aging and Alzheimer's disease (AD). We recently showed for the first time that ketogenic diet (KD), which stimulates endogenous production of BHB similar to fasting, improves survival in aging mice and prevents age-related declines in memory. We also found that KD improves memory in the hAPPJ20 AD mouse model, and reduces abnormal epileptiform discharges that contribute to memory decline. KD is a complex intervention, and though it is now being studied in clinical trials of AD, a better understanding of which aspects of KD are most helpful should lead to better targeted and more effective therapies. We have successfully developed an innovative toolset of dietary, chemical, and genetic tools to isolate the individual components of KD, including carbohydrate restriction, BHB, energy provision by BHB, and cellular signaling activities of BHB. We will use these tools to uncover the specific mechanisms by which BHB improves memory in normal aging and in AD mice (Aim 1), and reduces epileptiform discharges in AD mice (Aim 2). We will characterize key molecular changes that BHB causes in the proteomic landscape of the brain, including mapping the acetylome and new BHBylome (Aim 3). This project combines expertise in both geroscience and AD with a deep understanding of BHB biology to carry out closely aligned mechanistic studies using both aging and AD models. It examines the intersection of a molecular mechanism that is broadly relevant to aging (ketone bodies as metabolic signals) with one highly specific to AD (aberrant epilepsy-like network hypersynchrony). It is highly likely to stimulate further progress on AD because the mechanistic framework it generates will directly inform translational studies involving ketone body compounds and ketogenic diets. These data will help establish criteria for designing effective interventions, provide relevant intermediate biomarkers, and permit deeper investigation into the downstream molecular targets most relevant to AD.

PROJECT ABSTRACT/SUMMARY Aging is by far the main risk factor for chronic conditions that jointly account for most morbidity, mortality, and health care costs. Geroscience-guided therapies seeking to alleviate such disorders as a group by targeting basic aging processes are now entering early stage clinical trials. The discovery, validation, and implementation into routine clinical care of such transformational therapies will require the creation of a robust and diverse geroscience workforce and training pipeline. The focus of this application is to address manpower, training, and educational gaps that were identified at a 2017 conference on this topic funded by an earlier Geroscience Network R24 grant (AG044396) with findings published in JAGS (Newman et al., 2019). We are now proposing to create the NIA Geroscience Education and Training (GET) Network through the R25 funding mechanism (PAR-20-095) as a complementary ?sister? network to the Translational Geroscience Network (TGN; R33 AG061456), since educational, curricular, and training goals outlined in this proposal were not suitable for inclusion in a R33 grant. More specifically, we are proposing the creation of a network model designed to leverage and integrate relevant expertise, knowledge, and resources across multiple institutions and organizations to address the following Specific Aims: Aim 1: Develop shared geroscience curricula and educational materials initially targeting: 1A. Medical and 1B. PhD students needing foundational geroscience knowledge irrespective of career plans 1C. Geriatric Medicine Fellows who require a deeper level of geroscience knowledge Aim 2: Develop a Certificate in Geroscience Research Program to train the next generation of geroscience researchers by offering multidisciplinary training in geroscience. Track 1 will address the specific training needs of basic scientists Track 2 will focus on clinicians and others conducting human subject research. This cross-institutional program would be accessible to all eligible trainees wishing to pursue a career in geroscience. Aim 3: Ensure optimal dissemination of the educational materials developed through this award. 3A. Videotaped lectures and other educational materials will be posted on POGOe with feedback surveys 3B. Our longer-range goal is to create a Geroscience Section in UpToDate®?an evidence-based, continually updated resource to ensure sustainability beyond the life of this NIA award

PROJECT SUMMARY Delirium is a geriatric syndrome of fluctuating confusion that is a common complication of surgery and hospitalization in older adults, and is associated with increased risk of death, disability, and dementia. People with Alzheimer's Disease and Related Dementias (ADRD) are at especially high risk for delirium. The pathophysiology of delirium is not well understood, but is thought to include neuroinflammation and brain energetic disruption. These features also link delirium to ADRD. Impaired cerebral glucose metabolism is a chronic feature of ADRD, and an acute feature of delirium. Similarly, chronic neuroinflammation is thought to be an important contributor to ADRD, and acute inflammation is associated with delirium. In this translational project we propose to test an innovative molecular link between acute-on-chronic brain inflammation and metabolic dysfunction, using cell systems, mouse models, and biospecimens from a human delirium cohort. Ketone bodies provide a non-glucose energy source for the brain during fasting, and ketone body metabolism remains intact in ADRD even with impaired glucose metabolism. We recently found that disrupted glucose metabolism is an important driver of behavioral changes in mouse models of delirium. We also recently showed that a ketogenic diet improves memory in both aging mice and an ADRD mouse model. We developed an innovative toolkit of compounds and genetic models to mechanistically study ketone bodies experimentally. We hypothesize that energetic support from ketone bodies might help compensate for inflammation-induced neuronal impairments in glucose metabolism. We also elucidated a new mechanism linking inflammation to metabolism, showing that activation of peripheral macrophages induces enzymes that degrade the key metabolic mediator NAD+. Inflammation-driven NAD+ depletion occurs chronically in aging and ADRD, and may occur acutely in delirium. We will use an inflammation model of delirium with normal mice and two ADRD models to test if ketone bodies or NAD+ can rescue acute delirium-like behavioral changes, and identify the relevant mechanisms (Aim 1). We will use cultured cells and an in vivo brain inflammation model to determine if activated microglia deplete NAD+ similarly to macrophages, and whether preventing this also rescues delirium-like behaviors (Aim 2). Finally, we will use cerebrospinal fluid samples from a large clinical study of postoperative delirium to determine how endogenous ketone body and NAD+ levels differ between patients with vs. without delirium (Aim 3). This collaborative project links basic science expertise in ketone body and NAD+ biology relevant to ADRD, with basic and clinical research expertise in delirium. It will open a new area of mechanistic study on inflammation-induced metabolic deficits in delirium, guiding development of translational interventions.